Good afternoon everyone and thanks for joining the REGENXBIO session. Our pleasure always to have Curran Simpson, CEO, Steve Pakola, CMO, and now Mitchell Chan, CFO. Yes, and I think we come at a time when gene therapy seems to have come back to a certain degree in favor, although the FDA is certainly throwing a wrench in the works for some people. Still, I think there's some increasing optimism, let's just say, for gene therapy. I guess in that vein, I think it's fair to ask you the question, what sets REGENXBIO apart from, I would say, some of the other companies in the space who've seen a little bit more volatility and hits and misses, and maybe you can just talk about how you're standing in this space.
Yeah, I think there's a benefit to being. We've been doing this for 15 years and so gene therapy as a field I think has continued to evolve. I think the area I would highlight is immune suppression. I can remember only seven or eight years ago we weren't anywhere near as advanced as we are now in terms of how to manage delivery of AAV. With the near term focus on safety for gene therapy, I think we've spent a lot of time doing really methodical, careful, phase I/ II studies that allowed us to learn and benefit. Now we're applying what we learned into the pivotal programs. I just think the probability of success we feel is very high because of that homework we did early.
You also have quite a manufacturing capacity already well established. Maybe talk about how that sets you apart from the others.
Sure, yeah. We are well through BLA review for the Hunter program and as part of that in the summer we had an FDA inspection, five inspectors, five days, the normal routine. I think for a brand new facility and effectively a brand new technology, which is I think a more modern manufacturing capability, suspension bioreactor process. We got out of the audit with no observations, which not many companies can boast about, which we do a little bit. More importantly, that's the anchor for these late stage readouts that we have. We've already got drug manufactured and in vials for the Hunter program ready to hopefully get a label on them. It's the core of, I think, our Duchenne program as well to have really high yielding processes. The process for Duchenne looks very similar to what we just were audited on in Hunter.
In a way it de-risks any CMC issues from those programs. That was a decision we took four years ago. I think you never know how early you should build that capability. It seems either too early sometimes or too late in other cases. I think we got it just about right in terms of where it fits in our development.
Can you just review the capacity that you have? Is this for all the programs or just the rare disease programs at this point?
Yeah, we can manufacture for all of our program. So we are the primary supplier for the retina program with AbbVie for bulk drug and then for Duchenne and for the Hunter program. All are made in Rockville and we actually have an identical second train that we can activate to expand our capacity further if we need to. 2,500 doses a year for Duchenne and I think something closer to 100,000 doses a year for the retina programs. Obviously much lower vector concentration. AbbVie manages the fill finish at a site that they control for the retina program. Long story short, capacity is absolutely in hand, I would say for the next four to five years. We can obviously expand that if we choose to.
Just for everyone, to be clear, you're in three phase III programs if not filed for one program. All of those programs were studied with the commercial drug that you're going to be using?
Yeah. We were able to move quickly enough in all three programs to a commercial level process that in each of the pivotals that material has been used. Product profile in our pivotal programs will be identical to what is seen in the commercial setting, which reduces, again, our goal has been to reduce risk associated with CMC from day one. I think about half the CRLs that were issued are due to CMC and that looks like something that so far we've navigated well.
That's great. Speaking of reducing risk, let's talk about the biggest risk component right now, which is a little bit out of your control, but I guess maybe you have a little bit more of a front row seat to how the FDA is handling gene therapy, given some of the developments in the space. It has been a bit of a roller coaster comparing or approving drugs on natural history. Presumably you can do it for these very rare conditions, but we're seeing that perhaps in some cases you can't. If you could go into that with us a little bit and tell us why you think your situation is different.
Sure. I'll let Steve comment a bit on the protocol design for Duchenne. I think what we're seeing in real time with the Hunter program is a pretty straightforward review. As you know, that study as well does not include a placebo arm. We haven't had any questions regarding the design of the study. One thing that I think has changed that we were prepared for from the beginning. We've always known for a program that uses a surrogate biomarker that clinical data supporting that would be required, not a full data set, or else you're doing a traditional approval. By planning ahead for that, we've been able to supply FDA to show the correlation between the two. Maybe specifically on the Duchenne program, you want to talk about the natural history control scheme.
I think one of the key things writ large, even outside this particular indication, of course, is what you prospectively say you're going to do. I think that's an important aspect when you think of the different programs. For both 121 for Hunter and also 202 for Duchenne, the plans that we put forward have stayed the same. Current described the 121 aspect. On 202, we're utilizing external match controls. I think this is something. There's a benefit within the Duchenne space of recognizing that baseline age and baseline function are critical predictors of how patients are going to do. You can really get a better sense of, well, is treatment having an effect if you can match very closely based on age and function from large databases. That's what we've accumulated.
