The imbalance between the supply and demand for gene therapy manufacturing capacity is creating opportunities for contract development and manufacturing organizations. Forge Biologics is seeking to leverage its expertise in AAV gene therapy as a CDMO while developing its own pipeline of experimental gene therapies. We spoke to Tim Miller, co-founder and CEO of Forge Biologics, about the company’s hybrid business model, how it hopes to differentiate itself through its shared experience with its customers, and its emerging pipeline of gene therapies to treat rare diseases.

Daniel Levine: Tim, thanks for joining us.

Tim Miller: My pleasure. Thanks for having me.

Daniel Levine: We’re going to talk about gene therapy, Forge Biologics, and where Forge sits in the gene therapy continuum. Listeners may remember you as a co-founder, CEO, and chief scientific officer of Abeona Therapeutics. You left that company at the start of 2020. I’m wondering what that experience, developing gene therapies, taught you, the challenges you faced, and how it might have informed what you’re doing at Forge.

Tim Miller: Great question, Danny. It was a great experience at Abeona. We took that company from ground zero, with me as the only employee, up to almost a billion dollar market cap. There were a lot of really wonderful learning experiences that came through that. Probably one of the most important experiences was learning that the human element and the expertise that goes around the table for developing a gene therapy is one of the most critical aspects for its success. Part of the lessons that we learned was that developing something like a phase 3 cancer drug just doesn’t equate to some of the gene therapy development, manufacturing, and regulatory experience, because gene therapy is different. That was really one of the key lessons that I think came out of that experience.

Daniel Levine: People may be a bit confused when talking about Forge, which is a contract development and manufacturing organization, but also has a pipeline of gene therapies that it is developing through subsidiaries. I’d like to go through both aspects of the business, but what’s the rationale for combining these two businesses? What’s the business model?

Tim Miller: It’s interesting how we’ve seen in the gene therapy CDMO and therapeutic space, how a number of companies have adopted this hub and spoke model. This is the model where you usually have a private LLC as a holding company and you have subsidiaries that are usually C corporations. What we did, and again this is another reflection of previous experience, was to think about how we could be good stewards of manufacturing technology as one of the biggest rate limiters in the gene therapy space, but also take the expertise that we all had and use that to help not just our own pipeline, but also help a number of our colleagues. So, that’s how we started Forge as part of this hub and spoke model.

Daniel Levine: Forge just focuses on AAV gene therapies. Why AAV and do you foresee expanding into the use of other vectors down the road?

Tim Miller: AAV is the most commonly used delivery vector in gene therapy to date. It’s wonderful for delivering gene replacement strategies, particularly when there’s a single autosomal recessive gene that can fit in the packaging scheme of AAV. We wanted to start there because a lot of us had therapeutics development expertise and a lot of the leadership team had previously either built-out or done AAV manufacturing facilities. So, that’s really where we wanted to exquisitely focus on. For Forge, when we look out over the next 12 to 18 months, Forge is really well positioned to be the leader in the world for companies that focus exclusively on AAV manufacturing. For us, maybe we’ll see some expansion down the road. We’ll be in the top three for the number of bioreactors in place and liters being able to produce per year. We think about other ways that we can expand. We’ll see down the road, we’re a bit opportunistic at this point as well.

Daniel Levine: What’s the need from a manufacturing point of view? There’s been a fair bit of new capacity that’s been coming online. What’s your sense of where we are in terms of the balance between demand and the ability to satisfy that?

Tim Miller: Well, we talk a lot about how many sneezes or how many COVID vaccine injections does a particular bioreactor take. As you see more and more money dumped into this space to try to build out a greenfield or renovate an old building, expertise in AAV manufacturing and scale up to commercial has been one of the biggest rate limiters. In just the past two weeks, there’ve been a couple of articles published about how it’s great to see a lot of money being put into gene therapy manufacturing, but where is the expertise and where are you getting these people to do that? I think the field, in general, is moving towards more people getting into the CDMO manufacturing, even companies that are developing their own internal workforce to be able to manufacture their own programs. There is a balance between that but even as early as 2020, you still see some publicly available articles that’ll talk about the supply versus demand, and as CRISPR, prime editing, and base editing expand into the field, and many of them will use AAVs to deliver their technology, the demand is just not keeping up. So, that’s part of where we see our value proposition: to serve our clients and our partners in this space.

