Thank you for holding. Good morning, and welcome to the Passage Bio Conference Call. At this time, all participants are on a listen-only mode. Following the formal remarks, we will open the call for your questions. Please be advised, this call is being recorded at the company's request. At this time, I'd like to turn the call over to Stuart Henderson, Senior Vice President of Corporate Development and Investor Relations. Stuart, please proceed.
Thank you, operator, and good morning, everyone. Today, we will review interim results from the global IMAGINE-1 phase I/II clinical trial of PBGM01 in infantile GM1 gangliosidosis. Please refer to the press release issued earlier today and the slides that we will be using on today's call on the Investors and News section of the Passage Bio website. Before we begin, I'd like to remind you that our presentation this morning will contain forward-looking statements based on our current expectations and beliefs of future events as of today. These statements are subject to a number of risks and uncertainties, including those risk factors from our latest 10-Q, that could cause actual results to differ materially and adversely from those presented. It is now my pleasure to turn the call over to CEO, Dr. Will Chou. Will?
Thanks, Stuart, and good morning, everyone. I'm excited to share encouraging data from the first 8 patients treated in our global IMAGINE-1 phase I/2 trial of PBGM01 in infantile GM1 gangliosidosis. On today's call, Dr. Mark Forman, Chief Medical Officer, will provide an executive summary of our IMAGINE-1 study. Dr. Samiah Al-Zaidy, Vice President of Clinical Development and our GM1 Program Lead, will share the interim results and the program update. Finally, I will close out with what's next for the program before opening the call for Q&A. With that, I'd like to now turn the call over to Mark.
Thanks, Will. I'll first begin by summarizing our approach and the findings from this interim analysis. Turning to Slide 5, our program for GM1 gangliosidosis was designed to address the high degree of unmet clinical need for this underserved patient population. GM1 is a fatal pediatric lysosomal storage disorder caused by loss-of-function mutations in the GLB1 gene, leading to a deficiency in the enzyme beta-galactosidase. There are no approved disease-modifying therapies. PBGM01 utilizes a next-generation proprietary AAVhu68 capsid to deliver a functional GLB1 transgene encoding beta-gal to the brain and peripheral tissues via intracisterna magna or ICM delivery. In preclinical models, we observed a clear dose-response effect and meaningful transduction of both CNS and peripheral organs. On Slide 6, it's important to highlight that GM1 presents along a continuum, affecting patients of different ages and resulting in varying disease severity.
In the case of a rare disease like GM1, natural history studies play an important role in refining our understanding of disease progression, with the potential to provide controlled data for a clinical trial. GM1 is a progressive disease with continuous decline, and the natural history shows that patients who lose milestones almost never regain them. Published data has shown that the more severe the disease, the lower the enzyme activity level of beta-galactosidase, with some degree of overlap between patient categories. The infantile forms of the disease are the most severe, and our IMAGINE-1 study focuses on these patient populations. Turning next to Slide 7, IMAGINE-1 is our first-in-human study for PBGM01, and the key objectives are focused on establishing the safety, tolerability, and pharmacokinetics of our investigational gene therapy.
First and foremost, we need to establish the safety profile of PBGM01 in patients with infantile GM1 gangliosidosis. This includes assessing potential adverse events, toxicities, and any safety concerns associated with the administration of treatment. Another crucial goal of the study is to identify the optimal dose of PBGM01 that achieves the most significant therapeutic effect in patients with infantile GM1. We are evaluating dose-response relationships to find the right balance between effectiveness and safety, ultimately guiding our dose selection for a pivotal study. Finally, we hope to obtain a comprehensive understanding of the benefits of PBGM01 treatment across various patient populations affected by infantile GM1. This includes assessing its effect in both early and late-onset cases, as different populations may respond differently to the treatment. Today, we're excited to present our latest findings as we make steady progress against these study objectives.
On slide eight, we provide a summary of key interim findings from the first eight patients treated with PBGM01, highlighting the promise of this treatment. First, we're excited to see that PBGM01 continues to be well-tolerated and has a favorable safety profile, with follow-up now available from eight patients up to 28 months after treatment. Next, we're encouraged to see initial evidence of improved survival in study participants who received PBGM01 treatment compared to published natural history data. Finally, focusing on two key biomarkers in the CSF, we have observed dose-dependent increases in beta-galactosidase activity, the enzyme of interest, and these increases were sustained for up to 12 months following treatment. We also observed dose-dependent decreases in CSF levels of GM1 gangliosides, a key substrate of beta-galactosidase, with Dose 2 able to achieve healthy control levels. With that, it's now my pleasure to turn the call over to Dr.