It also gives us the perspective or context of what's been seen previously with Elevidys, for example, using that approach. There's also the ability to do sensitivity analyses with different ways of doing that type of exact matching. A totally different approach is using this recognized cTAP modeling to compare to what you're seeing with the boys that you treat with your product. We've presented data from our phase I/II study where at both the lower dose and also the higher pivotal dose, we're seeing real improvements on all these different ways of looking at how the boys are doing. We've seen this across the age range.
I think what's been most notable is in the older boys, so the eight and older, where traditionally we know with Elevidys and other gene therapies in ambulatory boys that age, you don't get very good or consistent microdystrophin expression. Then maybe not surprisingly, you don't see functional benefits. What we're seeing is not only stabilization in those older boys, but actual improvements. The separation from natural history is even more dramatic. Going forward, how is this all going to be looked at? I think part of the aspect is, what is the magnitude and consistency of what you're actually seeing compared to a methodical, prospectively defined approach?
We're excited at the fact that we just completed our epithelial enrollment in the Duchenne program in one and above boys, where we're going to have the primary endpoint, microdystrophin, three month readout in early Q2 of next year and also have available whatever patients we have available with clean data, with 12 month functional data. We feel we're in a strong position to hit our primary endpoint, but also have additional functional data to show that correlation that we'll need.
Okay, before we get too much in the weeds on DMD, I just want to go back to MPS. This is going to be the first gene therapy for Hunter's disease and it's in a market that is completely served by enzyme replacement therapy. Even though there is an enzyme replacement therapy that's presumably in development that could cross the blood brain barrier, you have the potential to potentially go in there and disrupt it. Though Denali is sitting at a $3 billion valuation, you guys are sitting around a $500 million-$600 million valuation. I guess how should we think about this disconnect, number one. And number two, how do you think this market evolves with some of the development products that are coming in and how gene therapy can disrupt that? I know that DMD, there is a high desire for gene therapy.
What is the Hunter market like? It's much smaller, but clearly still meaningful as far as a size of market for a product.
Yeah, there's roughly 500 patients in the prevalent pool and on incidence, that's roughly 50 per year. It is ultra rare. I think the one area that will be distinctly different with a gene therapy being offered is it's a one and done treatment. We have patients that are out several years now showing very durable effect. The burden of treatment with enzyme replacement therapy is going to an infusion center once a week for several hours. As a parent, that is a huge toll for the caregivers to manage. I think that we will make a significant inroad into the market based upon dramatically reducing the burden of care and, more importantly, the element that we didn't necessarily know would occur. We were always convinced the CNS manifestation of the disease would be addressed by the treatment.
In addition to that, oddly, because we treated patients in Brazil where ERT was not available, we also saw they were getting a systemic benefit. So 80% of the patients treated in the pivotal are able to stay off of ERT. I think we really have something that's going to be very compelling. This is what we hear from the patient advocacy groups. They've just been waiting. There's an urgency on their end, you know, to get us through the finish line and to have options available. We're happy to see multiple options come into the market, but we feel like we have a good proposition.
How strong is that advocacy group?
Really strong. I think probably .
Not DMD strong, maybe.
Yeah, no, the MPS Society there are incredible. Where are the patients? That's one of the first questions. There's very strong patient registries available for MPS, so it's actually including now newborn screening coming into play and helping identify them early is just when we really want to treat. I think locating the patients and having centers available to do the treatment, which is a sophisticated methodology, we know where those centers are. We've already done our clinical work there, and they've handled commercial product before. This is, I think, going to be a great first program to launch. I think we know where the patients are and we have the support of the advocacy groups.
Is there a warehouse of patients waiting for treatment?
Oh, yes, absolutely.
As far as the age range that you study, you studied very young populations below five years, which was typically seen with ERT. You are up to two years old, I think.
Yes.
Once they have the newborn screening, that pool of patients should be pretty readily available.
Yes.
Okay. All right, great. Okay, back to the DMD program. Obviously you've completed enrollment. That's excellent. Right now, what are some of the characteristics, clinical characteristics, about your program that gives you the greatest confidence at this stage?
Sure. I kind of hearken back to what Curran mentioned about all the careful work we did up front that ultimately is leading to what we're seeing in terms of clinical characterization. We really, methodically, from all the 15 years of leadership in this space, took into account optimizing the construction, number one. It was very important for us to make this as close to naturally occurring dystrophin as possible. The key aspect there is inclusion of the C terminal domain. We showed preclinically that that makes a difference, that constructs with the C terminal domain have better outcomes in DMD animal models than constructs that do not. That was number one. Number two, it is not just the molecule, it is the actual overall product.
