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Diagnosis is just the beginning of the battle

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The UK lags behind other countries in getting the right treatments to rare disease patients, but promising developments are underway in a bid to help improve access

Published in association with

Martin Barrow

Contributors Martin Barrow

Danny Buckland

Emily Hill

Edd Gent

James Gordon

Magda Ibrahim

John Illman

Rossalyn Warren

Former health editor, news editor, foreign news editor and business news editor at The Times, he specialises in the NHS and social care.

Freelance journalist and author, she is the former commissioning editor at The Spectator and feature writer for The Mail on Sunday.

Award-winning health journalist, he writes for national newspapers and magazines, and blogs about health innovation and technology.

Freelance science and technology writer, his work has been published in the BBC, New Scientist, Science and MIT Technology Review.

Journalist and executive writer, he has written extensively on business, technology, logistics, manufacturing and sport.

Award-winning journalist, she writes for London Evening Standard and specialist media including Campaign, Third Sector and PRWeek. Freelance journalist and feature writer, her work is mostly published in The Guardian and CNN.

Author, former newspaper health editor and medical correspondent, he is a visiting lecturer at the University of Cambridge and University of Westminster.

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he first thing to be said about rare diseases is that they are not actually that rare. A rare disease is defined by the European Union as one that affects fewer than five in ten thousand of the general population. That may sound like your chances of being directly affected are very small indeed. But there are thousands of known rare diseases and more are being designated each week. In fact, more than 3.5 million people in the UK will be affected by a rare disease at some point in their lives, which is comparable to the number of people with diabetes. Yet while awareness of diabetes is high and the NHS has clear care pathways for that condition, this is certainly not true of rare diseases. All too often a diagnosis is just the beginning of a battle for access to what are known as orphan drugs for rare diseases, which can add many years to life expectancy as well as improve quality of life. This is problematic, for the aim of clinical research in the 21st century is, effectively, to turn conditions such as cancer into rare diseases. Personalised medicine, which is seen as the future of healthcare, is about tailored treatment for individual patients based on their genetic signatures and clinical characteristics. This means breaking down a condition such as breast cancer into hundreds or thousands of genetic mutations and finding an effective treatment for each one, just as we do for rare diseases at present. Patients do better and the NHS wastes less money on drugs and medicines that we know do not work. The UK has made progress in recognising the importance of providing care for people with rare diseases in recent years, with an increased focus on early diagnosis, better care and information sharing. But it still lags behind other EU countries in developing the right systems to bring these treatments through to patients. Take cystic fibrosis, one of the better-known rare diseases. Cystic fibrosis is a genetic disorder that most affects the lungs, but also the pancreas, liver, kidneys and intestine. There is no known cure, however a new type of drug has been developed that makes a profound difference to about 40 per cent of patients, who have a particular genetic mutation. But Orkambi remains out of reach in the UK, to the frustration of patients and their loved ones. The

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reason? Price. There is no doubt that Orkambi does what it says on the tin. But at £104,000 a year, for life, the watchdog National Institute for Health and Care Excellence (NICE) has decided that it does not represent value for taxpayers’ money. Orkambi has been approved in Europe and a number of countries in the EU, including France and Germany, make it available to patients. But in England there is a standoff between the NHS and the manufacturer of Orkambi, Vertex Pharmaceuticals, which claims the cost reflects the investment in research and development of a drug for a small patient population (story continues on page 15). Can these positions ever be reconciled? The answer is of immense

importance, not just to cystic fibrosis patients, but to patients suffering from what we now consider to be rare diseases. As personalised medicine becomes more widely available, the future of the NHS will depend on equitable access to high-quality services, treatment and support. New cancer drugs which, like Orkambi, target the underlying genetic causes of the disease, will also cost significantly more than earlier treatments, presenting NICE with challenges to its existing approval criteria. NICE has a Highly Specialised Technology evaluation, which has seen a number of innovative pricing and reimbursement deals done with companies to bring drugs for rare diseases to NHS patients. However,

MISDIAGNOSIS REMAINS A BIG PROBLEM On average, rare disease patients can expect the following before receiving the correct diagnosis

misdiagnoses

consultations with doctors

years to receive the correct diagnosis

Rare Disease UK 2019

many rare diseases do not qualify for this pathway and must, therefore, be appraised via its standard Single Technology Appraisal (STA) process. According to market access consultancy MAP BioPharma, just 13 per cent of the 24 completed STA reviews of rare disease medicines between 2013 and 2017 were recommended for the full eligible population. This compares with a full recommendation for more than two thirds of other medicines. The UK’s strategy for rare diseases has a strong focus on addressing unmet need through the discovery of new drugs. The jewel in the crown is the 100,000 Genomes Project, which is sequencing whole genomes from NHS patients. The project’s focus is on rare diseases, as well as some common cancers and infectious diseases. The full 100,000 milestone was reached in December 2018. The continuing progress of the project and the concurrent development of a genomic testing strategy will underpin the development of new genomic medicine services for the NHS. This is a long-term investment in the future of healthcare through personalised, targeted treatment, but the knowledge harnessed by the project is already yielding benefits. In June, Simon Stevens, chief executive of NHS England, announced that the health service was preparing to fast track tumour-agnostic drugs that target tumours according to their genetic make-up, rather than where they originate in the body. Last year NHS England signed a landmark commercial deal to make pioneering CAR-T therapy available to cancer patients. CAR-T is a type of immunotherapy, which involves collecting and using the patient’s own immune cells to treat their condition. Mr Stephens says: “These exciting new breakthroughs in cancer treatment are the latest example of how the NHS can lead the way in the new era of personalised cancer care. “Preparations are underway to make sure the NHS can adopt this next generation of treatments, but manufacturers need to set fair and affordable prices so treatments can be made available to those who need them.” Finding ways to ensure patients with rare diseases have equitable access to the drugs and treatments they need is a significant challenge for the NHS. But it also offers a great opportunity. For helping people stay healthier for longer is key to creating a sustainable health and care service.

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RARE DISEASES

Diagnosis is just the beginning of the battle

Distributed in

The UK lags behind other countries in getting the right treatments to rare disease patients, but promising developments are underway in a bid to help improve access

Published in association with

Martin Barrow

Contributors Martin Barrow

Danny Buckland

Emily Hill

Edd Gent

James Gordon

Magda Ibrahim

John Illman

Rossalyn Warren

Former health editor, news editor, foreign news editor and business news editor at The Times, he specialises in the NHS and social care.

Freelance journalist and author, she is the former commissioning editor at The Spectator and feature writer for The Mail on Sunday.

Award-winning health journalist, he writes for national newspapers and magazines, and blogs about health innovation and technology.

Freelance science and technology writer, his work has been published in the BBC, New Scientist, Science and MIT Technology Review.

Journalist and executive writer, he has written extensively on business, technology, logistics, manufacturing and sport.

Author, former newspaper health editor and medical correspondent, he is a visiting lecturer at the University of Cambridge and University of Westminster.

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Digital content executive

Managing editor

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Justyna O'Connell

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Francesca Cassidy

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MISDIAGNOSIS REMAINS A BIG PROBLEM On average, rare disease patients can expect the following before receiving the correct diagnosis

misdiagnoses

consultations with doctors

years to receive the correct diagnosis

Rare Disease UK 2019

RARE DISEASES

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Commercial feature GENETIC SCREENING

OPINION

Why newborn screening divides opinion Christian Bowen/ Unsplash

Babies are tested for a number of conditions soon after birth, but varied approaches to screening worldwide highlight how fragmented the medical profession remains over this vital process

Globally, decisions on what diseases should be included in genetic screening are generally based on the Wilson and Jungner criteria outlined in a 1968 World Health Organization report. Recommendations include that diseases should be well understood and a significant health problem, there should be reliable tests and early treatment should be more effective. How these criteria are interpreted varies considerably. While in America, most states screen for 29 of the 35 conditions recommended by an advisory committee, the UK tests for just nine and four were only added in 2015. Many European countries screen for more than twice as many as the UK, including Sweden, Italy, Poland and Austria.

Genomics set to shake up newborn screening The cost of unraveling someone’s genetic code has fallen dramatically in recent years. This is opening up the tantalising prospect of screening babies for genetic diseases using DNA sequencing. Robert Green, medical geneticist at Brigham and Women’s Hospital and Harvard Medical School, is running the first US trial of newborn genomic sequencing. Half of the 325 babies in the programme have had their genomes sequenced and early results are promising. “Some 11 per cent had a diseaseassociated mutation in a singlegene disease, which is crazy high,” says Dr Green. “About half the things we found have conventional treatments that can alter the course or minimise morbidity.”

ith one in seventeen of us likely to be affected during our lifetime, every single person will know and care about someone who has a rare disease, perhaps without realising it. In the UK, every year around 40,000 babies are born who are destined to be diagnosed with a rare disease. Not all these children will show signs of their rare disease in childhood. But around a third of those who do, and a third of the 6,000 babies who are born with complex needs and no diagnosis will die before their fifth birthday. The stark reality is rare diseases account for most deaths in under-fives. The great news is that the outlook for patients with once unsurvivable rare diseases is being transformed. Growth in research, advanced therapies and surgical techniques is being matched by improvements in diagnosis, and we stand on the brink of a genomic medicine revolution. If we, the public, patients, industry, regulators, policymakers, healthcare professionals, researchers and politicians, collectively embrace our genomic future, we stand to transform the prospects for diagnosis and treatment of rare and common diseases alike. You might imagine then that diagnosing and treating rare diseases early in life and providing the best evidence-based care would be an absolute priority. You might think that research into rare diseases would receive financial support on a par with research into common conditions. Sadly, the reality for the majority of rare disease patients tells us this is not the case. We’ve been screening newborns for rare diseases in the UK since 1969, when screening for phenylketonuria began, analysing bloodspots collected a few days after birth. Today, 50 years on only eight additional diseases have been added to the newborn screening programme. This compares poorly to the majority of high-income countries where it is routine to screen for between 25 and 50 rare conditions. Consequently, babies in the UK with treatable rare diseases are falling through the net and in some cases die needlessly. It is time to consider the potential not only of those technologies already in use for newborn screening, but also the potential use of whole genome sequencing in newborns.

Edd Gent or babies born with certain rare diseases the first few days after birth can be the difference between life and death. Genetic screening can catch many of these conditions, but there’s controversy over how many to test for. Screening babies for genetic diseases is common practice in most high-income countries. A few days after birth, blood from a small heel prick is placed on a piece of card and used for a series of biochemical tests for conditions that can be effectively treated if caught early. If any come back positive, follow-up tests confirm a diagnosis. “Some of these disorders will present in the first few days of life and could do irreversible harm or end in death for the child,” says Beth Tarini, researcher at the Children’s National Health System in Washington, who specialises in newborn screening. “So there is a time urgency in the newborn period.”

