RARE Daily

A Gene Therapy Developer that Embraces Different Models for Reaching Patients

May 9, 2024

The work of gene therapy pioneer Genethon, a non-profit organization created by the patient association AFM-Telethon, has already seen its research lead to Zolgensma, the gene therapy for spinal muscular atrophy, as well as a growing pipeline of candidates for other rare diseases. But it came to realize it needed to pursue more than just licensing agreements to ensure its work ultimately benefited people who needed its therapies. As a result, the organization has taken a range of different approaches to ensure the development of its gene therapies. We spoke to Frederic Revah, CEO of Genethon, about the limits of licensing out its discoveries to biopharma, the different development strategies it pursues, and how it determines the best path for a particular development program.

Daniel Levine: Frédéric, thanks for joining us.

Frédéric Revah: Yeah, my pleasure. Thanks for inviting me.

Daniel Levine: We’re going to talk about Genethon, the work it does to develop gene therapies, and how it uses different models beyond traditional licensing agreements with industry to ensure patients benefit from its work. I think most people who pay attention to the field of gene therapy will be familiar with Genethon, but for listeners who don’t know what it is, can you describe how the organization came about and what it does?

Frédéric Revah: Yeah. So Genethon was born in 1990. It was created by a patient association, the French Muscular Dystrophy Association, the AFM-Telethon, which is one of Europe’s largest patient organizations, if not the largest. The AFM-Telethon organizes the yearly telethon in France since 1987. And with the financial success of the telethon via the AFM-Telethon, found itself in a position to build an ecosystem system dedicated to addressing the issues of therapeutic innovation for rare genetic diseases. So really beyond only muscular dystrophy, but more globally for rare genetic diseases, the AFM-Telethon has created an ecosystem of several R&D organizations. And the first historically has been Genethon. So we were created in 1990, really with the mission of developing therapies for rare genetic diseases. But remember in 1990, the human genome was not deciphered yet. And clearly participating in the deciphering of the human genome was a first and very important objective since 80 percent of all rare diseases are genetic in origin. So, we did start by participating to the human genome endeavor. And in fact, we did establish the first high resolution maps of the human genome that was between ’92 and ’96, which were published in several high profile articles. And really, these high resolution maps have been true accelerators of the field in terms of discovering genes responsible for rare genetic diseases. Then in ’97, we switched from genetics and genomics to therapeutics, and we engaged in the field of gene therapy at a time where, frankly, there weren’t that many people out there that believed that gene therapy could deliver, could become a therapeutic reality. I mean, the principle of gene therapy was well known. I mean, it had been spelled out since the sixties, basically. But putting gene therapy in action seemed really so difficult. There were no pharma companies interested. There were very few investors interested. And the idea of our mother organization, the AFM-Telethon, was really to engage into gene therapy, which really seemed the right way to address rare genetic diseases. And over the years, we build the know-how, the capacity, and the pipeline that we’ll talk about.

Daniel Levine: Even if listeners aren’t familiar with the Genethon name, I suspect they’ll know your work. I think here of Zolgensma, the gene therapy for spinal muscular atrophy. Can you explain Genethon’s involvement in the discovery and development of Zolgensma?

Frédéric Revah: Yeah, definitely. So, there’s really the involvement of Genethon in Zolgensma, but there’s the involvement of our mother organization, the AFM-Telethon more generally on R&D for spinal muscular atrophy. As for Genethon, I mean, the story started in 2006 with a group leader at Genethon, Martine Barkats, who had the idea of testing gene therapy in spinal muscular atrophy mice and using the SMN gene, made a construct, tested different types of vectors, and demonstrated that using the AAV9 vector, adeno-associated virus serotype 9, using this AAV9, using the right construct, you could almost virtually cure these mice, which would normally die within 25 days. I mean, these mice, after treatment would live for more than 200 days for most of them by simple intravenous injection, which was also important for a disease, which is a disease of the central nervous system. And really by doing this, Martine laid the basis for gene therapy for spinal muscular atrophy. She published her work, she patented both the construct, the vector to be used, the mode of administration, and basically all these elements are the key basic elements in Zolgensma. But even before that, the gene responsible for spinal muscular atrophy was discovered by a group that was funded itself by the AFM-Telethon, by the French Muscular Dystrophy Association. That was the group of Judith Melki in Paris at who really discovered the SMN gene and which really laid the basis for every therapy that came after that.

