Gene Therapy for Rare and Prevalent Conditions: ARM Studios Interview with Curran Simpson

Sure. Yeah, Ken was CEO for REGENXBIO for 15 years. We started out early on, literally the origins of the company, we were at Jim Wilson's lab up in Pennsylvania. Initially we started out as a licensing organization. The license, for example, for the first gene therapy ever approved, Zolgensma, originated out of our technology. About six or seven years into that process, the decision was taken that rather than license out technologies, and the intent was to put AAV8 and AAV9 into the hands of as many developers as we could, why don't we start internally developing programs? That sort of began the process for what now are late-stage programs, many of which are moving into Phase 3, and one of which next year may be a commercial program. So we're real excited about that.

Yeah, roughly speaking. The RGX-314 program is partnered with AbbVie, and we're in the process of enrolling two global studies for the pivotal program. The number of patients is well over a thousand combined for those two studies, so probably the largest ongoing gene therapy study worldwide. And 2026 is the targeted date for the filing. We'll expect next year to be able to talk about closing out enrollment, and then there's a year from last patient in to when we'll have last patient last visit.

Yeah, we have made really good progress in the last 18 months. We started Phase 1/2 only about 18 months ago. Initially we wanted to demonstrate that we could get to what we felt from our preclinical data would be our pivotal dose, which is 2E14 per kilogram of patient weight. We were able to safely dose escalate up to what we call dose level two, which is also now the pivotal dose, within about six months, dosing just a few patients. One of the things that predicates the whole program is there's a differentiation aspect to our construct. The microdystrophin we're producing has what's called the CT domain, which is different from other constructs in development but more like full-length dystrophin. Our hope is that that will result not only in high levels of microdystrophin expression, which we've already shown in the clinic, but obviously functional benefit to the patients. I think the need in general for Duchenne is there has to be convincing both functional data and durability shown for this to be a growing therapy in the field. But we're real excited. We think the Elevidys approval was great for the sector and showed a lot of flexibility on the part of FDA, and we intend to leverage the accelerated approval pathway for our program.

Yes. I think the combination of absolutely clear effect, meaning the children dosed in the past really had poor outcomes, and Zolgensma was the first one where literally the patients' lives were extended significantly through the therapy. I think that the combination of unmet need, safe administration, a good safety profile for the drug, and then followed by ultimately really positive efficacy — if you have that combination, you're going to have a successful program. In gene therapy, where programs have struggled is where there's an existing therapy available that does meet the need, even if it's inconvenient. For example, on RGX-314, our ocular program, that's what we have to wrestle with as we're doing development: is there an iterative improvement with an ocular treatment one time that's going to supersede things like Lucentis and Eylea? The feeling we get talking with investigators looking at our data is that there's a real need there. We have investigators come into the site and talk to us about patients — some of their patients they don't see for six months, a year, they go to Florida, they're not getting treated, they start to lose vision, then there's a rebound treatment applied. Those type of patients are a perfect fit for gene therapy. So we're real excited about that.

Yeah, I feel really strongly about the opportunity to be an ambassador for GROW. It's been, I think, five years in the making. I've seen so many of the candidates that are selected and do internships. The real end game for this, I think, is to diversify our workforce, to bring new ideas into organizations, and to enrich the résumés that we receive every single day to ensure that there's a diverse population applying for new positions. The kids that we bring in are brilliant. If you meet any of them, you're going to instantly come away with an impression of, 'Wow, I feel really good having this person get the exposure to our field.' They're going to be motivated to come back. I know a number of the people selected for the GROW program have then gone on to work for that company or another one within the network. So I just think it's a great program, and we see it in the number of applications we get and the amount of interest we get from the sector.

Appreciate it. Appreciate it.