BioScience Journal 5

BioScience BIOSCIENCE JOURNAL SUMMER 2015

BSc

JOURNAL SUMMER 2015

Climate Change and the challenges facing mankind

Bio Similars Cell Therapy manufacturing Medical Science

BIOSCIENCE JOURNAL SUMMER 2015

WELCOME z

Welcome

Food for thought as millions starve Welcome to the latest edition of the Bioscience Journal, which includes a look at the dramatic way in which climate change is expected to affect human health in the decades to come.

You can argue as long as you want about the causes and scale of climate change but while the blame game rages, one thing is certain; change is happening. It is, after all, what climate does. Always did, always will.

John Dean

Editor in chief

However, amid all the sensational headlines about the effect on human health of rampant swarms of mosquitos carrying malaria and fearsome heatwaves causing choking smog, there is another challenge that some say is often overlooked by decision-makers, namely the need to tackle the threat to food production.

According to the World Health Organization, rising temperatures and volatile rainfall is likely to decrease the production of staple foods in many of the poorest regions by up to 50% by 2020 in some African countries.

That, in turn, will increase the malnutrition and under-nutrition which currently causes 3.1 million deaths every year, says the WHO. Scary figures indeed yet these are deaths that can, in many cases, be avoided with the right support; whereas reducing carbon emissions by the levels needed to make a difference, can sometimes seem such a hopeless task, the threat to food production is something that our scientists can tackle in such a way that short-term gains are possible. Slowing down the rate of global warming is a long-term project, rather like turning the proverbial oil tanker, but offering the right level of support to food producers offers the potential for much more immediate gains.

Indeed, the work is well under way. All over the world, bioscientists are working on ways to make crops more resilient, be it better able to tolerate the drought that comes with climate change, more capable of repelling the pests that thrive in a warming world or better equipped to increase yields.

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The importance of the work, and the need for political support, was underlined at the recent UN Climate-Smart Agriculture conference held in Montpellier, France, which issued a declaration urging governments to do more to harness the work of scientists.

One of those speaking out was Allahoury Amadou, from Niger, a member of the UN high-level panel of experts on food security and nutrition, who told the conference that farmers are facing difficult conditions due to climate change but that policymakers are stalling on solutions.

He, and others, urged governments and international organisations to focus on improving farmers’ ability to produce food in today’s changing climate by harnessing the scientific breakthroughs being made, some of which are detailed in the pages of this magazine on a regular basis.

It has often been said that it is criminal that people starve on such a rich planet where trillions are spent on consumables but it happens and happens too often. With climate change flexing its muscles, it is indeed food for thought for our politicians.

BIOSCIENCE JOURNAL SUMMER 2015

CONTENTS

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BIOSCIENCE JOURNAL SUMMER 2015

CONTENTS z

Contents

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Introduction/Foreword

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Contents

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UK News

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World News

20-37 Biosimilars 38-53 Cell Therapy

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38-53

54-59 Climate Change 60-66 Medical Science

Editor

John Dean john.dean@distinctivepublishing.co.uk

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Design

Distinctive Publishing, Unit 6b, Floor B, Milburn House, Dean Street, Newcastle Upon Tyne NE1 1LE Tel: 0845 884 2385 www.distinctivepublishing.co.uk

Contributors

John Dean & Francis Griss john.dean@distinctivepublishing.co.uk

Advertising

Distinctive Publishing, Unit 6b, Floor B, Milburn House, Dean Street, Newcastle Upon Tyne NE1 1LE Tel: 0845 884 2343 email: john.nielson@distinctivegroup.co.uk www.distinctivepublishing.co.uk

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Distinctive Publishing or BioScience Journal cannot be held responsible for any inaccuracies that may occur, individual products or services advertised or late entries. No part of this publication may be reproduced or scanned without prior written permission of the publishers and BioScience Journal.

BIOSCIENCE JOURNAL SPRING 2015

z NEWS

Findings could be good news for wheat farmers Scientists have announced a breakthrough in work to protect wheat against disease.

Disease cost farmers worldwide millions of pounds in lost and damaged crops but work carried out in the UK promises to improve testing and protection methods.

The team from the John Innes Centre (JIC), the National Institute of Agricultural Botany (NIAB) and the Sainsbury Laboratory (TSL) transferred a receptor that recognises bacteria from their model plant Arabidopsis thaliana - a dicot – to wheat.

Their work showed that the receptor can trigger a defensive response which enables increased resistance to bacterial disease.

Drs Henk-jan Schoonbeek and Christopher Ridout, the lead and corresponding authors of a paper published on the work, first developed diagnostic tools which test wheat for responses to pathogen-associated molecular patterns (PAMPs).

PAMPs are often essential parts of fungi or bacteria and without them they would find it difficult to mutate without affecting their own survival. Receptors enable a response to PAMPs.

The JIC scientists worked with TSL and the crop transformation team at NIAB to transfer a receptor gene to wheat, which enabled recognition of the widespread bacterial protein EF-Tu, and used their diagnostic tools to show that the receptor was working.

our analysis of receptor genes in dicots, we hope to identify more genes that can be used to develop durable resistance, not only to bacterial diseases, but to the most important fungal pathogens of wheat such as yellow rust, Septoria and powdery mildew.”

The receptor gene, EFR, works like an antenna that activates defence elements already present in wheat and makes the plants more resistant to bacteria. EFR was first identified by Professor Cyril Zipfel, Head of TSL, a co-author of the paper.

This research was funded by BBSRC and the team also received support from Gatsby Charitable Foundation and the Two Blades Foundation.

Bacterial wheat diseases are widespread in Asia and Africa, and also present in the USA so the work done in the UK could have global applications.

The diagnostic tool that has been developed can be used to help breeders screen seed varieties for PAMP recognition and resistance to bacterial pathogens.

Chris Ridout said: “Our work demonstrates the importance of developing this type of resistance in wheat. As the wheat genome is sequenced further and we continue

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NEWS z

Trial starts

F-star, a UK biopharmaceutical company working in oncology and immunooncology, has started a phase 1 clinical study of FS102, its lead compound for treatment of HER2-positive breast and gastric cancer.

The clinical study is being conducted in the United States by Bristol-Myers Squibb, which acquired exclusive rights to the programme in October 2014.

FS102, an antibody fragment derived from F-star’s Modular Antibody Technology, demonstrated in preclinical studies that it could eliminate of certain types of HER2 positive tumours.

z An example of Septoria leaf blotch (STB)

Research ‘could stop devastating plant disease’

Scientists have discovered a genetic mechanism that could stop the spread of a disease that threatens wheat crops.

Septoria leaf blotch (STB), which is caused by a fungus, is the most significant threat to wheat yields in most areas of the world, partly because it is increasingly resistant to currently available fungicides.

Researchers at Durham University, working with partners from Newcastle University and Rothamsted Research, have now devised a technique that could to stop extensive spreading of STB disease.

The work centred on a key feature of STB, the long symptomless growth of the fungus called Zymoseptoria tritici, which can affect the host plant’s cells before it becomes apparent and destroys the plant’s leaves.

The researchers found that a wheat protein, TaR1, was key in enabling Zymoseptoria tritici to maintain this symptomless growth.

By manipulating TaR1 protein levels in wheat, either by conventional breeding or genetic modification in plants grown in laboratories, the researchers demonstrated that they could activate the plant’s defences earlier.

The work is important because more than a third of wheat yield can be lost due to STB and it is the most significant disease of wheat in Europe and many other temperate climates.

Lead author Dr Ari Sadanandom, in the Durham Centre for Crop Improvement Technology, Durham University, said: “The foundation of global food security is built on three cereals, wheat, rice and maize, and wheat is the leading source of vegetable protein in human food.

“STB drastically affects yield by destroying the leaves on wheat plants, reducing their capacity to carry out the photosynthesis needed for grain production.

“It’s a significant threat as the fungicides that are currently the only control for this disease become less effective.

“However our findings show that by manipulating the TaR1 protein we can create unfavorable conditions preventing the spread of STB in the plant, potentially providing a new strategy for combating this devastating disease.”

The research was funded by the Biotechnology and Biological Sciences Research Council (BBSRC), Syngenta and the European Research Council (ERC).

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Centre opens

The University of Nottingham has opened a Synthetic Biology Research Centre, which is designed to support scientists working on breakthroughs in chemicals research.

The centre was made possible by £14.3m of funding from the Biological Sciences Research Council and the Engineering and Physical Sciences Council.

Company acquired

American firm Biogen Idec has agreed to acquire UK-based Convergence Pharmaceuticals, a biopharmaceutical company with a portfolio of ion channel-modulating product candidates for neuropathic pain.

Biogen Idec plans to use Convergence’s expertise in chronic pain research and clinical development to accelerate the growth of its own pain portfolio.

Convergence will continue to operate out of Cambridge in the UK. Biogen Idec Headquarters Building, Weston, MA

BIOSCIENCE JOURNAL SPRING 2015

z NEWS

z Artists impression of Hepatitus C virus

Cracking the code could be key to tackling infections Researchers have made a major breakthrough in tackling infections caused by a major group of viruses including the common cold and polio.

The team has cracked a code hidden in the sequence of the ribonucleic acid (RNA) that makes up this type of viral genome.

But a paper published by a group from the University of Leeds and University of York has shown that jamming the code can disrupt virus assembly, which can stop it functioning and prevent disease.

Professor Peter Stockley, Professor of Biological Chemistry in the University of Leeds’ Faculty of Biological Sciences, who led the study, said: “If you think of this as molecular warfare, these are the encrypted signals that allow a virus to deploy itself effectively.

“Now, for this whole class of viruses, we have found the ‘Enigma machine’ – the coding system that was hiding these signals from us. We have shown that not only can we read these messages but we can jam them and stop the virus’ deployment.”

Single-stranded RNA viruses are the simplest type of virus and were probably one of the earliest to evolve. However, they are still among the most potent and damaging of infectious pathogens.

Rhinovirus, which causes the common cold, accounts for more infections every year than all other infectious agents put together (about 1 billion cases), while emergent infections such as chikungunya and tick-borne encephalitis are from the same ancient family.

Other single-stranded RNA viruses include the hepatitis C virus, HIV and the winter vomiting bug norovirus.

Dr Roman Tuma, Reader in Biophysics at the University of Leeds, said: “We have understood for decades that the RNA carries the genetic messages that create viral proteins, but we didn’t know that, hidden within the stream of letters we use to denote the genetic information, is a second code governing virus assembly.

“It is like finding a secret message within an ordinary news report and then being able to crack the whole coding system behind it.

“This paper goes further: it also demonstrates that we could design molecules to interfere with the code, making it uninterpretable and effectively stopping the virus in its tracks.”

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Professor Reidun Twarock, of the University of York’s Department of Mathematics, said: “The Enigma machine metaphor is apt. The first observations pointed to the existence of some sort of a coding system, so we set about deciphering the cryptic patterns underpinning it using novel, purpose designed computational approaches.

“We found multiple dispersed patterns working together in an incredibly intricate mechanism and we were eventually able to unpick those messages. We have now proved that those computer models work in real viral messages.”

The next step will be to widen the study into animal viruses. The researchers believe that their combination of single-molecule detection capabilities and their computational models offers a novel route for drug discovery.

The research was funded by the Biotechnology and Biological Sciences Research Council (BBSRC) and the Engineering and Physical Sciences Research Council (EPSRC). Professor Twarock’s Royal Society Leverhulme Trust Senior Research Fellowship and Dr Dykeman’s Leverhulme Trust Early Career Fellowship also supported the work.

BIOSCIENCE JOURNAL SUMMER 2015

NEWS z

More action needed

More Britons than ever are aware of the links between lifestyle and cancer risk but many of them are not making the necessary changes in their lifestyle, according to research by the World Cancer Research Fund.

The Fund is urging government, charities and health professionals to do more to support people in making healthier lifestyle choices.

Can register prevent asthma deaths? z Artists impression of Neurons/synapses firing

New approaches to fighting neurodegeneration to be funded Stevenage Bioscience Catalyst (SBC), the UK’s first open innovation bioscience campus, has announced that six academic research projects have been selected for support under its open innovation challenge in neurodegenerative disease.

Covering a range of approaches to tracking, diagnosing and treating disorders, the successful applications came from the Universities of Oxford, Cambridge and Manchester, as well as UCL and Imperial College London.

They were selected on the basis of a range of criteria, including impact potential, the level of innovation and opportunities for collaboration.

Recognising the need for new approaches to tackle diseases such as Alzheimer’s and Parkinson’s, SBC worked with MIMIT1 and the universities’ Academic Health Science Centre Technology Transfer Organisations to develop the scheme, which was launched last year.

It is designed to provide small amounts of funding to kick-start research and is supported

by Astex Pharmaceuticals, Alzheimer’s Research UK, Eli Lilly, GE Healthcare Life Sciences and GSK, who are also contributing their extensive expertise.

This will be invaluable to the selected projects, which focus on biomarkers for diagnosis and stratification, and the role of inflammation in neurodegeneration.

Ray Hill, President Emeritus, British Pharmacological Society & Chair of the OI Challenge Review Panel, said: “Everyone on the panel was impressed by the quality and breadth of the project proposals submitted for review by the academic researchers. It’s great to see exciting new approaches to neurodegenerative disease being generated by the UK’s strong science base, with the SBC open innovation challenge providing vital support for further investigation.”

Martino Picardo, CEO of Stevenage Bioscience Catalyst, said: “We’re delighted to have concluded successfully the initial step in our initiative to bring benefit to neurodegenerative disease patients through open innovation - hopefully the first of many such schemes.

Bringing together a diverse range of players is vital for driving innovation.”

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Researcher Dr Andrew Wilson, from the University of East Anglia, has been awarded £1.7million from the National Institute for Health Research to allow the Asthma UK Centre for Applied Research to identify people most at risk of an attack.

Three people die of asthma every day in the UK and research suggests that two thirds of the deaths could be avoided.

Dr Wilson’s research will examine whether introducing a register of people at risk and offering specialist support will help.

Device helps control blood pressure

A revolutionary device has been shown to significantly lower blood pressure among patients with uncontrolled high blood pressure, compared to those treated with usual drug measures, according to research from Queen Mary University of London.

The device – developed by ROX Medical and named the ‘Coupler’ – is a paper clipsized implant inserted between the artery and vein in the upper thigh and was tested at the Barts Blood Pressure Clinic at Barts Health NHS Trust in east London.

BIOSCIENCE JOURNAL SUMMER 2015

z NEWS

Salts support bone health

Research from the University of Surrey has found that the potassium salts bicarbonate and citrate, which are plentiful in fruit and vegetables, play an important part in improving bone health.

The results showed that the salts reduce bone resorption, the process by which bone is broken down, therefore increasing strength.

Lead author Dr Helen Lambert, from the University of Surrey, said: “Our study shows that these salts could prevent osteoporosis, as our results showed a decrease in bone resorption.”

Funding will help develop bladder cancer test

A Cancer diagnostic company located in Sunderland and Cambridge has secured £2m to further developing a non-invasive urine test for the detection of prostate and bladder cancer.

The company, UroSens Ltd, received the funding in a round led by Longwall Venture Partners, with participation from shareholders including Northstar Ventures, Esperante BV, Cambridge Capital Group and other shareholders.

UroSens says the money will allow it to expand its commercial and technical team, finalise product development and commercialise its UroSens Mcm5-ELISA diagnostic test.

Mcm5 is a protein which only appears when cells divide, and is a marker for the presence of dividing cancer cells.

The company is seeking to undertake further clinical trials in Europe and the United States to expand the applications of the Mcm5 test.

UroSens says that, although there are more than 40,000 new cases of prostate cancer and 11,000 of bladder cancer each year in the UK, current diagnostic tests are unreliable, resulting in many unnecessary and invasive biopsies.

For both diseases, the UroSens Mcm5-ELISA diagnostic test is expected to significantly reduce the number of patients undergoing invasive procedures.

Dr Ian Campbell, CEO at UroSens, said: “This investment round will enable us to expand our team and bring our novel assay to the market, providing patients with a simple non-invasive test for both bladder and prostate cancer.”

David Denny, of Longwall Venture Partners, said: “The clinical trial results evidence the diagnostic capability of the UroSens technology and the strength of the team. This is an exciting year as the company develops and launches its first products and we are delighted to be involved and able to support.”

Alex Buchan, Investment Manager at Northstar Ventures, said: “This technology is really exciting because for the first time, it is possible to detect the presence of cancers using urine samples rather than unpleasant, invasive methods. The speed and cost of the test makes screening a real possibility and there is a tremendous potential for tests for other cancers as well.”

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Hearing loss research receives £4m

The charity Action on Hearing Loss and BBSRC are investing £4m into research.

The funding will support 13 projects that investigate how hearing changes as we get older, support research into tinnitus treatments, identify genetic causes of hearing loss and develop more accurate hearing tests.

Dr Sohaila Rastan, Executive Director of Biomedical Research at Action on Hearing Loss, said: “These pioneering projects will improve our understanding of the causes of hearing loss, which is vital to developing new treatments to protect and restore hearing.”

Dementia funding

The UK Government announced a $100m Dementia Discovery Fund at the World Health Organization’s first ministerial conference dedicated to the condition.

Major pharmaceutical companies Biogen, GlaxoSmithKline, Johnson & Johnson, Lilly and Pfizer have all committed in principle to invest in the project, alongside Alzheimer’s Research UK and the UK government.

BIOSCIENCE JOURNAL SUMMER 2015

NEWS z

University invests in science

The University of Cumbria is investing £1.2m to find the next generation of scientists.

