RARE Daily

Forging a Faster Path for Gene Therapies

April 11, 2024

The Bespoke Gene Therapy Consortium, a public-private partnership backed by the Foundation for the National Institutes of Health, in February published its first playbook. The playbook provides a roadmap for streamlining product development and navigation of the regulatory pathway for AAV gene therapies with the goal of getting new treatments to patients sooner. We spoke to Courtney Silverthorn, vice president of strategic alliances and innovation for the Foundation for the National Institutes of Health; and Sharon King, manager of advocacy and community engagement for Aldevron and founder and president of Taylor’s Tale; about the Bespoke Gene Therapy Consortium, its new playbook, and how it will help gene therapy developers get their medicines to patients faster.


Daniel Levine: Courtney, Sharon, thanks for joining us.

Courtney Silverthorn: Thank you.

Sharon King: Thank you for having us, Danny.

Daniel Levine: We’re going to talk about the Bespoke Gene Therapy Consortium, it’s first recently published playbook, and how the work it’s doing is being done to accelerate development and reduce the cost for producing gene therapies to treat a wide range of ultra-rare diseases. Let’s start with the Bespoke Gene Therapy Consortium. Courtney, for listeners not familiar with the program, what is it?

Courtney Silverthorn: Sure. The Bespoke Gene Therapy Consortium is a public-private partnership under a broader program called the Accelerate Medicines Partnership Program. And these are pre-competitive public-private partnerships that bring together the resources of the NIH, the private sector, advisory participation from the FDA, [and a] strong focus on nonprofits and patient advocacy groups to solve challenges that neither the government nor the private sector could solve on their own. And so, the Bespoke Gene Therapy Consortium was launched in 2021 with the goal of improving our understanding of adeno-associated virus or AAV biology and a focus on the manufacturing, preclinical testing, and regulatory processes, and streamlining those processes to make it easier and more efficient to bring forward a gene therapy.

Daniel Levine: I’m confident most of our listeners will be familiar with the National Institutes of Health, but they may not know what the Foundation for the National Institutes of Health is. Can you explain what that is and what it does?

Courtney Silverthorn: Yes. We are the 501c3 nonprofit that was established by Congress in 1990 to support the mission of the NIH. And we do that in a number of different ways: supporting patients, supporting clinician scientists, but the largest way that we do that currently is through the design, fundraising, and management of very large and very complex public-private partnerships like the Bespoke Gene Therapy Consortium. And since our inception, we have raised over $1.5 billion in support of NIH public-private partnerships, and ultimately their mission.

Daniel Levine: What problems is the Bespoke Gene Therapy Consortium trying to solve?

Courtney Silverthorn: We saw in the field of AAV gene therapy that there were a lot of variation in the applications that were being submitted to the FDA for review, that there were challenges in manufacturing, that there was a lack of consistency in how the preclinical testing was done, how the paperwork was submitted to the FDA, and how things ultimately got into a phase 1 clinical trial. These can be very lengthy and very expensive challenges. And so, what we wanted to do was to develop a more robust and repeatable pathway that would allow others to follow the same processes that the BGTC is using, follow the same protocols, the same sets of testing in your manufacturing, in your preclinical studies, and really give people a roadmap for how to bring something forward through an IND, an Investigational New Drug application, and into a first in human clinical trial.

Daniel Levine: You mentioned that this is funded through the Accelerating Medicines Partnership. Why did the FNIH decide to fund the program and how does it fit in with the broader mission of the Accelerating Medicines partnerships?

Courtney Silverthorn: Yeah, the BGTC is a little bit unique amongst the other Accelerating Medicines partnerships programs. Many of the other programs are focused on clinical data, on identifying biomarkers for patient identification, for therapeutic development. The BGTC is really the only partnership that is focused on a platform, AAV gene therapy, rather than a specific disease, and the only one that’s really focused on these consensus protocols, but it is still very much within the ultimate vein of the Accelerating Medicines Partnership Program in that it is looking for pre-competitive ways to advance therapies.

Daniel Levine: Well, let’s bring Sharon in here. Sharon, you’re a patient advocate, someone who lost a daughter, Taylor, to the rare genetic disease, CLN1, a former of the neurodegenerative condition Batten disease. What were you told when Taylor was first diagnosed?

