All right, welcome. Hello, everyone. I'm Joe Schwartz from the Biotech Equity Research Team at Leerink Partners. It's my pleasure to host this fireside chat with PepGen. We're very pleased to have James McArthur, CEO, and Paul Streck, Executive Vice President and Head of Research and Development, with us. Perhaps we can start with a brief level set just to bring folks up to speed on the overall story here. Then we'll dive into each of the various parts and pieces.
Sure, great. No, thanks for the invitation. Paul and I are really pleased to be here to share updates with you. Obviously, this has been a big year for us so far. We announced the first data from our Myotonic Dystrophy Type 1, EDO DM1 program. Those results, in terms of correction of missplicing, which underpins and drives all of the pathology of this disease, far exceeded our expectations. We were hoping for perhaps a 3% improvement at our starting dose, a 10% improvement at our second dose. Instead, what we observed was a 12% improvement at our starting dose of 5 mg/kg, and a 29% improvement at our second dose, 10 mg/kg, after only a single dose. This level of correction of missplicing has not been seen, even with other approaches, through nine-month multi-dose clinical studies.
Given that that really drives all the pathology of this disease, we're really pleased for what it's going to show for us as we move forward with this study to higher dose levels, and as we move forward with our multiple ascending dose study, which is open, and what we can do with longer-term therapy. Very, very pleased with the safety profile, as well as pleased with the efficacy in terms of biomarker movement that we've seen to date. Our DMD program also continues to advance and will be announcing data from our 10 mg/kg cohort. That's four doses and an open-label multiple ascending dose study, where we've already reported very high levels of exon 51 skipping at lower dose levels. We anticipate this will drive higher levels of dystrophin production when we report out the 10 mg/kg data.
A very exciting year with a lot of readouts from these two programs and already the potential to set best-in-class opportunity for myotonic dystrophy.
Yeah, that's a great intro. Thanks for that, James. Maybe we can keep on that theme. How are you thinking about this data in the context of the rest of the field, the data we've seen from others? Granted, it's only a single dose. What does your analysis suggest that this could look like with longer-term dosing and higher doses, for that matter?
Yeah, first, what does this do in terms of speaking to the platform technology? Myotonic dystrophy is a disease where you've got to get the oligonucleotide into the nucleus to be able to impact the toxic foci. By demonstrating these kinds of levels of correction of missplicing, we're demonstrating very clearly that we're getting high levels of oligodelivery to the nucleus. We're also demonstrating with this novel approach that specifically targets the CUG repeat that drives the pathology of this disease, as opposed to indiscriminately binding both pathogenic and nonpathogenic DMPK transcripts, that indeed we've successfully been able to liberate MBNL1 and correct missplicing, as evidenced by our using the 22-gene splicing panel. Very pleased by those results. We've seen in our animal pharmacology that with higher doses, we see higher levels of splicing. With more doses, we see more splicing improvement.
We know from the natural history of this disease that if you go and see higher and higher levels of splicing correction, you will see higher levels and superior levels of functionality in terms of 10-meter walk-run, where we did see a trend for improvement, improvement in terms of hand grip strength, improvement in terms of ankle dorsiflexion, and to a lesser extent, vHOT. Very pleased with these results and think it could really be a game changer for patients and really create a tremendous amount of value for the people who believe in our story.
Great. You must be learning a ton as you're executing this program. What might you be doing going forward as a result of some of these learnings? Can you talk a little bit about patient enrollment? I think you had an inclusion criteria that seemed to be steering you towards sicker patients. Is that the goal going forward? Can you talk about your learnings from the data so far?
Yeah, I'll let Paul Speak to our learnings on the vHOT and our inclusion/exclusion criteria and how we're adapting to that.
Yeah, sure. We found that vHOT, or video hand opening time, which is indicative of myotonia, is highly variable. One of the things that we did in the study, in the SAD study, was to enroll patients who had more severe myotonia or a longer amount of time to open their hand up. Inevitably, it seems as though when you have a more severe patient, these patients tend to have the best ability to improve. Thus, we did see patients who were enrolled in the trial who were in the placebo arm have the most severe myotonia who showed significant improvement. Now, if we were sitting here and it was enrolled in the active arm, we'd be like, oh, this is great. Obviously, it was in the placebo arm. We see that this variability needs to be corrected.