Samia Al-Zaidi, our clinical lead for the PBGM01 program, to review the interim results in more detail.
Thank you, Mark. It's a pleasure to be here this morning to share these findings. Let me first begin by reviewing the IMAGINE-1 trial design on slide 10. As depicted on this slide, our IMAGINE-1 study evaluated Dose 1 and Dose 2 of PBGM01 in both early and late infantile GM1 patients. As Mark mentioned earlier, our approach utilizes a proprietary AAVhu68 capsid and an ICM administration method. For immunosuppression, we are using daily corticosteroid regimen for one month, followed by tapering. IMAGINE-1 is a two-year study with rollover into a long-term follow-up study. As the first-in-human study of PBGM01, the aim of the initial dose escalation phase of the trial is to assess the safety and tolerability of PBGM01.
Additionally, this phase explores the efficacy of PBGM01 to enable design of the confirmatory study, including selection of dose and GM1 population that will most likely benefit from PBGM01. Today's discussion will highlight data available from the first four cohorts in the dose escalation portion of the study, with each cohort consisting of two patients. Cohort 1, late infantile at Dose 1; Cohort 2, late infantile at Dose 2; Cohort 3, early infantile at Dose 1; and Cohort 4, early infantile at Dose 2. The baseline characteristics for each of the first eight patients are summarized on Slide 11. I'd like to highlight that this is the first time we are sharing data from Cohort 4, which includes patients seven and eight, our early infantile patients at Dose 2.
As Mark described earlier, GM1 patients present along a continuum, and you can see the range represented across the first eight patients in the study, with onset of symptoms ranging from birth to 14 months of age. There is also a wide range of ages at baseline, ranging from 6-31 months of age, which results to a diverse set of patients with wide ranges of developmental delay at the time of treatment. However, all patients have very low or undetectable beta-galactosidase activity, as expected. Next, on Slide 12, we are encouraged to see that PBGM01 continues to be well-tolerated with a favorable safety profile. Over a follow-up period ranging from 8-28 months post-dosing across study participants and as of the data cutoff, there were no treatment-related serious adverse events. All treatment-related adverse events were mild to moderate in severity.
There were no clinically significant changes in liver function requiring intervention. There was no evidence of dorsal root ganglion or DRG toxicity as measured by nerve conduction studies. There were no complications related to the ICM administration method. Finally, PBGM01 continued to show a favorable immunological profile with no clinically significant immune responses requiring adjustment of immunosuppression. Next, on Slide 13, we see that there is initial evidence of improved survival among IMAGINE-1 study participants compared to natural history. This chart is a Kaplan-Meier curve of the overall survival for IMAGINE-1 study participants, depicted in red, against published natural history data, depicted in blue. The natural history survival data in this chart is from a meta-analysis by Lang et al. that evaluated 154 cases of infantile GM1 gangliosidosis with symptom onset between birth and 12 months of age.
These data, plotted in blue, show a mean infantile GM1 survival of 18.9 months of age and no survival beyond 35 months. In the IMAGINE-1 study, across our cohorts, six out of our eight participants meet the Lang et al. criteria for infantile GM1 gangliosidosis, and three of these participants have been followed in the study beyond the mean age of survival in the natural history study. As you can see, IMAGINE-1 study participants had a 100% survival in subjects older than 20 months, indicating improved survival relative to the natural history data. This, combined with no deaths in the IMAGINE-1 study across all participants, is an encouraging signal for PBGM01 in this patient population. Next, I'll review results from teo key CSF biomarkers at each of the first two dose levels tested.