Staff are using the money to develop a new teaching programme of science, technology, engineering and mathematics (STEM) subjects and a high-spec laboratory in Carlisle.

The investment is the result of two successful bids to England’s education funding authority, HEFCE, and to the Cumbria Local Enterprise Partnership (LEP), as well as matched investment from the university. The bids were for £256,000 and £748,000 with the university making up the remaining £256,000.

The first phase of work will provide new high-quality teaching laboratory space at the university’s Fusehill Street Campus, Carlisle, fitted out with the technology and equipment to support teaching of the new STEM subject courses.

The plan is for the labs to be finished in time for next academic year starting in September.

The first three new STEM courses to be offered this year include BsC (Hons) Biology.

For 2016 onwards, the university will develop new courses in chemistry, biomedical science and other related areas of STEM. Peter Strike, Vice Chancellor of the University of Cumbria, said: “Our aim is to increase the number, the attractiveness and the accessibility of STEM careers for our university students. By promoting closer co-operation with our local further education colleges, we

intend to create a ladder of opportunity for training in STEM subjects in Cumbria and beyond.”

Participation in higher education in Cumbria is traditionally low, particularly in the STEM subjects.

The university’s hopes that the skills and knowledge acquired from studying applied bioscience and analytical chemistry degrees, together with professional body accreditations, will create a wider pool of skilled graduates to supply the regional economy.

When the investment was announced, Councillor Colin Glover, Leader of Carlisle City Council, said: “We recognise and wholeheartedly support the efforts of the University to develop its offer in Carlisle. We see great value in creating a STEM facility.

Attracting and subsequently retaining high value graduates and post graduates within our city region is another key target for the Council and its partners.

“This new STEM offer will help bring higher value skills and jobs to our city region and in turn help stimulate other new opportunities for investment and development along the M6 corridor and within the city area. We applaud the university’s commitment to Carlisle.”

The work is particularly important because there will be an increased need for biosciences

“We buy and sell used lab equipment” www.lvscientific.com Email: rob@lvscientific.com 11

graduates in Cumbria with the development of the new GlaxoSmithKline (GSK) £350m biopharmaceutical facility in Ulverston and an increase in demand from Sellafield for scientists.

Pat McIver, Site Biopharm Lead, GSK Ulverston, said: “The new factory will require STEM jobs at all levels, including apprentices, graduates and post graduates.

“The university’s investment will respond to our needs, improve progression into higher education in key disciplines of biology and chemistry and will help us to recruit from the local area.

“This is a great opportunity for Cumbria to secure valuable resource for its young people.

It will not only benefit GSK, but also other science and technology companies based in Cumbria, thereby making a contribution to economic growth and our local communities.”

In addition the university will create programmes to increase the pool of qualified teachers of STEM subjects. There are acute shortages nationally of teachers in some areas of the STEM curriculum such as chemistry and physics.

Peter Strike, Vice Chancellor of the University of Cumbria

BIOSCIENCE JOURNAL SUMMER 2015

z NEWS

Research funding seeks to tackle diseases in farmed livestock UK scientists have been awarded more than £6m to be spent on research to improve the health of farmed livestock.

Footrot is very common in sheep in the UK, affecting more than 95% of flocks.

It is caused by Dichelobacter nodosus, a bacterium that causes inflammation of the skin of the foot which leads to lameness.

The study will determine which molecular factors in Dichelobacter nodosus and which managements in sheep are most important.

The money has come from BBSRC’s Animal Health Research Club and eight studies will take place at institutions around England and Scotland into farmed fish, poultry, sheep, pigs and cattle to better understand diseases which cost farmers millions of pounds a year. A total of £5.8m came from BBSRC with just over £800,000 from the Scottish Government.

Separately, a team will work to better understanding inflammatory processes in ovine footrot to support vaccine design. The work will be done by Dr Sabine Totemeyer, Dr Tracey Coffey, Dr Jasmeet Kaler, Dr Richard Emes and Mr Peers Davies from the University of Nottingham in collaboration with Prof Gary Entrican and Sean Wattegedera for Moredun Research Institute

Dr Celia Caulcott, BBSRC Executive Director, Innovation and Skills, said: “By targeting these livestock diseases the Animal Health Research Club projects have the potential to protect farmed animals and food supplies and save UK farmers and the wider economy millions of pounds a year.”

Another team to benefit from funding is Professor David Hume, Professor David Burt, Dr Lonneke Vervelde, Professor Helen Sang and Professor Peter Kaiser from The Roslin Institute, University of Edinburgh, who will look at how best to protect poultry against a wide range of pathogens.

The projects include an investigation into Porcine Reproductive and Respiratory Syndrome virus by Professor Alan Archibald, Professor Stephen Bishop, Dr Tahar Ait-Ali and Professor Tanja Opriessnig from The Roslin Institute, University of Edinburgh.

Some of the current methods, including the use of antibiotics, are becoming less effective or have been banned because of hazards to human health.

Porcine Reproductive and Respiratory Syndrome (PRRS) is a viral disease of pigs that accounts for a third of infectious disease costs to the US pig industry, approximately $600m annually. It is also the most costly disease to the European pig industry. By identifying genetic markers, the study will provide tools to help select pigs with increased PRRS resistance.

Also being funded is an inquiry into footrot

by Professor Laura Green, Dr Kevin Purdy and Professor Matthew Keeling from the University of Warwick, in collaboration with Dr Jasmeet Kaler from the University of Nottingham.

Researchers have identified a protein in birds called CSF-1 which controls the numbers of macrophages – a type of white blood cell important in immune response. The study will test the capacities of the protein.

Resistance to cryptosporidiosis in cattle will be the focus of work done by Professor Elisabeth Innes, Dr Frank Katzer and Dr Emily Jane Hotchkiss from Moredun Research Institute, in collaboration with Dr Liam Morrison, Dr Neil Mabbott and Dr Jayne Hope at The Roslin Institute, University of Edinburgh and Dr Mintu Nath, The James Hutton Institute.

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Cryptosporidium parasites are a major cause of intestinal disease in farmed livestock worldwide, and are also a leading cause of infant diarrhoea in humans. There are no safe and effective treatments or vaccines currently available and the project will provide the fullest exploration yet of how cattle resist infection.

One of the other projects will seek to develop a vaccine to control teladorsagiosis worm in sheep, with the work being done by Professor Jacqueline Matthews, Dr Alasdair Nisbet, Dr Tom McNeilly and Dr Stewart Burgess from the Moredun Research Institute in collaboration with Dr Simon Babayan from the University of Glasgow.

Worm infections are the most costly endemic disease affecting sheep in the UK but dewormers are becoming less effective as resistance to the drugs increases. Recently, the research group discovered an effective vaccine prototype for control of Teladorsagia circumcincta, the dominant worm present in the UK sheep industry, and the study will investigate to developing a commercially viable vaccine.

THE OTHER PROJECTS ARE:

Development of oral vaccination strategies for Atlantic salmon, by Professor Chris Secombes and Dr Jun Zou, from the University of Aberdeen; Professor Sandra Adams, Professor James Bron and Professor Randolph Richards from the University of Stirling; Professor Gordon Allan, Dr Mark Mooney from Queen’s University of Belfast. The work will investigate disease in farmed salmon *Work to improve control of infectious bronchitis virus by Dr Lonneke Vervelde, Professor Peter Kaiser from The Roslin Institute, University of Edinburgh, in collaboration with Professor Paul Britton, The Pirbright Institute. Infectious bronchitis virus is an endemic virus that causes severe disease outbreaks in chickens worldwide.

BIOSCIENCE JOURNAL SUMMER 2015

WORLD NEWS z

Therapy takes big step forward

Neurocrine Biosciences has been granted orphan drug status by the United States Food and Drug Administration for NBI-77860, a corticotropin-releasing factor 1 receptor antagonist used to treat congenital adrenal hyperplasia (CAH), which affects 30,000 people in the United States.

Malcolm Lloyd-Smith, Chief Regulatory Officer of Neurocrine Biosciences, said: “This status represents a significant regulatory milestone for the CAH programme and underscores the importance of bringing a safe and effective CAH therapy to market.”

Further studies into the therapy are under way.

Anti-inflammatory process ‘may trigger Alzheimer’s’ Researchers at the University of Florida in the United States have uncovered the mechanism by which antiinflammatory processes could trigger Alzheimer’s Disease.

The link between inflammation and the disease has long been known but the new work suggests that simply reducing inflammation might not be the best way forward.

According to the team, the anti-inflammatory process might actually trigger the build-up of sticky clumps of protein that form the plaques that block brain cells’ ability to communicate, a well-known characteristic of the illness.

The findings suggests that Alzheimer’s treatments need to hone in on which forms of Apolipoprotein E, a major risk factor for Alzheimer’s disease, patients carry in their genes.

The researchers say that the anti-inflammatory protein interleukin 10, or IL-10, can increase the amount of apolipoprotein E, or APOE, protein, and thereby plaque, in the brain.

NSAIDs, might protect people from the onset of Alzheimer’s by dampening inflammation that released harmful proteins. Though NSAIDs were effective in some studies, other research did not show any clear protective benefit.

Todd Golde, M.D., Ph.D., director of the Center for Translational Research in Neurodegenerative Disease and the lead author on the new paper about the Florida study, said: “There are many different kinds of NSAIDs. Not all NSAIDs are equal and it wasn’t clear what else they were doing when they were addressing their intended target.”

Previously, researchers had hypothesised that a flood of proteins, called cytokines, involved in promoting inflammation in the brain contributed to the formation of plaque in Alzheimer’s disease. However, the new study suggests that anti-inflammatory stimuli may increase plaque instead.

Paramita Chakrabarty, Ph.D., a member of the UF Center for Translational Research in Neurodegenerative Disease, an assistant professor in the UF College of Medicine department of neuroscience and the paper’s co-author, said: “This is another piece of evidence that overturns the long-held hypothesis that a ‘cytokine storm’ creates a self-reinforcing, neurotoxic feedback loop that promotes amyloid-beta plaque deposition.”

In the 1990s, researchers theorised that nonsteroidal anti-inflammatory drugs, or

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Companies sign agreement

Swiss firm Novartis has signed collaboration and licensing agreements with Intellia Therapeutics to support the development of new medicines.

The work will use CRISPR genomeediting technology to develop drug discovery tools and involve experts at Intellia and Caribou Biosciences, two of the leading biotechnology companies developing the technology.

CRISPR allows scientists to precisely edit the genes of targeted cells and is used to create very specific models of disease for use in drug discovery.

Japan the target for drug programme

HUYA Bioscience International, which helps to develop biopharmaceutical products originating in China, is pressing ahead with plans to use the cancer drug HBI-8000 for the treatment of adult T-cell leukemia/lymphoma (ATL) and peripheral T-cell lymphoma in Japan.

The company says that there is an unmet medical need in Japan where ATRL is responsible for 700-1,000 deaths per year.

HTLV-1, the virus that causes ATL, infects more than a million people in Japan.

Worldwide, the figure is more than ten million.

BIOSCIENCE JOURNAL SUMMER 2015

z WORLD NEWS

Research fellowships awarded

The Pancreatic Cancer Action Network and the National Cancer Institute’s Frederick National Laboratory for Cancer Research in the United States have awarded fellowships to support research on gene mutations.

John Hunter, Ph.D., at the University of Texas Southwestern Medical Center, and Lynn McGregor, Ph.D., at the University of California, San Francisco, are examining KRAS, the most commonly mutated gene in the RAS family, which is involved in 95 per cent of pancreatic cancer cases and a high percentage of other cancers.

Funding partnership to continue

Initiative steps up vaccine support A group of private sector organisations has created a partnership with Gavi, the Vaccine Alliance, to support children’s health in 73 of the world’s poorest countries.

The three-year partnership between Gavi and the International Federation of Pharmaceutical Wholesalers (IFPW), a global association of pharmaceutical wholesalers, aims to strengthen regional supply chain training centres in Benin and Rwanda, serving countries across Africa.

IFPW, whose members include Walgreens Boots Alliance and McKesson-Celesio, will provide support including expertise and US$1.5 million to help students receive training to become supply chain managers.

Ornella Barra, IFPW’s chair and CEO of Wallgreens Boots Alliance, said: “We look forward to sharing our industry’s knowledge, expertise and resources with Gavi and its partners to strengthen developing countries’ medical supply chains and to improve the availability of and access to vaccines for the children who need them.”

programme to improve the capability of local supply chain leaders.

Gavi CEO Dr Seth Berkley said: “One of the largest obstacles to immunising children in poor countries is getting the vaccines to them.

“Vaccines are temperature-sensitive, and the infrastructure in poor countries often is lacking. Partnerships, such as this one with IFPW which represents engagement of a whole new industry, are bringing new thinking and resources to help the Vaccine Alliance reach every child.”

Gavi also announced two partnerships focused on improving injection safety. These are: A collaboration with Star Syringe, a UK-based medical research, design and development company, to take advantage of royalties on the company’s patented K1 auto-disposable syringe which will provide up to US$ 2 million in cost savings to Gavi and developing countries

A funding partnership worth millions of pounds to researchers in Ireland has been renewed.

Science Foundation Ireland, the Health Research Board) and the Wellcome Trust have announced the renewal of the SFI-HRB-Wellcome Trust Biomedical Research Partnership.

The partnership, established in 2010, has provided more than €4 million for biomedical and clinical science research in Ireland, including an investigation of dietary factors influencing cardiovascular disease, cell division in cancer and memory function.

Ebola funding continues The Wellcome Trust’s contribution to research into the ebola virus has topped £10 million.

Its funding is part of an emergency package to tackle the ongoing epidemic in West Africa. A dozen grants have been awarded so far, ranging from developing and testing new treatments and vaccines, to monitoring and predicting the spread of the disease and assessing the social challenges associated with an epidemic.

An agreement by the Indian company Hindustan Syringes & Medical Devices to support of a WHO global injection safety campaign.

Gavi, the Vaccine Alliance is a public-private partnership committed to increasing access to immunisation in poor countries.

Gavi is also working with UPS to develop an executive training and mentorship

Ebola virus

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BIOSCIENCE JOURNAL SUMMER 2015

WORLD NEWS z

America’s funding research ‘on the wane’ A piece of research has suggested that America’s role in the financing of global biomedical research is declining.

The study by the Boston Consulting Group and Partnering Health-Care Institution revealed a decline in the growth of spending on biomedical research and health service innovation, from 6 per cent per year from 1994 through to 2004 to 0.8 per cent per year from 2004 through to 2012.

That decline was reflected in the country’s global influence. Although the US still has a strong lead in absolute terms, some observers are speculating that China’s total investment could bypass US spending in the next decade.

Sarah Cairns-Smith, PhD, a senior partner with The Boston Consulting Group (BCG) and a co-author of the study said: “We were struck by the fact that rather than doubling down on

research during this golden age of biomedical science, US funding growth is declining, and, in real terms, funding for early-stage research is falling.

“Given current trends, the US risks failing to reap the benefits of previous medical advances and relinquishing its historical international leadership in medical innovation.”

“The natural cycle is for funding in basic biology to crack open areas for therapeutic innovation.

“We’re seeing that now play through in areas such as HIV and cancer, but if we don’t fund other basic research sufficiently, our time line for addressing highly debilitating diseases such as diabetes, Alzheimer’s and schizophrenia stretches out.”

The study is based on publicly available data from the US and the 40 largest developed nations. The analysis was performed by BCG, Alerion Advisors, John Hopkins Medicine and the University of Rochester School of Medicine and Dentistry.

MAJOR FINDINGS INCLUDED:

From 2004 through 2012, US government research funding declined from 57 per cent to 50 per cent of the global total, and that of US companies declined from 50 per cent to 41 per cent Industry accounted for 58 per cent of US research funding in 2012, an increase in share from 46 per cent in 1994, but it also shifted investment away from earlystage activity to late-phase clinical trials Industry funding has increasingly focused on commercially attractive therapeutics for cancer and rare diseases.

As the US share of global research funding declined, spending in Asia increased dramatically from 2004 through to 2012. Total spending increased from $1.6 billion to $14.6 billion, and spending by China tripled to $4.9 billion from $1.6 billion. China’s investment in the science and technology workforce has been especially strong The US share of patents, often cited as a key measure of research output, also declined from 73 per cent to 59 per cent of the most valuable patents from 1981 through to 2012

We were struck by the fact that rather than doubling down on research during this golden age of biomedical science, US funding growth is declining, and, in real terms, funding for early-stage research is falling.”

Sarah Cairns-Smith, PhD

Senior Partner, Boston Consulting Group

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Funding for health services innovation would increase $8 billion to $15 billion yearly if firms would increase their innovation funding to even the levels reached by other industries in the top in 20 for R&D spending. Private insurers ranked last and health systems ranked nineteenth among 22 industries in their investment in innovation.

BIOSCIENCE JOURNAL SUMMER 2015

z WORLD NEWS

Grants allow research to go ahead

Four teams of scientists have been awarded research grants from the John S. Dunn Collaborative Research Awards in the United States.

Antonios Mikos, of Rice Univeristy in Houston, and Dimitrios Kontoyiannis, of the University of Texas MD Anderson Cancer Center, are seeking a way to treat nectrotising invasive mould infections suffered by patients with suppressed immune systems.

The infections are difficult to treat because the mould disrupts blood vessels needed to deliver anti-fungal medications.

Losing your mobile ‘could be more than simply irritating’ We all know that feeling when we misplace our mobile phone. Irritation and frustration can ensue and, in more extreme cases, bouts of anger.