‘If we embrace our genomic future, we stand to transform the prospects for diagnosis and treatment of rare and common diseases alike’

Genetic predictions can be imprecise because many conditions are caused by complex gene interactions, which has raised concerns of unduly worrying parents. There are also ethical issues around detecting diseases that appear later in life. “If we identify babies with predispositions to become ill in adult life, you remove their right not to know,” says Professor Jim Bonham, consultant at Sheffield Children's Hospital. But Dr Green says all medical diagnosis deals with risk factors. High blood pressure is only indicative of heart problems, it doesn’t guarantee them, for example. Both he and Professor Bonham agree that the challenge is finding better ways of conveying this information.

It’s not a question of capacity, says Professor Jim Bonham, consultant at Sheffield Children's Hospital, who was recently awarded an MBE for his role in the 2015 expansion of UK genetic screening. An explosion in testing followed the introduction of tandem mass spectrometry, a technique that identifies markers of many diseases from a single blood sample. It’s already used in the UK, so adding new conditions wouldn’t be complicated, he says. But adding tests also carries risks. Those with many false positives, where children are wrongly labelled with a condition, can cause families huge stress and erode trust in the medical system, says Professor Bonham. Others that fail to distinguish between mild and severe forms of a disease can unnecessarily medicalise patients, and some identify diseases with questionable treatment options. The UK National Screening Committee (NSC), a panel of public health and medical professionals governed by Public Health England, follows strict criteria for reviewing evidence of medical impact and cost effectiveness for new tests. “I think some countries have been less cognizant of understanding the harms around just adding in more and more conditions,” says Professor Katherine Payne, health economist at the University of Manchester. They are also often less conscious of cost effectiveness, she adds. That’s crucial in a publicly funded system where money could have greater impact elsewhere. Nonetheless, the UK’s approach can be ponderous. Professor Bobby Gaspar, paediatrician at Great Ormond Street Hospital in London, has been petitioning since 2011 to add a genetic screening test for severe combined immunodeficiency

(SCID), which makes children highly vulnerable to infections. The test is standard practice in many countries and there’s strong evidence catching SCID before infections set in dramatically improves survival, says Professor Gaspar. However, the NSC insists on doing its own evaluation study, which was agreed in 2017, but won’t begin until next year and is likely to take a couple of years. “It’s been a frustrating process,” says Professor Gaspar, who is also chief scientific officer at Orchard Therapeutics, which is designing gene therapies for SCID. “We need to get this implemented as soon as possible because this has the potential to save lives.” Hard evidence is difficult to come by with rare diseases, says Maximilian Zeyda, technical director of Austria’s newborn screening lab, because data is intrinsically scarce. Austria screens

for 28 diseases based largely on recommendations from a panel of specialist paediatricians. “There is not so much hard scientific evidence and much more evidence by experience,” he says, adding that newborn screening is an area where expert opinion should carry more weight. Finding a balance is tricky though, says Dr Tarini. In the United States, the fragmented medical system means there’s little information on cost effectiveness and public health impact for the various state genetic screening programmes, which makes informed debate difficult. The bias should be towards including tests, she says, but going forward there’s a need for robust data collection to enable educated reassessments. “This gives you the benefit of action with re-evaluation,” says Dr Tarini. “We have not generally done that in a systematic way.”

RARE DISEASE DIAGNOSTICS MARKET BREAKDOWN Global market share by end-user

8.2%

36.4%

Other

Hospital laboratories

13.3% Cancer research laboratories

15.2% Genetic testing laboratories

26.9% Diagnostic laboratories BIS Research 2018

We compare poorly to comparable high-income countries in terms of routine access to rare disease medicines too. Around half of orphan, or rare disease, medicinal products proven safe and effective are not routinely prescribed in the NHS. The majority of patients diagnosed with one of the 6,000-plus known rare diseases have no specialised service and knowledge of their disease, and how best to treat these patients remains a challenge for healthcare professionals. It is also disheartening to witness the earliest manifest impacts of Brexit, notably the loss of UK leadership of six of the twenty-four European Reference Networks that link clinicians across Europe, facilitating diagnosis and excellence in care for rare disease patients. In 2013, with the launch of the UK Strategy for Rare Diseases, we were promised a brighter future for those affected by rare diseases through improvements in diagnosis, treatment and care, and through harnessing research. The current strategy takes us through to 2020, but already it has been rendered moribund by the rapid pace of change. The rare disease community has called on the UK government to review and refresh this strategy to no avail. With so much potential for so many aspects of rare disease research, diagnosis and treatment, a strategic approach is more important and more valuable than ever. A new rare disease strategy for the UK remains a top priority for the community we represent, for the one in seventeen.

Jayne Spink Chief executive Genetic Alliance

New possibilities for people affected by genetic diseases Gene therapy is becoming a treatment option for people diagnosed with certain rare conditions, says Nicola Redfern, UK general manager of bluebird bio, which is developing treatments for genetic diseases and cancer ccording to Rare Disease UK one in seventeen people, or almost 6 per cent of the population, will be affected by a rare disease at some point in their lives, of which 80 per cent have a genetic component1. The impact of living with a rare disease cannot be underestimated. For some, life can be dominated by invasive treatment requiring many hours in hospital. For others, life expectancy may be significantly reduced. Aside from the impact on the individual, there is the impact on families and carers as well as wider society if people are unable to attend school or go to work. There is also an impact on the health and social care systems given the significant resources required to deliver treatment and wider support. Clearly, there have been many treatment advances over the years. These have enabled those with certain rare genetic conditions to benefit from an improved quality of life and extended life expectancy. Yet, given the sheer volume of different rare conditions that exist, with an average of 260 to 280 rare genetic diseases being discovered a year between 2012 and 2015, a significant proportion of people with rare diseases therefore face limited treatment options. The desire to fill this gap and give patients and their families fresh hope is a key driver behind the commitment of the scientific and medical community, along with the pharmaceutical and biotech industry. These industries are looking to

harness the power of cutting-edge science to address the genetic basis for a given disease. Among the technological advances, which have the potential to provide alternative choices for those affected by a rare genetic disease, gene therapy is now starting to become a real treatment option for people in the UK diagnosed with certain rare conditions. Rather than just treating symptoms, the aim of gene therapy is to correct the underlying genetic cause of disease with the objective of reducing or eliminating the signs and symptoms of the condition. There are many different approaches to gene therapy which are being explored: “turning off” genes that are causing problems; replacing a defective gene with a functional gene; or adding functional copies of a healthy gene. The UK government has been vocal about its commitment to life sciences and to fostering an environment which is conducive to furthering the development of gene therapies. This has been strongly supported by initiatives such as the establishment of the Cell and Gene Therapy Catapult, as well as the work of Innovate UK. As a result, it is encouraging to see that, according to the Cell and Gene Therapy Catapult UK clinical trials data base, there are 85 trials in progress, a 37 per cent increase over the last year.3 The willingness of the NHS to embrace the potential of gene therapies is exciting. For example, the National Institute for Health and Care Excellence approved the first ex-vivo stem cell gene therapy to

treat patients with a very rare disease called adenosine deaminase deficiency, or ADA-SCID, in 2018 and will evaluate emerging gene therapies as they become licensed. This is a strong indicator that we are entering a new chapter in the approach to tackling rare genetic diseases in the UK. However, if we are to ensure that patients are able to benefit from the increasing number of gene therapies being licensed, there also needs to be a willingness to explore non-traditional funding and reimbursement models so that they can reach the clinic. This includes outcome-based schemes where payment would be tied to the achievement of specific clinical outcomes, over an extended period of time. This will be an ongoing conversation between the industry and the NHS, and is one we are actively taking part in.

1 Rare Disease UK. What is a rare disease? [ONLINE] Available at: https://www.raredisease.org.uk/what-is-arare-disease/ Last access: July 2019

Boycott K.M. et al International cooperation to enable the diagnosis of all rare genetic diseases. Am. J. Hum. Genet. 100, 695–705 (2017)

Catapult Cell and Gene Therapy. The Cell and Gene Therapy Catapult UK clinical trials database. [ONLINE] Available at: https://ct.catapult.org.uk/resources/celland-gene-therapy-catapult-uk-clinical-trials-database Last access: July 2019

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Commercial feature GENETIC SCREENING

OPINION

Why newborn screening divides opinion Christian Bowen/ Unsplash

Babies are tested for a number of conditions soon after birth, but varied approaches to screening worldwide highlight how fragmented the medical profession remains over this vital process

‘If we embrace our genomic future, we stand to transform the prospects for diagnosis and treatment of rare and common diseases alike’

RARE DISEASE DIAGNOSTICS MARKET BREAKDOWN Global market share by end-user

8.2%

36.4%

Other

Hospital laboratories

13.3% Cancer research laboratories

15.2% Genetic testing laboratories

26.9% Diagnostic laboratories BIS Research 2018

Jayne Spink Chief executive Genetic Alliance

1 Rare Disease UK. What is a rare disease? [ONLINE] Available at: https://www.raredisease.org.uk/what-is-arare-disease/ Last access: July 2019

Boycott K.M. et al International cooperation to enable the diagnosis of all rare genetic diseases. Am. J. Hum. Genet. 100, 695–705 (2017)

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Commercial feature Eggy Sayoga/Getty Images

PRICING

Need more leads, brand awareness and thought leadership? Get in touch to find out how we can support your marketing efforts and improve ROI agency@raconteur.net

Pricing puzzle: where science, finance and ethics collide Current methods to determine the right value for orphan drugs remain controversial, yet the fast-tracking of new therapies marks a big step forward for the industry Danny Buckland unding of drugs for orphan conditions is where science, finance and ethics grind against each other, and regularly dislocate into controversy. Orphan drugs may be defined as drugs that are not developed by the pharmaceutical industry for economic reasons, but which respond to public health need. It’s an arena of leading-edge clinical discovery, eye-watering costs and potent emotion. The joy felt by a few families told there is an effective treatment for an incurable disease is often dashed by the towering charges faced by healthcare systems. The complexity of devising a mechanism, which encourages research and development, creates a fair price for a pharmaceutical company that, in turn, synchronises with arcane reimbursement systems, is a gargantuan task. A research paper from the Office of Health Economics, Establishing a Reasonable Price for an Orphan Drug, navigated its way through a minefield of competing interests and regulations to highlight the challenge to construct a complex equation for a potential drug approval measurement of a cost effectiveness threshold. There is a method, but their caveat about the influence of “societal

judgments” underscores that the best efforts could be derailed by external pressures. The jagged edges of science, hard business and the hope of patients – many rare diseases impact children with devastating consequences – are difficult to even out.