Daniel Levine: And how is the organization funded today? And do licensing deals or royalties play a role in its funding?

Frédéric Revah: Yeah, definitely. I mean, licensing and royalties do play a role in our funding, but most importantly, it’s really the resources from the telethon have played a major role for us. I mean, so the yearly telethon allows the AFM to gather around 90 million euros per year. And of course, not all of that comes to Genethon. But then an important sum does come to Genethon every year. And since our inception in 1990 approximately 75 percent of our resources came from the telethon. So that’s important. It’s not been a 75 percent all years, I mean several years it was more, and several years it was much less than that thanks to royalties and thanks to the licensing deals that we do have.

Daniel Levine: From the outside, Genethon has a pipeline that would make it look like a good size biotech focused on gene therapy. How big is the organization today?

Frédéric Revah: Well, so there’s today 220 people working at Genethon and working on different aspects of gene therapy. We have a group of 110 – 120 people working on translational research, designing the gene therapy—the gene therapies themselves adapted to a number of disease on which we’re working, but also developing new capsids, working on the immune response to the vectors, which is something which is very important, both from a toxicology point of view, but also to be able to read those vectors. So that’s one part of the organization. There’s another very important part—45 people working on CMC that is really developing the methods to produce the vectors. And basically, I mean, we’ve had to invent some of those methods. When we started in 1997, nobody knew really how to manufacture these drugs at large scale. So, we came into that space and we have been pioneers in some of the process that are used today at large scale for AAV and lenti manufacturing. We also have a clinical development department. We have a business development department. So, you could compare us to, I would say, a mid-size biotech company, but being non-for-profit.

Daniel Levine: Genethon has at least a dozen programs in development all focused on rare disease. Given the large number of rare genetic diseases that exist, how does the organization determine what programs it’ll pursue?

Frédéric Revah: So, this really is a choice that is based on multiple parameters. I mean, first parameter is really the probability of success. That is the quality of science that we both have internally or with our collaborators. Of course, we’re not working only on our own. We have more than 40 ongoing collaborations with academic and clinical institutions worldwide. So really the first element is how good is the science, because the quality of the science is an important parameter in the chance of success of the program. So that’s going to be the first element in choice. Second element is that we want to be working on diseases where we will learn as we move down the road. We’ll learn elements, we’ll learn lessons that can be used for other indications. I’ll give you an example. I mean, we did a lot of work on the myotubular myopathy, which is a very severe type of myopathy. Fifty percent of the kids affected will die before the age of two. And then we designed a product which is today developed by Astellas. While doing that, what we learned both in terms of designing those drugs, manipulating this vector, manufacturing this vector at large scale, everything we learned that we also then could use for another program, which is very important to us, which is Duchenne muscular dystrophy. And then what we develop for Duchenne muscular dystrophy, we are using now for limb girdle muscular dystrophy. So clearly we want that each of those products and each of those programs that we have, we want it to be a lesson for other programs. So that’s a critical element in the way we choose our programs.

Daniel Levine: And do you look at other strategies for addressing genetic diseases such as gene editing, or are you solely focused on gene therapies?

Frédéric Revah: No, definitely, we are looking into gene editing with different types of approaches. We have a program on metabolic diseases using gene editing, which is still at the preclinical stage. And definitely this is something we want to develop not only for ex vivo gene therapy, because we’re using lentiviral-based ex vivo gene therapy, but also trying at one stage to use gene editing for in vivo gene therapy, and hopefully one day for neuromuscular diseases.

Daniel Levine: The organization came to realize that it needed to create different development strategies beyond out-licensing for its discoveries to biopharma. Why is that?