On slide 14, the chart on top shows CSF β-gal activity, while the bottom chart shows CSF GM1 ganglioside levels for patients treated at Dose 1. You'll also note that the late infantile patients are plotted with a circle, while early infantile patients are plotted with a square. First, looking at β-gal activity at Dose 1, there was a modest increase in CSF β-gal activity, with a 1.5- to 4.8-fold increase relative to baseline at 30 days post-dose. While these increases were largely sustained beyond one year, none of the patients maintained a level of β-gal activity at or above healthy adult controls. Moving now to GM1 ganglioside levels at Dose 1. While Dose 1 of PBGM01 did not result in a substantial reduction of GM1 gangliosides, low levels were maintained over time in some patients.
Focusing on patient 3 in the dark gray, you will see a rise in ganglioside levels between six months and one year post-dose. This patient showed only a modest increase in CSF β-gal activity, and the increased ganglioside levels were temporarily associated with clinical worsening as measured by imaging studies. In summary, we see that PBGM01 at Dose 1 exhibited modest effects on key CSF biomarkers. On the next slide, we show the data for Dose 2. Again, on this slide, the chart on top shows CSF β-gal activity, while the bottom shows CSF GM1 ganglioside levels for patients treated at Dose 2, which is 3 times higher than Dose 1. Beginning with β-gal activity in three of four participants, Dose 2 PBGM01 resulted in CSF β-gal levels that exceeded average levels seen in healthy adults and average levels seen in GM1 patients.
Healthy adult levels were determined from a sample of 30 adults, while GM1 patient levels were determined from a natural history study of eight pediatric GM1 patients. In these three children, there was a 4.7 to 16.1 fold increase in CSF beta-gal activity at day 30 compared to baseline. Additionally, we observed sustained beta-gal activity for six to 12 months in all patients treated at Dose 2. Moving now to GM1 gangliosides, Dose 2 resulted in decreased levels for all patients after dosing. GM1 ganglioside levels continued to decline over time, achieving normal adult levels at one year post-dose for patient 4. Overall, Dose 2 resulted in robust increases in CSF beta-gal activity and decreases in GM1 ganglioside levels, demonstrating a dose-dependent response to PBGM01 that corroborates the preclinical findings referenced earlier by Dr. Forman.
To summarize these findings on Slide 16, we are very encouraged by the interim safety, clinical, and biomarker data shown in our first eight patients. To date, PBGM01 has demonstrated a favorable safety profile in both early and late infantile GM1 patients. The absence of serious adverse events related to study treatment, DRG toxicity concerns, and complications related to ICM administration underscores its potential as a safe therapeutic option for patients. PBGM01 also shows initial evidence of improved survival relative to historical controls. The biomarker data, notably for dose two, positions PBGM01 as a promising treatment option for infantile GM1 gangliosidosis. Data showed that PBGM01 can achieve healthy control levels of the missing beta-gal enzyme and the deleterious substrate.
In three of four patients, dose two resulted in CSF beta-gal activity that exceeded average levels seen in healthy adults and in our GM1 natural history study. Dose two also reduced GM1 gangliosides in the CSF to normal adult levels. Finally, PBGM01 demonstrated durability of biomarker responses up to 12 months after treatment in a dose-dependent pharmacodynamic effect in treated patients. Based on these results from the first two doses, we are now continuing the study to evaluate a higher dose, dose three. In the next few slides, I'll review the key preclinical and clinical evidence supporting rationale for dose three, as well as key elements of our amended study protocol. First, moving to Slide 18. We're excited to share that we've advanced our IMAGINE-1 program to evaluate dose three to further inform optimal dose selection and maximize potential clinical benefit.
The preclinical rationale for dose escalation is grounded in the expectation of achieving a further increase in β-gal activity, which could lead to improved lysosomal pathology. Supporting evidence from preclinical studies is detailed in the table on the left of the slide. The data in this table is from studies of a mouse model of GM1 gangliosidosis, the Glb1 knockout mouse, which develops some biochemical and pathology signs akin to those described in GM1 patients. In this study, 4 ascending dose levels were tested, which resulted in a dose-dependent increase in the levels of β-gal activity in both brain and CSF. Importantly, the highest dose levels also corresponded to reduced LAMP1 staining, which demonstrates improved lysosomal pathology. I would like to point out here that the highest dose tested in these mice was equivalent to the highest dose tested in non-human primates.