One of the things that we're doing is we're having multiple baseline evaluations, one at screening, one at time of dosing, to ensure that we are minimizing this variability, at least with the vHOT. Certainly, in other measures that we looked at, more specifically 10-meter walk-run, we saw an improvement at 10 milligrams. Certainly directionally correct. I do think as we go up in dose, increase dose, we're looking for more of the functional improvements. The functional assessments in terms of feasibility in the SAD studies have been very fruitful.
I think it really speaks to our approach to looking across multiple outcome measures. We saw a seven-second improvement in the placebo group of vHOT, which again underpins the variability of this outcome measure. We think it's important with a robust movement of the biology of splicing that we should, in the longer-term repeat dose study, see a robust movement in terms of a multitude of functional measures.
OK. What are the benefits of seeing data from the SAD before you see the MAD? Does this allow you to calibrate off of any of your preclinical modeling, or are there other reasons to report the data in such a fashion?
Yeah, so I think we've highlighted the learnings we're taking from looking at things like vHOT and how in the repeat dose study we'll have multiple baseline measurements, which will give us a better readout with selected different groups of patients who are less prone for variability. Beyond that, we're seeing levels of splicing correction at 10 mg/kg that really surprised us, much higher than we would have anticipated, and suggest that 10 mg/kg today is a dose level that could very easily be the dose level we move forward with. We will explore the 15 mg/kg dose level and see what we see both in terms of splicing correction, outcome measures, and of course, safety. We'll probably take those learnings and use them in terms of deciding what our top dose level will be in our multiple ascending dose study.
We're very pleased with the safety profile. We have not seen any indication of kidney modulation with the single dose study, unlike what we had seen with the 51 program in our single dose study to date. We are very hopeful that as we proceed, we'll be able to identify a dose that is both highly functional and very well tolerated.
Great. How does the preclinical data that you've generated in various systems and species guide what we might be able to expect in humans in terms of safety in DM1? At some point, we'll get to the DMD program and ask about those learnings.
Yeah, so the mouse pharmacology indicated that with higher dose levels and with repeat dosing, we see greater accumulation of oligo in the tissue, greater modulation of splicing, and greater modulation of the myotonia that can be seen in the videotapes, which I've shared with many people of the mouse model. We are very hopeful that that biology will continue in humans. With higher dose levels and with repeat doses, we'll see greater splicing and greater impact on functional outcome measures as well. I think all of this, what I like is all of the directionality of this data points in the direction that we may indeed have a drug that has an opportunity to be best in class for this disease.
Have you had the chance to show the data to physicians and KOLs and get their feedback? Can you share some of that with us?
We have. Needless to say, when we disclose something publicly, we like to make sure all of our investigators have it, and so they're not reading about it through the wires. Extremely excited, I think, was really the bottom line associated with it. They were quite surprised at the level of splicing, are very optimistic that this will translate into a functional benefit. Ultimately, I think, as you alluded to earlier, raises the level of enthusiasm and comfort to enroll patients into subsequent dosing or into the multiple dose study. I think all things moving in the right direction feel very good about what the coming readouts will look like, and in a timely fashion as well, which I think is very important to us.
Yeah, perfect segue. What is the time frame that we can expect the next data from FREEDOM-DM1 and also FREEDOM2-DM1?
Yeah, so we've communicated that the 15 mg/kg single ascending dose cohort will read out second half of this year. We're looking forward to bringing that in so that we can share that data as soon as possible. That'll speak, I think, terrifically to, again, our ability to build upon both the efficacy, but also really speak about the safety profile of this drug. It was at 15 mg/kg in particular that 51 in the single dose study began to show some engagement of the kidney. We're really looking forward to those data. The multi-dose data early next year, that'll be the 5 mg/kg multiple ascending dose data set. After that, the 10 mg/kg multiple ascending dose data set.
Great. How are you thinking about continued development beyond FREEDOM2-? Assuming you see what you want to see, what would a phase three program look like?