However, now new research has suggested that there could be medical implications as well, with users being placed at risk when separated from their beloved devices.

Research from the University of Missouri in the United States found that being separated from cell phones or iPhones can have serious psychological and physiological effects, including a significant increase in anxiety, heart rate and blood pressure levels.

The researchers say the findings suggest that iPhone users should avoid parting with their phones during situations that involve a great deal of attention, such as taking tests, sitting in conferences or meetings, or completing important work assignments, because being separated could result in poorer performance.

Russell Clayton, a doctoral candidate at the MU School of Journalism and lead author of the study, said: “Our findings suggest that iPhone separation can negatively impact performance on mental tasks.

“Additionally, the results from our study suggest that iPhones are capable of becoming an extension of our selves such that when separated, we experience a lessening of ‘self’ and a negative physiological state.”

To conduct the test, Russell, along with Glenn Leshner, former professor at MU, now at the

University of Oklahoma and Anthony Almond, doctoral student at Indiana UniversityBloomington, asked iPhone users to sit at a computer cubicle in a media psychology lab.

The researchers told the participants that the purpose of the experiment was to test the reliability of a new blood pressure cuff.

Participants completed the first word search puzzle with their iPhone in their possession and the second word one without their iPhone while the researchers monitored their heart rates and blood pressure levels.

While completing the first puzzle, the researchers recorded participants’ heart rate and blood pressure responses and asked them to describe their levels of anxiety and how unpleasant or pleasant they felt.

Next, and while in possession of their iPhones, those taking part were informed that their iPhones were causing “Bluetooth interference” with the wireless blood pressure cuff and that they needed to be placed further away in the room.

The researchers then provided a second word search puzzle and, while people, were working on them, the team called the iPhones. After the phones finished ringing, researchers again collected blood pressure and heart rate responses and asked those taking part to describe how they felt.

They found a significant increase in anxiety, heart rate and blood pressure levels, and a significant decrease in puzzle performance when the participants were separated from their iPhones as compared to when they had them.

Also, performance, measured via the number of words found on word search puzzles, decreased as compared to when iPhone users completed puzzles while in possession of their iPhones.

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Fred Pereira, of Baylor College of Medicine, and James Tour, of Rice University, will study ways to minimise the side-effects of widely-used cisplatin chemotherapy compounds that kill cancer cells by damaging DNA. One side-effect is damage to normal non-dividing cells in organs such as the inner ear, which can lead to high-frequency hearing loss that can progress to lower-frequency loss and tinnitus.

Jacob Robinson, of Rice University, and Russell Ray, of Baylor College of Medicine, are working to understand how neurons in the brain stem detect carbon dioxide.

The cells adjust breathing to balance blood oxygen and carbon dioxide levels but abnormalities in the process are suspected in a number of neurological and developmental disorders, including Rett Syndrome and sudden infant death syndrome and may also contribute to panic disorders and anxiety attacks in adults.

Eugene Zubarev, of Rice, and Sunil Krishnan, of MD Anderson, are working to improve the treatment of tumours with radiation after intravenous administration of extremely small quantities of gold nanoparticles.

The Dunn Foundation is a longtime supporter of collaborative research through the Gold Coast Consortia (GCC), which builds biomedical research teams that involve the computational, chemical, mathematical and physical sciences.

GCC member institutions include Baylor College of Medicine, Rice University, the University of Houston, the University of Texas Health Science Center at Houston, the University of Texas Medical Branch at Galveston and the University of Texas MD Anderson.

BIOSCIENCE JOURNAL SUMMER 2015

WORLD NEWS z

Development could transform rice production

Two companies have announced a development which could transform life for farmers battling against harsh conditions caused by climate change.

Arcadia Biosciences, an American agricultural technology company, and Asian business Maharashtra Hybrid Seeds Co. Ltd. (Mahyco), say that they have taken a major step forward in the development of a more efficient form of rice.

Rice plays a critical role in ensuring food for more than half of the world’s population and fears have been growing that burgeoning populations will struggle to find enough to eat, a situation exacerbated by the impact of the changing climate.

Arcadia has been working to improve crops in conditions which hinder healthy yields and are associated with climate change, including severe drought.

For example, based on current growth rates, India is expected to overtake China as the world’s most populous nation by the year 2030. However, the United Nations Food and Agriculture Organization estimates that 221 million people in India, or about one-fifth of the population, are undernourished.

The companies say that WUE rice, which has been developed by Mahyco using Arcadia technology, is among that early examples of crops bred to withstand the varying environmental effects of climate change.

They say that the crop’s resilience, aided by its more efficient use of water, means that more land can be brought into use for crop production.

Mahyco says that its tests have demonstrated that Arcadia’s WUE technology has significantly increased plant growth under normal conditions and when water is in short supply, showing double-digit increases in plant performance.

The work is important because rice is the world’s most valuable crop and is grown on 162 million hectares globally with a harvest value of $334.7 billion in 2012.

Eric Rey, president and CEO of Arcadia, said: “At a time when farmers in India face significant pressure to increase productivity, factors such as urban growth, drought and rainfall variations are limiting water resources available for agriculture, particularly for water intensive crops such as rice.

“Through our collaboration with Mahyco on WUE and other agronomic technologies, we’re working to increase yields and improve efficiency in the use of key inputs, such as fresh water.”

Usha Zehr, chief technology officer of Mahyco, said: “With this milestone, we are closer to bringing the benefits of this technology to the farmers who are challenged with

17

reduced water availability on their farms and improving the overall productivity of the crop.”

Arcadia Biosciences is based in Davis, California, with additional sites in Seattle, Washington and Phoenix, Arizona.

Mahyco was created in 1964 by Dr Badrinarayan R. Barwale and has become a pioneer and leader in the Indian seed industry.

It works on plant genetic research and production of quality seeds for the farming community.

Currently, it is engaged in the research, production, processing and marketing of approximately 115 products in 30 crop species including cereals, oilseeds, fibre and vegetables.

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BIOSCIENCE JOURNAL SUMMER 2015

ADVERTORIAL

Trade Secrets - current and future protection

A trade secret is a piece of knowledge that gives you a competitive advantage over others in the field.

of breach of confidentiality, breach of fiduciary duty or unfair competition. This variation and complexity is particularly problematic for small companies acting across a range of countries which is often the case in our sector where even very small organisations can be involved in international trials.

It must not be widely known, the owner must have taken deliberate steps to keep it confidential ( including restrictions internally to those who need to know) and it must have value because it is a secret. Trade secrets can be things like formulae, industrial processes and methodologies but might also be supplier or customer lists. Often these cannot be patented or a company chooses not to patent because the product is still at an early stage of development or because if it can be kept a secret the advantage may be extended beyond the 20 years of a patent.

Clearly you can do a lot to protect yourself through carefully constructed contracts and limiting access to the information however that will not cover every eventuality so the European Union is looking to bring in a directive to specifically protect trade secrets.

This would make it much easier for small companies to understand and enforce their rights and would not only allow actions to prevent use or disclosure of the trade secret but would also allow seizure of goods made through the use of misappropriated information. This type of remedy is generally available in the US but can be difficult to obtain in some European countries including the UK as you have to use laws that were really designed for other purposes and are often dependent on their being some pre existing relationship between the parties and so particularly difficult where there has been a third party theft.

While most of the developed world offers some protection the manner in which you can enforce your rights and the remedies available vary enormously. Some countries such as the US have specific laws while in Europe for example there is no specific law and so the victim must pursue actions through principles

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Although widely supported by industry the proposals are opposed by those who fear that public interest whistle blowing could be stifled and there has also been some concern that workers might be discouraged from moving job for fear of accusations of breach of the new laws if they were employed on a similar project with a new employer.

This last concern seems misplaced however as workers in sensitive positions usually have clauses in their employment contracts at least as tight as any proposed law. The other concern is more serious and I think that some form of safeguard will be included before the directive finally becomes law. Industry must be vigilant to ensure that any such exemption is fair and balanced and that any ongoing attempts to refine the various definitions in the draft do not weaken their current rights as to material covered and rights of action.

By Patricia Barclay Bonaccord

BIOSCIENCE JOURNAL SUMMER 2015

z FEATURE

With

Great promise comes great responsibility In the world of drug production, the search is relentless for treatments that can reduce the planet’s spiralling pharmaceutical bill by curing illness.

One reason for that trend is the upcoming expiration of patents owned by some drug companies, which is effectively opening up the market.

However, although billions of pounds is ploughed into developing new drugs, attention is increasingly focusing on making more use of what we already have in the form of the emerging ‘biosimilars’ market.

The promise of reduced costs is a key reason why regulatory bodies are working so hard to support the market; they can see that the availability of cheaper drugs offers potential savings for healthcare services at a time when spending on pharmaceuticals is rocketing.

Biosimilars, which are biological products that are ‘highly similar’ to licensed biological products apart from minor differences, are attractive to manufacturers because of the commercial opportunities and, with the promise of more choice for patients and cost-savings for health services, they are also interesting governments.

Biological products, on which biosimilars are based, are defined as products that are made using human or animal materials and include vaccines, blood, blood components, allergenics, somatic cells, gene therapy, tissues, and proteins.

According to the US Food and Drug Administration (FDA), one of the regulatory bodies wrestling with the issues presented by biosimilars, distinctions should be drawn between biosimilar and generic treatments.

The FDA says that generic refers to small-molecule drugs that are deemed bioequivalent to an existing drug but to be deemed ‘biosimilar’ the product has to be ‘interchangeable’ with the already-approved version and produce the same clinical result.

According to those who champion the industry, the benefits of supporting biosimilars include an increase in patient access to treatments because more companies are being drawn into the industry.

The increase in manufacturers becoming involved not only allows more products to be available but also drives down costs for those prepared to invest, not least because a significant amount of the research has already been done.

One estimate for the United States alone estimates that biosimilars could save the US Government $25 billion over the next ten years and it is the same story in other parts of the world.

However, there are challenges for biosimilar manufacturers, including the fact that they are obliged to notify the company they will be directly competing against that they are developing a similar drug to the original biologic.

Another challenge is the need to prove that the drugs are safe even though they are closeely related to existing products. The FDA in the United States, for example, has set up a system in which biosimilar manufacturers need to test and validate their drugs “to ensure the quality, safety and efficacy of a biologic.” Such requirements are also in operation in Europe for drug manufacturers.

Despite the challenges, biosimilars could prove to be a significant part of the pharmaceutical market in the near future; an IMS Health report released in December 2011 predicted that by 2020, the US biosimilar market alone may be as large as $25 billion.

Similar growth is expected elsewhere, including Europe.

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As the sector grows, the United States is among countries witnessing a lot of support for biosimilar development.

The first biosimilar approved under the new FDA regulations was ZarxioTM (filgrastimsndz) from Sandoz, which gained clearance in March.

Sandoz, a Novartis company, was given clearance for the cancer therapy drug after analysis of non-clinical, and clinical data assured regulators that it met the biosimilar criteria.

The drug treats people with neutropenia, who have an unusually low number of neutrophils, a type of white blood cell in the immune system that helps the body fight infection.

People who have neutropenia are at increased risk for developing serious infections and it occurs in about half of people with cancer who are receiving chemotherapy. It is a common side effect in people with leukemia.

The decision to grant it approval delighted Carol Lynch, Global Head of Biopharmaceuticals & Oncology Injectables at Sandoz, who said: “FDA approval of Zarxio marks a significant milestone for the United States healthcare system and for patients who might suffer from neutropenia.”

Dr. Louis Weiner, chairman of the department of oncology and director of the Lombardi Comprehensive Cancer Center at Georgetown University, said: “Biosimilars have the potential to increase access and the approval of Zarxio may reduce costs to the healthcare system. The comprehensive data set supports its use in clinical practice.”

Among other companies spending big is Oncobiologics, Inc., a biotherapeutics company that develops monoclonal antibody (mAb) biosimilars, which recently completed the construction of a new manufacturing facility at its headquarters in Cranbury, New Jersey.

BIOSCIENCE JOURNAL SUMMER 2015

FEATURE z

CONTINUED ON PAGE 25

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BIOSCIENCE JOURNAL SUMMER 2015

ADVERTORIAL

Facing a Changing Biosimilar Marketplace Most people associate passage of the US Patient Protection and Affordable Care Act or ACA, (otherwise known as Obamacare) with extending health benefits to the under- and uninsured.

But the legislation, signed into law in 2010, also includes the Biologics Price Competition and Innovation (BPCI) Act, which created an abbreviated licensure pathway for biological products demonstrated to be “biosimilar” to or “interchangeable” with a biological product licensed by the Food and Drug Administration (FDA).

In March 2015, the FDA finally approved the first biosimilar drug for use in the US—Sandoz’ immune-boosting drug Zarxio® for cancer patients undergoing chemotherapy. How this approval, and presumably others to follow, reshapes the world’s largest biologics market remains an open question.

The trade magazine Chemistry World recently reported that, as of October 2014, the FDA had received nearly 80 requests from companies for initial meetings to discuss biosimilar development programs for 14 different originator products, and had received 28 Investigational New Drug Applications (INDs) for biosimilar development programs.

The European Medicines Agency (EMA), which issued final versions of the guidelines in 2005, and authorized the sale of biosimilars the following year, has since approved 20 biosimilar products, with more on the way. In early May 2015, the EMA said it would review a biosimilar candidate for the rheumatoid arthritis drug Enbrel® (etanercept).

Analysts estimate the advent of biosimilars could produce anywhere from US$44 billion to US$250 billion in US health-care savings over the next decade. This wide range in estimates goes to the heart of just how many unknowns are circling this nascent industry. There are many different factors impacting whether

the biosimilar industry will be successful and what constitutes success.

each nation or state is allowed to make a decision on interchangeability.

Right now, many companies are developing biosimilars to the same originator product. In Europe, for instance, there are four different biosimilars for the cancer drug Avastin that are all competing against each other. It has been predicted that they will come in 20% to 30% cheaper than the originator, but if the biosimilar market is then fragmented, lower sales may not support this pricing. Unlike a generic small-molecule drug, there are less cost-savings because you still have production costs—which are high—and on top of that the whole application process for a biosimilar can be hundreds of millions of dollars.

The Zarxio approval by the FDA could help drug developers by enabling them to finally go back and look at source documents for the biosimilar to see what was done for that program. This is important because taking a biosimilar and comparing it to the originator is complex. It is a challenge for companies to obtain enough lots of the originator product, in different regions in the US and Europe, to do the necessary studies. And while there are a lot of regulatory documents out there, they do not specifically outline how to design these studies. What we do have now, though, with the Zarxio approval, is a package of documents that the public can review that show what a particular company did to prove biosimilarity.

And unlike Europe, the US Freedom of Information Act (FIA) provides access to these documents.

The BPCI Act contains two different layers of approval: biosimilarity and interchangeability.

It grants 12 years of data exclusivity to the branded biologic before approval of the biosimilar, which the biotech industry pushed for strenuously, and exclusive rights of 12-14 months to the first biosimilar of a branded biologic found to be interchangeable.

But there are still significant questions to be sorted out regarding the development, licensing and regulation of biosimilars. For instance, the FDA is the only regulatory agency that makes a distinction between biosimilarity and interchangeability—whether the biosimilar is the same as the originator—but lack of specific guidance from the FDA has, in the opinion of many, slowed the development and approval process.

For interchangeability to happen, the FDA will expect the biosimilar to produce the same clinical result as the originator product in any given patient. Additionally, the risk of alternating between the biosimilar and the originator product is no greater than sustained use of the originator product. Over the long run, having interchangeability means the biosimilar can be substituted by the pharmacist for the originator product without the involvement of the health care provider who wrote the initial prescription, which is the case now for generic drugs. If the producer of the biosimilar product can establish interchangeability, sales of biosimilars will be greater and more beneficial to the Sponsor. In Europe, where biosimilars are on the market,

With that said, it is unlikely that the US will grant interchangeability any time soon. The FDA has been very cautious because even minor changes in the production process can have a significant impact on the efficacy and safety of the end product. This happened when the formulation of the anemia drug epoetin-α. was changed by the originator after it was marketed outside the United States and caused pure red cell aplasia. And this change was made by the originator. So it is possible the FDA has likely concluded that if one manufacturer can’t control their own product, what are the chances a biosimilar can do the same thing?

By Christina Satterwhite & Niall Dinwoodie Charles River Laboratories

Christina Satterwhite is Director of Laboratory Sciences at the Preclinical Services site in Reno, Nevada and Niall Dinwoodie is Global Coordinator for Analytical Testing within the Biologics Group at the Tranent, U.K. site within Charles River Laboratories. This article is based on a Charles River Eureka blog post that appeared in February.

To learn more about how we can help support your biosimilar research and development, visit www.criver.com/biosimilars or contact us at askcharlesriver@crl.com

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BIOSCIENCE JOURNAL SUMMER 2015

ADVERTORIAL

But the legislation, signed into law in 2010, also includes the Biologics Price Competition and Innovation (BPCI) Act, which created an abbreviated licensure pathway for biological products demonstrated to be “biosimilar” to or “interchangeable” with a biological product licensed by the Food and Drug Administration (FDA).

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BIOSCIENCE JOURNAL SUMMER 2015

FEATURE z

Regulation that governs the biosimilar industry CONTINUED FROM PAGE 21

One of the major hurdles for biosimilars manufacturers is meeting the rigorous demands of regulators who are coming to terms with the challenges that the new industry provides.

In the European Union, for example, a legal framework for approving biosimilars was oiriginally established in 2003, which meant that that biosimilars can only be approved centrally via the European Medicines Agency (EMA) and not on the basis of decision by individual nations.