In most cases, and specifically in England, the way a therapy is valued is oversimplified

Advances in gene therapy, CRISPR gene editing, 3D bioprinting and immunotherapy are encouraging novel therapeutics. But two new drugs, for spinal muscular dystrophy and blood transfusion-dependent thalassemia, were price tagged respectively at $2.1 million and $1.8

million per patient, the most expensive drugs on the planet. Even with staged and landmark payments, they are huge burdens for strained healthcare systems. One of the core issues of developing orphan therapies is that, by nature, there are less patients for clinical trials and the data is therefore limited. A report by MAP BioPharma, which works with 70 global biopharmaceutical and technology companies, stated that the pharmaceutical industry would welcome closer collaboration with government regulatory agencies to recalibrate how evidence is gathered, assessed and valued for orphan drugs. Its Access to Orphan Medicines: A Case for Change, published in February, urged the government to take a more nuanced approach. The Genetic Alliance, which represents 220 patient organisations, believes the current assessment protocols are riddled with systemic failings and that the patient voice needs to be central to a restructured service. “With respect to NHS access to orphan drugs, there are 16 different decision-making processes in the UK. In England only one of these, the Highly Specialised Technology Appraisal process, was specifically set up for the purpose,” says Jayne Spink, the charity’s chief executive. “The result is slow and often overburdened processes that have resulted in only around half of orphan drugs being routinely available on the NHS and around a fifth not having been assessed. “The conversation is often polarised, with criticism being laid either at the door of the decision-makers or with the pharma companies in

relation to pricing and ending in frustration because we’re collectively failing to bring any fundamental solutions to the table.” Genetic Alliance UK has embarked on a major, patient-led in-depth project, Resetting the Model, which aims to address these complex issues. A report and recommendations, due in the autumn, are expected to advance radical solutions. Analysts at Deloitte, who regularly probe this sector of healthcare, believe the disparate elements are coming together to establish new agreements. “These agreements, which can be based on cost, evidence and risks,

see a more collaborative relationship forming between pharma, payers, providers, physicians and patients where all members work together to improve patient outcomes and the performance of healthcare,” says Karen Taylor, director at Deloitte Centre for Health Solutions. “In some of these approaches, pharma provide healthcare providers with services that decrease the administrative burden, improve operational and financial performance, and improve patient outcomes.” Not for the first time, medical discovery is outstripping regulatory movement, but flexibility from the US Food and Drug Administration and the European Medicines Agency is fast-tracking new therapies to patients. “This is a big step forward and has acted as a stimulus for the industry and, while there is still work to be done, we are certainly moving in the right direction,” says Steve Arlington, president of the Pistoia Alliance, a not-for-profit organisation working to lower barriers to innovation in life science and healthcare R&D. “Collaboration is absolutely key, helping to share knowledge, lower costs and shorten the time it takes to bring new discoveries to the patient. “One way to accelerate the path to effective treatment and reduce costs is through drug repurposing, which is currently being looked at for a number of rare diseases, including chronic pancreatitis and retinitis pigmentosa. Using drugs already on the market makes use of existing research and shortens approval processes.” But Dr Arlington re-emphasises that current value assessments are blunt instruments at best. “In most cases, and specifically in England, the way a therapy is valued is oversimplified. It appears to be all about saving money on the drug budget, whereas it should be about true socio-economic benefit within the total social services framework and health economic equation,” he concludes.

COST IMPACT OF RARE DISEASES ON THE NHS Based on an analysis of hospital episode statistics over the past ten years Rare disease diagnosis

Comparative population

Total cost

£3.4bn £160.8bn Average cost per patient

AI-POWERED REPURPOSING VERSUS CONVENTIONAL DRUG DEVELOPMENT AI-powered repurposing

Conventional drug discovery

TIME

3-5 years

12-14 years

COST

$50m

$2-3bn

SUCCESS RATE

25%

References: Lin S et al. (2017) Drug Repurposing: The New R&D. Rare Disease Review. Schuhmacher A et al. (2016) Changing R&D Models in Research-Based Pharmaceutical Companies. Journal of Translational Medicine.

AI company offers hope for rare disease patients Finding a treatment for a rare disease can be a lifetime’s mission, while funding it is always an act of faith few can attain stute and targeted use of artificial intelligence (AI), combined with pharmacological expertise and patient group insight, is transforming drug discovery from an expensive and uncertain expedition to a manageable challenge. To the 350 million people in the world living with a rare disease, 95 per cent of whom don’t have an approved treatment, the pioneering application of science and technology from Cambridgebased drug discovery company Healx offers a paradigm shift. The company, which uses data, AI and expert pharmacology to repurpose existing drugs, allows novel treatments to be developed at a fraction of the cost and average time of traditional drug development. The pharmaceutical industry is reticent about targeting rare diseases because of the often-ruinous developmental metrics, but Healx has proved that its system – interrogating millions of datapoints from gene expression signatures to patient responses – offers a dynamic alternative. The speed and accuracy of its Healnet AI platform provides new hope for a global cohort of patients living with

£13,064 £5,910 Total hospital attendances

1.76m 88.52m

NHS England 2018

Healx’s AI platform provides new hope for a global cohort of patients living with 7,000 different rare diseases

7,000 different rare diseases as the company scales up to advance 100 treatments towards the clinic by 2025. “The cost and risk of failure of the big pharma approach means patients with rare diseases are poorly served,” says Dr Tim Guilliams, who founded the company in 2014 with Dr David Brown, co-inventor of the blockbuster Viagra drug. “We combine the power of AI with scientific knowledge to examine data from thousands of existing drugs to discover relevant connections that could benefit other diseases. We collaborate with patient groups and use every piece of information out there to find cures for these patients. It’s about using existing knowledge to predict new knowledge.” Healx’s AI engineers have built the most comprehensive knowledge graph of rare disease information, comprising data from a host of sources such as scientific literature, clinical trials and proprietary data. A suite of complex algorithms is deployed to pinpoint relationships between drugs and diseases that have the potential to deliver therapeutic benefit. This is layered with critical oversight delivered by a multi-disciplinary team of rare disease experts, patient advocates and drug discovery scientists. This rich matrix of intelligence predicts new treatments, around 80 per cent faster and 90 per cent cheaper, than traditional research and development, and can reach the patient in three to five years. It’s a world away from the average concept-to-drug timescale of 12 to 14 years and its £2-billion to £3-billion price tag. “Our platform uses the most advanced technology available with the sharpest scientific insights,” says Dr

Guilliams, the company’s chief executive. “Yet our collaboration with patient groups is also hugely important as we have to understand their challenges and needs to best work towards finding effective treatments.” Its success with fragile X syndrome – the most common genetic cause of autism and learning disabilities, which still has no effective treatments despite decades of research – is concrete evidence of efficacy. Healx identified eight candidate drugs for repurposing within six months and the most promising of these drugs are now progressing to phase-2a clinical trials. Healx collaborated closely with the FRAXA Research Foundation, which is pursuing cures for the condition which affects one in 4,000 males and one in 8,000 females. Dr Michael Tranfaglia, FRAXA’s medical director, says: “Healx has energised the search for new rare disease treatments and their technology is exciting for everyone in the field, particularly the patients.” The team at Healx is working on a number of rare diseases with a plan to expand the portfolio ten-fold over the next five years, backed by recent £7.6-million series-A funding to scale up its operations. Dr Guilliams sums up the company’s ethos: “Healx has a simple but profound goal: to transform the lives of rare disease patients. Our technology helps us to find treatments where none currently exist.”

For more information please visit www.healx.io

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In most cases, and specifically in England, the way a therapy is valued is oversimplified

COST IMPACT OF RARE DISEASES ON THE NHS Based on an analysis of hospital episode statistics over the past ten years Rare disease diagnosis

Comparative population

Total cost

£3.4bn £160.8bn Average cost per patient

AI-POWERED REPURPOSING VERSUS CONVENTIONAL DRUG DEVELOPMENT AI-powered repurposing

Conventional drug discovery

TIME

3-5 years

12-14 years

COST

$50m

$2-3bn

SUCCESS RATE

25%

£13,064 £5,910 Total hospital attendances

1.76m 88.52m

NHS England 2018

Healx’s AI platform provides new hope for a global cohort of patients living with 7,000 different rare diseases

For more information please visit www.healx.io

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Commercial feature Rossalyn Warren rom Alzheimer’s to breast cancer, many of us are well informed about the most widespread diseases around the world. But what’s often overlooked are the rare diseases that affect far fewer people. And as there’s less attention on these diseases, treatment can be sidelined, especially in developing countries. Individually rare, but collectively common, rare diseases affect more than 350 million people worldwide. Scientists have detected between 6,000 and 8,000 rare diseases, ranging from forms of blood disorders, such as hemophilia, to rare conditions which affect the respiratory and digestive systems, including cystic fibrosis. Millions more people have specialised conditions. Treatment and research is also limited and underfunded, which means there are usually prolonged delays in diagnosis. And relatively common symptoms can also often hide underlying rare conditions, leading to misdiagnosis. While progress in rare diseases treatment has grown rapidly in Western countries, poor provision of healthcare in developing countries means this hasn’t been reflected worldwide. As there’s a lack of access to healthcare and essential medicines in developing countries, treatment and research for rare diseases and conditions is usually far from a top priority. This is an issue Dr Lucia Monaco and her colleagues at the International Rare Diseases Research Consortium (IRDiRC) are working to tackle. Their aim is to enable all people living with a rare disease to receive an accurate diagnosis, care and available therapy within one year of coming to medical attention. The IRDiRC and other organisations have been instrumental in leading a surge of global research into rare diseases treatment over recent years, so new orphan drugs and therapies are being found at a much faster rate. But improved communication and collaboration between countries around the world is critical in addressing rare diseases treatment from all angles and ensuring rare disease patients have equal access to treatment. “There’s been tremendous advancements in rare diseases research that nobody would have dreamed of a few years ago,” says Dr Monaco. “But what’s known about rare diseases is focused on countries in the Western world, across Europe, North America, Canada, Japan, but everywhere else it’s understudied and under-represented.” The continent of Africa remains especially vulnerable to rare diseases. The high presence of communicable diseases, such as malaria, creates further issues for those affected by rare conditions, as funds and resources are limited. There is also currently no rare diseases registry in Africa.

ACCESS

Equal access to treatment needs global collaboration

Westend61/Unsplash

Rare disease patients in developing countries and rural regions are often neglected, and in need of diagnosis backed up by treatment and research

Elsewhere, in Europe the EU has established the European Reference Network to support patients and families affected by rare diseases which requires much specialised knowledge, treatment and resources. “We are now at a level of sharing knowledge; the goal is to support patients globally and improve their lives. This will of course require efforts from the scientific community. Beyond this, we need to scale up on a political and economic level too,” says Dr Monaco.