Under Curran's leadership from a very early stage, we wanted to have state-of-the-art production suspension cell, not only high yield, but high purity, importantly, particularly in a space like systemic gene therapy where there's such a high viral load. We have an optimized construct, but also highest purity in the field with over 80% full capsid. Lastly, as Curran mentioned as well, careful immune suppression regimen. We started out with what others are learning over time. Unfortunately, given some of the events that have happened in the space to really, right from the beginning, target what are the really detrimental side effects that can happen. The two main buckets are complement activation and the later adaptive immunity T cell, B cell response, leading to such adverse outcomes like liver injury and unfortunately, liver failure.
To address those in a targeted fashion, right from the initial protocol, we included eculizumab, a complement inhibitor, for just a couple weeks and sirolimus for two months with a one month taper in addition to the standard steroid regimen that's used in these gene therapy trials. What we're seeing with this constellation in our phase I/II study is excellent safety. We have no SAEs, no adverse events of special interest, and most notably that is zero liver injury. Although it's just phase I/II, it's 13 patients with existing gene therapy, we know that that rate is 40% liver injury. There's already differentiation in terms of that with Elevidys, for example, which also gives us more confidence about preventing other more serious events.
We also see zero thrombocytopenia, which we think is potentially due to the constellation of the three-legged stool of characteristics that I described, which is a finding that's seen with other programs. Given these good results and the feasibility of applying this regimen, the investigators are very happy with this approach. I've talked about safety, but safety directly links to efficacy in that it's because we pulled all these things together that allowed us to go to what is generally thought of as a target dose to get to 2e14 vector genome per kg. We're the only ones who've been able to get to that. We think a big component of that is all these safety aspects, where we really took that into account right from the beginning.
The construct aspect and some of these other aspects are translating into efficacy signals already in the phase I/II . First, the whole goal is you want to get a functioning microdystrophin and you want that expressed. What we see, very good and robust and consistent expression across the age range. Starting with that biomarker aspect, you have to take age into account when you think of microdystrophin expression, since the younger boys, not surprisingly, can have higher microdystrophin expression because of the healthier muscle. Then over older ages 8 and above, it is much harder to get good gene expression. For example, in 8 and above ambulatory boys treated with Elevidys, it is low double digits, 11-12%. I think on average we are seeing consistently higher microdystrophin levels. Most notably in the 8 and above we see on average 40% microdystrophin.
On that aspect we're very happy. What really matters is that translating into functional benefit. That's where we're seeing. We've shown results in the dose level one and also in the pivotal study with four boys across the board. We're seeing the patients are doing better on the functional assessment. On the different ways of comparing to external natural history that I described, the boys are doing better than you would have expected them to do based on these comparisons. They're also doing better based on different ways of measuring function. The NSAA and also the time function test, we went in expecting NSAA, crude test, it's not as sensitive, maybe that won't show as much. Actually we're seeing very good response on NSAA, including in those eight and above boys that are the hardest to treat.
All in all, this just has us very excited to go into having pivotal top line results in early Q2.
That's great. Just one more question on the point of safety. The prophylaxis that you use is for a set period of time when some of these safety issues come up. Obviously it's a one and done thing. Does it usually show up within months, a year, two years? How do you get comfortable with that safety issue?
Yeah, that's a great point and we know a lot about that also based on what the mechanism of the side effects are. For example, complement mediated adverse events tend to occur in the first couple weeks. You kind of have a peak in complement activation generally with gene therapy as early as five days. If you get through those first couple weeks without any issues, you pass that stage. The liver injury and some of the other adaptive cellular based responses tend to occur more in the six week to eight week to up to three month period. The nice thing as far as monitoring and characterizing safety, if you get through that time window, you have a very good sense that you've mitigated against those two categories of events.
That also has us excited about the top line data because we'll have at least three month follow up for all the boys in the pivotal study because the primary endpoint's three month microdystrophin. By definition we'll also have the safety data of at least that long for all the boys, which we'll be able to disclose at that time.
Yeah, and I guess despite the drama that occurred with Elevidys, it seems that the interest in DMD for gene therapy has not waned, given that you pretty rapidly enrolled your study ahead of schedule. Would you say that that's characterized as correctly?
Yeah, I think just as you said, we earlier were projecting out to late this year and we brought it in. The enrollment did ramp up, the interest ramped up and in part because of various reasons we did this, but certainly the ability to keep treating patients with open centers. We just continued enrolling into our confirmatory study.
Right.
As soon as we completed enrollment in the pivotal, we are seeing that increased interest and I think the more data we come out with on safety and efficacy is just helping the community recognize potential differentiation that may exist here.