Our clinical Dose 3, which is 2x higher than Dose 2, is below the maximum dose tested in our NHP toxicology study. By this, we maintain a safety window. Clinically, advancement to Dose 3 is supported by the absence of dose-limiting toxicities in both early and late infantile GM1 patients, as well as a dose-dependent response to key CSF biomarkers observed in Cohorts 1 through 4. As we reviewed earlier, Dose 2 showed the ability to achieve normal adult levels of GM1 gangliosides at one year post-dose. By moving to Dose 3, we hope to further increase CSF beta-gal levels and determine how consistently and quickly PBGM01 can decrease GM1 gangliosides. Lastly, our existing drug product supply can support treating patients at Dose 3.
Turning to slide 19, we will review key protocol amendments and an updated trial schematic that incorporates the addition of Cohorts 5 and 6 to the study. As depicted on the slide, Cohort 5 will enroll 3 late infantile patients, and Cohort 6 will enroll 3 early infantile patients treated at Dose 3, which is 2.2e11 genome copies per gram of estimated brain weight. Notably, our amended protocol allows for concurrent dosing of early and late infantile GM1 patients. In addition, we have modified eligibility criteria based on our clinical experience to date, with an aim to reduce intra-cohort patient variability and to target patients with the greatest potential to demonstrate PBGM01 treatment effect.
For early infantile GM1 patients, the age at enrollment has been decreased from 4-24 months to 1-12 months, enabling patients early in their disease progression to participate in the study. For late infantile GM1 patients, the upper age limit at enrollment has been decreased from 36 months to 24 months, focusing on a more specific age range for the subgroup. Additionally, a minimum function requirement of sitting without support has been added to the inclusion criteria for late infantile patients. The amended protocol has been approved at clinical trial sites in multiple countries, including the United States, Canada, Brazil, and Turkey. We've made significant progress, and I am thrilled to share that we treated the first patient at Dose 3 in July, and that enrollment in both Cohorts 5 and 6 is currently active, with multiple additional patients being evaluated for study eligibility.
With that, let me now pass the call over to Will for closing remarks.
Thanks, Samia. Moving to Slide 21. You heard our key study objectives earlier from Mark. Now I'd like to highlight the progress we've made in meeting each of these objectives. First, PBGM01 continues to exhibit a favorable safety and immunological profile at our first two doses. Second, we're making great progress in determining the optimal dose of PBGM01 for maximal therapeutic effect. Our data shows that Dose 2 is able to achieve healthy control levels of CSF β-gal activity and GM1 gangliosides. Furthermore, these biomarker responses have shown durability up to 12 months following treatment. Overall, for the program, we've seen the dose-dependent biomarker effects observed pre-clinically, successfully translate into the clinic. Considering all of these factors, we hold confidence in the potential of Dose 3 to further enhance biomarker response and therapeutic effect.
Regarding the assessment of PBGM01's benefits across infantile GM1 patient populations, we've observed initial evidence showing that PBGM01 has improved survival compared to historical controls. As we proceed with enrolling patients under our latest study protocol, we are targeting patients earlier in their disease progression, with the goal of optimizing the potential for clinical benefit in these patients. Lastly, slide 22 describes the anticipated next steps for this program. First, we're thrilled to have already treated the first patient at Dose 3 and look forward to continuing enrollment of cohorts five and six. Based on our recruitment estimates, we plan to share initial safety and biomarker data from Dose 3 patients by mid-2024. As data become available from Dose 3 patient cohorts, we will then look across the totality of our data to determine the optimal dose to advance into the confirmatory study.
Lastly, as our clinical data matures, we are planning for continued interactions with regulatory agencies to align on the design of our confirmatory study and the appropriate pathway to a BLA submission. We're excited by the progress we're making to develop a potentially transformative therapy for patients with GM1, and I'd like to extend a sincere thank you to the patients, families, caregivers, and investigators in the GM1 community for their continued support. I would now like to open the call up for Q&A. Operator?
Thank you, ladies and gentlemen. If you have a question or a comment at this time, please press star one one on your telephone. If your question has been answered or you wish to move yourself from the queue, please press star one one again. We'll pause for a moment while we compile our Q&A roster. Our first question comes from Yaron Werber with TD Cowen. Your line is open.
