Good day and welcome to the FREEDOM- DM1, 5, and 10 mg per kg Clinical Data Update call. Today's conference is being recorded. At this time, I would like to turn the conference over to David Bora. Please go ahead.
Good morning. I'm David Bora, Head of Investor Relations at PepGen. Thank you for joining today's call to discuss results from our ongoing FREEDOM Phase I study of PGN-EDODM1 in patients with myotonic dystrophy type 1, or DM1. Today, we issued a press release reviewing data from the study, which you can find on our website. Before we begin, I'd like to remind everyone that we'll be making forward-looking statements today that are subject to the safe harbor provisions provided under the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from these forward-looking statements as a result of various important factors, including those discussed in the risk factors section of our Form 10-K, which was filed today. These statements represent our views as of today's date, and we disclaim any obligation to update these statements. On today's call will be Dr.
James McArthur, President and CEO of PepGen, Dr. Paul Streck, Head of R&D at PepGen, and Dr. Michelle Mellion, Chief Medical Officer of PepGen. Dr. McArthur will lead off with key takeaways from the data, along with an overview of DM1 and our EDO platform. Dr. Streck will follow with a description of the FREEDOM clinical trial design and a review of the clinical data from the 5 and 10 milligram per kilogram cohorts. We will then hand the call back to Dr. McArthur for closing remarks. The operator will then open up the call for Q&A, where Doctors McArthur, Streck, and Mellion will be available to answer questions. At this time, I'd like to hand the call over to James. James?
Thanks, Dave, and thanks to everyone dialing into the call. This morning, we reported encouraging initial results from our placebo-controlled, single-dose FREEDOM study with PGN-EDODM1 in patients with myotonic dystrophy type 1. Before we review the results, though, I want to briefly mention we also issued Q4 results and filed our 2024 10-K this morning. If anyone has questions regarding the Q4 results, our CFO, Noel Donnelly, will be available during the question-and-answer portion of the call. We're very pleased to report that we saw a favorable emerging safety profile of PGN-EDODM1 at 5 and 10 mg per kg in DM1 patients, where the majority of treatment-related adverse events were either mild or moderate in severity, and all treatment-emergent adverse events were reversible, strengthening our conviction of the potential of our technology to improve the lives of patients as we advance to higher and multiple doses.
Notably, we saw an extremely robust level of mean splicing correction using the 22-gene panel in the 10 mg per kg of 29% following a single dose. This level of splicing correction is higher than those reported with other modalities following multiple treatment doses over longer treatment periods of up to nine months in other DM1 clinical trials. Moreover, we were pleased to see clear dose-dependent responses across multiple measures between our 5 mg per kg and 10 mg per kg dose cohorts. Missplicing is the underlying cause of DM1, and we believe that greater splicing correction has the potential to lead to significant patient benefits. We look forward to reporting the results from our ongoing FREEDOM 2 clinical study, where patients are receiving multiple doses of PGN-EDODM1 over a longer treatment period.
At PepGen, we are dedicated to developing therapies that may one day transform the lives of people living with devastating neuromuscular and neurological diseases. People like Jubo and his family who motivate us to come to work every single day. There is a great need for better treatments for DM1. There are estimated to be over 110,000 people living with DM1 in the US and EU. DM1 is a devastating disease driven by missplicing, which is caused by a mutation in the DMPK gene. Symptoms vary but can include myotonia, muscle weakness, cardiac arrhythmias, loss of lung function, and fatigue. We are excited about today's results because we believe we have a real opportunity to improve the lives of Jubo, his family, and other DM1 patients. Missplicing is the known cause of DM1.
In the schematic on the left in the healthy individual cell, you can see free MBNL1 proteins in the nucleus available to mediate the splicing of RNA exons together to create mature mRNAs that can be read and translated into proteins. On the right, in DM1 patient cells, the MBNL1 proteins are trapped by toxic CUG repeat DMPK foci in the nucleus. This prevents normal splicing of mRNAs and leads to abnormal protein production. Our blocking approach is different from some others in the DM1 space, whose mechanism is focused on indiscriminately degrading DMPK. Approximately half of a DM1 patient's DMPK mRNA is normal and does not contribute to the disease and therefore, in an ideal world, would not be degraded. Our approach targets the other 50%, the pathogenic DMPK. We are not wasting drugs on binding and degrading the healthy DMPK RNA.