Daniel Levine: At what point in the development of an experimental gene therapy do you engage with a customer and is the expectation that Forge would manufacture clinical trial doses as well as commercial product?

Tim Miller: This is part of the fun part. Our current client base is really a bell curve. We work with customers and clients right now that are pre-series A stage, as well as multi-billion-dollar public companies that have a pipeline that they’re working on, on their own. Everyone needs process development for their programs. Everyone needs analytical development. These are two of the often overlooked value adds from a CDMO’s perspective, but we engage at all stages of the life cycle. Right now we can produce clinical trial doses and within a year we’ll be able to be commercial.

Daniel Levine: What’s the range of services Forge is offering?

Tim Miller: One of the things that differentiates Forge from a manufacturing aspect is that we offer our Blaze research production, which is a very fast turnaround. This is a way for clients to come in and get started with Forge. They can use our ignition cell line, which is a proprietary HEK 293 cell line. If you come in very early in your life cycle development, you can use that cell line and you can extend that into your toxicology grade and into your clinical grade. One of the things the regulatory agencies have focused on is bridging work. A couple of recent press releases on some public companies have talked about how, “we did some comparability work between our early stage clinical and our late stage product and, hurray, they’re comparable.” If you come with Forge now, part of that differentiation is that you can use that cell line, and it’s same process all the way through. So, it saves you time, saves you money, and gets you easier to scale.

Daniel Levine: In many ways, Forge looks more like a gene therapy company than a CDMO. Do you see that providing you with any competitive advantage as you work with customers?

Tim Miller: Absolutely. A lot of us have a very strong therapeutics background. So, it’s very easy for us to sit around a table with potential clients and say, look, we’ve been on your side of the table, we know the challenges, we know that you want great work, you want it as fast as possible, and you want to get into the queue. Of course there’s a pricing aspect as well. So, it’s not surprising looking at the leadership team that we look more like a gene therapy company than CDMO. We’re good with that because we are a gene therapy CDMO. I think that is one of our secret sauces, that really resonates with a lot of the client discussions that we have.

Daniel Levine: Let’s talk about your pipeline. You’ve only disclosed one program and listed a second preclinical program but have not identified the indication. Before we talk about the lead program, what’s the approach you’re taking to building a pipeline? What constitutes a potential gene therapy for Forge? Are you bringing programs into development from your own discovery engine or are you looking to in-license programs?

Tim Miller: Great question, and one really fun to talk about. With the teams’ deep expertise in developing gene therapy products, one of the things that we look for are things that are different or the next stage of evolution for gene therapy and building out an AAV pipeline. As you think about that, you get into things like multiple routes of administration and multiple capsids for any particular disease, because it’s our belief that is what’s going to be the best for the patient. So, more shots on goal, so to speak, that you can give to a patient for their chances to get to all the target tissues that they need to correct their disease, the better we think a potential gene therapy pipeline product.

Daniel Levine: How big a pipeline are you’re looking to build at this time? Is there some sweet spot between resources and shots on goal you’re thinking about?

Tim Miller: As we think about bringing additional programs, one of the things that we have focused on, particularly in our Krabbe program, is a bone marrow transplant plus a systemic AAV, the first of its kind in the world. It’s more of a platform about how we think about safe and efficacious dosing due to some of its immune modulation strategies. We’re looking to develop some of that on our own, or we always have the potential to do some in-licensing as we think about that. I’m super excited because we get this opportunity to look at our own manufacturing and that really takes off a big level of consideration because we can take our manufacturing and use it for our own pipeline to accelerate and reduce a lot of the costs.

