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#2 • 2017

CombiGene – World-leading Swedish gene-therapy research THIS ISSUE: Gene therapy, new start for a 2 Milestones according to 2 Interview – Susana Ayesa 3 A big deal in gene 3 Famous author with 4 International 4 If someone has a 4

This newsletter has been produced by CombiGene AB, June 2017.


Gene therapy works! � Gene therapy is still a young branch of medical science and advances are reported daily. In this issue of Ingeneious you’ll meet a French boy whose sickle-cell anaemia has been successfully treated with gene therapy. The treatment involved replacement of the boy’s defective cells with healthy ones. Soon after the treatment, he was free of symptoms – a very encouraging example of how gene therapy can make a huge difference.


Gene therapy gave a 16-year-old boy a new start � Every time a new drug is tested on a disease for which existing treatment alternatives are ineffective, anticipation and expectations run high. Will it work? Will the patient really feel better? Such was the case in a French clinical study in which a gene-therapeutic drug for the serious blood disease sickle-cell anaemia was tested. The study was conducted at Necker Children’s Hospital in Paris and sponsored by the American company Bluebird Bio. Like Combi-

Gene, the company has specialized in developing new gene therapies to help patients with some of the most difficult-to-treat diseases. Owing to a defective gene, the red blood cells of sufferers of sickle-cell anaemia are unable to transport oxygen around the body effectively.

and was able to stop using his usual medication. No negative effects were observed and the benefits were long-lasting and showed no signs of diminishing. This meant that the patient no longer suffered bouts of severe pain or complications that affected his lungs, bones and spleen.

In the French study a 16-year-old boy received therapy whereby functional genes were introduced into his cells to replace defective ones. Shortly after the treatment he was free of symptoms

Thanks to the encouraging result, more clinical trials are planned, which is essential before the new treatment can be offered to the many sickle-cell patients throughout the world.

We at CombiGene continue to follow our ambitious plan for development. After getting the final results from our dose-response study early in the year, we have now begun work on the very important long-term study, which is expected to reach completion during the first half of 2018. Heading the study is Professor Merab Kokaia, one of CombiGene’s scientific founders. Concurrently with the longterm study we are working intensively to prepare for GMP manufacturing, which is a prerequisite for making our candidate drug for coming clinical studies. We are also participating actively in various meetings and conferences to secure valuable contacts by presenting CombiGene in the international arena. One example is a recent conference which we attended in Boston. I would also like to take this opportunity to welcome our new board member, Susana Ayesa Alvarez. Susana brings some very valuable knowledge and a great deal of energy to CombiGene. Jan Nilsson CEO

EDITORIAL STAFF Contact: Legally responsible publisher: Jan Nilsson Production: Wiberg & Co Reklambyrå. Text: Michael Vallinder English translations: Mark Wilcox CombiGene AB (publ) Medicon Village, SE-223 81 Lund, Sweden The company is listed on AktieTorget. Please read our press releases and newsletters, available on our website.

Casper Götzsche, Chief Scientific Officer, CombiGene, in discussion with My Andersson, Senior Scientist at Lund University.

CombiGene’s epilepsy is reaching milestones according to plan � How much of CombiGene’s

also important for another reason: it gave us the specific dose that we are using in our long-term study.

an ideal model for testing the anti-epileptic effects of CombiGene’s candidate drug, CG01.

That’s an important question, now that we have valuable new information after completing a successful dose-response study. Gene therapy is unique compared to other drugs, since the patient receives medication only once, after which the body takes over treatment. It is therefore important to know how much of the substance the body will itself produce after a given dose of gene therapy. In the recent dose-response study we tested many different doses of CG01 and were able to get a clear indication of the amount needed for treating patients with epileptic seizures. This study was

The long-term study: A decisive preclinical proof-of-concept study The long-term study is headed by Professor Merab Kokaia, one of CombiGene’s scientific founders. For the long-term study to produce a relevant result it is important that test model approximates the human disease as closely as possible.

The model includes use of MR scanning (magnetic resonance) and EEG examinations (electroencephalography); i.e., exactly the same methods that are used for examining patients at a clinic. The preclinical proof-of-concept study began in April and results are expected during the first half of 2018.

candidate drug CG01 is needed for treating epilepsy?

A model at Professor Merab Kokaia’s laboratory at Lund University does precisely that. The model resembles the disease and the symptoms of human temporal lobe epilepsy, which makes it

This newsletter has been produced by CombiGene AB, June 2017.