Sharon King: Taylor was, until she was in first grade, she was just a genuinely happy little girl. She was razor smart, a little bit sassy. She was an undeniable leader. Her older brother and sister could confirm that we were really perplexed when as a first grader, she didn’t do very well on her standardized test scores. This was a child who was reading early on who all of a sudden her reading readiness just was non-existent. In testing, teachers were describing a lack of focus, attention deficit disorder, and then we noticed vision problems—she couldn’t see in low light situations. It took almost two years to receive that CLN1 disease diagnosis, and we were told that she was going to lose her ability to see, to talk, to walk, to swallow, and that the disease would eventually take her life. It was the worst thing we could ever hear and so my husband and I asked the geneticist, “So what’s next? Where do we go? Who do we see?” And we were told there was nothing that we were going to be able to do in her lifetime and very likely our own lifetimes. We were told it was an ultra-rare condition and it was simply too small. And to hear those words from a geneticist, it was the most hopeless thing we could ever hear.

Daniel Levine: And what happens in CLN1? How does the condition progress?

Sharon King: Well, for Taylor, it started with this lack of ability to focus. We started seeing learning problems. I think the big thing we saw was this effect on her vision—that she was getting closer and closer to screens and in lowlight situations, she would stumble and fall. We first noticed it [when] we were going up steps. We were in an exhibit and going up dimly let steps, and she was looking for each step with her toe. It was just so obvious that her vision was affected. And still, it took almost two years to get a correct diagnosis. Her first diagnosis was retinitis pigmentosa.

Daniel Levine: You’ve seen the advent of gene therapies, but we still only have a handful of these medicines available today. What do you hear from parents of children like yours?

Sharon King: Parents? I know so many parents who’ve taken the same—started the same journey that we started with Taylor’s Tale, going out, learning, trying to learn as much as possible about the science. Danny, I’m not a scientist by any stretch of the imagination. I’m a musician by training. No one ever thought I was going to need science. But when Taylor was diagnosed with CNL1 Batten disease, I needed science desperately. Parents are still today–Tim was diagnosed in 2006—and today I still know parents that are starting that same journey that I started almost 17 years ago, going out, trying to learn the science, trying to connect with researchers, walking through a process over and over and over again to try to get to a meaningful treatment for their child. I’m not a unique story, but it continues to happen over and over again. And it’s why when I learned about the Bespoke Gene Therapy Consortium, I was so interested in playing a role, doing my part to help move this forward. It’s essential that this move forward.

Daniel Levine: As someone who’s lived through a condition like this, what’s it like to see the Bespoke Gene Therapy Consortium come into being?

Sharon King: It has been a privilege to be a part of this effort, which can straighten in this pathway. I like to describe the various stakeholders in this ultra-rare space as brick masons, brick by brick. Together, we’re building a pathway to potential treatments for these very small population conditions, but we need a design. We need a roadmap that we can all follow to get to this shared destination more efficiently, a potential treatment for people like Taylor. And I believe the BGTC playbook can be this roadmap.

Daniel Levine: What do you think the potential here is to change the meaning of getting a diagnosis like the one Taylor had?

Sharon King: I think this gives families like mine hope that Jim and I didn’t have. Literally, we felt, we started with a distinct feeling of hopelessness. But I think the difference for us is we never accepted impossible. We had to believe that it was possible to move forward a treatment for kids like Taylor. And when we started funding the gene therapy for CLN1 disease, we knew at that point that it was not going to be in time for Taylor, but it was going to be in time for another family’s child. And that’s the kind of hope—you know, hope changes. You never lose hope, but sometimes it can change forms. And that’s what happened for us. We have stayed committed to this process and to making and to straightening out the path for the families that have followed us.

Daniel Levine: You also work as a patient advocate for Aldevron, part of the tools conglomerate Danaher, which is part of the BGTC. What’s it like to be involved in this program that way?