Yeah.
Some of the sites that we're dosing at clinically now haven't previously or have discontinued dosing the commercial products. I do think that speaks to interest in our program and potential for differentiation.
That's interesting to know that. Speaking of interest, I want to move to 314 for wet AMD really quickly because gene therapy for wet AMD has suddenly gained a little bit more interest from larger strategics. Obviously we saw the Adverum takeout, we saw 4DMT in the Otsuka licensing. You obviously had a very big partner or have a very big partner in AbbVie. Yet the investor community still does not believe wet AMD is a market. What do they know, what do you know, and what do we all have wrong? Maybe you can just characterize it like that, set the stage here.
I think I have to start with thanking everyone for their patience. We ran the two largest gene therapy trials that have ever been conducted. That was something that we felt strong about, powering the study the way we did, having two doses which helps de-risk the outcome, I think. AbbVie has been investing for the last three to four years heavily in this. It does take a long time to enroll those types of studies. Here we are, we finally have a stake in the ground. Finished enrollment in September and we're really excited that we'll have top line data on the program at the end of next year. I think AbbVie is continuing to invest not just in subretinal, but in suprachoroidal.
I think what we're differentiated on and why there's enthusiasm around our program is this demonstrated safety of subretinal administration and efficacy. We have a nice therapeutic window to operate in where we're continuing to show long term results that are really what people want, to not go and get their eye injected every month or two months, whatever the new interval is. I think on top of it, people are seeing new developments in ocular therapy changing what's considered current practice. I think people felt like for years the current practice or the prior practice with Eylea and Lucentis was impenetrable. Now we're seeing new components come into the market and so there's, I think, more receptiveness that gene therapy could disrupt even further that.
You're obviously speaking to Vabysmo and the Port and all of those different developments. Okay, maybe we can just talk on one component that investors have had a hard time wrapping their heads around, which is the subretinal versus intravitreal. I would say the street sees it as a big stumbling block to commercializability. How do you see it? How do retinal specialists see it? Maybe you can just give us a little color there.
Yeah, Steve, you might want to reflect on ASRS.
Yeah. Even before these recent deals in this space, as you know, the annual ASRS PAT survey of I think it's close to 1,000 retina specialists now asks a lot of intriguing questions each year. One of them this year was of all the different pipeline approaches out there, what are you most excited about? Half of the respondents, way more than any other category, said gene therapy.
Was this specific to you or a specific gene therapy period.
Gene therapy in general, with the other categories being tyrosine kinase inhibitors and some other aspects. I think that speaks to this concept of the one time treatment option that is more than an incremental benefit, which, while important, and the market has proved it's important with things like Vabysmo and high dose Eylea, and hopefully tyrosine kinase inhibitors will be another. They're still incremental and they still mean injections for the rest of your life. I think that's why there's so much interest in gene therapy now for us. I think why AbbVie came in on this and is bullish and advancing both subretinal and suprachoroidal.
Of course with suprachoroidal diabetic retinopathy even going into pivotal first half of next year is both of these have the advantage of being compartmentalized local delivery, so you do not have the same safety issues that have plagued other programs, specifically immune mediated inflammation and the retina specialist. These are surgeons who like doing surgery and do a lot more complicated things than a subretinal bleb or in-office suprachoroidal injection. We have been able to scale this with the largest studies ever done in terms of subretinal and suprachoroidal with a lot of experience in the community giving that injection. We are not seeing any barrier in terms of being able to go into these areas and obviously neither is AbbVie.
Okay Mitchell, I didn't forget you, but I keep hearing the largest gene therapy studies ever conducted. Why don't you tell us about how this is being paid for and maybe you can talk about some of those sources of cash that are coming in that are almost as sizable as your market cap.
Great question. These studies are fully enrolled as we speak and we're very fortunate to have a great partner with AbbVie. Our balance sheet will get us into. The early parts of 2027, but that's not including any non-dilutive financing optionalities which includes a monetization of the PRV. For example, as well as the DR Milestone which we're expecting to receive $100 million from AbbVie as well, with just those two as an example. That will get us into the early parts of 2028 which is well past. Data readout and well into commercial launch f or some of these products.
The milestones that you get from an approval in MPS are also.
Yeah, we haven't disclosed publicly the exact amount, but we are eligible to receive i ncremental regulatory milestones from NS Pharma for o ur MPS program as well.
Just to be clear, market cap of $600 million, about $350 million in non-dilutive finance and coming and you still have your cash and you have other milestones coming. I just thought I'd level set that for you guys. For anyone who's interested in a good value play with lots of catalysts, this is it. We're totally out of time and I think that's a good place.