I think certainly we'd like to duplicate as much of what we saw in a phase two program that is reliable and predictable. I do think that time is of the essence in terms of ensuring there is adequate time for patients to respond to drug, have changes in functional benefits. We'd want to see what those look like at three months. I do believe mechanistically and with the level of splicing that we have, we could see more rapid movement of some of these functional benefits. We would assess those at those times. I think we'll continue, Joe, to look at what's the most appropriate dose and potentially changing the SAD program, which can go up to 20 milligrams. Currently, the MAD also has 20 milligrams.
To modulate that and then really try to move this into registration as quickly as possible with as high a level of predictability on the functional pieces that we would hope to flush out in the MAD study at three months.
I think importantly, other companies have put forward the concept that with splicing correction of 25%, they can correlate that with benefit and are working to get regulators' buy-in to that. Obviously, if we're showing even higher levels of splicing correction, we would expect to see even higher levels of modulation of those secondary endpoints. Folks who are going down this path right now, that information will be incredibly helpful to us to design the best, fastest study we can to get to the end. This is a case where I think we won't be first, but I do believe we can be best.
OK. Other companies have emphasized neurological symptoms. What do you think about this? Is this something that you're exploring?
Yeah, so we've got a variety of patient-reported outcome measures in our studies that capture a variety of things, both functional measures of daily quality of life as well as cognitive components of it as well. We have observed oligo in the CNS. We don't know whether or not it's at functionally high enough levels that it'll modulate those. But we believe with our ability to target so many different organs with the EDO technology, that we'll be able to impact many things that really fundamentally change a patient's life, their ability to put on pants, to make the bed, to be able to swallow food, the cardiac manifestations that result in the loss of perhaps 10 or more years of life from patients. Really profound aspects of this disease which shape a patient's life.
What is it about the EDO technology do you think that's enabling these potential best-in-class features? Can you talk to us a little bit about what it is and where it comes from, how it was designed?
Sure. When I originally began looking at the technology, it had been designed to allow better uptake of oligos into cells. As we've really dove into the science, we've realized it's not simply getting into the cells that's important. It's important that we be able to get out of the endosome. The endosome is where all oligos go, no matter what technology is used to go and deliver them. Most of these technologies essentially disassociate with the oligo in the endosome, and the oligo is left to its own devices to be able to get out of the endosome. That's not the case with EDO. With EDO, it stays conjugated to the oligo and allows better exiting of the endosome, which gives it access to the cytoplasm and ultimately to the nucleus.
We've been able to demonstrate in cells, in non-human primates, and in healthy volunteers that we can achieve very high levels of nuclear delivery of oligo. That is critical for diseases like DMD and particularly DM1, where the toxic foci are present only in the nucleus. That is where you've got to get the drug to be able to liberate MBNL1. That is where you need to be able to correct missplicing. That is where you begin to change this disease.
OK. Maybe we can touch on DMD a bit. As a segue to that, why do you think the tolerability has been or it looks better in DM1 relative to what we've seen in DMD so far?
I'll speak to the drug, and then Paul can speak to the patient component of that question. These are two different drugs. Although we're using the same EDO technology and same backbone chemistry, the oligos are different. The cargos are different. We have a smaller oligo in our DM1 program, and it has a very different GC content. We think both of those together may be responsible for what is a differentiated safety profile both in non-human primates and to date in our single dose study in humans as well. We believe that potentially a superior safety profile than what we saw with our 51 program, combined with this very high level of splicing correction at our starting doses, is what gives us an opportunity to really move the needle for patients and create value here.
Yeah, I think the DMD patient from a renal perspective certainly has a number of insults going on. DMD patients are classically on steroids long term. They many times receive bisphosphonates for their bone metabolic health. They're on an ACE inhibitor and many times kept dehydrated simply because caretakers don't want to have to take them to the bathroom, especially when they're immobilized. Certainly a number of things going on from a kidney perspective that cause them to be a bit more fragile than the DM1 patient.
OK. What is the latest status of the CONNECT1 study currently?