Sharon King: As an advocate and someone who’s been an advocate for 17 years since, I mean, I can put a date on it, July 24th, 2006, the day Taylor was diagnosed. I have been a patient advocate from that day forward. As an advocate, I have a unique role at Aldevron, and it’s a somewhat unexpected role given we’re not a patient facing company, but I think it underscores that shared commitment to the patient communities that our clients aim to serve. And it’s been a privilege to work with this group of innovators as they develop and manufacture the essential components for advanced therapies and those who need them, the components for therapies that as a mother and as an advocate through Taylor’s tale, I’ve been pushing for many years. So many times, I walk into our manufacturing facility, and I still have this feeling of awe about what happens in those suites knowing that. I remember early on when I first joined Aldevron, I was in Fargo on Taylor’s birthday, and I remember standing behind the windows and watching what was happening and thinking hope is made here. So, it has been such a unique perspective, and then to have the opportunity through my employer to participate in the BGTC has truly been a privilege because I’m watching full circle my advocacy journey.

Daniel Levine: Courtney, gene therapies I’d argue are deceptively simple. The idea is you take a piece of genetic code that someone’s lacking, put it inside a vector and deliver it to the patient. The idea with BGTC is to take a platform approach. Where are the bottlenecks that BGTC can address?

Courtney Silverthorn: Yeah, there’s a couple of different stages where we think that we can add something to the process. I love Sharon’s metaphor of straightening the pathway because we’ve seen different routes and side detours and mountains to climb. And so, the work that we do, I really hope, will provide that very straightforward, efficient process to move things forward. We’ve seen challenges in the manufacturing, and right now across the AAV gene therapy space manufacturing is very proprietary to individual companies. And so, everyone has a different way of manufacturing, a different way of testing the manufactured product. And it can be very challenging to transfer those processes or to start manufacturing at a new location. So, bringing some consistency to that process, we hope, will make things faster and more efficient. The other thing is that every time you do a new process, a new manufacturing run, a new manufacturing location, you have to repeat a lot of the work that you’ve already done. And so, we’re hoping that as we start to build out the IND submissions for the BGTC’s clinical portfolio, that that will start to build a knowledge base that can then be reused for other applications. One of the most wonderful things about the public-private partnership and why I don’t believe that something like the BGTC could have ever happened without the FNIH, and the structure of the public-private partnership is that we can make almost everything relative to the process of our clinical portfolio publicly available. We can share our SOPs for manufacturing testing, the methodology that we used for those tests, the acceptance criteria that we used. We can share preclinical testing protocols. How many animals do you need to use in your studies? When is it appropriate to use small animal models versus non-human primates, which can be very expensive and very time consuming to source. And we can make our regulatory submissions publicly available so that people have a step-by-step process and know exactly what type of documentation they need to submit to the FDA in their own journey. So, some of those resources that the BGTC will continue to add to the playbook as it’s updated over the next several years will really be the opportunity to inform the community on the most efficient way to move something forward without compromising safety or efficacy.

Daniel Levine: The Bespoke Gene Therapy Consortium recently published its initial regulatory playbook. What is the playbook? Who is it for and how do you expect it to be used?