Omnitrope (somatropin) was the first product approved in the EU as a biosimilar in 2006 and, to date, the EMA has approved 21 biosimilars for use in the EU within the classes of human growth hormone, granulocyte colonystimulating factor, erythtropoesis stimulating agent, insulin and tumour necrosis factor (TNF)-inhibitor.

Two approvals were subsequently withdrawn, leaving 19 biosimilars approved for use in Europe.

In the United States, law-makers have been taking similar action and a raft of measures were enshrined in the Patient Protection and

Affordable Care Act (Affordable Care Act), which was signed into law by President Obama in 2010.

The Act created regulations governing biosimilars that are proved are be ‘interchangeable’ with a biological product already licensed for use by the FDA on the basis that both treatments have the same effect.

Under the Act, a biological product may be demonstrated to be biosimilar only if research data shows that, among other things, the product is ‘highly similar’ to an already-

Biosimilars will provide access to important therapies for patients who need them. Patients and the health care community can be confident that biosimilar products approved by the FDA meet the agency’s rigorous safety, efficacy and quality standards.

Margaret A. Hamburg, M.D, Commissioner

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approved biological product. Only minor differences in clinically inactive components are allowable in biosimilar products under the terms of the legislation. Fail to meet those stipulations and it will not be regarded as a biosimilar.

Under the law, once approved an interchangeable biological product may be substituted for the original drug by a pharmacist without going back to the doctor who issued the original prescription.

The FDA says that it requires licensed biosimilar products to meet the agency’s rigorous standards of safety and efficacy, pointing out ‘that means patients and health care professionals will be able to rely upon the safety and effectiveness of the biosimilar or interchangeable product, just as they would the reference product.’

Commissioner Margaret A. Hamburg, M.D, can see great benefits in new sector as long as the regulations are correctly administered.

She said: “Biosimilars will provide access to important therapies for patients who need them. Patients and the health care community can be confident that biosimilar products approved by the FDA meet the agency’s rigorous safety, efficacy and quality standards.”

Providing the formula for successful recruitment.

www.chemify.co.uk

Image ©Shutterstock, Inc & RoyaltyStockPhoto

BIOSCIENCE JOURNAL SUMMER 2015

Cell Line Development in CHO, NS0 & Sp2/0

with enhanced PQA assessment for biosimilar development

Antitope offers CHO, NS0 and Sp2/0 biosimilar cell line development programmes with bespoke quality assessment tailored to individual projects

Enhanced PQA assessment

Continuous assessment of product quality attributes (PQA) during cell line development helps ensure biosimilars retains the desired product characteristics and function, avoiding redevelopment costs and delays to the market. PQA assessment includes: • Product integrity • Product activity • Product aggregation • Product glycan profiling • QC testing

Delivering on expectations

Efficient production is key to biosimilar development and Antitope has developed technologies such as Composite CHOTM and pANT vectorsTM to ensure key cell line development requirements can be met, including: • High expression levels of your antibodies or proteins • Free of animal derived products throughout the process in a chemically defined medium • Management of transfer to a GMP facility for a smooth transition to scale-up • No downstream milestones or royalty payments

Visit www.antitope.com/biosimilar-cell-line-development

BIOSCIENCE JOURNAL SUMMER 2015

ADVERTORIAL

Robust, ready-to-use cell-based potency assays for biosimilar development

By Jane Lamerdin, Ph.D., Abhishek Saharia, Ph. D. DiscoveRx Corporation, Fremont, CA 94538, USA

Biosimilars are defined as drugs that are “highly similar” to or “interchangeable” with an approved biologic. The lack of a clearly defined path to demonstrate such biosimilarity leaves the burden of proof on developers. Showing efficacy, quality, biopotency and clinical safety often requires a panel of assays, including analytical, biochemical, cell-based and even in vivo assays.

Cell-based assays offer significant advantages over in vivo studies, offering lower resource requirements and cost, with improved speed and performance characteristics. We discuss here some examples and how they help reduce internal costs and timelines, as well as offer excellent reproducibility across global sites.

Biosimilar developers face challenging decisions in determining the best pathway to proving the biosimilarity of their product.

These include whether to develop bioassays in-house or to incorporate commercial assays with said advantages. An ideal potency bioassay should mimic the mechanism of action (MoA) of the innovator drug while producing highly precise, accurate and reproducible data in a quality (GLP or GMP) environment.

Traditionally, bioassay developers have adapted cell proliferation and live animal assays that reflect events occurring well downstream of the drug target, with poor target specificity. These phenotypic assays suffer from lengthy, complex protocols, high variability and/ excessive cost. Furthermore, assays reliant on immortalized cell lines must incorporate additional resources for cell banking and continuous performance monitoring due to potential cellular drift.

Commercial cell-based potency assays greatly reduce the time and cost of assay development and validation as they are ready-to-use, well-qualified and often easy to adopt.

DiscoveRx (www.discoverx.com/biosimilars) has developed a wide array of such products that rely on native biology to directly measure functional potency of currently marketed biologic drugs, with the goal to aid development of biosimilars.

Figure 1 (overleaf) shows some of the over 30 well-validated PathHunter® assays for

innovator drugs in diverse disease areas including diabetes (GLP1, Exendin and Insulin), oncology (Bevacizumab) and inflammation (Anti-TNF’s). The cryopreserved thaw-anduse cells used in these assays offer greater operational flexibility as assays can be performed as and when needed without the requirement for cell bank creation.

Ultimately such convenience improves the success of assay transfers to global testing and manufacturing sites.

Case Study: Bevacizumab (Avastin®) Bioassay

To illustrate, qualification of a potency assay for the angiogenesis inhibitor bevacizumab is shown. VEGF-A activates VEGFR2 through receptor dimerization, promoting proliferation of endothelial cells. Bevacizumab binds to and inhibits VEGF-A; thus proliferation in human umbilical vein endothelial cells (HUVECs) is an existing bioassay for bevacizumab.

However, this assay requires >96 hours to run, utilizes cells that are difficult to culture and introduce performance variability due to changes in passage number, culture conditions and operator.

The PathHunter® Bevacizumab bioassay quantifies the inhibition of VEGF-A-induced dimerization of the VEGFR2 receptor. As shown in Figure 1D, the PathHunter assay generates data that is consistent with the HUVEC proliferation assay (VEGF-A: ED50 of 1-6 ng/ml; bevacizumab: ED50 of 50 ng/ml). Additionally, with its shorter assay time (<24 hours), simple ‘add and read’ protocol and cryopreserved thaw-and-use cells, the PathHunter assay has many advantages over the standard HUVEC assay.

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Importantly, this assay is suitable for potency testing as determined in a multi-day qualification exercise (Figure 2A, B), where the assay displayed very good accuracy (95.9%), excellent precision (4.1%), a relative standard deviation (RSD) <5%, and good linearity (r2 =0.985). Additionally, this assay demonstrates excellent matrix tolerance of up to 90% normal human serum (NHS) with little change in EC50 values or signal to background ratios (Figure 2C), enabling the use of this assay for neutralizing anti-drug antibody (NAb) detection when testing for clinical immunogenicity of the biosimilar.

As innovator drugs come off patent and global biosimilar development activity increases, the need for specific tools to accelerate and reduce costs of biosimilar development is evident.

Commercially available, ready-to-use cellbased assays will enable biosimilar developers to rapidly advance to the critical assay validation stage for potency and NAb assays.

Companies that are the quickest to demonstrate “similarity” of their molecule using available commercial tools can hope to be the first to market with their biosimilars.

ADVERTORIAL

Figure 1.

Select examples of PathHunter bioassays.

A. Insulin bioassay demonstrates high reproducibility. B. Bioassays for GLP1 and Exendin-4 use a cAMP readout. C. AntiTNFÎą bioassays enable benchmarking for biosimilars. D. Simple PathHunter bioassay for Bevacizumab.

Figure 2.

Here we tested the PathHunter VEGFR2 homodimer assay with VEGF-A, demonstrating a robust and reproducible response A. The VEGFR dimerization assay was tested with four test samples, from 50% to 150%, compared to a reference standard (100%). B. The measured relative potency was plotted against the expected relative potency.

C. Matrix effect on VEGFR2 bioassay was evaluated by addition of small volumes of normal human serum (NHS).

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DiscoveRx logo and DiscoveRx are registered trademarks of DiscoveRx Corporation. 20460 062415

ADVERTORIAL

Development of a Biosimilar

By Catriona Thomson, PhD

Associate Director of BioAnalytical Technical Services Global sales of the top seven biologics in 2014 were in excess of US$60 billion and of these molecules, six were monoclonal antibodies1 that have patents due to expire between 2016 and 20212. This patent cliff provides an impetus for companies to develop biosimilar molecules to maximise their impact on the current global market, as well as in emerging economies such as India, China, Mexico and Brazil. In order to capitalise on these opportunities, developers must work to a model where speed-to-market, low development costs and buy-in from consumers are of primary importance.

Therefore, the quality management concept of “Getting it Right First Time” is the cornerstone of biosimilar development. Definitions of biosimilar products stress the importance of demonstrating similarity to an innovator molecule (reference medicinal product, RMP), with emphasis on the safety and efficacy of the biosimilar for the patient3,4. This is reflected in the extensive physicochemical and biological characterisation performed early in development with the aim of reducing the scope or requirement for costly clinical trials due to the comprehensive analytical totality of evidence supporting similarity.

Having selected a clone with suitable genetic potential and productivity characteristics, advances in technology allow process development to be accelerated. Many permutations on a small scale can be assessed with the ability to rapidly upscale optimised conditions using components and materials that are identical, except in terms of size.

Access to an extended range of “off-the-shelf” binding and functional assays with high levels of sensitivity and sample throughput help to simplify the clone selection process, and accelerate the optimisation and monitoring of process reproducibility. This allows rapid elimination of clones and conditions that are not comparable to the RMP, and definition of the final process and key quality attributes of the molecule.

The ultimate goal is to produce a biosimilar product that has “fingerprint-like similarity” to the RMP. Although this description is yet to be fully defined, it will be based on the totality of evidence, so an extensive suite of assays is required to demonstrate biosimilarity.

Complete characterisation of the biosimilar covers everything from physicochemical analysis through functional cell-based assays, and should make use of orthogonal approaches in order to have every opportunity to define and describe differences between the RMP and biosimilar populations. Due consideration should be given to potential secondary mechanisms of action, as well as the primary ones. Over its lifespan, the biosimilar is compared to an appropriately sized RMP population that should be selected carefully to reflect its true variation.

Regulatory authorities acknowledge that biosimilars will show differences compared to innovators, and these may be accepted as long as they are not “clinically meaningful.”

Therefore, a robust approach using the most physiologically relevant assays available is required to address the differences observed.

Extrapolation of data for multiple indications was recently supported by both the FDA and EMA5. Regulators advocate that if biosimilarity can be demonstrated by analytical characterisation, and if the product is safe and efficacious for one indication, approval should be granted for all other indications that the innovator product is licensed for.

Using sensitive analytical methods to develop optimised biosimilars, rather than assessing the impact of differences using the relatively blunt tool of a clinical trial, is an approach to put patient safety at the forefront of biosimilar development.

Our experience in biosimilar characterisation indicates that the success of biosimilars will ultimately depend on rapidly producing a product with the required safety and efficacy profile, as demonstrated by comprehensive analytical characterisation using orthogonal methods, and addressing the potential clinical significance of observed differences using physiologically relevant methods. In addition to the appealing cost reductions that biosimilars offer national health care providers, interchangeability studies and an extensive data package should inspire confidence in patients and prescribers whose buy-in is required to develop the biosimilars market.

BioOutsource Ltd., 1 Technology Terrace, Todd Campus, West of Scotland Science Park, Glasgow G20 0XA

1 http://cellculturedish.com/2015/03/10-biologics-on-best-selling-drugs-list-for-2014/ 2 Calo-Fernández, B & Martínez-Hurtado, J.L.; Pharmaceuticals 2012, 5(12), 1393-1408; doi:10.3390/ph5121393 3 Section 7002(b)(3) of the Affordable Care Act, adding section 351(i)(2) of the PHS Act 4 Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues 18 December 2014 EMEA/CHMP/BMWP/42832/2005 Rev1 5 http://www.biopharma-reporter.com/Hot-Topics/Biosimilars/Regulators-skip-clinical-data-and-extrapolate-biosimilar-indications

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BIOSCIENCE JOURNAL SUMMER 2015

ADVERTORIAL

Rodeina Challand

Executive Director, Biosimilars Development – Scientific Affairs

Key success factors for biosimilars Global regulatory pathways for biosimilar development are continually evolving. Many countries throughout the world have established legal and regulatory pathways which allow development of biosimilar products.

The European Union (EU) was the first region in the world to have set a legal framework and a regulatory pathway for biosimilars.

To date, the European Medicines Agency (EMA) has approved 21 biosimilars within the product classes of human growth hormone, granulocyte colony-stimulating factor, erythtropoesis stimulating agent, insulin and tumour necrosis factor (TNF)-inhibitor, for use in the EU. The legislative route creating biosimilars for the United States (US) market was created by the enacted healthcare reform law, the Patient Protection and Affordable Care Act (PPAC Act), signed into law in March 2010. The new law also included a pathway for an interchangeable biosimilar, which is a biological drug that can be automatically dispensed without specific prescriber authorisation. To date, the Food and Drug Administration has approved one biosimilar, Zarxio (filgrastim-sndz), 06 March 2015.

But what are the key success factors for biosimilars in the market?

CLINICAL REQUIREMENTS

Biosimilars are approved on the basis of the ‘totality-of evidence’, quality, safety and efficacy. Clinical trials are costly and time consuming. It is critical that the data package requirement is assessed on a case by case basis to determine what non-clinical and clinical studies are required to demonstrate similarity. There is no one-fit-for-all. The result from each stage drives the next stage.

Significant advances in the scientific and analytical techniques e.g. in the field of physicochemical characterization are critical developments that help to reduce the clinical

32

data package requirement. Human testing may not be an across the board requirement though it is more likely albeit shortened ones.

Furthermore the clinical trials for biosimilars are not designed to prove efficacy per se, they are designed to demonstrate similarity using sensitive models and end points.

EXTRAPOLATION

Overall all Regulatory Agencies have indicated that if biosimilarity has been demonstrated in one indication, extrapolation to other indications of the reference product could be acceptable with appropriate scientific justification. If the relevant mechanism of action of the active substance and the target receptor(s) involved are the same then extrapolation can be justified. If different active sites of the biotherapeutic or different receptors of the target cells are involved in

BIOSCIENCE JOURNAL SUMMER 2015

different therapeutic indications, or if the historical safety profile of the reference product differs qualitatively between the different therapeutic indications, additional data may have to be generated to justify the extrapolation of safety and efficacy data.

This is critical as the cost of conducting clinical trials in each indication can be prohibitive.

However this concept is alien for prescribers.

Various medical societies have indicated that they will not use biosimilars in extrapolated indications without clinical data. This could severely hinder uptake.

NAMING

The World Health Organization established the International Nonproprietary Names (INN) system in 1953 to ensure the ‘clear identification, safe prescription and dispensing of medicines to patients, and for communication and exchange of information among health professionals and scientist worldwide’. The INN is intended to inform as to the active ingredient of a drug, otherwise known as the ‘generic’ name.

With the advent of biosimilars there has been ongoing debate on whether a biosimilar product proven through a comprehensive quality, non-clinical and clinical comparability studies to be similar to the originator should have the same INN. Some argue that biosimilars are not ‘identical’ and therefore should have unique INNs; traceability and attributions of adverse reactions have often been cited as a reason.

The biosimilar drug makers argue that the rationale offered by those supporting unique identifiers, namely traceability, is just a tactic designed to put doubt in the minds of the prescribers and the consumers about the quality of a biosimilar product hence blunting competition.

It is debatable whether unique naming for biosimilars offers any advantage to pharmacovigilance systems currently in place having been shown to work effectively. A distinct name for each biosimilar gives brand name drug makers a marketing advantage, as substitution will be more difficult for an already established product.

INTERCHANGEABILITY

Biosimilars are similar but not identical. To be considered interchangeable the safety and efficacy must not be greater than the risk of using the reference product. The new law in the US under the 2010 Biosimilar Price Competition and Innovation (BCPI) Act includes a pathway for interchangeable biosimilars but the Agency so far has only released limited information on the principles of interchangeability. Guidelines are eagerly awaited.

Biosimilars developed in line with EU requirements can be considered therapeutic alternatives to their respective reference products but the decision lies outside the

ADVERTORIAL

remit of the EMA/Committee for Medicinal Products for Human Use. A number of countries have legal, regulatory and political provisions to prevent substitution and others have introduced policies for switching. From 01 January 2014, French pharmacists are now legally permitted to substitute a biosimilar for the prescribed (reference) biological medicine as long as the prescribing physician has not marked the prescription as ‘non-substitutable’.

Price does matter.

In Germany pharmacist may substitute a biosimilar as part of the obligatory generic substitution ‘Aut-idem-Regelung’ and practice specific prescription volume target agreements for doctors. In April 2015 the Dutch Medicines Evaluation Board (MEB) has updated its position on biosimilars, stating that ‘biosimilars have been proven to have no relevant differences compared to an innovator biological medicinal product as far as quality, safety and efficacy are concerned’, a change from its position in 2010 which recommended to avoid switching.

There is a perception that biosimilars are inferior driven by lack of large studies in each indication. To engage physicians, manufacturers must make sure prescribers truly understand the clinical and economic benefits of biosimilars. Patients must be educated so they are willing to switch. In the US most patients will value products that offer similar efficacy to their current treatment but at a lower out of pocket cost. In other countries patients will have access to biologics that otherwise not available due to cost.