Frédéric Revah: So that’s a very important point. So remember, we were created by a patient organization. Our focus are rare genetic diseases, and there’s 7,000, so seven to eight thousands of these diseases out there. There’s only 5 percent of them for which there’s a cure or a treatment. And for many of them, for the large majority of them, probably more than 85 percent of them, the number of patients is quite low. And basically, there is no profitability model that would trigger the interest of a pharma company for these diseases. I mean, these diseases, they’re very numerous. There’s lots of them. And our point is that nobody should be left on the side of the road just because the disease they have is too rare to be interesting from a financial point of view. So clearly here for these thousands of disease for which many of them could benefit from gene therapy, we have to find other models than licensing out to biopharma. And hence, we have to be creative in the way we look at financing for these programs.

Daniel Levine: Well, I’d like to walk through a few of the different examples of strategies you pursue to advance gene therapies beyond licensing deals. In 2020, Genethon created its first spin out company. This was Atamyo Therapeutics to pursue a gene therapy for limb girdle muscular dystrophy. Why did you decide to set up a company for this gene therapy?

Frédéric Revah: So, to be precise, it is not our first spinoff. It’s our first spinoff with therapeutic products. But before that, we had spun out Genosafe, which is a company specialized in analytics. And we have also, very importantly, spun off YposKesi, which is a manufacturing platform for AAV and lentis, which is Europe’s largest manufacturing platform, and which is a spinoff for which we have now a minority share position. But really they were our two first spinoffs. Now, we created Atamyo around assets and programs, which are really centered on limb girdle muscular dystrophy. I mean, we strongly believe that there is a commercial model for limb gridle muscular dystrophy, otherwise we wouldn’t have done a spinoff. The company is currently developing those drugs. It’s right now a fully owned Genethon subsidiary. It’s currently undergoing a series A financing, and really it’s focusing on limb girdles, one product already in advanced clinical stage, another product which was CTA cleared, so ready to start its clinical trial in Europe, another program for which we could get CTA and IND clearance in one year from now. And then from the limb girdles also extend to other types of indications, more with frequency like cardiomyopathies. And the reason we decided to do that is that we thought we were mature enough to create our own spinoff in that field and probably keep a larger share of the value of the company by doing that.

Daniel Levine: And where is it in development efforts, and is it expected to build a pipeline beyond a gene therapy for limb girdle muscular dystrophy if it’s successful in bringing that to market?

Frédéric Revah: Yeah, the point is really focusing on gene therapy, but there’s currently LGMDR9, which is in advanced clinical trial, and LGMDR5, which is ready to start its clinical trial. But the expertise is really gene therapy. The idea is to benefit from every cutting edge innovation that can come out of Genethon, and the extension will come not from going out of gene therapy, but using gene therapy to other types of indications, which are a natural extension from myopathies, which are basically cardiomyopathies and which have a very important prevalence.

Daniel Levine: Genethon is also pursuing clinical development of therapies on its own. It’s conducting pivotal trials for a gene therapy for the ultra-rare liver disease, Crigler-Najjar syndrome. Why develop this program?

Frédéric Revah: Yeah, that’s an interesting example. I mean, the reason why we’re developing this in-house is that basically the condition is considered too rare to be attractive to biotech or to pharma organizations. We’re talking about really a prevalence here of one in a million. We are really in the field of what you could call ultra-rare disease. So, the profitability model here is too low to trigger the interest of pharma, classical pharma organization. So we decided that we would continue on our role. So that’s something we’re doing, and that’s probably not something that we’ll be able to do for all of these products. I mean, developing one of these drugs is expensive, whether it’s an ultra-rare or just a rare disease. So that’s where clearly there needs to be creative models to fund these developments for these ultra-rare diseases. There’s one model which is being developed in the United States, which is the Bespoke Gene Therapy Consortium to which we participate. But there’s also other models that we’re trying to pursue in Europe. And our position in Europe is that from the moment for these ultra-rare diseases that you set up a clinical trial, in fact, you offer an opportunity for therapy to the patient, and if there’s opportunity for therapy, somehow it could be reimbursed by the social security system. So what we’re trying to set up here in France first and then in Europe is to engage the payers that is the social security system in supporting the development of these drugs on the basis that the development is an actual opportunity for treatment, such as would be the registered compound.