Courtney Silverthorn: Yeah, this was such an exciting milestone for us and represents the work of so many subject matter experts across the consortium, between our steering committees, our sub-teams, our patient advocates, our clinical PIs. There are over 200 people contributing to the BGTC in some way. And a lot of that went into that first version of the BGTC regulatory playbook. The version that was released on February 6th, which was actually in conjunction with the 10 year anniversary celebration of the Excel Medicines Partnership program, was mostly a compilation of publicly available resources. Some added information based on our subject matter experts longstanding expertise, whether in scientific development, whether regulatory development, whether it’s the voices of the patient advocates like Sharon and others, starting to build out what we hope will be a one-stop shop resource. And so, this first version of the playbook has information about the various FDA processes and regulatory guidance. It exists in different places on the internet, but we’ve compiled a lot of that information together into a single location. It talks about the IND process and the different types of documentation that are required for an FDA submission, as well as some of the accelerated program designations that a gene therapy for a rare disease might be eligible for like an orphan drug designation or an accelerated approval process. It offers some information about how to think about designing a clinical trial for these very small patient populations. The gold standard of a double-blind placebo controlled trial with thousands of patients just doesn’t serve these communities, so looking at opportunities to leverage natural history studies or biomarkers or outcome criteria that can show that the therapy is having an effect in those small patient populations. And then it also compiles a lot of information about best practices for how to work with the patient communities as these therapies are moving forward. The FNIH has a strong commitment to the voice of the patient and patient and community engagement, and about 18 months ago, set the standard for all of our public private partnerships that we have patients with lived experience or advocacy groups or caregivers informing every step of the development process of our partnerships. But the BGTC was really the exemplar for that. We had patient groups involved in the design of the project. We have patient advocates and caregivers on our steering committee and at each of the clinical project teams, we’re also incorporating the voice of the patient there as well. So just a really robust set of resources for the community. And we think that the primary audiences for these resources are going to be smaller biotech companies, academic clinicians who have been working with a patient group for, in some cases, numbers of years, and are looking to try to bring a therapy forward for that small group of patients, foundations that are seeking fundraising for their own development of a gene therapy for a small patient population. And one of the ways that I like to think about this is training for a marathon when you really only need to run a 5K. Some of these patient populations are so small that by the time you do your phase 1 clinical trial, you might not have any other patients in the United States. But we still have standards and processes that are designed to take things all the way through the FDA process and into the market where there could be thousands or millions of patients receiving that therapy. And if you only need to think about 10 patients a year, it’s a very different type of calculus. And those are the audiences that we’re hoping to target with the playbook.

Daniel Levine: The playbook is expected to be updated over time. Is this something that’s expected to be done in real time through different additions or releases?

Courtney Silverthorn: Yeah, I think we’re expecting that it’ll be a couple of different additions or releases. This first edition was sort of our compilation of what already existed in the communities. But what I think will really make this playbook so powerful is once we have real world information through our own clinical portfolio. So, the BGTC has a clinical portfolio of eight different rare diseases that we’re taking all the way through the preclinical regulatory submission IND process and into a first-in-human clinical trial. And at each step of the way, we are standardizing the processes across these very different diseases, different routes of administration, different types of AAV delivery vehicles, but using the same methodologies, the same regulatory template structures, and really serving as a proof of concept that this streamlined pathway or pathways can work for the rare disease community. And so, as each step of that process is validated, and ultimately I think the ultimate validation would be the acceptance of multiple INDs for different clinical indications that will show us that this is a viable path forward, and then we’ll be making that information available. So, I would expect that there would probably be one release within the next year or so that will have the critical quality attributes, the things that you have to measure for your AAV vector after it’s manufactured. And that will be applied consistently across all of the BGTC products in all eight diseases, as well as maybe the first preclinical testing protocol for one of the three routes of administration. So, we’ll be developing consensus protocols for ocular diseases. We’ll be developing a consensus protocol for neurological diseases, and then a third protocol for what we call systemic diseases or diseases that would be treated through intravenous administration. And each one of those has multiple diseases associated with them so we can do the same thing two or three times in the same way and show that beyond the eight diseases in our clinical portfolio, that others can continue to use these processes going forward.

Daniel Levine: How will the FNIH evaluate the success of the program and what would constitute a success in your mind?

Courtney Silverthorn: Yeah. Well, we certainly hope that we have eight successful clinical trials and that across that clinical portfolio that we successfully treat 60 or 70 patients across those eight diseases. But I would say that if that was the only thing we did, we wouldn’t consider ourselves a success because it is really about enabling the process for not just those eight rare diseases, but for hundreds or thousands of rare diseases for potentially millions of patients. And so, I think for us, success would be that others are able to use this process, and we hope that they’ll be able to share additional data as they move forward with their own gene therapies that can continue to help validate and strengthen the BGTC processes. We start with these first eight diseases, but then if there’s eight more that follow the same process outside of the consortium and then eight more after that, it really starts to make the BGTC processes the gold standard for developing AAV gene therapy for a rare disease.

Daniel Levine: Courtney Silverthorne, vice president of Strategic Alliances and Innovation for the Foundation for the National Institutes of Health, and Sharon King, manager of Advocacy and Community engagement for Aldevron, and founder and president of Taylor’s Tale. Courtney, Sharon, thank you both for your time today.

Courtney Silverthorn: Thank you.

Sharon King: Thank you so much, Danny. It’s been a pleasure.

This transcript has been lightly 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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