The Agency’s decision to change this position was based on ‘a careful study of the most recent literature and experiences in the evaluation of biosimilars’. This, says MEB, led it to the conclusion that ‘this strict condition is no longer valid’.

In May 2015 the Finnish Medicine Agency recommended switching and stated that there is no evidence for adverse effects due to a switch from a reference product to an approved biosimilars and the ‘theoretical basis of such adverse effects’ is weak.

Switching is critical for the success of biosimilars as well as the opportunity to collect real data for the continuous support of biosimilars.

COST

The high cost of biologics is an important issue in the battle concerning ever increasing healthcare cost. Biosimilars have the potential to curb health care cost as well as allow a robust and steady supply of biologics reaching far-flung patient populations. However cost reductions have to be significant to encourage uptake.

Biosimilars in the EU are usually priced 15-30% below their reference products but they have achieved little market share because of lack of interchangeability. A major exception is Germany where Germany’s Federal Healthcare Committee has encouraged the use of biosimilars and is able to negotiate for rebates.

There is reluctance to switch for a small cost saving in particular where the originator company is offering high level of patient support. A significant price decrease could turn the tide. Recently in Norway Orion discounted its biosimilar infliximab (Remsima) by 69%. The move paid off quickly and by March 2015 the biosimilar grabbed half the market.

33

EDUCATION:

There has been a great deal of progress in developing the scientific pathway of biosimilars but the focus is shifting towards educating the stakeholders. The paradigm of similarity is a difficult concept for prescribers and users.

CONCLUSION:

The regulatory pathways for the approval of biosimilars are well developed and tested globally. The challenge is successful uptake in the market. Understanding the science of biosimilars is crucial.

There is a perception that biosimilars are inferior to the originator and consequently not safe.

The evidence so far is clearly the opposite. Biosimilars have been in the market for nearly 10 years in Europe and as evidenced by the Finnish Agency, the ‘theoretical basis for such adverse effects’ is weak. Cost matters as clearly seen in Norway. Education is key. Robust pharmacovigilance monitoring is essential for continuous monitoring of the safety of biosimilars.

Member states of the EU have to apply biosimilar policies as they are critical for achieving sustainable health care systems.

TOGETHER WE ARE FINDING THE SIMILARITIES T O M A K E T R E AT M E N T S R E AC H A B L E FOR THOSE WHO NEED THEM MOST.

COMPREHENSIVE PHASE I-IV BIOPHARMACEUTICAL DRUG DEVELOPMENT PRA is poised to help our clients succeed in the new era of biosimilars drug development. Our Biosimilar Development team is a cross-functional collaboration that leverages a structured and focused approach combined with a comprehensive understanding of this space’s challenges and opportunities. With each and every biosimilar trial, we’re working with our clients to change lives and to make the world a better place.

In the end, we all share the same goal — to get life-improving treatments to the people who need them. Together, we realize that to save lives, or enable people to live better lives, is no small thing.

With every biosimilar drug that we help bring to market, we not only improve the lives of the individuals who need it, but also all the lives that they touch. www.pr ahs.c o m

BIOSCIENCE JOURNAL SUMMER 2015

ADVERTORIAL

Looking for a partner for your biosimilar clinical trial?

BioKinetic Europe is one of the UK’s leading early phase clinical research organizations with experience in over 400 clinical trials.

Our Phase I portfolio comprises BE/BA studies, SAD/MAD/Proof of Concept, TQTc, DDI, vaccine and medical device studies.

populations have included: adults and adolescents with asthma/COPD; tuballyligated women; and women with PCOS. For each of these studies we exceeded our agreed recruitment targets and were the top recruiting site in Europe.

VOLUNTEER DATABASE

MULTI-CENTRE APPROACH

At BioKinetic we pride ourselves in the meticulous management of our volunteer database, because we know that fully informed, compliant volunteers recruited in a timely fashion are imperative to a successful trial. Our volunteer database currently boasts 20,000 active volunteers, made up primarily of healthy volunteers aged between 18-55 but also various patient populations including rheumatoid arthritis, women with uterine fibroids, asthma/COPD and diabetics (Type 1 and 2).

The BioKinetic team works collaboratively with Sponsor personnel to clearly define protocol requirements and inclusion/exclusion criteria. As a result, we consistently provide and even exceed our number of required participants for trials.

For particularly difficult to reach populations or studies involving a large number of subjects, we routinely devise bespoke recruitment strategies and design advertising campaigns with a partner advertising agency to ensure we meet the trial timelines and targets.

Where large numbers of volunteers are required, we are comfortable acting in a multicentre setup as a coordinator or participant.

We work with various sites in Germany, Belgium and France to expedite overall recruitment and study timelines and can bring on some or all of those partners as each study’s needs dictate.

FAST AND FAVOURABLE REGULATORY ENVIRONMENT

Based in the UK, we benefit from the 14-day approval timeline for Phase I CTAs and REC. Our regulatory team at BioKinetic have good working relationships with local regional ethics committees and the UK competent authority, MHRA which gives every study the best possible chance of being approved first time.

CASE STUDY: AGILITY IN STUDY START-UP

BioKinetic was approached by a client CRO to run a trial they had committed to but could no longer accommodate in-house. The Sponsor needed an experienced Clinical Pharmacology Unit that could run a dose-escalation trial for a biosimilar product with the fastest possible set-up times and the CRO needed to use a unit they could trust to deliver for their client.

Regulatory approval had already been granted so a Substantial Amendment and REC approval were required.

The BioKinetic team moved swiftly to review the protocol, set up a client site qualification audit and provide a detailed timeline and Gannt chart to illustrate approval timelines and trial deliverables through to CSR. The time between the initial phone call enquiry to first subject first visit was under 8 weeks. All cohorts were recruited and dosed as scheduled with database lock secured as per original agreed timeline with client CRO. The outcome was that the CRO retained their important client and the Sponsor has promised us repeat business.

To find out more about BioKinetic’s capabilities and how we can help in your biosimilar trial, please contact us on clients@biokineticeurope.com or call us on +44 (0) 2890 81 83 81

EXPERIENCED IN COMPETITIVE RECRUITMENT

BioKinetic has participated in a range of studies across a range of therapeutic areas where a competitive recruitment approach was employed by the Sponsor. Specific

35

Scientific and Regulatory Services DURING DEVELOPMENT Feasibility Assessment and Regulatory Roadmaps (including FDA) Scientific Advice Procedures with National Authorities, EMA and FDA Paediatric Investigation Plans (12 successful PIPs since 2008) Orphan Drug Designations (13 ODDs granted since 2010)

REGULATORY STRATEGY All EU and FDA Procedures Centralised Procedure Experts FDA Strategy & US Agent Services Global Roll-Outs Due Diligences (for Seller and Buyer) WRITING AND AUTHORING Complete CTD Creation for all Products and Procedures Gap analysis of CMC, Clinical and Non-Clinical Documentation All Documentation for Development, Registration and Maintenance Expertise in a wide range of Therapeutic Areas

SUBMISSION MANAGEMENT EU, FDA and RoW Applications 15 Centralised Procedures up till 2015 DCP submissions to all EU countries FDA: IND, NDA, Art. 505 (b)(2), ANDA, DMF submission expertise eSUBMISSION Support for all EU & FDA Submissions (including all Electronic Gateways) >150 eCTD Sequences per year RIM Consulting xEVMPD Experts (>20,000 Records sent) Software Support and Hotline PRODUCT MAINTENANCE & PHARMACOVIGILANCE EU, FDA, RoW Lifecycle Management, Complete Maintenance Outsourcing Coordination of National Phases in EU Pricing and Reimbursement Audited PV System. Set up of Quality System EU-QPPV and Local QPPV. PSMF, RMP, PSURs, Case Management

TRAINING Regulatory Affairs seminars for Experts and Beginners FDA basic and in-depth Training Technology workshops for eSubmission and Software Implementation

Ou r w o r k : s h a r i n g o b je ct i v e s, a d d in g v a lu e .

T +34 93 238 59 45 info@asphalion.com www.asphalion.com

ADVERTORIAL

Biosimilars - What are the critical regulatory milestones during development and registration?

The ever increasing complexity of regulations and drug approval pathways has converted regulatory intelligence into one of the key assets during any kind of drug development.

This situation is even more pronounced in the case of biosimilar drug development, where regulations are rather new and lack of (international) consensus exists even regarding critical issues. Delays and drawbacks are inevitable unless the company is truly up to date with national, regional and international regulations and agency opinions.

Let’s have a look at common regulatory objectives and hurdles that most companies will face during a biosimilar development programme in Europe.

EARLY REGULATORY MILESTONES •

Choice of reference (originator/ comparator) product as well as foreign comparator product, if applicable

•

Definition of physicochemical and biological characterisation programme and analytical methods

•

Preparation of Investigational Medicinal Product Dossier (IMPD) and Investigator’s Brochure (IB)

•

Definition of non-clinical and clinical development programme; submission of Clinical Trial Applications (CTAs)

ADVANCED REGULATORY MILESTONES •

Successful conduct of Scientific Advice (SA) with EMA (one or several)

•

Consensus with EMA regarding the comparability exercise, data to establish biosimilarity

•

Set up of expert medical and scientific writing team

•

Definition of calendar and allocation of resources for writing of CTD modules

FINAL STAGE REGULATORY MILESTONES •

Pre-Submission Meeting with EMA; agreement on critical issues such as immunogenicity data, extrapolation of safety/efficacy data from different indications, justification of indications, etc.

•

Final draft of Risk Management Plan and Summary of Product Characteristics

•

eCTD compilation, publishing and Quality Check

•

Dossier submission via eSubmission gateway (and Common Repository / CESP)

The figure above summarizes some of these points along a hypothetical 6-year timeline.

There are many further steps in addition to the ones listed above, yet importantly they all share common principles. For example, most of the regulatory milestones are both timecritical and successive in character, meaning that failing at any one of them will typically affect overall timelines and negatively influence other parts of the project. Trying to save money via a limited effort while working towards regulatory objectives will eventually

37

cause delays and financial losses. In the worst case, inadequate regulatory effort/knowledge will bring irreparable consequences, such as unfavourable outcome of SA meetings or even (partial) negative opinions for the Marketing Authorisation Application.

Conversely, high quality regulatory work is a fundamental element towards compliance with the overall project goals, calendar and budget.

For more information, please contact ASPHALION at info@asphalion.com

BIOSCIENCE JOURNAL SUMMER 2015

z FEATURE

The age of

Cell Therapy Industry that takes advantage of pioneering research For a cutting-edge technology, cell therapy has a surprisingly long history. Indeed, the idea of injecting living cells into a patient originated in the nineteenth century.

Although scientists’ early rudimentary attempts did not really work, subsequent research proved more fruitful and today the technology has led to massive investment from research institutions and companies seeking to grow the cells needed for the procedures.

There are two categories of cell therapy, which is also known as cellular therapy or cytotherapy. One is used in mainstream medicine when a human cell is transplanted from a donor into a patient and, although such research has can be controversial when it involves human embryonic material, by and large the feeling is that it holds great promise.

The second category is more controversial and is practiced in alternative medicine where it continues the practice of injecting animal materials in an attempt to cure disease. However, the practice is beset by

claims that it is not backed by medical evidence.

The origins of cell therapy can be traced to Charles-Édouard Brown-Séquard (1817– 1894) who unsuccessfully injected animal testicle extracts in an attempt to stop the effects of aging.

His work was followed in 1931 by Paul Niehans, who attempted to cure a patient by injecting material from calf embryos.

Niehans claimed to have treated many people for cancer with the technique, although his claims have never been fully validated by research.

In 1953, more credible breakthroughs were made with researchers discovering through tests on laboratory animals that rejection of transplanted organs could be prevented by pre-inoculating them with cells from donor animals, followed in 1968, in Minnesota, USA, by the first successful human bone marrow transplant.

Today, the procedure has been extended to other kinds of therapy such as treating damaged knee cartilage and the use of stem cells.

T cells have shown themselves capable of fighting cancer cells as part of immunotherapy treatment and research is offering hope to victims of neurodegenerative diseases, heart disease and diabetes.

38

BIOSCIENCE JOURNAL SUMMER 2015

FEATURE z

CONTINUED ON PAGE 40

39

BIOSCIENCE JOURNAL SUMMER 2015

z FEATURE

A colorized scanning electron microscope picture of a nerve ending that has been broken open to reveal the synaptic vesicles (orange and blue) beneath the cell membrane.

CONTINUED FROM PAGE 39

All of this activity places pressure on the cell therapy manufacturing industry with a major problem being the move towards personalised treatments which require smaller runs of product rather than a mass produced off-theshelf one.

One of the breakthroughs came when scientists at The University of Nottingham developed a new substance which could simplify the manufacture of cell therapy.

There are two phases in the production of stem cell products; proliferation (making enough cells to form large tissue) and differentiation (turning the basic stem cells into functional cells).

The environments required for the two phases are different and, up until the teamâ&#x20AC;&#x2122;s breakthrough, a single substance that does both jobs had not been available.

However, the researchers have created a new stem cell micro-environment which allows both the self-renewal of cells and their evolution into cardiomyocyte (heart) cells.

The hydrogel they devised contains two polymers and creates an alginate-rich

environment which includes a chemical switch which makes the environment collagen-rich when the cell population is large enough, a change that triggers the next stage of cell growth.

Nottingham University Professor of Advanced Drug Delivery and Tissue Engineering, Kevin Shakesheff, said: â&#x20AC;&#x153;The discovery has important implications for the future of manufacturing in regenerative medicine.

The discovery has important implications for the future of manufacturing in regenerative medicine. This field of healthcare is a major priority for the UK and we are seeing increasing investment in future manufacturing processes to ensure we are ready to deliver real treatments to patients when products and treatments go to trial and become standard.

Kevin Shakesheff

Nottingham University Professor of Advanced Drug Delivery and Tissue Engineering

40

BIOSCIENCE JOURNAL SUMMER 2015

FEATURE z

1. and 2 (below): Combined hydrogels containing human embryonic stem cells that are designed to grow and self-renew stem cells or switched to differentiate them.

would make it more cost- effective to make something personalised rather than mass produced.

“Manufacturers are looking for technologies that are economically viable and since we made the announcement, work has continued to develop the idea.

“Although we concentrated on heart cells, we are also looking to expand it into a variety of applications. It’s about new ways of thinking and pushing the boundaries.”

Manufacturers can also see the potential and a lot of investment has gone into a sector which has attracted some significant players.

For instance, this year alone has seen a number of major announcements, including from Lonza, a global leader in cell therapy manufacturing, and biopharmaceutical company TiGenix who signed an agreement for the supply of TiGenix’s eASC product, Cx601, which is being developed for the treatment of Crohn’s Disease ,with much of the work happening in Walkersville, Maryland, US. Other developments have included an announcement from WuXi PharmaTech (Cayman) Inc, which operates in China and the United States, that it will begin construction of a new, 145,000-square-foot cGMP facility in Philadelphia for the manufacture of cell therapy products.

The plant will concentrate on viral vectors such as chimeric antigen receptor T cell (CAR T cell) therapies, cells harvested from a patient’s body, engineered to target specific cancers then reintroduced into the body.

The complex will be WuXi’s third cell therapy manufacturing facility when it becomes operational in mid-2016 and Dr Ge Li, Chairman and CEO of WuXi PharmaTech, said: “Cell therapies like CAR T cells offer important new treatment options for cancer patients.”

In addition, US biopharmaceutical firm NeoStem, Inc. announced the expansion of manufacturing services under an agreement between its wholly-owned subsidiary PCT, and Kite Pharma, Inc. For Dr Robert A. Preti, Chief Scientific Officer of NeoStem and President of PCT, such investments will support new thinking in the cell therapy manufacturing industry.

“This field of healthcare is a major priority for the UK and we are seeing increasing investment in future manufacturing processes to ensure we are ready to deliver real treatments to patients when products and treatments go to trial and become standard.”

“If you take bone marrow transplants, that has been successful and is well developed, but people don’t always associate it with cell therapy. Other applications such as the use of stem cells are not yet as well advanced.

Also part of the team was Glen Kirkham, a post-doctoral researcher in stem cells at the university, who believes that much remains to be achieved in the field.

“What drives our work at Nottingham is the needs of medicine and the thing the manufacturers said would assist them was a product that could make it easier to produce cell therapies.

He said: “Assessing where we are with stem cell therapy depends on which aspect you examine.

“Medicine is going is towards personalised treatments rather than off-the-shelf products so we set out to develop something that

41

He said: “The expansion of NeoStem’s arrangement with Kite allows us to continue providing innovative, reliable and high quality manufacturing expertise to cell therapy developers who are researching potentially life-changing treatments for patients across many therapeutic areas.”

BIOSCIENCE JOURNAL SUMMER 2015

ADVERTORIAL

Critical Factor for Industrializing Cell Therapies: Quality Attributes and Quality Assurance of the Manufacturing Raw Materials Slowly but progressively more Advanced Therapy Medicinal Products (ATMP), including Cell Therapy Products, are reaching the market and a significant number are getting closer to a marketing authorization submission. One of the challenges in the development of Cell Therapy Products is the transfer from the preclinical to the clinical stage. As one of the key issues, the safety and quality of raw materials is critically evaluated by regulatory authorities.