Daniel Levine: If you’re successful, is there a plan to bring that gene therapy to market?

Frédéric Revah: Yeah, yeah. Well, the point is yes we want to bring it to the market, at least we want to bring it to patients. So, for such a rare indication, I mean, what does it mean, bring it to the market? Did you have to have a full registration? Do you want to have an open-ended clinical trial and have every patient being able to join? So these are elements that we’re currently considering, but really definitely if this is successful, we want to make it available to patients.

Daniel Levine: Finally, Genethon has a partnership with Sarepta Therapeutics for the co-development of a gene therapy for Duchenne muscular dystrophy. Under that agreement, Genethon is responsible for commercializing the product in Europe, and Sarepta is responsible for the rest of the world. Does this mean Genethon will be creating a commercial organization?

Frédéric Revah: Yeah, that’s something we are considering. It could be either internally or it could really be spun out, but that’s really something we are considering.

Daniel Levine: What determines the model you’ll pursue for the development of a gene therapy? What are the factors you consider?

Frédéric Revah: Okay, one point we consider for each case is really, is there a commercial model for this therapy that we’re developing? Is there a profitability model? Is it going to be profitable enough to attract an external partner be it either an investor or an investor in a specific company that we would set up or a pharma company? That’s really one element which is critical in choosing a path for development. But if there is no profitability model, it’s not a reason for us to let go. I mean, we do not choose our programs based on the number of patients or based on a potential return on investment. And this is clearly not the type of decisions that we want to make, but clearly in orienting the development towards either internal development or partnering, clearly the existence of a sufficient profitability is a key element.

Daniel Levine: Well, I’m wondering if you can expand on that as a not-for-profit. You’re driven by mission rather than shareholders. What’s the effect that has on what you’re able to do or how you’re able to do it?

Frédéric Revah: First thing is that what we’ve done and what we’ve achieved is really due to the fact that we were supported by a patient organization and that we are, I mean, no other type of organization would have taken the risks that we’ve taken. When we started gene therapy in 1997, there were so many voices telling us, “Well, this is the wrong thing to do. You shouldn’t get involved into that. It’s too risky. It’s science fiction. It’ll never work.” Okay. And clearly this risk-taking approach and the fact that somehow we were not constrained by the idea of having a short-term or even midterm return on investment gave us the possibility to deploy the competencies, the programs, and to move into the clinic. I mean, one of the first programs we brought into the clinic was Wiskott-Aldrich and Wiskott-Aldrich is an ultra-rare disease. But to us, it was really the first step into the clinic and learning what clinical development was about and what production was about. Really learning everything about bringing gene therapy to the patients, but starting with a disease, which we knew had very limited commercial revenue. So clearly what we have done and the way we have done it was made possible because we are a not-for-profit. So that’s really what we are able to do now, what we are not able to do. I mean, the limitation is on the other hand. We rely so much on external donation on the telethon. That of course, to a certain extent that does limit probably the financial resources we can allocate to each of our programs. But then it’s also being a non-profit and being financed the way we are financed is an element of longevity and being able to look for long-term development and make sure we stay a pioneer, rather than focusing on the quarterly reports such as a listed company would do, and focusing on what’s going to happen the next day. We focus on what’s going to happen in the years to come.

Daniel Levine: Frédéric Revah, CEO of Genethon. Frédéric, thank you so much for your time today.

Frédéric Revah: Thank you.

This transcript has been edited for clarity and readability.


The RARECast podcast is made possible through support from the Global Genes’ Corporate Alliance. The members of the Corporate Alliance support Global Genes’ mission and programs, work to meet the vital needs of people with rare diseases, and address inequities they face. To learn more about the Corporate Alliance or how your organization can become a member, click here.


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