CONNECT1 is fully enrolled with four patients. We've initiated protocol amendments for these patients. We will have guided that we will have a readout of these individuals second half of this year, the earlier half of the second half as opposed to the latter half. We'll certainly be looking for dystrophin levels from a safety profile perspective, how that looks. We're pleased in terms of the cohort because the AEs that we've seen around hypomagnesemia have been reversible, treatable with relatively low doses of oral magnesium. I feel good about that aspect of it. All in all, I'm excited to see what the dystrophin looks like because ultimately, I think if we see considerably higher dystrophin levels, the benefit risk obviously will change for these patients. Excited, optimistic about that. Look for that discussion coming up in the next few months, hopefully.
Great. I know that you recently announced a voluntary pause of enrollment in CONNECT2. Why was that?
I mean, first and foremost, we think that as Paul mentioned, the CONNECT1 results, which will be available relatively shortly, will be incredibly informative. It'll be informative in terms of where we go with the CONNECT2 study. It'll be informative in terms of our addressing the FDA clinical hold on the CONNECT2 program in the United States. It'll really inform us about what we can do for patients with Duchenne muscular dystrophy amenable to an exon 51 skipping approach. It also allows us as a company to be hyper-focused on generating those next data in DM1, which we've talked about already, appreciating that this is an opportunity for us to really set a new standard in terms of treatment of patients. We want to do everything we can to drive that forward.
OK. Can we talk about safety a little bit more in terms of the hypomagnesemia that you've seen as well as the kidney function measurements? How are your signals different from what's been seen with other peptide conjugates?
Sure. I think first and foremost that the level of lower magnesium that we're seeing is just below the lower limit of normal. It's reversible with oral intervention. That always makes me feel a great comfort. Certainly, we're only seeing a single electrolyte disturbance, not multiple electrolyte disturbances such as potassium or other things. From an eGFR perspective, we had one patient in the open label extension that had a decreasing GFR. We dose-paused them in that. Kidney function has been recovering. We're considering re-challenging the individual when they get back to baseline. I would say that, A, the doses that we're looking at are considerably lower. B, the severity of the AEs are much milder. Certainly, they're reversible and don't seem to be recurrent.
Yeah, very helpful. Can you help us understand there was some suggestion that eGFR was decreased in a patient, but then as it turns out, when they were tested via a more rigorous manner, it suggested that there was no perturbation there?
Correct. Correct.
What happened there?
GFRs tend to be estimated with variables that are measured in the blood. The estimated GFR was decreasing. We stopped the drug. To get a real measure of what the GFR was, we did a nuclear medicine scan to evaluate what that number was. That was within normal limits. We did not have a baseline to compare it to, but nevertheless, there was a discrepancy between the estimated and the actual measured GFR in the patient. You cannot look at creatinine in these patients simply because of the muscle aspect of it. Really just trying to hash out what is the best way to ensure that we have an accurate measure of what is going on from a renal perspective.
You are correct. The calculated measurement may be a reflection of the disease that Paul's already talked about, whereas the direct measurement by nuclear scan indicated they were in the normal range.
Right. Yeah, super interesting. Thank you for that clarification. Back to the efficacy or potential efficacy profile, what would you hope to see at 10 milligrams that would suggest that there's a good therapeutic index risk-benefit for this program?
Yeah, I mean, we'll look at the totality of data, both the safety data as well as the dystrophin production data. We saw levels of exon 51 skip transcript at 5 mg/kg after three months that a competing technology achieved at a twofold higher dose and twice as long dosing. That's what gives us great hope that indeed our dystrophin number may be considerably higher than what people are expecting. That'd be a terrific result for ourselves and for certainly patients. We'll look at all of that data together and decide what's best for the development of this drug.
OK, great. I guess anything else that I did not ask you that we should be thinking about?
I think one of the interesting things is there's been a consistency of this data, really high levels of exon 51 skipping in DMD patients, extraordinarily high levels of nuclear delivery in healthy volunteers, very high levels of correction of splicing in DM1 patients. It really speaks to the profound nature of this platform technology to go across multiple diseases. We have other applications that we are looking at in our research portfolio as well. We look forward to updating folks on where else we can take this technology and potentially create again best-in-class drugs that really move patient care forward.
Great. Thank you so much for the update today. We look forward to following the continued progress.
Great. Thank you.