Specifically, we are focused only on the pathogenic CUG repeat expansion in the DMPK RNA. This is illustrated on the next slide. As I mentioned before, in DM1 patients, these expanded CUG repeats in the DMPK RNA form stem loops trapping MBNL1 proteins, which are crucial for normal splicing. When proteins like MBNL1 are trapped, this leads to missplicing. On the right, you get a sense of how PGN-EDODM1 may work to bind to the CUG repeat opening stem loops. This liberates MBNL1, which should lead to splicing correction. The results we're reporting today further strengthen our confidence in the potential of our EDO platform, as we believe they demonstrate our ability to deliver therapeutic oligonucleotides at meaningful levels into the nucleus of cells in patients with DM1.
As you can see on this slide, there is a clear contrast between naked oligonucleotide on the left, unable to enter the blue stained nucleus of a DM1 patient cell, and PGN-EDODM1, an oligonucleotide conjugated to our EDO technology, which is able to efficiently deliver drug to the nucleus. We believe this ability to deliver therapeutic oligonucleotides to the nucleus at these levels is unique to PepGen and has the potential to lead to fundamental improvements in the treatment of DM1 as well as other neuromuscular diseases. It's now my pleasure to hand the call over to Dr. Paul Streck, PepGen's Head of R&D, to review the FREEDOM clinical trial design and clinical data. Paul?
Thank you, James. It's a privilege to discuss this program and especially these highly promising clinical data. FREEDOM is a randomized placebo-controlled single ascending dose study.
Today, we are reporting on the 5 and 10 milligram per kilogram dose cohorts, with the 15 milligram per kilogram dose cohort expected to read out in the second half of this year. This study is taking place in the U.S., Canada, and the U.K. Baseline characteristics among the DM1 patients in the study are mostly similar across placebo and the two dose groups. There is a notable difference in the baseline BHOT in the placebo group, which is higher than either of the other two baseline BHOT numbers. It is also worth mentioning that the 10 milligram per kilogram baseline splicing index was lower than the placebo and the 5 milligram per kilogram cohorts, indicating that the 10 milligram per kilogram cohort had a slightly more moderate splicing index at baseline. There is no evidence that these baseline differences in splicing have an impact on splicing outcomes.
Overall, we believe PGN-EDODM1 has a favorable emerging safety profile based on the results from the first two cohorts in the FREEDOM study. As you can see, most adverse events were mild or moderate in severity. Importantly, there were no adverse events related to electrolytes or renal biomarkers. There was one treatment-related serious adverse event. The patient received a prohibited medication in the morning with a known AE profile that includes abdominal pain and was later dosed that day and subsequently experienced severe abdominal pain. I should also point out that one of the patients had a biopsy that resulted in a pseudoaneurysm and, as a result, inadequate tissue was obtained for use in the study analysis. This slide shows creatinine levels following dosing with PGN-EDODM1 in the FREEDOM study.
As you can see, following treatment with PGN-EDODM1, creatinine levels for both dose cohorts were at normal levels. All patients in both cohorts remained below the upper limit of normal as well. The dose-dependent and substantial increase that you can see here in muscle tissue concentration parallels the dose-dependent increases we saw in splicing correction. Specifically, we saw a greater than twofold increase in muscle tissue concentration by doubling the dose of PGN-EDODM1. On slide 17, we're showing our mean splicing correction numbers compared to placebo. 12% improvement in the 5 milligram per kilogram dose cohort and 29% improvement in the 10 milligram per kilogram dose cohort, while placebo increased or, in other words, worsened by about 7%. We're extremely pleased with these numbers.