Daniel Levine: Let’s talk about that lead program in Krabbe disease. This is a rare lysosomal storage disorder. For listeners not familiar with Krabbe disease, what is it?

Tim Miller: Krabbe is a leukodystrophy. We focus on the infantile and early infantile form. It’s a lysosomal storage disorder that, in these types of patients, they demyelinate a lot of their nerves. It’s very similar to a disease called spinal muscular atrophy, and unfortunately has a mortality of close to 90 percent by the age of three. We take an approach where the standard of care right now is to do a bone marrow transplant, but we add a systemic AAV using an RH10 vector to deliver. What’s important about this is the standard of care using a bone marrow transplant corrects a lot of the central nervous system pieces of the disease, but unfortunately, a lot of these kids wind up developing peripheral manifestations, so loss of ability to walk, to speak, and eventually to breathe. So, our approach has shown, and I think a number of other groups have shown, that AAV10 is the best at delivering via a systemic route for targeting the peripheral neuropathies that have developed. We’re trying to solve for a lot of those other manifestations. We’ve got on our website a bunch of dog videos that are able to show that the combination approach for this disease really is synergistic for patient benefit.

Daniel Levine: What’s the prognosis for patients today with Krabbe disease?

Tim Miller: Unfortunately, most of them will die between the ages of two and three if not before.

Daniel Levine: Are there treatment options that exist?

Tim Miller: Other than bone marrow transplant, No.

Daniel Levine: Why start with Krabbe disease? How did you come to the program?

Tim Miller: The founder of the program, Dr. Maria Escolar, is an old friend. We had worked together on some different clinical programs and she was a fan of what we were putting together at Forge and wanted to potentially bring those programs here. We had some great conversations. When you look at some of the preclinical data, I saw some things that I’d never seen before in 15 years of developing gene therapies. When we think about how you do an immune modulation and immunosuppression for the safety of the patient, this will be a new way of looking at doing gene therapy for rare disease.

Daniel Levine: Walk me through the process. What does the therapy consist of and how is it administered to a patient?

Tim Miller: We dose patients that are under a year of age. We bring them in and they go through Immuno-ablation. So, you basically treat them to get ready for a bone marrow transplant. They undergo a bone marrow transplant. We wait a couple of weeks and then we give them a systemic, through a vein in the arm, the AAV.

Daniel Levine: What’s known about this from preclinical studies to date?

Tim Miller: So, there are mouse models and dog models of the disease. When you do this combination approach, we are essentially able to almost completely correct both the peripheral and the central nervous system deficits in the animal models.

Daniel Levine: What’s the development path forward and where are you in development right now?

Tim Miller: Right now, the FDA allowed the IND to go forward. So, we’re screening and potentially enrolling patients. We’re really looking forward to sharing some data.

Daniel Levine: You’ve been successful at raising money—a total of $160 million disclosed to date. How much of that has gone into building your manufacturing facility and how much runway does that leave you to build your pipeline?

Tim Miller: I never would have thought at the beginning of 2020 that there’d be a pandemic. Trying to raise money, raising a series A and then a series B in the middle of a pandemic is certainly a new experience. I think that our vision and the team that was put together has certainly resonated with investors. A lot of that has gone into our manufacturing facility and in building out our team. We opened the company in January of 2020, we closed the series A with four people and $40 million in July of 2020, and now closing at $120 million in April, we are upwards of 90 people today and look to hire another 40 to 50 people in the next six to nine months. So, really rapid growth. More than 50 percent of the team has come from internal references, demonstrating that people like to follow good leaders and they like to follow a track record of success. We’re really well positioned, I think, going into the second half of 2021 as we all come out of the pandemic and really get ready to show some promise and watch biotech ramp it back up again.

Daniel Levine: Tim Miller, co-founder and CEO of Forge Biologics. Tim, thanks as always.

Tim Miller: Thanks again. Great talking.

 

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