What’s known about rare diseases is focused on countries in the Western world, but everywhere else it’s understudied and under-represented

Due to the diversity of rare diseases, research needs to be international. Scientists, experts, clinicians and organisations are attempting to bridge the gap by building connections in developing countries. Their focus is now on sharing rare diseases knowledge and research, and building collaborative tools which enable ethical data sharing for and with patients. Many say clinical and scientific research should be

transferred to a global network for further study. This year, the IRDiRC is leading task forces dedicated to addressing rare diseases in indigenous populations around the world, for a six to eight-month period. However, initiatives such as this face logistical challenges, including language barriers between patients and medical staff, as well as relocation issues associated with conducting global trials for small patient populations. Still, while rare diseases treatment remains an acute problem, progress has been significant, much of which has been due to tireless efforts to raise awareness globally. The rare disease community has been an important driving force, advocating the development of new diagnostic and therapeutic procedures. And every year, the last day of February marks Rare Disease Day, which aims to raise awareness among policymakers and the public of rare diseases and their impact on the lives of patients. In 2019, events were held in more than 100 countries, including many developing nations. At the heart of raising awareness are patients. Rare disease patients face isolation as a result of their diagnosis. And for those in developing countries, who haven’t even had the chance to be diagnosed, they can end up suffering in silence. Dr Monaco stresses that raising awareness is key to supporting all rare disease patients, so the public is reminded they’re people deserving of medical support as much as anybody else. “Every disease is important and every life is important,” Dr Monaco concludes, “and so we should not neglect anybody in our pursuit of this.”

ACCESS TO TREATMENT: RARE DISEASE PATIENT COMPARED WITH THE GENERAL POPUL ATION Survey of European patients only; percentage of those not receiving treatment due to the following reasons Rare disease patients

24%

General population

15%

Lack of availability in own country

19%

Inability to pay for it

Long waiting lists

Working together to bring hope to more patients with rare diseases NICE review offers a chance to improve access to medicines and treatments

ulmonary arterial hypertension (PAH) is a rare disease affecting around 7,000 people in the UK. It is an incurable and progressive illness that affects the blood vessels supplying the lungs, making it harder for the heart to pump blood there. Eventually, patients can struggle to breathe, even at rest. Left untreated, the prognosis is poor with an average life expectancy after diagnosis of two to three years. Thankfully, advances in PAH treatment have had a dramatic effect, with seven-year survival increasing from around 30 per cent to 60 per cent. Dr Gerry Coghlan, who developed the pulmonary hypertension service at the Royal Free Hospital in London, says: “Being able to access medicines that help to slow the progression of the disease allows patients and their carers to live a normal life for as long as possible.” However, many PAH patients in England struggle to get the right medication and treatment when they need it, says Dr Coghlan. “Access is based on measures that don’t really reflect the latest evidence and current understanding of PAH,” he says. “The system is really struggling.” For people living with the condition, quick access to the right medicines is a matter of life or death. PAH is an exemplar of the current landscape for the treatment of rare diseases in the UK. Scientific advances in our understanding of rare diseases such as PAH have led to a wave of medicine innovation, offering new hope to patients. The number of medicines being developed and approved in Europe for treating rare diseases is increasing every year. Also new initiatives, leading to earlier diagnosis, are enabling treatment to start sooner, bringing hope to people affected by the condition. But public health systems like the NHS are struggling with the rising

number of applications for funding. The regulatory system has evolved to encourage the development and availability of medicines to treat rare conditions, but NHS funding processes are struggling to keep pace and make them rapidly available to patients. The systems for deciding what medicines will be funded for use on the NHS vary around the UK, with different bodies tasked with assessing whether new medicines represent good value for taxpayers’ money. In England this responsibility lies primarily with the National Institute for Health and Care Excellence (NICE). In Scotland the role is taken by Scottish Medicines Consortium and in Wales by the All Wales Medicines Strategy Group. Assessing the value for money of medicines developed for small groups of patients has a number of innate challenges. Most new therapies for rare diseases will have small patient populations and may have few existing treatments with which they can be compared. Although NICE is internationally recognised as a gold standard in assessing the value of medicines, its standard methods were designed nearly 20 years ago for different types of medicines, for larger groups of patients. Because of these challenges, Scotland and Wales have recently amended their reimbursement processes for rare diseases. One key change made by them emphasises the importance of both the patient and the clinician’s experience of treating, or living with, rare conditions which decision-makers may often not be familiar with. The assessment processes also take into account issues around interpreting data, which can only be obtained from small patient populations. In England there are two main mechanisms when a new medicine for a rare disease is assessed by NICE. Firstly,

the same technology appraisal process used by NICE to assess conditions with larger patient numbers can be applied. This can be problematic when looking at medicines to treat smaller patient numbers as cost effectiveness, which NICE assesses, can be difficult to quantify. Secondly, the Highly Specialised Technologies programme, which was specifically designed for patient populations of around 500 people or fewer across the country, can be used. This programme recognises challenges inherent in standard NICE processes being used for assessment of medicines in conditions with small patient populations. However, most medicines for rare conditions are not eligible for this programme.

By working together, the NHS, patients, clinicians and the research-based pharmaceutical industry can create a system that works to the benefit of people affected by rare conditions

NICE currently uses a one-size-fitsall evaluation approach by applying a fixed cost-effectiveness threshold to judge all medicines. But the NICE Quality Adjusted Life Years threshold in standard technology appraisals can be discriminatory for evaluating some medicines for rare diseases, due to limited data and uncertainty in the figures produced when there are small patient numbers. The good news is that NICE has committed to undertaking a review of its methods over the next year. This is a major opportunity for patients and other stakeholders to engage and ensure meaningful change can be delivered for rare disease patients. Jayne Spink, chief executive at Genetic Alliance UK, says: “Patient groups and clinicians feel that in populations with a rare disease, where there are small groups of patients, there should be a more holistic interpretation of value, as in Scotland through its orphan medicines process.” A solution is needed for the medicines that are not suitable for assessment using methodologies designed for larger patient populations and which are not eligible for assessment under NICE’s Highly Specialised Technology programme. These medicines are currently falling between cracks in the system. New approaches between pharmaceutical innovators and the NHS are likely to be needed, which address some of the uncertainty about the cost

effectiveness of medicines for small and very small groups of patients. Drawing on international examples, the UK could seek to provide patients with access to life-changing treatments as close to them being licensed and made available to patients as soon as possible. Any data gaps could then be filled by gathering real-life experience to generate the additional cost and impact data that might be required, and to enable further assessment, incorporating this real-world data, at a later date. This type of conditional reimbursement is already practised for some cancer medicines. Carina Righetti, director of market access and external affairs at Actelion UK, concludes: “Novel approaches like these could help patients with rare diseases by giving them faster access to new, transformative treatments. The system must also be futureproofed to ensure that it can respond to scientific innovations. “By working together, the NHS, patients, clinicians and the researchbased pharmaceutical industry can create a system that works to the benefit of people affected by rare conditions.”

For more information please visit www.actelion.co.uk

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ACCESS

Equal access to treatment needs global collaboration

Westend61/Unsplash

Rare disease patients in developing countries and rural regions are often neglected, and in need of diagnosis backed up by treatment and research

What’s known about rare diseases is focused on countries in the Western world, but everywhere else it’s understudied and under-represented

24%

General population

15%

Lack of availability in own country

19%

Inability to pay for it

Long waiting lists

Working together to bring hope to more patients with rare diseases NICE review offers a chance to improve access to medicines and treatments

By working together, the NHS, patients, clinicians and the research-based pharmaceutical industry can create a system that works to the benefit of people affected by rare conditions

For more information please visit www.actelion.co.uk

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When it comes to rare diseases, incidence rates per condition are low. But their collective impact on populations and healthcare systems is huge and often underestimated

of those diagnosed are children

have identified genetic origins, while others are the result of infections, allergies and environmental causes

Pugatch 2019

Rare Diseases Europe 2019

of known rare diseases still lack treatment

BUT COLLECTIVELY COMMON

PREVALENCE RATE OF SELECTED RARE DISEASES

ORPHAN DRUG SALES FORECAST

Number of sufferers per 100,000 people worldwide

Orphan drugs are commercially undeveloped pharmaceuticals intended to treat diseases considered too rare for traditional research and development

6-7k

estimated number of existing rare diseases in total Various sources

1 in 17

100

109

118

131

136

150

169

192

217

Multiple sclerosis 90

Worldwide sales ($bn)

Narcolepsy 50

people in the UK will be affected by a rare disease at some point in their lives

Primary biliary cholangitis 40

Rare Disease UK 2018

Spinal muscular atrophy 13 Retinal dystrophy 13 X-linked hypophosphatemia 5

Hemophilia 20

Cystic fibrosis 25

Fabry disease 30

Percentage of total prescription drug sales 10.5

2010

10.8

2011

11.6

2012

12.8

12.4

2013

2014

13.4

2015

14.1

2016

15.8

14.9

2017

2018

2019

17.6

16.7

2020

2021

18.6

2022

2023

Torreya Partners 2017

RARE DISEASE DEFINITIONS DIFFER BY REGION/AUTHORIT Y

250

Maximum number of people affected by a disease for it to be considered rare

1 in 2,000

20.3

19.6

Pulmonary arterial hypertension 3 Cerebral adrenoleukodystrophy Urea cycle 3 disorders Hereditary 3 angioedema 2 AA amyloidosis 1.5 Cushing’s Syndrome 1

European Union

242

United States

200,000 (1 in 1,600*)

2024

EvaluatePharma 2019

ORPHAN DRUG SALES BY THERAPEUTIC CATEGORY Global non-oncology orphan drug sales in 2018

Central nervous system 16.4%

new conditions are described in medical literature every year

Immunomodulators 10.3%

Endocrine 5.6%

Systemic anti-infectives 4.6%

European Medicines Agency 2016

Japan

50,000** (1 in 2,500*)

Taiwan

1 in 10,000

350m people worldwide suffer from a rare disease

* Based on current population estimates ** Threshold widened to include “intractable diseases” in 2015, affecting up to 180,000 people in Japan

Global Genes 2019

Other 1.1% Blood 31.4%

Respiratory 11.4%

Cardiovascular 9.8%

Musculoskeletal 5.1%

Gastro-intestinal 4.3%

EvaluatePharma 2019

RARE DISEASES

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When it comes to rare diseases, incidence rates per condition are low. But their collective impact on populations and healthcare systems is huge and often underestimated

of those diagnosed are children

have identified genetic origins, while others are the result of infections, allergies and environmental causes

Pugatch 2019

Rare Diseases Europe 2019

of known rare diseases still lack treatment

BUT COLLECTIVELY COMMON

PREVALENCE RATE OF SELECTED RARE DISEASES

ORPHAN DRUG SALES FORECAST

Number of sufferers per 100,000 people worldwide

Orphan drugs are commercially undeveloped pharmaceuticals intended to treat diseases considered too rare for traditional research and development