It's worth noting that the 10 milligram per kilogram dose cohort, we believe this is the highest splicing correction level ever reported from a single dose study and greater than the highest reported figures from nine-month multiple dose studies based on published data of third parties. A few points I'd like to make about the splicing results. We used the gold standard, 22-gene panel, as the assay to measure splicing. Two patients had to be excluded from this splicing analysis. One that I previously mentioned had a biopsy which resulted in a pseudoaneurysm and yielded no muscle sample for analysis. The second had a splicing index measured both at baseline and at day 28, indicating missplicing below the lower limit of the assay, which was outside of the pre-specified range and therefore excluded from the analysis.
Five of the six patients in the 5 milligram per kilogram cohort showed splicing improvement, and three out of four did in the 10 milligram cohort. With respect to 16-week splicing numbers from our 5 milligram per kilogram cohort, overall, we did not see a meaningful change from baseline at 16 weeks. As we look at this slide, first, it is important to note that no one has reported a benefit in functional measures in DM1 after a single dose. Similarly, we did not see a clear benefit in functional measures following a single dose of PGN-EDODM1 at 5 milligrams per kilogram and 10 milligrams per kilogram. While directionally, we saw encouraging signs in the 10-meter walk-run test, we think it will be important to look at these measures in studies with multiple doses over longer time periods, which we are dosing in FREEDOM 2.
We believe strongly that robust splicing correction, which addresses the underlying cause of disease pathology, has the potential to result in functional improvements for patients. With that, I'll turn the call back over to James. James?
Thanks, Paul. I hope you can see why we're so excited by the results we're sharing today, showing a robust 29% mean splicing correction rate with a single 10 mg per kg dose of PGN-EDODM1. We believe these results validate PGN-EDODM1's potential to deliver a therapeutic oligo to the nucleus to liberate MBNL1 and improve splicing. As we move forward with FREEDOM 2, our multiple ascending dose study currently underway, we are enthusiastic about the potential of PGN-EDODM1 to have a long-term positive impact on patients' lives. Before we finish and move to Q&A, I'd like to review our FREEDOM 2 study. We'll be exploring four doses of PGN-EDODM1 over 12 weeks, starting with a 5 mg per kg cohort that has already been initiated.
FREEDOM 2 provides the opportunity to see where splicing correction levels can go with repeat dosing, as well as to confirm that our investigational compound is safe and well tolerated. Finally, I wanted to take a minute to review our milestones for the coming year and let you know what you can expect from us. In DM1, we expect to have FREEDOM data from the 15 mg per kg single dose cohort in the second half of this year. We're advancing FREEDOM 2 and expect to have clinical results from our 5 mg per kg cohort in the first quarter of 2026. Finally, our Connect One 10 mg per kg dose cohort in patients with DMD is fully enrolled, and we look forward to reporting these results from that trial by the end of the third quarter. With that, Dr. Streck, Dr.
Mellion, Noel Donnelly, and I will be available to take your questions. Operator, I'll turn the call back over to you for the question and answer session. Thank you.
Thank you. If you would like to ask a question, please signal by pressing star one on your telephone keypad. If you're using a speakerphone, please make sure your mute function is turned off to allow your signal to reach our equipment. To ensure everyone has an opportunity to ask a question, we ask that you limit your questions to one question and one follow-up before requeuing. Again, press star one to ask a question. Our first question is going to come from Paul Matteis from Stifel. Please go ahead.
Hey, thanks for taking my questions. I had one on splicing and one on safety. As it relates to the splicing data, I was wondering, James, could you help define for people what a responder is on splicing, saying that three out of four benefited at the high dose and maybe just give us some qualitative color, quantitative if you can, on whether there was an outlier effect in the high dose that could have driven this benefit? As it relates to safety, encouraging to see what you've seen from a single dose. Certainly, we'll see more data as you go into the MAD, but at least from the SAD data, how does a single dose safety profile here compare to what you saw from the DMD program? Thanks so much.
Great. Thank you, Paul. This is James McArthur. I'll take the splicing question and then hand it over to Dr. Streck for the safety question. On splicing, a responder is anyone who showed a positive movement compared to baseline in terms of the splicing index. I will say at the 10 mg per kg cohort, all individuals showed robust change of at least 10% change from baseline. In terms of the safety, certainly, as we reported out in our last press release, we continue to feel very good about our DMD safety profile. We don't have any single ascending dose data for our DMD program, but if we compare single dose in healthy volunteers to single dose DM1 patients, we see serum creatinine levels in normal range for the DM1 patient, which is slightly lower than we saw with the spike associated in healthy volunteers after single dose.