Casper Götzsche, Chief Scientific Officer, CombiGene



Susana Ayesa Alvarez, researcher and board member of CombiGene AB Tell us a little about yourself: your background, education, experiences and current engagement. My journey in the world of science began in Spain, where I did a five-year degree programme in chemistry in my home town, Logroño, in La Rioja, and at the University of Zaragoza. The wine district of Rioja offered potential job opportunities and I did a course in viniculture with the thought of perhaps starting my own business or working with the family vineyard. But deep inside I dreamed that I might some day develop medicines that would help people to live a better life, so I set my sights on the pharmaceuticals industry. In 1993, as a newly graduated chemist, I moved to Stockholm to work for Pharmacia. After several enriching years, I felt I was ready to make my mark. An important milestone came in 2000, when I left Pharmacia for Medivir, a spin-off from Astra’s former virus research group. During my time at Medivir I worked in several different disease areas and with projects ranging from the preclinical phase to more advanced stages, which gave me knowledge in various scientific disciplines. The entire journey has been characterized by passion, drive and the will to find new drugs that meet major medical needs. Today, I am pleased and proud that my contribution to pharma research has resulted in several candidate drugs, an approved drug and many patents and scientific papers. In 2013 I was elected to the board of Medivir as an employee representative. This engagement gave me good knowledge of, and insight into, the entire pharmaceuticals development process, including strategy and other business aspects. In late 2016 I felt it was time to move on. It was time for new horizons, new knowledge and new development.Then, just as I was looking to broaden my knowledge, new opportunities presented themselves and I landed a job at Johnson & Johnson Vision, where I have a senior position in GMP quality assurance. In this capacity, I both deal with, and gain insight into, various regulatory and quality issues. I will also participate in coming inspections by the FDA and other regulatory bodies, which will be very instructive.

”The enthusiasm and commitment I have seen in CombiGene is a good starting point for development and success.” Backed by a successful dose-response study, the epilepsy project is now in an exciting phase with implementation of the long-term study.

But the journey isn’t over; it has only just begun. In my current commitment with CombiGene, I am looking forward to it with great anticipation, and the passion, innovation and drive are with me.

or missing genes, or complement functioning genes with new functions. Another great advantage with gene therapy is that it produces a long-term effect after just one or a few treatments.

What is your general view on gene therapy?

The hope is that gene therapy will become the standard choice of treatment for a broad range of diseases. I am convinced that the great potential that gene therapy now holds and all of the collective research in the field will soon enable many innovative and successful treatments.

Gene therapy has a unique position, in the sense that it is an alternative to traditional pharmacological treatments. Great progress has been made in molecular medicine and gene therapy since the first clinical study was done more than 20 years ago and there are now several approved gene therapy products on the market. The possible applications are broad ranging and cover many different types of disease, such as eye diseases, diseases that affect the central nervous system, cancer and inherited immunodeficiency diseases. Major advances have also been made in addressing some of the challenges facing gene therapy, and current development is based on research surrounding new generations of vectors that enable greater efficacy and improved delivery. I think that the most exciting thing about gene therapy is that it offers the very great possibility of addressing diseases where there is a great medical need, since the unique technology can be used to target treatment to replace defective

Multi-milliondollar deal in gene therapy – potential win-win for many

This newsletter has been produced by CombiGene AB, June 2017.

What, in your view, is the most exciting thing about CombiGene? A high level of innovation and enormous potential are usually a winning combination for a company and I think CombiGene has this combination. This is the only pharmaceutical company with gene therapy that is listed on the stock market in Sweden. This, together with the great possibility gene that therapy offers in the form of benefit for the patient, makes CombiGene a very exciting company. The enthusiasm and commitment I have seen in CombiGene is a good starting point for development and success. Backed by a successful dose-response study, the epilepsy project is now in an exciting phase with implementation of

� In mid-May, American pharma

giant Pfizer signed an agreement with Sangamo Therapeutics for the rights to Sangamo’s preclinical gene-therapy programme for treatment of haemophilia A. According to the agreement, Sangamo will receive a 70-million-dollar advance from Pfizer. Potential milestone payments amount to $475 million.

the long-term study. Besides epilepsy, the concept seems to be applicable to a range of other neurological diseases, which may eventually expand the project portfolio and take the company to new heights.