6-7k

estimated number of existing rare diseases in total Various sources

1 in 17

100

109

118

131

136

150

169

192

217

Multiple sclerosis 90

Worldwide sales ($bn)

Narcolepsy 50

people in the UK will be affected by a rare disease at some point in their lives

Primary biliary cholangitis 40

Rare Disease UK 2018

Spinal muscular atrophy 13 Retinal dystrophy 13 X-linked hypophosphatemia 5

Hemophilia 20

Cystic fibrosis 25

Fabry disease 30

Percentage of total prescription drug sales 10.5

2010

10.8

2011

11.6

2012

12.8

12.4

2013

2014

13.4

2015

14.1

2016

15.8

14.9

2017

2018

2019

17.6

16.7

2020

2021

18.6

2022

2023

Torreya Partners 2017

RARE DISEASE DEFINITIONS DIFFER BY REGION/AUTHORIT Y

250

Maximum number of people affected by a disease for it to be considered rare

1 in 2,000

20.3

19.6

Pulmonary arterial hypertension 3 Cerebral adrenoleukodystrophy Urea cycle 3 disorders Hereditary 3 angioedema 2 AA amyloidosis 1.5 Cushing’s Syndrome 1

European Union

242

United States

200,000 (1 in 1,600*)

2024

EvaluatePharma 2019

ORPHAN DRUG SALES BY THERAPEUTIC CATEGORY Global non-oncology orphan drug sales in 2018

Central nervous system 16.4%

new conditions are described in medical literature every year

Immunomodulators 10.3%

Endocrine 5.6%

Systemic anti-infectives 4.6%

European Medicines Agency 2016

Japan

50,000** (1 in 2,500*)

Taiwan

1 in 10,000

350m people worldwide suffer from a rare disease

* Based on current population estimates ** Threshold widened to include “intractable diseases” in 2015, affecting up to 180,000 people in Japan

Global Genes 2019

Other 1.1% Blood 31.4%

Respiratory 11.4%

Cardiovascular 9.8%

Musculoskeletal 5.1%

Gastro-intestinal 4.3%

EvaluatePharma 2019

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M E N TA L H E A LT H

Fighting the isolation of a rare disease diagnosis

Magda Ibrahim ith more than four in ten rare disease patients affected by depression, and significantly higher rates of illnesses such as anxiety, mental health problems are a pervasive pandemic. Considering globally there are up to 8,000 different rare diseases, with around three million people in the UK affected, the burden is enormous. “There is an urgent need to provide holistic care that covers the spectrum of the health, social and everyday needs of people living with a rare disease,” says Raquel Castro, social policy director at the European Organisation for Rare Diseases (EURORDIS). “Mental health is a crucial piece of this puzzle.” The reasons for increased mental health problems in rare disease patients, and their families, are myriad. Most rare diseases are complex and chronic, potentially life-threatening conditions, and go hand in

hand with reduced quality of life. Access to adequate care is often limited, while information can be sparse and fewer patients means a smaller rare disease support network. There can be issues around a disease’s visible attributes leading to discrimination, while conversely a lack of visibility can mean disbelief or misunderstanding from other people. In its recent report on the mental health effects of living with a rare condition, campaign group Rare Disease UK found health professionals’ attitudes played a major role. The findings were stark with 88 per cent of patients and carers saying poor awareness of their condition by health professionals had a negative impact on their mental health, while 80 per cent were negatively affected by health professionals not believing them. The lack of knowledge means many people can be left waiting

years for a correct rare disease diagnosis, which Rare Disease UK chief executive Jayne Spink says is “enormously anxiety inducing”. “It can also be quite shocking to have a diagnosis of a condition you have never heard of or have little information about,” Dr Spink adds. “There is little reassurance.” Researchers at the University Medical Center Hamburg-Eppendorf have been gathering evidence on the extent of the problem. Research associate Natalie Uhlenbusch has been working with a team, including Professor Bernd

DEPRESSION MORE COMMON AMONG RARE DISEASE PATIENTS European respondents were asked how often they had felt unhappy and/or depressed over the past four weeks* Numbers may not equal 100 per cent due to rounding

General population

37%

27%

25%

Rare disease patients

17%

36%

19%

18%

Never

Seldom

Sometimes

*Comparative survey of the general population was taken in 2011

The future is now: Orchard’s potentially curative gene therapies ‘Working with my illness rather than against it’

Mental health is fast being recognised as the missing piece of the puzzle in support for people with a rare disease

Often

Very often

European Organisation for Rare Diseases 2017

Löwe and Dr Miriam Depping, to explore how mental health problems impact on rare disease patients. In the team’s study, 42 per cent of patients had symptoms of moderate or severe depression, while 23 per cent suffered anxiety. “Given that 80 per cent of all rare diseases cannot be cured due to their genetic origin, effectively addressing depression and anxiety may be one of the few ways we can improve patients’ quality of life,” says Ms Uhlenbusch. “Physical and mental health cannot be treated as separate issues. Having a mental disorder in addition to a physical disease affects patients’ quality of life and can even decrease life expectancy. “Providing sufficient psychological rare disease support, in addition to the best possible medical care, is therefore crucial for patients’ overall health.” In its study, Rare Disease UK also pinpointed that patients can be mislabelled as neurotic, or having health anxiety, while trying to obtain their rare disease diagnosis. Those with previous mental health problems are particularly vulnerable, making it even harder to get recognition of their physical symptoms. “Some patients with rare diseases face a stigmatisation of having psychological or psychosomatic problems because their symptomatology is unusual and not identified by health practitioners,” explains Mary Gillam, Elsevier’s Clinical Solutions medical editor and American Board of Internal Medicinecertified endocrinologist.

However, Dr Gillam points out that understanding the relationship between a rare disease and a mental or psychiatric condition is not always straightforward. “A psychiatric disorder can occur as a primary manifestation of the disease itself, such as in the congenital condition Prader-Willi syndrome,” she explains. “On the other hand, a neuropsychiatric condition can develop as a complication of a rare disease too, such as in patients with Cushing’s syndrome, where endogenous hypercortisolaemia provokes a steroid psychosis that can resemble mania. “Finally, patients afflicted with rare, chronic conditions are heavily burdened by persistent symptoms and poor quality of life, which can trigger mental health issues like depression and anxiety.” Baroness Blackwood, government health minister responsible for rare diseases, has been lobbying to raise awareness after her own

There is an urgent need to provide holistic care that covers the spectrum of the health, social and everyday needs of people living with a rare disease

Commercial feature

Andrew Draper/Unsplash

Although Thomas Smith was diagnosed with cystic fibrosis at six weeks old, it was only in his teens the rare disease began to majorly impact his life and mental health. The now 31 year old says he was in denial about his condition, which affects one in two thousand five hundred people, and internalised his feelings. “I didn’t think there was any alternative,” explains Thomas. “In the depths of my struggles in the early-2000s, the words ‘mental health’ weren’t really part of the British public’s register.” Being severely underweight led to bullying at school and, at the age of 18, Thomas underwent a gastrostomy procedure when a feeding tube was inserted into his abdomen. “The gastrostomy destroyed any sense of positive body image,” he says. “I felt such shame.” Thomas never directly shared details of his condition with anyone, but says he felt people saw him as having a “weakness”. “The paranoia and sense of vulnerability is extremely real,”

experiences during a 30-year wait to be diagnosed with Ehlers-Danlos Syndrome, a condition that affects connective tissues. During that time, health professionals encouraged her to see a psychiatrist and prescribed drugs that worsened her condition. “I know first hand the huge impact a rare condition can have on physical and mental health, and I’m determined to do all I can to raise awareness and improve rare disease support for all NHS patients,” she says. “Early diagnosis of a rare condition is extremely important. Not only does it end the often very stressful and exhausting diagnostic odyssey for a patient, it also means they can get the support they need much earlier, including for their mental health. “We want to see a more holistic approach where treatment for mental health conditions is more closely integrated with the rest of a patient’s care. “Expanding the mental health workforce and raising awareness

he explains. “When you are a male patient and the prevailing social and cultural wind is to be strong, then being underweight and told you’ll have fertility problems can damage your feelings of masculinity.” Although mental health wasn’t specifically mentioned in his treatment, Thomas was evaluated by a clinical psychologist during organ transplant assessments and says he feels fortunate to receive support every six weeks, as well as taking anti-depressant drugs daily to keep him “on the straight and narrow”. Now working as executive chair of the Empower Middlesbrough social regeneration board, Thomas is keen to raise awareness of rare diseases and tackle stereotypes. “My life began to change three years ago when I started working with my illness rather than against it,” he says. “Until then, I felt deeply ashamed of my disease. Cystic fibrosis is incredibly isolating, so mental health awareness is very important.” Thomas can be found on Twitter at @pro_patient

of mental health conditions among healthcare professionals is key to this. This will take time, but we are making progress.” The health minister says the government is working with the NHS and partner organisations, such as the National Institute for Health and Care Excellence, to improve the care rare disease patients can expect through the UK Strategy for Rare Diseases, the NHS LongTerm Plan and upcoming Genomics Healthcare Strategy. Meanwhile, EURORDIS has launched its campaign paper for achieving holistic patient-centred care, recommending an entitlement to psychological rare disease support. It also calls for an annual mental health assessment for rare disease patients and their families. “It is vital that healthcare professionals are provided with the skills, knowledge and capacity to demonstrate awareness of the emotional challenges of living with a rare disease, so they are equipped to handle discussions about mental health sensitively,” Ms Castro concludes.