Cytokines, growth factors, and cell culture media are commonly used in the processing of cells during the manufacture of ATMPs. They come in contact with the therapeutic products during manufacturing but are not intended to be part of the final cell product. Nevertheless quality, safety and efficacy of clinical cell products are largely influenced by these raw materials (RM, in the USA called ancillary materials). United States Pharmacopeia (USP) chapter <1043> states that „The quality of an ancillary material can affect the stability, safety, potency, and purity of a cell, gene, or tissue-engineered product“. This is why the cell manufacturers are obliged by their authorities not only to produce their ATMP in compliance with Good Manufacturing Practice (GMP), but also to qualify the critical raw materials and their vendors or manufacturers.

In recent years regulatory agencies recognized an increasing need for guidance for raw materials used for the production of ATMPs and started developing guidelines that outline general risk-mitigation strategies and qualification programs which can be used to select appropriate reagents. USP general chapter <1043> provides valuable tools for “Ancillary materials for cell, gene, and tissue-engineered products”, or European Pharmacopeia (EP) monograph 5.2.12 for “Raw materials for the production of cell-based and gene therapy medicinal products” (currently in preparation). Furthermore there is USP Chapter <92>, which outlines specific quality attributes for “Growth factors and cytokines used in cell therapy manufacturing”.

Despite arising guidance in this area, manufacturers of ATMP have to identify critical quality requirements to meet increasing quality and safety concerns.

Therefore, the origin, composition, manufacturing process, quality control (QC) methods and release specifications of RM have to be shared by the suppliers of critical raw

materials with cell therapy manufacturers and regulatory agencies. Since no certification by regulatory bodies of critical raw materials is foreseeable in the near future, the quality of raw materials has to be critically evaluated in the manufacturing process of cell therapy products. We propose three major quality standards for critical raw materials: •RM must be safe. The origin and impurity profile of all raw materials used in the manufacture of RM must be assessed and procured from reliable manufacturers and suppliers. This implies clear definitions of “animal-free”, “xeno-free”, or “animal-derived component-free”. This implies not only the absence of animal- or human-derived materials in the RM, but also the exclusive use of safe and traceable materials throughout the RM manufacturing process. Recombinant products must be derived from and fully traceable to well-characterized Master Cell Banks as starting materials, following guidance of EP chapters 5.2.12 and 5.1.7.

•RM should be produced following applicable GMP guidelines to provide documented evidence of purity, potency, consistency, and stability. Since traceability is a key requirement, the quality assurance system must comprise major GMP procedures including change control, deviation and OutOf-Specification procedures. Manufacturing and QC must be performed according to Standard Operating Procedures (SOPs) by qualified and trained personnel following validated and consistent processes, including manufacturing, cleaning and QC. The RM should be derived from well-characterized cell banks, product quality should be monitored at each manufacturing step by In-Process Controls (IPC). A clean room facility and qualified equipment should be available for

42

manufacturing. Product quality should be tested by validated analytical methods, and product stability should be validated by stress, accelerated & real-time studies. Product release must be certified according to pre-defined specifications by an independent QC. •RM must comply with regional regulatory requirements. The RM manufacturers must be prepared to provide technical and regulatory support, incl. on-demand customized documentation of their RM products for regional authorities. Moreover, the RM manufacturer should provide proactive information about major product changes.

As a consequence, the use of GMP grade and animal-derived component-free (ADCF) manufactured RM, derived from wellcharacterized cell banks, will significantly reduce qualification and validation efforts of ATMP manufacturers. All these factors help to ensure consistency, safety and purity of the final cell therapy products and contribute to the seamless transition from research to commercialization.

Bernd Leistler CellGenix GmbH

Director Development and Production E-Mail: leistler@cellgenix.com Phone: +49 761 88 88 9 - 0 CellGenix GmbH Am Flughafen 16 79108 Freiburg, Germany

BIOSCIENCE JOURNAL SUMMER 2015

GMP

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In North America and a few other countries CellGro® reagents are marketed under CellGenix™.

BIOSCIENCE JOURNAL SUMMER 2015

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Growing the UK cell and gene therapy industry Cell and gene therapies are at the very cutting-edge of medical research and the creation of the Cell Therapy Catapult’s state-of-the-art £55 million manufacturing centre at the Stevenage Bioscience Catalyst, will help Britain be a real leader in this fast developing industry.

Subject to planning approval, the large-scale, good manufacturing practice (GMP) facility will create up to 150 jobs and will be at the focus of a cluster of related companies creating many more jobs.

It will bring additional inward investment from global companies, as well support the SME biotech and life sciences companies based in the UK. Although it was only established in 2012, the Cell Therapy Catapult has become a centre for excellence to bridge the gap between scientific research and full-scale commercialisation, and help accelerate the growth of the cell and gene therapy industry in the UK. Regenerative medicine, of which cell therapy is a part, is one of the UK government’s eight great technologies that support UK science strengths and business capabilities. The Cell Therapy Catapult manufacturing centre is a unique global business proposition based in the UK that will provide national and international developers with a steppingstone into the EU, US and other growing international markets.

Building a cluster of excellence in cell and gene therapies at the Stevenage Bioscience Catalyst is a prime objective, and start-ups such as Plasticell, Progenitor Labs, Tokyo Electron Europe and Trakcel, as well GE Healthcare, which has a technology lab based there, demonstrate they’re on track.

GSK is also a neighbour and the Cell Therapy Catapult is another welcome addition to this growing family of innovative companies. The site provides a unique and thriving bioscience community with the benefit of excellent UK and international logistics. Companies coming to the Cell Therapy Catapult’s manufacturing centre will also be able to access its expertise, networks and scientific facilities traditionally associated with multinational pharmaceutical companies.

Keith Thompson, CEO of the Cell Therapy Catapult said: “This centre demonstrates the investment the UK government is making to advance the industry into becoming a world leader in advanced therapy development and commercialisation. The manufacturing centre will complement the existing UK capability, enabling companies to operate at the scale needed for Phase III clinical trials, and we look forward to working with global scientific

and medical communities to assist in their research into products that have the potential to address many unmet medical needs.”

Dr Martino Picardo, CEO of Stevenage Bioscience Catalyst said: “The UK cell therapy industry has huge potential, and investments such as this will allow the sector to progress from a strong R&D base to the manufacture of commercial stage products. For the Stevenage campus, this is another milestone in enabling it to become a landing pad in Europe for cell therapy and other disruptive technology companies. We look forward to welcoming other like-minded activities to the Campus.”

In its 2013 annual survey of Good Manufacturing Practice, the Cell Therapy Catapult identified Manufacturing and Supply Chain as one of the barriers to the translation of research into commercially viable products. The UK is strongly positioned for early clinical phase manufacturing and the large-scale GMP manufacturing centre will help in growing a UK- based global industry.

The centre and its associated cluster, will enable companies to develop the systems and supply chain that allow their manufacturing processes to operate at scale. In addition it

will be operationally very efficient, enabling the growth of organisations by reducing or spreading the costs and risks of establishing and running a specialist manufacturing facility between up to 12 firms simultaneously in the 7200m2 securely segregated space. The innovative design is being developed in close relationship with the Medicine and Healthcare products Regulatory Agency. The carefully designed and market tested concept will help accelerate global expansion opportunities by reducing cost and increasing speed of growth using a flexible, replicable clean-room design which can accommodate multiple processing methodologies, including viral vectors, stem cells and tissue engineering. All customers will have access to the Cell Therapy Catapult’s world-leading services, including regulatory advice and health economics analysis, as required, whilst maintaining confidentiality and control over their own process, in-house knowledge and IP. For rapidly growing companies and inward investors, the wide range of expertise available from both the Cell Therapy Catapult and the Stevenage Biocatalyst, places the location in an enviable position in the world.

This centre demonstrates the investment the UK government is making to advance the industry into becoming a world leader in advanced therapy development and commercialisation. The manufacturing centre will complement the existing UK capability, enabling companies to operate at the scale needed for Phase III clinical trials, and we look forward to working with global scientific and medical communities to assist in their research into products that have the potential to address many unmet medical needs.

Keith Thompson

CEO of Cell Therapy Catapult

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BIOSCIENCE JOURNAL SUMMER 2015

Growing the UK cell and gene therapy industry, delivering health and wealth.

The Cell Therapy Catapult large-scale GMP manufacturing centre opening in 2017 at the Stevenage Bioscience Catalyst campus.

Catapult is an Innovate UK programme.

BIOSCIENCE JOURNAL SUMMER 2015

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Replace FBS with Human Platelet Lysate The manufacture of clinical-grade cellular products often requires ex vivo culture and expansion of human cells.

Fetal bovine serum (FBS) is frequently used as a supplement to basal cell culture media during expansion; however, its use poses risks including the potential for viral and prion transmission, and the possibility of adverse immunological reactions. Consequently, regulatory bodies across the globe are advising against the continued use in cell manufacturing.

A Xeno-Free Alternative

In view of these considerations, xenogenic-free culture conditions are desirable. Among the options available to replace FBS, the human platelet lysate PLUS™ Cell Culture Supplement has become the superior choice. It is a rich, cell-free supplement produced from human donor plateletpheresis products that contains a broad spectrum of growth factors, including platelet-derived growth factor (PDGF), epithelial growth factor (EGF), vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), hepatocyte growth factor (HGF), and transforming growth factor β1 (TGF-β1), that support cell adhesion, growth, and proliferation.

Commercial Scale Reliability

Traditionally, similar products have been prepared by individual laboratories in small batches using protocols that differ in the number of platelet units pooled, the processing of platelets, and the requirement for heparin. These small batches are typically not compliant with good manufacturing practices (GMP), which is an important consideration when translating manufacturing processes for clinical applications.

Additionally, many smaller-scale providers utilize heparin to prevent fibrinogen clotting upon contact with calcium in culture medium; not only is commercially available heparin derived from porcine sources (nullifying efforts to remove all xenogeneic supplements), it does not remove fibrinogen, which has been shown to negatively affect the immunomodulatory functions of cultured stem cells. These differences can significantly impact stem cell growth, morphology, and functionality.

A solution to these issues is the use of PLUS™ which is manufactured using a highly standardized, industrial-scale production process. Each lot is produced by pooling platelet units from at least 100 donors, resulting in a product with very consistent growth factor profiles and cell culture performance. Additionally, PLUS™ is available as a GMP-grade product, providing a safe, efficacious, reproducible, and xenogeneic-free alternative to FBS. As a human-derived product, PLUS™ does not harbor the risk of xenogeneic immune reactions or infections with bovine pathogens, and the GMP-grade product is already being used in FDA-approved clinical cell therapy protocols, reducing the risk in translating research to the clinic. Prior FDA approval for use of PLUS™ in clinical trial protocols has set a precedent for future approvals for manufacturers looking to switch from FBS to a human platelet lysate.

Proven Results

PLUS™ has been shown to promote the efficient proliferation and migration of a range of human cell types, including bone marrow and cord blood-derived mesenchymal stromal cells (MSCs), adiposederived MSCs (ASCs), human umbilical vein endothelial cells (HUVECs), keratinocytes, fibroblasts, and is currently being tested and optimized for use with NK cells and T-cells.

Stem cells have been shown to expand extensively in medium supplemented with PLUS™, with significantly higher yields than when cultured in FBS. When expanded over multiple passages, stem cells of multiple derivations have also been shown to maintain their spindle morphology, expression of characteristic surface markers, and are more easily detached from plastic with trypsin. Stem cells cultured with PLUS™ maintain their differentiation ability. The immunosuppressive activity is comparable between PLUS™ and FBS-expanded hMSCs/ hASCs due to PLUS™’s minimal fibrinogen concentration.

Lower Costs

The higher proliferation rates and lower doubling times seen with PLUS™ imply a greater cell yield compared to FBS. These higher cell yields translate into more cost and time savings for manufacturers.

Using PLUS™ throughout the entire cell manufacturing process, from isolation of cells, to ex vivo expansion, and cryopreservation can reduce overall costs, when compared to using FBS. Compass Biomedical’s technical support team is able to assist you with your research protocol transitions, production scale-up and clinical regulatory support to help you make the switch from FBS to PLUS™.

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BIOSCIENCE JOURNAL SUMMER 2015

applied cell therapy

we make cell therapy work for you apceth is a leading clinical-stage biopharmaceutical company building a pipeline of next-generation cell-based therapeutics.

Our lead program, Agenmestencel, is the first-in-man genetically-modified mesenchymal stem cell (MSC) treatment for cancer. And we are further expanding our modular platform technology to develop novel candidates for the treatment of lung diseases, inflammation and beyond.

The unique features of our platform technology allow the highly targeted expression of any therapeutic protein directly into the disease site.

Based in Munich, Germany, we provide our know-how, expertise and GMP-certified production facilities to industry and academic partners around the world.

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ADVERTORIAL

Product Characterization for Cell Therapy GMP Manufacturing The specifications, QC and release testing of cell therapy products can make the difference between success and failure Stefanos Theoharis, Suncana Kern and Christine Guenther, apceth GmbH & Co. KG All manufactured products require measurable parameters, called specifications, which confirm each manufacturing run has met the specifications. Quality Control (QC) is the process of establishing and testing them.

The more complex and sophisticated the product, the more parameters must be tested and cell therapy products are among the most complex. Cells are living organisms with multiple features determining their therapeutic function. Product specifications must reflect those critical features, and QC tests must be developed for the starting material, the process-related parameters and the end product, characterized by these mandatory criteria: Identity: The identity of product is established using unique distinguishing characteristics, usually cell-surface proteins. For example, all haematopoietic stem cells express CD34 and all T-cells CD3. Mesenchymal stem cells (MSCs), a very common cell type in clinical trials, must be positive for CD73, CD105, CD90 and negative for CD45 and CD34. Other markers may also be tested for absence (e.g. CD14/CD11b, CD79alpha/CD19 and HLA-DR). They are also able to differentiate to osteoblasts, adipocytes and chondrocytes. So, for MSC products a panel of at least 5 surface molecules and 3 differentiation tests are common practice.

Engineered cells, like the genetically modified MSCs developed by apceth (e.g.

Agenmestencel-T currently in Phase II clinical trial), also feature a new gene and its gene product. Itâ&#x20AC;&#x2122;s therefore necessary to test for this with appropriate thresholds to ensure therapeutic efficacy and safety.

Purity: Itâ&#x20AC;&#x2122;s impossible to ensure that the final cell population will be 100% homogenous, since the starting material is human material and the manufacturing process involves multiple steps which affect cells differently. A cut-off for minimum purity must be decided based on the mode of action of the cell product.

Likewise, there should be a cut-off for cell viability, post-production or post-thawing, and for all other cellular components.

Sterility/mycoplasma/endotoxin: All pharmaceutical products are manufactured

under aseptic conditions to ensure sterility and are tested for bacterial, fungal, mycoplasma and endotoxin contamination. These tests are standardized and straightforward, but must be validated for each product.

Allogeneic cell products are based on donorderived cells, expanded to yield multiple doses (off-the-shelf product). This is possible without any modifications for MSCs and has multiple advantages concerning the quality and reproducibility, cost, logistics and product availability. Allogeneic products additionally involve donor testing for transmissible diseases (similar to cord blood donations).

Potency: This category refers to tests that predict the product will exhibit the necessary functionality for therapeutic efficacy, every time. They may include expression of relevant proteins, the genomic signature of cells or an

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in vitro functional assay. Itâ&#x20AC;&#x2122;s best to keep these very simple, with clear readouts. A reference standard may be useful.

Stability/ genetic stability: The in-use stability is critical for delivering reproducible results of cell products (freshly applied or frozen) influencing significantly the product quality.

Genetic stability refers to the expanded cultivation process of some cell types which might influence the product quality and safety.

In conclusion, the specifications of cell therapy products are complex and QC is cumbersome.

Automation is likely to reduce the workload and cost of QC and manufacturing, but the prime consideration must always be to ensure high standards that translate to therapeutic benefit for patients in need.

BIOSCIENCE JOURNAL SUMMER 2015

ADVERTORIAL

Vericel: Improving multicellular therapy through advanced manufacturing Founded in 1989, Vericel (formerly Aastrom Biosciences) is dedicated to the development of patient-specific expanded cellular therapies for use in the treatment of patients with severe diseases and conditions.

The company currently markets two cell therapy products in the United States: Carticel® (autologous cultured chondrocytes), an autologous chondrocyte implant for the treatment of cartilage defects in the knee, and Epicel® (cultured epidermal autografts), a permanent skin replacement for the treatment of patients with deep dermal or full thickness burns. Vericel is also developing MACI™, a third-generation autologous chondrocyte implant product, as well as ixmyelocel-T, a patient specific multicellular therapy for the

treatment of advanced heart failure due to ischemic dilated cardiomyopathy (DCM).

Leaders in cell therapy manufacturing

Vericel’s historic focus on cell therapy and regenerative medicine took a major step forward in May 2014 when the company acquired the global marketing rights to three landmark autologous cell therapies from the Genzyme division of Sanofi: • CARTICEL is the first and only FDAapproved biologic product used to repair articular cartilage injuries in the knee. It is manufactured using a patient’s own cartilage cells and is implanted in a surgical procedure known as autologous chondrocyte implantation (ACI). Once implanted, the cells have been shown to form new hyaline-like cartilage, with properties similar to normal cartilage, and may reduce pain and improve knee function.

• EPICEL is FDA approved as a humanitarian use device (HUD) and is indicated for use in patients who have deep dermal or full thickness burns comprising a total body

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surface of greater than or equal to 30%. EPICEL, which is essentially thin sheets of epidermis, is manufactured from a small sample of patients’ skin.