What will you bring to the company? My longstanding experience of pharmaceuticals research and development, in both large and small companies, and collaboration in academia give me a strong foundation. Hopefully, the experience I am now acquiring in the area of GMP will prove useful in the phase in which CombiGene now finds itself. I also bring experience gained from working on the board of a listed pharma company, with all that entails in terms of regulatory aspects, business acumen and a scientific foundation. I’m sure that this experience will be a great advantage in my current commitment with CombiGene. I like to look at things from different angles and see the opportunities. I usually have a critical eye and I enjoy working in dynamic settings with a culture that promotes dialogue. My aim is to always do my best for the company. Not least, I want to contribute my cheerfulness, enthusiasm, drive and a will to learn.

Sangamo is also entitled to a two-digit royalty on future net sales. According to the agreement, Sangamo will be responsible for realization of phase I and II studies and some manufacturing. Pfizer will be responsible for subsequent development, manufacturing and commercialization.


Fyodor Dostoyevsky – one of many epilepsy sufferers Society’s attitude towards epilepsy has long been characterized by superstition and fear. The disease was associated with impurity and it was thought that it was caused by evil spirits and you could get it simply from touching someone who had it. In Sweden it was an obstacle to marriage and it was not until 1969 that all epilepsy sufferers were allowed to marry.

figures with epilepsy have nonetheless achieved fame and success. One example is Fyodor Dostoyevsky, author of some of the world’s great literary classics, among them, Crime and Punishment, which he purportedly wrote in 26 days with the help of a stenographer, and The Brothers Karamazov.

Although society has had a negative view of the disease, many historical

Read all of our news in one place

CombiGene is an active member of the global gene-therapy alliance

We would like to keep you well informed about what is happening in the company. herefore, we are now launching CombiGene’s digital newsletter to allow you to read all of our news first-hand.

When you’re developing advanced therapeutic treatments like gene therapy there is a lot to be learned, even for experienced drug developers. Since gene therapy is still young (there are only three approved products in Europe and none in the USA), everyone – developers, regulatory bodies and manufacturers – still has a lot to learn about the best way of managing this promising field. To be a part of this process, CombiGene became a member of ARM (Alliance for Regenerative Medicine) in 2016.

Subscribe via our website, where you can register the e-mail address to which you wish the newsletter to be sent. Use the link ”Subscribe to our newsletter” at the top-right corner of the page. The subscription is free of charge and you can cancel it whenever you please. Read ”More from the company” and our Press Releases at:

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ARM is the largest international association of pharma developers and all of the leading players in gene therapy are represented here.

First aid

conference Gene Therapy for Rare Disorders, in Boston, together with representatives from the EMA (the European Medicines Agency), the FDA (the Food and Drug Administration in the USA), biotech companies and Big Pharma (among others, Pfizer, GSK and Sanofi). “For CombiGene, it is vital to be at the forefront and keep abreast of trends and regulations within the rapidly changing field of gene therapy. I feel we are now in a good position, where we have a good overview of what it takes to develop a gene-therapeutic medicine for a disease like epilepsy,” says CEO Jan Nilsson.

� What can we do when someone experiences an epileptic seizure? An epileptic seizure can take different forms. In the case of a major episode (a tonic-clonic seizure), the patient may lose consciousness, fall down, and experience cramps or muscle spasms. Most epileptic seizures end on their own. In that case, as a bystander, the best thing is to wait. However, transport to hospital may be necessary if the seizure does not end, if the patient sustains injuries or if you are unsure whether it is, in fact, an epileptic seizure. You can help by doing the following: • be calm; • remove all nearby objects; • don’t put anything in the person’s mouth; this could damage the teeth; • cushion the head; • loosen the neck tie or belt, remove eyeglasses; • once the cramping or jerking has stopped, gently place the person in the recovery position (on one side, with the head low); • remain with the person until they are able to manage on their own; • keep curious onlookers at a distance.

Recently, CombiGene’s CEO Jan Nilsson and Casper Götzsche, Chief Scientific Officer, participated in the

Source: Swedish Epilepsy Association

For many sufferers, there is no help – yet. We hope to change this. We are in the process of developing a world-leading method for treating epilepsy. The potential is enormous, the outlook is good. For millions of people worldwide. CombiGene AB (publ)  Medicon Village, SE-223 81 Lund, Sweden

CombiGene Ingeneious no 2  
CombiGene Ingeneious no 2