A wave of innovation is delivering breakthrough treatment options for rare inherited diseases that were once considered too challenging or impossible to treat rchard Therapeutics, a biotech with roots in the heart of London, is among leaders of a genetic revolution. “When the human genome was mapped nearly 20 years ago, the notion that this genetic blueprint could advance therapies capable of finding and possibly fixing the genes responsible for some of the world’s most devastating diseases was an idea of the future,” says Bobby Gaspar, professor of paediatrics and immunology at the UCL Great Ormond Street Institute of Child Health. Professor Gaspar, who has led multiple successful gene therapy clinical trials in immune deficiencies and other rare genetic diseases, is chief scientific officer at Orchard. A global entity with offices in London, Boston and the San Francisco Bay area, Orchard has the European-approved, commercial gene therapy product, Strimvelis®, together

Giovanni and Cecilia Price hold a photo of their sister, Liviana, who died at an early age from MLD, a diagnosis they share

Remembering Liviana Amy and Brad Price’s daughter Liviana was born with a fatal genetic disorder called metachromatic leukodystrophy, or MLD, a fast-advancing disease of the brain for which no approved treatments exist. Within days of Liviana’s diagnosis, the Prices’ other children were tested for MLD and the family learnt their younger son Giovanni also had the genetic defect responsible for this devasting condition. The Prices heard about a clinical trial in Milan evaluating an investigational gene therapy to treat MLD in certain infants and young children. While Liviana’s disease was too advanced for

with six clinical-stage gene therapy products in development and a robust pre-clinical pipeline, all aimed at potentially curing a range of rare diseases with a single administration of gene therapy. Orchard’s gene therapy approach is highly individualised and utilises gene-modified blood stem cells to target the underlying cause of disease. Blood stem cells are taken from the

her to participate in this trial, Giovanni was eligible. He, and later his younger sister Cecilia, received the investigational treatment now referred to as OTL-200. Today, the children enjoy going to school, playing sports and finding ways to remember their sister. “Although Livi is no longer physically here with us, she has left an important and lasting imprint on the tapestry of our family,” says Ms Price. “Our love for her endures and we keep her memory alive always.” This story represents a single patient experience in a clinical trial of OTL-200, an autologous gene therapy for the treatment of MLD. The safety and effectiveness of OTL-200 for MLD have not been established, and OTL-200 is not an approved therapy in any country.

patient, genetically modified outside of the body by inserting a functional copy of a missing or faulty gene, and then transplanted back in the patient to potentially cure the disease through a single administration. Mark Rothera, a seasoned biotech executive who has spent most of his career bringing treatments to patients with rare diseases, took the helm at Orchard in September 2017 after spending nearly 30 years in the industry and has grown the company from 35 employees to more than 200. Mr Rothera and his team took the company public last October and continue to add new programmes to the company’s growing portfolio, each of which leverages Orchard’s gene therapy approach. “Everything I’ve launched previously has focused on slowing disease progression and trying to improve quality of life, but at Orchard we have the potential opportunity to take a child on a path to dying at five years of age, and with a single administration, provide them with a more normal life,” he says.

For more information please visit www.orchard-tx.com

RARE DISEASES

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M E N TA L H E A LT H

Fighting the isolation of a rare disease diagnosis

General population

37%

27%

25%

Rare disease patients

17%

36%

19%

18%

Never

Seldom

Sometimes

*Comparative survey of the general population was taken in 2011

The future is now: Orchard’s potentially curative gene therapies ‘Working with my illness rather than against it’

Mental health is fast being recognised as the missing piece of the puzzle in support for people with a rare disease

Often

Very often

European Organisation for Rare Diseases 2017

There is an urgent need to provide holistic care that covers the spectrum of the health, social and everyday needs of people living with a rare disease

Commercial feature

Andrew Draper/Unsplash

Giovanni and Cecilia Price hold a photo of their sister, Liviana, who died at an early age from MLD, a diagnosis they share

For more information please visit www.orchard-tx.com

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Martin Godwin

Commercial feature

Driving innovation in treating rare diseases

Families cannot be expected to remortgage homes, crowdfund or potentially go bankrupt to fund essential medicines

reating uncommon conditions, those that affect fewer than five people in ten thousand, represents one of the greatest challenges for medicine globally, today. The patient population is small and dispersed, there’s a high cost of bringing drugs to market, as well as a limited understanding of disease pathology. “Finding patients can be difficult, sometimes with only a few per country, and it takes a lot of time to recruit for clinical trials, slowing development times for drugs. Small populations also create issues in generating data of sufficiently robust statistical standard,” explains Liz Gray, market access director for Ipsen UK and Ireland, who are focused on this sector. Ms Gray continues, “Often we may not know much about the natural history of a disease, so you don’t always understand the likely diversity within the disease course. Drug development

is also inherently unpredictable, and the problems are hugely increased with rare diseases where there is so little knowledge or data.” Tackling rare diseases represents a new chapter in medicine and how the pharmaceutical business model functions. The standard way of working shifts, since developing financially viable therapies for such tiny markets is difficult. Yet there’s increasing interest amongst governments, health systems, doctors and patients to tackle uncommon conditions, many of which are genetic, debilitating and affect the young. Despite being termed “rare”, they collectively affect roughly three million people in the UK . It’s why the use of so-called orphan or novel drugs is on the rise. “For patients, the biggest challenge is getting access to treatments with a high level of efficacy and a high

Clementia, an Ipsen company

The availability of new medicines is a hot topic within the healthcare profession. Everyone has their own issues from market access to pricing, reimbursement to efficacy. When the lens is focused on rare diseases the issues are hugely exacerbated

Marin, living with fibrodysplasia ossificans progressiva Hamilton, Canada

probability of getting the benefit, with minimal side effects, there are simply too few that offer this in the current system,” states Eric Low, former chief executive of Myeloma UK. “Pharmaceutical companies understandably want to make a fair return on their research and development, since they want the maximum return for their investors. However, it’s becoming increasingly difficult for companies to charge high prices for medicines that may only have marginal or uncertain benefits, even when there is huge unmet need,” explains Mr Low. Certainly, there’s a trade-off between creating economic incentives to tackle rare diseases and the spiralling cost of treating growing numbers OVERVIEW OF ORPHAN MEDICINAL PRODUCT DESIGNATION PROCEDURE SINCE 2014 of ever-smaller patient populations. The Eurordis data highlights how few orphan medicines make it to product authorisation How can pharmaceutical companies maintain the impetus for innovation if diseases are too small for the industry to see a return on their investment, or only at a price that’s unaffordable for Applications submitted 329 258 330 260 203 healthcare systems? Yet, is it fair that patients with a rare disease have less access to medicines? It’s these issue that healthcare professionals are Positive COMP opinions 196 177 220 144 152 grappling with. “We need to question why the cost of rare disease medicines is so high in the first place. This is an ethical quesApplications withdrawn 61 94 82 96 79 tion, as much as it is an economic question,” states Mr Low, who 20 years ago founded the only UK charity focused solely on multiple myeloma 2 1 2 2 3 Negative COMP opinions a rare bone marrow cancer, for which there’s no cure. The National Health Service in England is largely concerned with Designations granted how it allocates scarce health187 190 209 138 126 by the Commission care resources to derive maximum health benefits for the population as a whole. Their challenge is that the Orphan medicinal 15 14 14 14 12 budget is capped and there is not products authorised enough money to pay for everything. Priorities have to be made. The treatment of rare diseases may not always be top of the list, if the data EURORDIS 2014 2015 2016 2017 2018

Yet, is it fair that patients with a rare disease have less access to medicines

to support their use in uncertain, and prices very high. “However, even if there was more money in the drugs budget, that doesn’t mean to say there should be a higher willingness or threshold to pay for treatments with marginal or uncertain benefits,” says Mr Low. The move to an “outcome-based system” for drugs used to tackle rare diseases is one option, where pharmaceutical companies have to show that high prices actually reduce overall healthcare costs. Health providers may find that new drugs are more cost-effective in the long run for chronic, life-shortening rare diseases, in these cases, there may be a willingness to pay prices that allow corporations to make a profit. “To stimulate research into new medicines in rare diseases, we have to ensure that investment and research, as well as development will be rightly rewarded where improvements in treatment options are found,” says Ms Gray, who works at Ipsen, which is a company with 90 years of experience in the pharmaceutical sector and a provider of rare disease therapeutics. “We have to ensure that the system rewards those companies who consider thoughtfully their trial design. Conversely, as an industry, we have to be clear that it’s not reasonable to

expect reward for mediocrity either. Doing the best for patients at every phase of a drug’s development should ensure success and, by association, reimbursement for our innovation.” The system is evolving to address the problems. In England, the National Institute for Health and Care Excellence (NICE) has a dedicated Highly Specialised Technology (HST) appraisal process for rare diseases. Scotland and Wales have similar systems. This is seeing a number of innovative reimbursement and pricing deals done with companies to bring orphan drugs to NHS patients. “It is an improvement, but it’s not ideal. There are still rare diseases with all the attendant problems in data generation and disease understanding, they’re just not quite rare enough for HST . However, the process is at least recognition that there are nuances associated with the appraisal of medicines for rare diseases,” explains Ms Gray. “While not yet perfect, we recognise that this process is still young and will evolve with time and understanding, including NICE’s latest consultation on the use of broader data and applied analytics. We hope that these mechanisms will generate fair outcomes for those with a rare disease and will encourage more innovation in drug development through reimbursement for products, which can demonstrate a benefit and cost effectiveness for patients,” states Ms Gray. For more information please visit www.ipsen.com This content is authored and sponsored by Ipsen Limited Date of preparation: July 2019 ALL-UK-000910

Christina Walker with her son Luis, who is using a DNase nebuliser medicine which thins mucus

CYSTIC FIBROSIS

Buyers' clubs: the last option for desperate families How an ongoing pricing battle between the NHS and an American biopharmaceutical giant led to a buyers’ club for cystic fibrosis drugs in the UK

James Gordon o child should ever have to write a letter to the prime minister pleading for life-changing drugs to be made available on the NHS, but that’s exactly what nine-year-old Luis Walker did last May. Luis, who has cystic fibrosis, also wrote to Vertex Pharmaceuticals, a US biopharmaceutical company, which owns the patent on Orkambi, the drug in question. Sadly, it seems that Luis’s plight has fallen on deaf ears. With Orkambi costing £104,000 per person a year, the National Institute for Health and Care Excellence (NICE) says it cannot afford to meet the cost of the drug in England despite the fact that it could, according to the Cystic Fibrosis Trust, benefit 3,968 children and young people. After three and a half years with no agreement in sight, some desperate parents felt they had no option but to pay for the drug themselves. Take Robert Long, for example. In July 2018, after

consulting with his son Aidan’s medical team, Robert spent savings originally intended to fund his retirement to meet the £8,666 monthly cost of Orkambi. He says: “We’d do anything for our children and the drug has worked wonders for our nine year old’s health. Before taking it, Aidan suffered from breathing difficulties. But within days of taking Orkambi, he could breathe more easily. The modulator drugs are so important in stopping the decline caused by cystic fibrosis that we will do whatever it takes to keep our son on them.” But Robert admits to being surprised there has been no breakthrough agreement between the NHS and Vertex. He says: “We were hoping that we would only need to self-finance the drugs for a few months, but we had a fall-back position in place that has meant we’re able to cover the cost for a number of years if required. “However, we know that not everyone has this option. That’s when we decided to start the Cystic Fibrosis Buyers’ Club so we could import Orkambi at a much cheaper price.” After conducting extensive research, they discovered that Vertex’s patent did not extend to Argentina. But what really excited them was that Gador, an Argentinean drugs firm, had produced a generic copy of Orkambi. Gador agreed to provide them with the drug for a fraction of the cost at around £23,000 per person a year. And best of all, the more patients who join the buyers’ club, the greater the discount. Luis’s mother Christina says that 280 people have joined the buyers’ club since it was founded less than