• MACI is a third-generation ACI product for the treatment of articular cartilage injuries in the knee. It has been approved but is not currently marketed in Europe. In June, Vericel announced that following discussions with the U.S. Food and Drug Administration (FDA) the company plans to submit a Biologics License Application (BLA) to the FDA by the end of 2015 for MACI for the treatment of focal chondral cartilage defects in the knee. MACI has potential advantages of a shorter, less-invasive surgical procedure and a faster recovery period than CARTICEL. For more than 20 years, the research and production teams responsible for CARTICEL and MACI have been focused on superior performance in autologous cell therapy manufacturing establishing industry standards.

A) CARTICEL PROCESSING: Vericel’s cell processing manufacturing facility uses specific enzymes to free cartilage cells (chondrocytes) from the cartilage matrix. The chondrocytes

BIOSCIENCE JOURNAL SUMMER 2015

then begin the initial culturing (multiplying) phase, lasting approximately 14 days. At this point, cultured chondrocytes are placed into cryopreservation until implantation surgery is scheduled.

B) FINAL PHASE: Prior to the implantation, the chondrocytes are removed from cryopreservation to begin the final culturing phase. The chondrocytes are cultured until there are approximately 12 million cells per vial; up to 4 vials per patient.

C) QUALITY AND SAFETY. Every step of the manufacturing process is vigorously monitored to ensure the highest quality and safety possible.

In the manufacturing process, the focus on quality and safety affects every stage of production, beginning with careful lot segregation and closed culture conditions to prevent cross-contamination. Visual inspection for sterility is based on the use of state-of-the-art technology. Cell culturing is supported by continuous monitoring of cell growth morphology and sterility. Prior to release, products undergo viability, identity, sterility, endotoxin, and morphology testing.

Multicellular therapy to improve patient health

IXMYELOCEL-T PROCESSING. To manufacture ixmyelocel-T, a small amount of bone marrow is collected from the patient. The therapy is

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then developed using a proprietary cellprocessing system that is highly automated, fully closed and rigorously controlled. The production process is both scalable and reproducible to continually position Vericel to be able to meet demand for on-time therapy delivery through all stages of clinical research.

The production process for ixmyelocel-T expands the populations of naturally occurring cells in bone marrow that are believed to play a role in long-term tissue repair.

Targeting therapy with less risk

For patients suffering from complex, multifactorial, severe and chronic diseases such as DCM or CLI, ixmyelocel-T is manufactured based on several unique features that are critical for treatment success: •Patient-specific (autologous): The process uses each patient’s own cells to produce ixmyelocel-T. This helps to ensure that the cell therapy will not be rejected by the patient’s immune system.

•Expanded cell populations: The production process expands the number of CD90+ mesenchymal cells, CD14+ monocytes and alternatively activated macrophages, which are believed to play key roles in tissue remodeling, immuno-modulation and the promotion of angiogenesis.

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•Minimally invasive procedures: The aspiration procedure for removing a small amount of bone marrow and the administration of ixmyelocel-T can be performed in an outpatient setting.

• Focus on safety: Therapies derived from bone marrow have been used safely and efficaciously in medicine for over three decades. The production of ixmyelocel-T leverages this body of clinical research and medical experience. Based on clinical experience in the treatment in hundreds of patients thus far, there appear to be no significant safety issues associated with treatment.

With proven effective processes and technologies in place to support production of sensitive cell therapies on a global scale, Vericel will continue to work to identify additional opportunities to expand our pipeline with new cell therapies that reflect our ongoing commitment to innovation and research. Our goal is to be the leader in production of cell therapies that address more unmet needs for patients around the world.

BIOSCIENCE JOURNAL SUMMER 2015

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Bioscience Technology is moving so quickly that radical approaches have to be taken to ensure researchers have sustainable access to cutting-edge expertise, equipment and training. The Bioscience Technology Facility is an exemplar which proves that a central, open-access facility can be run effectively and sustainably.

To address the challenges of keeping up to date with new technology developments and maintaining expertise, Biology at York established the Bioscience Technology Facility, a group of dedicated core labs under one roof (side illustration). The Facility is open to both internal and external researchers (academic and commercial) who have benefitted from access to the integrated expertise, training, and instruments provided.

This integrated approach to technology access and development is vital for many cutting edge research programmes. A recent example of this has been the development of novel methods to quantify membrane transporters in collaboration with AstraZeneca which required input from across the breadth of the facility (see http://ow.ly/NRyXI).

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z FEATURE

Climate Change and the challenges facing mankind

Climate change is one of the biggest challenges facing mankind. Always has been, always will be, and that means that big changes lie ahead.

Many of those changes will impact on the work of scientists as they seek to find solutions to the predicted increase in illness caused as the planet warms and its weather becomes more unpredictable.

Numerous pieces of research suggest that warmer average temperatures are likely to lead to effects including hotter days and more frequent and longer heatwaves, which could in turn increase the number of heatrelated illnesses and deaths.

According to the World Health Organization (WHO), climate change is expected to cause 250, 000 additional deaths per year from malnutrition, malaria, diarrhoea and heat stress between 2030 and 2050.

Research by the US Global Change Research Program suggests that the impact of heatwaves could be especially severe in large metropolitan areas. For example, it says that in Los Angeles, annual heat-related deaths are projected to increase two-to seven-fold

by the end of the 21st Century, depending on the growth of greenhouse gas emissions.

Although its studies concentrate on America, they are just as applicable worldwide.

Indeed, the study says that the increase in heatwaves is actually more likely to affect northern latitudes more seriously because people are less prepared to cope with excessive temperatures.

Heatwaves, which lead to heat stroke and dehydration, are one of the biggest concerns because they are the most common cause of weather-related deaths, often accompanied by periods of stagnant air, leading to increases in air pollution and the associated health effects.

For example, ground-level ozone can damage lung tissue, reduce lung function and inflame airways, a particular problem for children, older adults and those with asthma and other chronic lung diseases.

According to the WHO: “Extreme high air temperatures contribute directly to deaths from cardiovascular and respiratory disease, particularly among elderly people. In the heatwave of summer 2003 in Europe, for example, more than 70,000 excess deaths were recorded.”

The US Global Change Research Program and WHO say that changes in climate may have other effects, including:

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•Higher air temperatures can increase cases of salmonella and other bacteria-related food poisoning because bacteria grow more rapidly in warm environments •Heavy rainfall or flooding can increase water-borne parasites such as Cryptosporidium and Giardia that are sometimes found in drinking water. The parasites can cause gastrointestinal illnesses •Heavy rainfall events cause stormwater runoff that may contaminate water bodies used for recreation such as lakes and beaches with other bacteria. The most common illness contracted from contamination at beaches is gastroenteritis, an inflammation of the stomach and the intestines that can cause symptoms such as vomiting, headaches, and fever. Other illnesses include ear, eye, nose, and throat infections •Climate is one of the factors that influence the distribution of diseases borne by vectors (such as fleas, ticks, and mosquitoes), which spread pathogens that cause illness.

Vector-borne diseases include Lyme Disease, dengue fever, West Nile virus,Rocky Mountain spotted fever and plague.

Mosquitoes, carriers of malaria, favour warm, wet climates. Studies suggest that climate change could expose an additional two billion people to the illness by the 2080s

BIOSCIENCE JOURNAL SUMMER 2015

FEATURE z

Extreme high air temperatures contribute directly to deaths from cardiovascular and respiratory disease, particularly among elderly people. In the heatwave of summer 2003 in Europe, for example, more than 70,000Â excess deaths were recorded.

WHO World Health Organisation

CONTINUED ON PAGE 60

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z FEATURE

CONTINUED FROM PAGE 59

•Climate change could be bad news for hayfever and allergy sufferers because it results in more frost-free days and warmer seasonal air temperatures, contributing to shifts in flowering time and the emergence of pollen •Climate change is expected to have global impacts on food production. The WHO said: “Rising temperatures and variable precipitation are likely to decrease the production of staple foods in many of the poorest regions – by up to 50% by 2020 in some African countries. This will increase the prevalence of malnutrition and under-nutrition, which currently cause 3.1 million deaths every year.”

For Janet McCabe, acting assistant administrator for the US Environmental Protection Agency’s Office of Air and Radiation on climate change, the warnings are there for all to see.

She said: “The science is clear and getting clearer: climate change threatens our health, our economy, our environment and our way of life in dangerous and costly ways – from superstorms and heatwaves to devastating droughts, floods and wildfires.

“The more we learn about climate change’s impacts on our health, the more urgent the need for action becomes.

“We know that impacts related to climate change are already evident and are expected to become increasingly disruptive across the nation throughout this century and beyond.

“The number of extremely hot days is already increasing, and severe heatwaves are projected to intensify, increasing heat-related mortality and sickness.”

Her concerns were echoed by the American Thoracic Society, which found that the majority of its members who responded to Janet McCabe

Mosquitoes can spread disease a survey believed that climate change has a negative impact on the health of their patients.

Sixty five per cent of respondents said that effects included more cases of acute and chronic lung conditions due to exposure to ozone or other pollutants and longer and more severe allergy seasons John R. Balmes, MD, Chair of the ATS Environmental Health Policy Committee, one of the survey’s authors, said: “Our physician members are seeing the effects that climate change is having on the well-being of their patients. These results talk to the importance of groups involved in healthcare taking a stand on this issue and educating their members and the patients that they serve that climate change is a healthcare issue.”

‘The time for action has arrived’

However, it is not a totally gloomy picture and action is already being taken in many countries with the central themes of tackling the long-term causes of warming while also doing more to mitigate its effects.

Janet McCabe in the US said: “Our most vulnerable populations – like children, minorities, communities already overburdened with pollution or poverty, and older Americans – are at greater risk from these impacts.

That’s why, under the American President’s Climate Action Plan, we are taking action now to reduce greenhouse gases such as carbon dioxide, methane, and hydrofluorocarbons.”

There is also action which can have a shorter term effect and among regions responding to the concerns is South Asia, which saw the expansion in April of the Heat Action Plan first introduced in Ahmedabad, the sixth biggest city in India.

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The move was timely because within weeks, India was hit by a major heatwave which claimed many lives, more than a thousand in the first week alone.

The plan was developed for just such scenarios and seeks to reduce the impact of extreme heat by operating an early warning system, providing training to medical and community workers and building public awareness of heat-related health risks.

It includes mapping high-risk areas, expanding work in vulnerable communities and improving the response of medical professionals and hospitals, including making ice packs more widely available for use during heatwaves.

The plan has been so effective that a wide range of organisations in the region, including governments and universities, are now working to see it implemented on a wider basis.

Anjali Jaiswal, director of the Natural Resources Defense Council’s India Initiative, said: “These heat action plans are a necessary response to climate change. Hundreds of thousands of people are already living on the threshold of what is tolerable heat-wise; even incremental changes in climate can push these temperatures over the line.”

Dr Dileep Mavalankar, Director of the Indian Institute of Public Health, Gandhinagar, said: “Unless we prepare to adapt our cities and rural areas to rising temperatures and heat waves, we may face serious health issues and mortality during future heatwaves.

“Ahmedabad’s Heat Action Plan is tailored to help the most vulnerable city residents cope with rising temperatures. Preliminary results of the Heat Action Plan in 2013 and 2014 showed that it was successful in saving many lives and raising the discourse around extreme heatwaves and health to a larger strata of society.”

BIOSCIENCE JOURNAL SUMMER 2015

FEATURE z

“People living in small island developing states and other coastal regions, megacities and mountainous and polar regions are particularly vulnerable. Children – in particular, children living in poor countries – are among the most vulnerable to the resulting health risks and will be exposed longer to the health consequences.

hay Fever due to high pollen count

“The health effects are also expected to be more severe for elderly people and people with infirmities or pre-existing medical conditions.”

World Health Organization

Report urges action on climate change

Concerns about the link between health and climate change were strengthened by a report launched jointly by The Lancet and London university UCL in June.

“Given the very hot conditions in north and central India, it is imperative to scale up the Ahmedabad Heat Action Plan. We hope that through this renewed expansion, other cities and states can use this innovative model as a foundation to craft their own plans.”

The Ahmedabad experience can be applied worldwide, according to Dr Jeremy Hess, Intergovernmental Panel on Climate Change author and Associate Professor of Emergency Medicine at Emory School of Medicine and of Environmental Health at the Rollins School of Public Health of Emory University in Georgia, USA. He said: “Local steps being taken by cities, like Ahmedabad’s heat action plan, are crucial in the global fight against climate change. The Ahmedabad Municipal Corporation has shown tremendous leadership, and I hope their experience will help other cities to implement on-the-ground solutions to growing threats such as extreme heat.”

For all the good work being done, though, there remains much cause for concern. And although a recent report published by the US Government emphasised the need for action, it remained cautious.

The report concluded: “Preventive and adaptive actions, such as setting up extreme weather early warning systems and improving water infrastructure, can reduce the severity of these impacts, but there are limits to the effectiveness of such actions in the face of some projected climate change threats.

Climate change presents a global public health problem, with serious health impacts predicted to manifest in varying ways in different parts of the world.”

Among other countries working on a similar approach is the United Kingdom, whose

Department of Health has just issued its latest issued guidance.

The UK heatwave plan has been published annually since 2004, following the devastating pan-European heatwave in 2003 when, for example, in Northern France unprecedented high day and night-time temperatures for three weeks resulted in 15,000 excess deaths, the vast majority among older people. In England, there were more than 2,000 excess deaths over the ten-day heatwave which lasted from 4 to 13 August, compared to the previous five years over the same period.

The plan outlines the system to alert those working with vulnerable people to an impending heatwave so that potentially lifesaving advice can be issued, everything from nursing homes and schools providing cool areas to ways of reducing heat in people’s homes.

In the foreword to the document, Professor Dame Sally C Davies Chief Medical Officer, says: “Although many of us enjoy the sunshine, as a result of climate change we are increasingly likely to experience extreme summer temperatures that may be harmful to health. For example the temperatures reached in 2003 are likely to be a ‘normal’ summer by 2040, and indeed globally, countries have already experienced record temperatures.

“We want to make sure that everyone takes simple precautions to stay healthy during periods of hot weather and when in the sun.

The purpose of this heatwave plan is to reduce summer deaths and illness.”

“Although global warming may bring some localised benefits, such as fewer winter deaths in temperate climates and increased food production in certain areas, the overall health effects of a changing climate are likely to be overwhelmingly negative.

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The report said that climate change is the biggest global health threat of the 21st Century with dangers ranging from heatwaves to food shortages.

Managing the Health Effects of Climate Change was written by UCL academics from disciplines across the university and the UCL–Lancet Commission based its findings on Intergovernmental Panel on Climate Change projections, from the optimistic average global temperature rise of 2 degrees C to the catastrophic 6 degrees C. Lead author Professor Anthony Costello, of the UCL Institute for Global Health, said: “The big message of this report is that climate change is a health issue affecting billions of people, not just an environmental issue about polar bears and deforestation.

“The impacts will be felt not just in the UK but all around the world – and not just in some distant future but in our lifetimes and those of our children. Young people realise this is the great issue of our age.

“We believe that all the main players in health, politics, science, technology and civil society must come together. We need a new 21st Century public-health movement to deal with climate change.”

BIOSCIENCE JOURNAL SUMMER 2015

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Understanding climate change and infectious disease: is the one health movement enough?

By Claire Heffernan1 and Kathy Maskell2

1 University of Reading, School of Agriculture, Policy and Development, Livestock Development Group 1&2 University of Reading, Walker Institute for Climate Research

In the coming decades, climate change is predicted to produce a range of direct and indirect impacts on both human and animal health.

At the most basic level, rising temperatures and changes to rainfall patterns have a direct impact on vector populations and thereby, vector-borne diseases (VBDs).

For example, human diseases such as malaria and dengue are now occurring at higher altitudes and latitudes, which historically have been free of the disease (Dhiman et al., 2010). This change has been directly attributed to climate warming. Outbreaks of livestock disease in new geographies such as blue tongue disease in Europe have also been linked to climate change (more specifically seven of the warmest winters in Europe on record during the late 1990s to early 2000s) (Tabachnick, 2010).

The extreme weather events (EWE) associated with climate change such as droughts and floods in addition to direct effects, may also have indirect impacts on the incidence and prevalence of infectious disease. Extreme flooding often causes a break-down in

sanitation, supporting an increase in waterborne diseases such as typhoid and cholera.

EWEs also often forge food and livelihood insecurity, which in turn supports shifts in both human and animal populations. Thus, while changes to vector populations may alter the geographic spread of a climate sensitive disease, the displacement of the host population (both human and animal) is equally influential to disease distribution.

Resident populations may be exposed to pathogens transferred by migrants or conversely migrants may be exposed to new pathogens in their new environment. Among pastoralist populations in Africa, droughts frequently displace populations into refuges camps. Recent epidemics of meningitis, hepatitis E and cholera have occurred in refugee camps in Kenya, Somalia and the Sudan (Ahmed et al., 2013).

Determining the role and influence of climate warming on disease highlights another issue: our approach to understanding this new disease landscape itself. Despite the drivers being the same for human and animal disease, historically, there has often been little synergy between veterinary and human disease investigations. However, in recent years the emergence of a range of threats originally attributed to animal pathogens such as Sudden Acute Respiratory Syndrome (SARS), Highly Pathogenic Avian Influenza (HPAI), Swine Flu and Ebola has underscored the need for a combined approach.

With this recognition has come the rise of the One Health agenda which aims â&#x20AC;&#x2DC;to promote and improve the health of humans,

REFERENCES

animals and our environment, (AVMA, 2008).