All right. Just one follow-up on the abdominal pain. You seem to think that this was caused by another medication, but I guess it was codified by the investigators as treatment related. Can you expand upon that at all on why you don't believe it's driven by drug? Can you say what the medication was or any other context?
No. We're not going to discuss what the medication was. I think, essentially, Paul, we feel as though that the SAE of abdominal pain is confounded by the fact that the individual did take a prohibited medication the morning before the day of receiving test medication. It is very difficult to interpret was the abdominal pain related to EDO DM1, or was it related to the fact that she had something in relatively close proximity? Again, we're not excluding the fact that it could be from a drug, but at the same time, it's obviously a hard interpretation. I think the main thing to take away is that the abdominal pain was self-limiting, treated with analgesics, and the patient has done well since.
Okay. Thanks, James. That's all. Appreciate it.
Our next question is going to come from Joe Schwartz from Leerink Partners. Please go ahead.
Great. Thanks very much, and congrats on this great progress. I was wondering if you could talk a little bit more about the inclusion criteria in trial design for FREEDOM 1, and are you thinking about making any changes to either FREEDOM 1 or FREEDOM 2 based on what you've seen to date in these patients randomized to drug as well as to placebo? Because it seems like there's obviously that imbalance and very high baseline BHOT in the placebo arm, which led to that placebo effect. I'm just wondering if you could help us interpret that. Thank you.
Michelle Mellion will address this question.
Thanks for the question, Joe. In FREEDOM, we learned a lot about these different functional assessments that have informed the design of FREEDOM 2, which is how the program was designed. Based upon our learnings from the FREEDOM study, we have amended the inclusion criteria for the FREEDOM 2 study to account for what we learned about BHOT as well as about the functional assessments, including repeatability of these assessments at baseline, specifically trying to reduce the variability in the BHOT assessment by doing a baseline assessment as well as an additional assessment prior to dosing to reduce that variability. We do believe that that will be helpful in understanding the potential impact of DM1 on the functional assessment.
Okay. Thanks. That's very helpful. If I could just ask a follow-up on safety. I'm really struck by what you're seeing or maybe not seeing here and how that compares to what has been seen in the DMD setting with similar technology at similar doses. It's a slightly different picture. I'm just wondering if you can help us understand why the safety profile might be so unremarkable here relative to the DMD setting.
Paul, take this question.
Sure. Yeah, Joe. First of all, I think inherently you have to look at just the patient type, a DMD patient, in terms of renal challenges that they have. The patients are typically chronically on steroids. Anytime they'll be taking other con meds, it can have impact on the kidney, including ACE inhibitors, bisphosphonates for bone health. I think that that's certainly different in the DM1 versus the DMD patient. Secondly, of course, as you know, in DMD, what we've seen thus far has been relatively mild and transient in terms of electrolyte disturbances, GFR changes that have recovered. In terms of DM1, again, why is there a difference in terms of what we're seeing?
I don't think we really have mechanistically a rationale other than the fact that we did not see any rises above the upper limit of normal in serum creatinine, cystatin C, or BUN in our DM1 program. We'll obviously continue to monitor renal function, but overall feel very good that any renal changes that we're seeing based on single dose certainly seem to be milder and less than anything that we've seen with DMD thus far.
Thanks for the helpful color.
If you'd like to ask a question, please press star one on your telephone keypad. Our next question is going to come from Laura Tico from Wedbush. Please go ahead.
Good morning. Thanks very much for taking the question. I guess just two for me. With respect to the data so far, have you seen any correlations between splicing correction and drug concentration exposure levels? Have you kind of examined that so far? I guess I'm just trying to at the patient level, is this kind of bearing out? I would presume yes, but just wanted to confirm that.