a month ago. “Gador has agreed to lower the price further to around £18,000 per person a year if we can reach 500 buyers,” she adds. However, Christina, who can only work part time due to Luis’s condition, says that she and many other families would still struggle to cover the cost of the Gador drug without government help. But even so, she believes that founding the buyers’ club has served a much wider purpose. “The Cystic Fibrosis Buyers’ Club has captured the imagination of the public. It has shone a light on the reprehensible and immoral behaviour of Vertex, and has also put greater pressure on the UK government to intervene, which it promised to do in early-June. Families cannot be expected to remortgage homes, crowdfund or potentially go bankrupt to fund essential medicines. That’s why we have the NHS,” she says. So if a deal cannot be brokered, what options are open to the government? Nick Medhurst, head of policy for the Cystic Fibrosis Trust, explains: “If the impasse continues, it [the government] may consider implementing a Crown use licence, which would effectively remove Vertex’s patent. However, this would be a last resort and an action we would not advise any government to take, as it would set a bad precedent that the UK does not respect patents.” Instead Mr Medhurst believes the best solution for cystic fibrosis patients is for NHS England and Vertex to reach an agreement. He says: “We understand why people with cystic fibrosis and their families are seeking extreme ways to access these vital medicines. The fact they feel forced to take such measures illustrates the impact of the failure of all parties to reach a deal. But the best way for people with cystic fibrosis to access lifesaving drugs now is for an agreement to be reached between the two parties without any further delay.” In a statement, the NHS says it has already “made two of the most generous offers of its kind” to Vertex. It adds: “The quickest way for patients to get access to Orkambi is for Vertex to accept our offer and engage with NICE [National Institute for Health and Care Excellence].” Describing Vertex “as an extreme outlier in pricing and behaviour”, NHS England claims that even the APBI, the trade body representing the branded pharmaceutical

industry in the UK, does not agree with Vertex’s stance. According to NHS England: “The APBI said the current NHS offer represents exactly the sort of flexibility industry wants and has warned companies they cannot just pick any price they like for a new medicine.” However, Vertex says the offer NHS England made last year represented a 90 per cent discount compared with how much some other countries in Europe are paying. While it wouldn’t reveal the price, Vertex says that if it were to accept the offer made by the NHS, it “would not be able to cover the annual R&D costs and would go out of business in a few years’ time”. For Christina, she has little sympathy with Vertex’s position. “Imagine if it was their son or daughter. How would they feel? All I know is that when Luis is older, I have to be able to look him in the eye and tell him that I did everything I possibly could. I won't give up until he has free access to Orkambi or a generic equivalent. It’s a basic human right,” she says.

£104k patient cost per year of the cystic fibrosis drug Orkambi

10k+ people in the UK have cystic fibrosis – the equivalent of one in every 2,500 babies born

CF Trust

100k people worldwide are affected by cystic fibrosis

CF Trust

2nd UK’s global position in terms of the number of cystic fibrosis patients

Vertex Pharmaceuticals

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Martin Godwin

Commercial feature

Driving innovation in treating rare diseases

Families cannot be expected to remortgage homes, crowdfund or potentially go bankrupt to fund essential medicines

Clementia, an Ipsen company

Marin, living with fibrodysplasia ossificans progressiva Hamilton, Canada

Yet, is it fair that patients with a rare disease have less access to medicines

Christina Walker with her son Luis, who is using a DNase nebuliser medicine which thins mucus

CYSTIC FIBROSIS

Buyers' clubs: the last option for desperate families How an ongoing pricing battle between the NHS and an American biopharmaceutical giant led to a buyers’ club for cystic fibrosis drugs in the UK

£104k patient cost per year of the cystic fibrosis drug Orkambi

10k+ people in the UK have cystic fibrosis – the equivalent of one in every 2,500 babies born

CF Trust

100k people worldwide are affected by cystic fibrosis

CF Trust

2nd UK’s global position in terms of the number of cystic fibrosis patients

Vertex Pharmaceuticals

RARE DISEASES

RACONTEUR.NET

Commercial feature

1 in 2,000

maximum prevalence of a disease for it to be considered rare, according to European Union definitions

1 in 50,000

U LT R A- R A RE D I S E A S E S

Diagnosing ultra-rare diseases remains an uphill battle Incredibly uncommon and hard to diagnose and treat, how can we advance the treatment of ultra-rare diseases if there are still so many unknowns?

John Illman hen Josh Horrobin, now ten, was born, he didn’t open his eyes at all. Doctors initially thought he had conjunctivitis, a common eye infection in children. But to his parents’ increasing alarm, his eyes remained firmly shut. Three weeks later, they took him to A&E. Josh’s mother, Wendy Horrobin, a former teacher of English as a foreign language and educational project manager, recalls: “The registrar in A&E shone a light in his eyes and said: ‘His eyes are not responding to the light. I don’t think he has any vision’. It was shocking. The first thing I did was to phone my husband Simon; your first thought is what can you do for your child.

“A more detailed examination a week later revealed that his retina was completely detached and disorganised, suggesting Norrie disease. The diagnosis was confirmed after extensive investigations and genetic testing.” A genetic condition causing either blindness or severe visual impairment from birth and progressive hearing loss in later childhood, Norrie disease is an ultrarare disease that can also produce cognitive impairment or autism. There is no effective treatment and there was, when Josh was born, little publicly available accurate information, which is typical of many ultra-rare diseases. “There was no dedicated UK support group. A lot of information on

maximum prevalence for a disease to be considered ultra-rare

the internet was incorrect. We were told not to believe everything we read,” says Wendy. “It was very isolating, but there is this desperate urge to understand what your child is dealing with. Any inaccurate information you come across compounds this feeling of isolation, as did the fact that we did not know of any other children with Norrie disease.” Like many other parents with children with an ultra-rare disease, Wendy filled the information vacuum by co-founding a parent-patient support group, the Norrie Disease Foundation. She says: “It is impossible to underestimate the importance of mutual family support. Affected families afflicted by ultra-rare diseases really understand one another; you just cannot get this kind of support elsewhere.” It is easy to see why so little is publicly known about ultra-rare diseases. While the European Union definition of a rare disease is one affecting fewer than five people per ten thousand of the population – or one in two thousand – an ultra-rare disease is classified as affecting one person in fifty thousand or fewer. Most ultra-rare diseases affect as few as one in a million people or less. How is an ultra-rare disease identified and classified? Professor Raoul C.M. Hennekam, who has two ultra-rare diseases named after him, explains: “What usually happens is that a doctor publishes a paper about a patient with unusual signs and symptoms they do not recognise.” A single report about just one patient is not enough to secure an ultra-rare disease classification. An additional report about a second or even a third patient is required. Professor Hennekam, who worked at London’s Great Ormond

Street Hospital for Children (GOSH), adds: “The author of the report describing the second or third patient then recommends that the condition should be named after the first author.” Latterly professor of paediatrics and translational genetics in Amsterdam, Professor Hennekam says support groups have a fundamental role to play in promoting research into the causes and treatment of ultra-rare diseases. Every affected family is a potential research subject. The Norrie Disease Foundation has 40 affiliated UK families. Globally there are 500 known affected families. “In the vast majority of rare disorders, there are sufficient numbers of patients to test treatments. For example, in a trial you can give one group of patients an active medicine and a second group a placebo – a chemically inactive substance – to see if there is a significant difference. This can be hard in the case of ultra-rare diseases because there are so few patients,” he says. Within the context of conventional medical research, with trials involving thousands of patients, 40 families is an extremely small investigative base, but it is the impetus behind a three-year research programme at University College London Great Ormond Street Institute of Child Health. The aim is to increase understanding about when and where hearing loss in Norrie disease occurs and to investigate possible therapies to improve quality of life. The challenge is daunting. For example, of 7,000 identified rare diseases, only 400 have a licensed treatment, according to the Cambridge-based charity Findacure, which works with healthcare professionals and unites patients and parents with rare conditions.

Currently around 50 per cent of children undergoing genetic testing in the UK won’t get a confirmed diagnosis

For every identified ultra-rare disease, many others are unclassified. The charity SWAN UK (Syndromes Without A Name) estimates that 6,000 children are born in the UK each year with genetic conditions so rare that they cannot be named. No diagnosis means no prognosis and no evidence-based treatment. SWAN UK says: “Currently around 50 per cent of children undergoing genetic testing in the UK won’t get a confirmed diagnosis. It is thought that about half of children with learning difficulties and approximately 60 per cent of children with congenital disabilities do not have a definitive diagnosis to explain the cause of their difficulties.” A definitive diagnosis may lead to the reclassification of a syndrome without a name into an ultra-rare disease. In turn, as in the case of Norrie disease, this can help to identify a stream of patients which in turn can create a new research platform. Global collaboration is helping to boost the numbers of patients available for research. The Norrie Disease Foundation, for example, is working with GOSH to establish a trans-European Norrie disease patient registry. This may ultimately help young patients like Josh towards a better future.

Three ultra-rare diseases

Hutchinson-Gilford progeria syndrome Reported to affect one in eight million children, this genetic condition causes rapid ageing in early childhood. Affected children typically look normal at birth, but then fail to thrive in the first year of life. Characteristics include prominent eyes, a thin nose, protruding ears and baldness. The condition is also associated with hardening of the arteries which may result in heart attacks or strokes. The average life span is estimated to be 14.5 years.

Ring chromosome 20 syndrome (R20) Everyone has 23 pairs of chromosomes which hold our genetic material. R20 arises from a break on each arm of chromosome 20. Affecting the

normal development of the brain, R20 can cause epilepsy, behavioural problems and mild mental impairment. The seizures can be notoriously hard to treat and drug resistant. The prevalence of R20 is unknown, but it is believed to be underdiagnosed.

ADA-SCID (severe combined immunodeficiency due to adenosine deaminase deficiency) About three affected babies are born each year in the UK. They lack immune protection from bacteria, viruses and fungi. Until recently the only treatment has been a stem cell transplant. But the National Institute for Health and Care Excellence has approved a new £505,000 oneoff treatment, Strimvelis, for children who cannot find a good match. The effects are believed to be lifelong.