Crucially, One Health fosters collaboration between veterinary, medical, public health and environmental disciplines across the global health arena (FAO, 2011).

Despite this focus on the environment and in particular, the interface between disease and local ecologies, One Health, has not been widely utilized as a framework to perform detailed explorations of the impacts of climate change on infectious disease.

Part of the problem is the very nature of the One Health discourse. While One Health has been a rhetorical force across the field of Global health it has been less sure-footed as an analytical device. Critical issues in operationalising One Health include problems with knowledge silos and the need for better metrics across projects and programmes (Kihu and Heffernan, 2015). Explorations of the role of climate change on disease require both a robust and yet inclusive analytical approach. Indeed, it has been argued that climate change is not a single driver of disease but rather an embedded context and as such, is likely to influence a range of diseases in the same landscape among resident human, livestock and wildlife hosts, at the same time (Heffernan, 2015).

At its best, the One Health approach has the ability to identify the synergies and interactions important to disease transmission at the systems-level. The longevity and usefulness of the One Health paradigm is likely to depend on widening the frame to focus on climate change at the systems, as opposed to individual disease, level.

Ahmed J., Moturi E., Spiegel P., Schilperoord M., Burton W., Kassim N., et al. (2013). Hepatitis E outbreak, Dadaab Refugee Camp, Kenya, 2012 [letter]. Emerg Infect Dis, 19(6): 1010-1011.

Heffernan, C. (2015). Climate change and infectious disease: is it time for a new normal? Lancet Infect Dis 15: 343-344.

AVMA (2008). One Health: A new professional imperative. One Health Initiative Task Force: Final Report. American Veterinary Medical Association, Chicago, IL. https://www.avma.org/KB/ Resources/Reports/Documents/onehealth_final.pdf

IPCC, 2014: Climate Change 2014: Impacts, Adaptation, and Vulnerability. Part A: Global and Sectoral Aspects. Contribution of Working Group II to the Fifth Assessment Report of the Intergovernmental Panel on Climate Change Cambridge: Cambridge University Press.

Costello A. et al. (2009). Lancet and University College London Institute for Global Health Commission: managing the health effects of climate change. Lancet 373:1693-1733.

Kihu, S. and Heffernan, C. (2015). One Health Metrics, Measures and Impacts. Report of a One-Day Think Tank, Sankara Hotel, Nairobi, Kenya. March 23, 2015.

Dhiman, R., Pahwa, S., Dhillon, G., Dash, A. (2010). Climate change and the threat of vector-borne diseases in India: are we prepared? Parisitol Res 106 (4): 763-73.

Perry, B. and Sones, K. (2007). Poverty reduction through animal health. Science (315): 333-334.

Tabachnick, W. (2010). Challenges in predicting climate and environmental effects on vector-borne disease episystems in a changing world. J Exp Biol 213, 946-954.

FAO (2011). One Health: Food and Agriculture Organization of the United Nations Strategic Action Plan. FAO, Rome.

Heffernan, C. (2013). The climate change infectious disease nexus: is it time for climate change syndemics? Anim Health Res Rev 14:151-157.

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Walker Institute

WALKER INSTITUTE FOR CLIMATE RESEARCH CLIMATE EXPERTISE AND ENGAGEMENT The University of Readingâ&#x20AC;&#x2122;s Walker Institute aims to understand the risks and opportunities from our changing climate.

The Institute brings together the unrivalled breadth and depth of climate expertise that exists at Reading, from meteorology and hydrology to health, social science and ethics.

We work with external partners to ensure our research has impact on policy and practice.

TRAINING The University also offers a broad range of undergraduate and postgraduate training in climate related areas which span physical and social science disciplines.

www.walker-institute.ac.uk

BIOSCIENCE JOURNAL SUMMER 2015

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Bolder Faster Stronger How far can we go in the battle against illness?

Earlier this year, Austrian researchers came up with the startling suggestion that life should be regarded as beginning at sixty five.

Researchers at the International Institute for Applied Systems Analysis examined predicted ageing rates up until 2050 and concluded that we should no longer view someone reaching retirement age as ‘old’.

All very encouraging. Or is it? Living longer would be terrific were it not for the long shadow cast by illness, a shadow that persists despite the breakthroughs being made by medical science.

Every day, diagnostics are improved, drugs developed, lives saved, cures found and some illnesses like smallpox even recede into memory yet people still become sick and millions die before their time.

All of which begs the question – how far can we go in eradicating illness? In this special feature we look at the way that scientists from different disciplines are waging war on ill-health

World Population Program Deputy Director Sergei Scherbov, who led the study, said: “What we think of as old has changed over time, and it will need to continue changing in the future as people live longer, healthier lives. Someone who is 60 years old today, I would argue is middle aged. Two hundred years ago, a 60-year-old would be a very old person.”

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Battlefront 1 - waging war on infection Twenty five per cent of deaths worldwide are caused by infectious diseases and scientists readily acknowledge that, although they can make advances in the fight against bacteria, it is one that they can probably never win.

Among reasons for such a conclusion is the remarkably adaptable nature of the bacteria.

This is an enemy that keeps rewriting the rules.

Professor Simi Ali, Professor of Immunobiology at the Institute of Cellular Medicine, part of Newcastle University in North East England, said: “We can probably never fully eradicate infectious diseases and one of the reasons I say that is the emergence of new forms of old diseases as bacteria become resistant to drug treatments.

“Bacteria can multiply at a rapid rate which means that they can mutate quickly and become drug-resistant, which reduces the effect of the antibiotics that we use to treat them.”

Another challenge, according to Prof Ali, is

changes in human behaviour over recent decades, including deforestation and unprecedented travel, which are increasingly bringing people into contact with bacteria that previously they would have avoided.

Prof Ali said: “A big challenge in the work to combat communicable diseases is the emergence in humans of ‘new diseases’. These tend not to really be new but actually old diseases to which humans become exposed.

“Take ebola as an example. It had occurred sporadically in humans before the recent big outbreak in West Africa but, because humans lived away from animals such as primates and bats which carried it, the outbreaks were isolated.

“Many of the Ebola outbreaks have occurred in forest fringe areas, where expansion of human populations is bringing them into contact with pathogens which they were not exposed to earlier.

“That change in population behaviour carries the risk of more transmissions from animals to humans of illnesses such as Avian Flu and SARS in the years to come.”

However, Prof Ali believes that advances are being made, saying: “There are reasons to be optimistic, not least because of our increasing understanding of the genome of bacteria. For the first time, we really have a handle on the genomics involved.

“One of the things that we need to do is use that information to better target the way we use drugs, targeting specific drugs at specific strains of bacteria, and genome sequencing technologies will improve the diagnosis and control of infectious diseases.

“I still think we will always be fighting the battle against bacteria but medical science could, in time, allow us to be one step ahead.”

I still think we will always be fighting the battle against bacteria but medical science could, in time, allow us to be one step ahead.

Professor Simi Ali

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Latest chapter in an old story offers hope

The idea that each generation of medical researchers moves closer to victory is illustrated in the story of an illness that has killed millions down the centuries and continues to do so.

Throughout history, people have died long and lingering deaths from the effects of infection, everyone from victims of the Black Death in the late Medieval period to 20th Century soldiers in two world wars as they succumbed to battle wounds.

Although treatment of sepsis, the illness caused by the body’s overreaction to infection, is continually improving, many millions of people still die from it. Now, a team including scientists from Teesside University has come up with a way of dramatically improving early diagnosis.

The project is being seen as a classic illustration of the way that different scientific disciplines, including bioscience, can work together.

Sepsis, which can be triggered by infection or may occur after medical treatment or surgery, has been recognised since the fifth Century BC and its story is an excellent example of how scientific advancement works.

For example, Ignaz Semmelweis, a 19th Century obstetrician at the Vienna General Hospital, noted that the death from fever of women waiting to give birth was a common complication. Semmelweis discovered that it was common for medical students to examine pregnant women directly after pathology lessons. By introducing hand-washing and surgical gloves, he reduced the mortality rate from 18% to 2.5% per cent.

Further adding to the knowledge were 19th Century French chemist Louis Pasteur, who discovered that tiny single cell organisms caused putrefaction, followed by Joseph Lister, who noted when he became chairman of a surgery department that about 50 per cent of patients with amputations died of sepsis. Lister pulled together work done by Semmelweis and Pasteur to develop skin and instrument disinfection with carbolic acid, known as the antiseptic method, drastically reducing postamputation mortality.

The mass introduction of antibiotics in the 20th Century continued to bring the death rate down and now the next step could have been taken by the team behind the £1.3 million CE-microArray project, which is coordinated by Teesside University and includes eight other European academic and SME partners.

Current methods of diagnosing sepsis involve analysing blood culture and can take up to 72 hours. In cases of severe sepsis, a diagnosis which brings forward the start of antibiotic treatment by just one hour could lead to a 6-10 per cent reduction in mortality rates.

The CE-microArray technique improves the

Dr Meez Islam (left) with Professor Zulf Ali working on the CE microArray project. sensitivity of blood tests. Taken in conjunction with the development of a more reliable biomarker for the diagnosis of risk, which will be undertaken by the Universities of Freiburg and Ulm in Germany, this could lead to a test which could be up to 100 times more sensitive than conventional ones.

The project, carried out under the EU Seventh Framework programme, is being coordinated by Dr Meez Islam, a Reader in Physical Chemistry in the School of Science & Engineering at Teesside University and one of the SME partners in the project is Anasyst, a company specialising in analytical systems which was spun out of Teesside University research.

Following completion of the project, the development of the sepsis test will also involve clinical trials. Dr Islam said: “Anything that can speed up the diagnosis times and start treatment earlier, even by a small amount, could potentially save thousands of lives each year.

“In the United States alone, the cost of treatment as a result of hospitalisation for sepsis is thought to be about $17 billion annually so it could have a huge benefit for healthcare budgets as well.. At the end of this project, we hope to have novel ways of testing for sepsis which could have a massive impact across the world.

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“It came about because we had developed the technology but did not really have an application for it. However, through the consortium it became clear that it could be used for more sensitive diagnosis for sepsis.

“I did not know much about sepsis at that time but this is how science will develop in the future, with scientists from different disciplines working together. It is all about choosing the right partners.

“I know colleagues in the physical sciences working on exciting ideas for which there is no application that they know of but take it to someone else and they can find the right application.

“In this case, we knew how to develop the technology but it needed someone else to identify an application. We could not have done it on our own, but working with the bioscientists and the engineers we came up with something that can save lives.

“Every scientist dreams of their work making a difference and we have. This kind of approach is the way science must go as we seek to reduce illness.”

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to a patient with advanced disease but we are making progress.

“Survival rates are improving due to scientific advances and that is because our methods of treatment are improving and because more people realise that they have to live healthier lives, eat better, not drink too much and not smoke.

“I think that it is a good idea for scientists in different fields to work together. For instance, Newcastle University has expertise in the study of the ageing process so we are working with those in that area to understood more about the increased frailty seen with age and the way it can impact on health and the ability to give cancer treatments.

“That kind of approach makes sense given that people are at risk of more health conditions the older they get. For scientists, being exposed to new ideas and new ways of thinking is exciting.”

Battlefront 2 - ageing populations brings severe health challenges

While there is hope in the fight against infectious diseases, that is only part of the picture because seventy per cent of deaths worldwide are caused by non-communicable diseases, a quarter from cardiovascular conditions, 11` per cent from cancer, eight per cent from respiratory conditions and five per cent from diabetes.

One of the big challenges for medical science is the increasing life expectancy for many people, particularly in the western world, which brings with it increased exposure to everything from dementia to cancer.

Battlefront 3 - could genetics hold the key to eradicating ill-health?

Talk to bioscientists about the chances of eradicating health conditions and the talk very rapidly makes its way to the potential offered by genetics.

“Without a doubt, the genetic revolution has been central to our understanding of and progress against cancer. From the early realisation that cancer was a result of mutations in our own genes, we’re now at a point where a person’s entire genome can be sequenced relatively cheaply and easily.

“But far from being a simple case of identifying a few broken genes and ‘fixing’ them, the wealth of genetic information has only made the realisation of the challenge we face starker. What’s emerging now is a bigger picture of just how complex an enemy we’re facing.”

For Dr Smith, the answer lies in a large-scale response. She said: “Understanding the genetic causes of cancer has led to the development of some very effective treatments but, in order to get a bigger picture of cancer, genetic sequencing is needed on a much grander scale.

“For people with a family history of cancer who have an increased risk of developing the disease, genetic screening could offer more ways to manage the risk better.

“There’s still a way to go before we fully understand the complexity of how genes interact with each other to affect our risk, and how best to factor in environmental and lifestyle factors too, but the technology is being developed.”

Cancer is one of the areas in which the involvement of geneticists is offering real hope for the future.

Dr Emma Smith, senior science communications officer for Cancer Research UK, said: “We’ve made incredible progress over the past 40 years. Survival rates have doubled, and half of all people now diagnosed with cancer survive.

Ruth Plummer, Clinical Professor of Experimental Cancer Medicine at the UKbased Northern Institute for Cancer Research, said: “Predictions suggest that we will move from one in four people developing cancer in their life time to one in two due to the fact that we are living longer.

“We do see younger people with cancer, of course, but the rates go up with people in their seventies. We are living longer than ever before and as we get older we contract more health conditions. That presents a major challenge for medical science.”

Prof Plummer, who is based at the Sir Bobby Robson Unit at the Freeman Hospital in Newcastle, named after the former England, Newcastle United and Barcelona football manager who died of cancer, supports calls for experts from different disciplines to work together to tackle the problem.

The professor, who was Sir Bobby’s physician, said: “We can never make the promise of a cure CONTINUED ON PAGE 70

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Minister sounds an optimistic note Bioscience Journal asked Life Sciences Minister George Freeman to assess the progress being made.

As the UK’s first ever minister for Life Sciences, I am determined to ensure that Britain remains the best place in the world to discover and develop 21st Century medicines and healthcare technology.

Our key priority is to harness these groundbreaking new technologies to provide better healthcare for NHS patients.

One of the key priorities in this area is the investment we have made in the 100,000 Genomes Project, where we are leading the world in taking genomics from a research environment into a clinical setting so NHS patients can begin to benefit from genomic medicine.

Our plans to sequence 100,000 genomes of patients with cancer or a rare disease and combine with hospital records will see us create a unique database that will position the UK as the premier place to carry out genomic research which could lead to earlier and more precise diagnoses and new and more tailored treatments.

By harnessing the UK’s unique strengths in research, the NHS, medical charities and a vibrant life science cluster of innovative companies, we can accelerate access to new treatments and attract major new investment and growth.

Our priority is to keep the UK is at the forefront of financing innovative biomedical treatments that have the potential to give real patient benefits. The Government’s National Institute for Health Research (NIHR) is a globally-unique integrated health research system in which the NHS supports outstanding individuals working in world-class facilities, conducting leading-edge research focused on the needs of patients and the public.

In the wider context, UK companies raised £734 million of capital in the first half of 2014, surpassing the £483 million raised in the whole of 2013.

Since the launch of our Life Sciences Strategy in 2011, we have secured more than £3.5 billion worth of investment in the UK’s life sciences sector, helping to create over 11,000 jobs. This is an exciting and growing sector and one that is vital to the future growth of the UK economy.

George Freeman Life Sciences Minister

Research is a vital part of overcoming new and emerging illnesses. That’s why through the NIHR we are investing £1 billion annually to fund, support and deliver the highest quality clinical research in the NHS. By working together, the Government, the NHS, companies, charities, clinicians and patient groups can ensure that this country leads in the fast-emerging field of precision and personalised medicine.

This year we are launching the Medical Innovations and Med Tech Review. This will be a ground-breaking piece of work which will set out plans to drastically accelerate the time in which cost-effective new medical innovations to get from the lab to NHS patients.

It currently takes on average over a decade and over £1 billion to develop a new drug – from the early pre-clinical research right through to being available for patients. The review will make recommendations to accelerate this, embracing ground-breaking developments in genomics and digital technology, to shave years from the time it takes to get new medicines, devices and diagnostics to NHS patients.

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As well as supporting earlier access to new medicines, we are also creating the water supply chain infrastructure to support our bioscience industry.

This year we’ve opened the country’s largest biosample centre in Milton Keynes. The NIHR National Biosample Centre will have the capacity to store around 20 million samples, making it a world leading location for researchers to store and get easy access to their samples. This new £24 million NIHR led centre will allow researchers to lead the way in finding diagnosis and treatments for conditions such as dementia and diabetes.

Regenerative medicine is another area where the UK is a leader in an important field of medicine which has the potential to truly change the way we treat disease. With our world class research, key infrastructure and an active commercial sector this area has great growth potential and can deliver the next generation of healthcare, offering treatments or possible cures for areas of unmet medical needs.

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NEWS

Protecting and improving the nation’s health

Knowledge, innovation and services for life sciences Public Health England (PHE) represents a significant national resource for government, industry, academia and healthcare sectors in protecting the public and supporting health improvement.

A specific function of PHE is to carry out research to advance knowledge on key public health issues. We do this by providing: •

robust systems for the detection, assessment, management and control of new and emerging threats to public health

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undertaking research in vaccine development and infectious disease control

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the application of genomics technologies to improve the treatment of individuals and support the wider control of disease

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evidence-based science and clinical practice in specialist microbiology in support of the wider public health systems and NHS hospitals

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a unified, integrated surveillance system capable of detecting changes in patterns of disease and its determinants to help target interventions

For more information and to discuss how we can help you access our capabilities please contact: business.development@phe.gov.uk or call +44(0) 1980 612768 www.gov.uk/phe 67