Thanks, Laura. This is a blinded study, and so we cannot correlate the various readouts, including drug concentration, splicing, and functional readouts to the individual patient level at this point in time. At the end of study, we will, of course, be unblinded, and we will perform that analysis to go and see how those correlations are.
Okay. Understood. One on the safety. Could you just remind us in the preclinical models, when were renal signals observed in the animals? I believe these were at higher dose levels, but was this on a single dose exposure?
Yeah. What we observed and what we presented today in terms of the creatinine signals could be observed to spike significantly following a single dose at higher dose levels in non-human primates. The signal we're seeing here in humans is very benign in nature and less so than what we had seen in the EDO 51 single dose study. We are very pleased with what we're seeing, and it's consistent with what we had observed with this drug in preclinical toxicology.
Okay. Last one. I'll sneak in here. Do the results change your view on the degree of correction that's necessary? I mean, 29% at the 10 mg per kg level certainly seems pretty high. Is this more of a function of just requiring multiple dosing to start to see functional benefit? Just curious if there's any changes there in terms of the degree of splicing correction that might be necessary. Thank you.
Yeah. No, appreciate the question. First off, no one has been able to demonstrate an improvement in a functional outcome measure following a single dose. The underlying biology probably takes some time to go and correct for all of these outcome measures. I think in addition, when we look at the BHOT dataset, it's confounded by the very high baseline measurement of myotonia that we observed. It was actually higher than what has been observed with any other drug that has been tested to date. This probably masked the effect given the disconnect between the placebo group and the 5, in particular, the 10 mg per kg dose groups. We anticipate that with repeat dosing, we will see a robust functional signal because splicing is at the basis of this disease.
If we correct the missplicing, we anticipate correcting the biology that drives all the pathology in this disease.
Thank you very much.
Our next question is going to come from Ry Forseth from Guggenheim. Please go ahead.
Hi everyone. This is Ry Forseth from Debjit's team. We were curious if the week 16 biopsy in the SAD will resample the same tibialis anterior region. If yes, is there a concern that that biopsy might have a bias because it's sampling from a previously injured tissue?
Yes, we will take a biopsy at 16 weeks from the tibialis anterior site. We tend to move from one side to the other side. Also, I think the other thing is that at 16 weeks, it is a punch biopsy. In that timeframe, I am less concerned about inflammatory response creating any change in tissue that would impact splicing index.
Got it. Thanks. Congrats on the data.
Thank you.
If you have a question, please press one on your telephone keypad. Our next caller is going to be Tavin Mohan from Bank of America. Please go ahead.
Hi. This is Jeremiah Laurence on for Tavin. Thanks for taking our question. We just had a quick question on splicing correction. Wondering if you could share any color on how splicing correction changes over time. Some of your competitors in the space have shared splicing data at later time points. Would you expect PGN-EDODM1 splicing correction to deepen over time? If so, what is an ideal splicing correction level?
Thanks for the question. We do anticipate, based on preclinical pharmacology, that with repeat doses, again, keeping in mind this is a single dose study, with repeat doses we should see greater levels of oligo in the muscle. With that, we should see greater splicing correction. Greater splicing correction should drive improved outcomes in patients. I think with other approaches, we've seen that there appears to be a plateau that is reached beyond which they cannot seem to drive additional splicing correction. It's our hope that with our novel mechanism that targets the CUG pathogenic DMPK RNA, as opposed to indiscriminately degrading or impacting DMPK, both normal and pathogenic, we can actually drive to higher levels of splicing correction. With that, drive to greater functional outcome measures.
We anticipate with both higher doses and certainly with repeat doses that we should see greater splicing correction and ultimately see functional outcome measures improve in patients with this.
Got it. Thank you.
I have no further questions in the queue at this time. I'd like to turn the conference back over to James McArthur for any additional or closing remarks. Please go ahead.
Again, I want to thank you all for joining our call today to learn more about our exciting results with PGN-EDODM1 in patients with myotonic dystrophy type 1. I also want to thank the patients and their families who participated in our studies and our amazing PepGen team who made all this possible. We look forward to updating you on our progress throughout the year. Thank you.
This concludes today's call. Thank you for your participation. You may now disconnect.