Engaging with patients and experts to develop new drugs Biotechnology companies engage with specialist firms to develop treatments which could transform the lives of sufferers from rare diseases efore any medicine can be made available to patients, it must undergo rigorous regulatory scrutiny, over a number of years, proving both its efficacy and relative safety. With common conditions, such as arthritis, colorectal cancer or hypertension, this rapidly becomes an exercise in managing big data. However, for the class of conditions considered “rare”, this is far from the case. While 7,000 rare conditions affect more than 400 million people globally, who could form the world’s third most populous country, individually each condition has relatively few sufferers and developing treatments is consequently very difficult. Lack of therapies for most rare diseases is an unacceptable reality for millions, with treatments only existing for 5 per cent of such conditions. Rare conditions mainly affect children, most are genetic in origin and three out of ten children born with a rare disease will not live to see their fifth birthday. The positive news is there’s a surge in interest to find medicines driven by new technology and scientific advancements, but issues exist. “The extraordinary challenge is that each rare disease affects a small number of patients. They are often frequently misdiagnosed. If new life-saving medicines are to enter clinical trials, it’s vital to engage with patients and multi-disciplinary medical professionals to fully understand their condition inside out,” explains Fabrice Chartier, chief operating officer of Simbec-Orion, a leading global, full-service clinical research organisation with a rare disease focus. “The medicines of tomorrow are utterly dependent on the goodwill and hope of patients today, without their altruism and dedication we could not develop new medicines.” It doesn’t help that those suffering from rare diseases are hard to find, they often have debilitating conditions and are geographically dispersed, many also

The medicines of tomorrow are utterly dependent on the goodwill and hope of patients today

10%

of people are affected by a rare disease

50%

30%

of patients diagnosed with a rare disease are children

of children diagnosed with a rare disease will not live to see their 5th birthday

years is the average time it takes for rare patients to receive an accurate diagnosis

Rare diseases impact more people then cancer and aids combined

Source: Global Genes. https://globalgenes.org/rare-facts/

have a limited ability to travel because of their ailment. Many are very young, which means taking part in clinical trials requires the consent of guardians, as well as their assistance; the odds are stacked against developing treatments. “It takes a lot of experience when developing and managing these clinical trials. You need sensitivity, skill and expertise, especially in paediatrics,” says Dr Chartier, whose company has dedicated 23 years to this sector. “Regardless of the condition, this needs to be fully understood and catered for. We’ve even created comic book-style information packs to help engage younger patients. “We are passionate about making trials as patient friendly as possible. We work with biotech companies developing new medicines to ensure all studies are patient centric, home based where possible or have travel organised to the hospitals involved and ensure the tests being measured are appropriate for the patients. We want to reduce disruption by bringing the study to the patient.” One of the biggest issues with rare diseases is they do not benefit from the economies of scale that drug development relies on with more common conditions. It’s the reason why so-called orphan drugs must be developed with a frugal approach. “This is not ‘big pharma’. The needs of smaller biotechnology companies

are different. We have to be budget conscious, yet super-effective. It often involves thinking outside the box, offering bespoke, modular and adaptive clinical trials,” says Doug Cookson, chief marketing officer at Simbec-Orion. “We also have to be agile hence our lean, flat operational structure with hands-on senior management. We manage the whole clinical development process, allowing our clients to focus on the medicine,” says Mr Cookson, whose firm enrolled more than 3,500 rare disease patients in 34 countries on four continents in the last five years. Rapid advances in science are transforming the treatment of rare diseases with an increasing number of promising drugs in development. “We’re going to be able to treat many more conditions, that’s why we are passionate about engaging with patients now about the value of their contributions,” Dr Chartier concludes. “The development of a new treatment for another life-threatening, rare disease could be just one trial away.”

For more information please visit wwww.SimbecOrion.com

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1 in 2,000

maximum prevalence of a disease for it to be considered rare, according to European Union definitions

1 in 50,000

U LT R A- R A RE D I S E A S E S

maximum prevalence for a disease to be considered ultra-rare

Currently around 50 per cent of children undergoing genetic testing in the UK won’t get a confirmed diagnosis

Three ultra-rare diseases

Ring chromosome 20 syndrome (R20) Everyone has 23 pairs of chromosomes which hold our genetic material. R20 arises from a break on each arm of chromosome 20. Affecting the

The medicines of tomorrow are utterly dependent on the goodwill and hope of patients today

10%

of people are affected by a rare disease

50%

30%

of patients diagnosed with a rare disease are children

of children diagnosed with a rare disease will not live to see their 5th birthday

years is the average time it takes for rare patients to receive an accurate diagnosis

Rare diseases impact more people then cancer and aids combined

Source: Global Genes. https://globalgenes.org/rare-facts/

For more information please visit wwww.SimbecOrion.com

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Andrew Brookes/Getty Images

DNA TESTING

Can at-home genetic tests improve rare diagnosis?

NATURALLY INSPIRED. ENGINEERED TO DELIVER. DRUGS TO TREAT RARE DISEASES.

The explosion of the direct-toconsumer DNA testing market could be transformative if genomics data is used in conjunction with the NHS to improve our understanding of rare diseases

Emily Hill f all the innovations issuing from Silicon Valley and transforming our lives, few have the potential to impact us quite so radically as home genetic testing of our DNA. For just a one-off fee and a swab of your saliva, companies such as 23andMe will reveal your predisposition to a growing number of diseases, including breast cancer, Alzheimer’s, Parkinson’s and type-2 diabetes, along with carrier status for conditions such as cystic fibrosis. But while common, complex disorders are increasingly well served in this brave new world, there are concerns about the lack of emphasis on rare diseases. A recent study by Imperial College Health Partners (ICHP) reveals the lengthy process of diagnosing rare diseases has cost NHS England £3.4 billion in the last decade. “The costs stated in our report are drawn from analysing the Hospital Episode Statistics NHS Digital database of over 60 million patients,” explains Julia Wilkins, head of data

and analytics at ICHP. “The research focused on hospital visits and activity in the lead up to diagnosis over the prior ten years, with an analysis of the data finding a higher number of hospital visits and accompanying costs per rare disease patient when compared to the general patient population.” But these figures only tell us part of the story, according to Nick Meade, director of policy at Genetic Alliance UK. “£3.4 billion is probably a vast underestimation of the impact on the state more broadly,” he says. If the sufferer from a rare disease can’t work, he or she will no longer pay taxes, will probably need to draw some form of state security, as well as coping with the massive cost to their own quality of life. “The classic example would be if you can deliver muscular dystrophy treatment when people can still walk then you’ll be able to stop them from having to use a wheelchair,” says Mr Meade. Last year, the Genetic Alliance produced a study in collaboration with

RARE DISEASE DIAGNOSTICS MARKET BREAKDOWN Global market share by end-user

17%

37%

Pharmacogenomic testing

Diagnostic genetic testing

34% 23% Carrier testing

Predictive genetic testing Swiss Re Institute 2019

Birmingham Children’s Hospital which concentrated on the undiagnosed community who suffer, he adds, from “a subset of rare conditions that are so rare they’re not that well understood and genetic tests won’t diagnose them because they just haven’t been defined properly yet”. The scale of the problem, particularly with very ill children, is huge. At present, home genetic testing indicates around ten health predispositions, as well as detailing carrier status, for as many as forty conditions and trait reports for even things such as freckles, red hair, bald spots, ice cream flavour preference and mosquito bite frequency. This makes it all seem like a bit of fun; the latest fad you can indulge in after having uploaded all your holiday photos to Instagram and arrived home a lot quicker after downloading Uber. But when it comes to getting our own DNA tested, most of us are entering a realm we do not understand. So can 23andMe, for example, help the NHS diagnose rare diseases? “One of the benefits of 23andMe is to act as a broad screen to identify genetic health risks that people might be unaware of, especially for those who do not qualify for clinical testing. Our Health + Ancestry service does report on various rare diseases, for example, MUTYH-associated polyposis [genetic risk for a specific colorectal cancer syndrome] and hereditary hemochromatosis [HFE-related genetic risk for iron overload],” the company says. This can, of course, have far-reaching consequences for those who use such services and receive worrying results. As the company explains:

“We’ve seen many cases of customers learning of genetic risks for certain conditions and discussing those results with their healthcare providers, which has led to follow-up testing and preventative measures being taken. “Our goal is to continue encouraging people to take a proactive stance to their health, using our reports as a prompt to initiate conversations with their healthcare provider.” If home genetic testing reveals something that looks worrying, the next step is to go to the doctor who, if also concerned, will order a fresh test through the NHS. Professor Sir Mark Caulfield, interim chief executive and chief scientist at Genomics England, explains: “At the present time, direct consumer testing, offered by 23andMe and others, predominantly uses analysis based on genotyping. There are the beginnings of offerings in the direct consumer space around whole genomes and exomes, but there’s still a lot to learn about how to interpret that data. “My view is people should be free to choose what they do and we know

There are the beginnings of offerings in the direct consumer space around whole genomes and exomes, but there’s still a lot to learn about how to interpret that data

about 175,000 UK citizens have done a 23andMe test, so there’s an appetite and curiosity out there. What we need is to make as much genomics usable in the health system so we can benefit people.” But Sir Mark is concerned about “implicit inequity” when it comes to home genetic testing in future. Yes, an ever-increasing number of people will be able to afford to send off DNA samples and decode their genetic information privately, but what about those who can’t afford it? That’s why bodies such as Genomics England are so focused on incorporating genomic medicine into the NHS. This is something that has made the UK a world leader in genomic medicine. Even home genetic testing companies such as 23andMe have noticed. Their spokesman adds: “We know genetic testing and genome sequencing for disease diagnosis and prevention is currently high on the agenda in the UK, for example with the 100,000 Genomes Project and the renewed bid to sequence five million genomes in the next five years.” To identify rare diseases as early as possible and make sure they are treated, Sir Mark hopes the NHS will eventually offer a genetic test at birth. “What might you find in early life if you use the whole genome?” he asks, explaining that a test could be conducted by taking a DNA sample from a baby’s umbilical cord. How ever genetic testing is conducted in the future, it seems certain the results will have not just a transformative impact on how we think about our health, but could significantly reduce the cost burden of rare diseases on the NHS.

EXOSOMES

are small nano-sized vesicles that are secreted by all cells are the natural way that cells safely and efficiently deliver proteins and nucleic acids to other cells

EVOX

is developing its own exosome-based drugs for treating life-threatening rare diseases is engineering exosomes to deliver protein and nucleic acid-based drugs to areas that are currently inaccessible

TO LEARN MORE EVOXTHERAPEUTICS.COM

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Andrew Brookes/Getty Images

DNA TESTING

Can at-home genetic tests improve rare diagnosis?

NATURALLY INSPIRED. ENGINEERED TO DELIVER. DRUGS TO TREAT RARE DISEASES.

The explosion of the direct-toconsumer DNA testing market could be transformative if genomics data is used in conjunction with the NHS to improve our understanding of rare diseases

RARE DISEASE DIAGNOSTICS MARKET BREAKDOWN Global market share by end-user

17%

37%

Pharmacogenomic testing

Diagnostic genetic testing

34% 23% Carrier testing

Predictive genetic testing Swiss Re Institute 2019

There are the beginnings of offerings in the direct consumer space around whole genomes and exomes, but there’s still a lot to learn about how to interpret that data

EXOSOMES

are small nano-sized vesicles that are secreted by all cells are the natural way that cells safely and efficiently deliver proteins and nucleic acids to other cells

EVOX

is developing its own exosome-based drugs for treating life-threatening rare diseases is engineering exosomes to deliver protein and nucleic acid-based drugs to areas that are currently inaccessible

TO LEARN MORE EVOXTHERAPEUTICS.COM

RARE DISEASES