Great, thanks for taking my questions, and, and congrats to the team. Nice to see this update. I have a couple of questions. Maybe first of all, with respect to the steroid tapering, I mean, it's nice to see that you're really not seeing any DRG, no immunological issues at all. What? Can you just give us a sense how fast are you able to taper patients? Are you starting in sort of all the same doses, and are they all on the same sort of regimen? Secondly, when you look at Patient 7, you know, the early infantile patient, what do you think is going on with that one specifically? Because nothing jumps out to me when I look at the baseline characteristics. Thank you.
Sure. Thanks for the question, Yaron. For the steroid question, I'm gonna turn that over to Samia to answer.
Hi, good morning. Thanks for the question. Excellent question. We've had a very successful overall kind of with the patients, the zero taper. We do have a regimen about approximately one month, and then we taper it over about four to six weeks, depending on the patient and their labs. We've been consistently seeing that we have been able to taper them off within the four to six week period after the full dose.
and they're only getting-
Yeah
steroids. They're not getting anything else?
Just the standard dose of steroids, correct?
Okay, great.
Then for Patient 7, I'll let Mark take that one.
Sure, and, and thanks for the question. As we indicated earlier, GM1 is a continuum with a degree of variability, even within the subtypes of the disease. In regards to the specific data that you, you, you mentioned, you know, we evaluated multiple potential factors. We looked at immune response, biodistribution, drug product, and didn't identify any specific cause for this individual's response. Thus, we're, we assume we're, you know, we're left with the the concept that the β-gal activity that we observed in this patient is likely due to patient-to-patient variability. I would point out, though, that while this patient's β-gal activity response is not as robust as others, we do see evidence of the CSF GM1, of a reduction in the CSF GM1 ganglioside.
We're encouraged that three of the four, four patients share a consistent trend that appears to be favorable for a dose response.
Great. And maybe just a final question. As you're thinking, and I know it's a little early, but as you're thinking for a pivotal, what, what do you think might be the primary? I mean, can you use survival as a primary? Did you have sort of enough data? How does an accelerated pathway potentially fit into all of this? Just give an updated new, kind of, overture on that. Thank you.
Sure. We, we can't give specific guidance on primary endpoints. What we have had is general feedback from the FDA that what they are most interested in is maintenance of milestones that otherwise would not be maintained, or achievement of milestones that would otherwise not be achieved. Any clinical data that we show has to have a comparator and has to be clinically relevant. That's why we started with sharing the survival data. This is a meaningful, objective endpoint where PBGM01 is already demonstrating benefit versus a comparator. For the other potential milestones, we have not had a full discussion with the FDA about what would be a primary.
Thank you. One moment for our next question. Our next question comes from Laura Chico with Wedbush. Your line is open.
Good morning. Thanks very much for taking the question. Okay, one clarification question. Is there any modification to the steroid regimen as you're moving up to the Dose 3, regimen? I, I think I might have missed it. I apologize.
Sure. Samiah, would you like to answer that question?
Sure. There is no modification of the steroid regimen. We've had a favorable immunological profile, so we have no evidence to support a modification of the immune suppression regimen at this point.
Fantastic. Okay, thank you. Then, Will, you're, you're indicating that you should have that, initial data from the third dose by the middle of 2024. I think that's just the, the initial safety and biomarker data. With that in hand, what happens next? Is that the point that you're engaging with regulators to discuss, a pivotal design? I guess if you could just kind of talk through the next steps at, at that point, that'd be helpful. Thank you.
Sure. Mid-2024, as we said, we expect to share initial safety and biomarker data from Dose 3. In terms of full regulatory discussions, we have to evaluate the full constellation of data that we get from Dose 3 and then decide on when to go speak to regulatory authorities.
Thank you.
Again, ladies and gentlemen, if you have a question or a comment at this time, please press star one one on your telephone. I'm not showing any further questions at this time, this also does conclude today's presentation. You may now actually, one moment, we just had someone queue for a question. one moment. Our next question comes from Deb, Debjit Chattopadhyay with Guggenheim. Your line is open.
Hey, good morning. When you mentioned the FDA is probably looking for maintenance or achievement of milestones which otherwise would not have been achieved and in a registration format, you don't expect running a randomized study in this setting, right? It would be clearly unethical. I'm just curious if the FDA is comfortable with the natural history database that you have so far.
Absolutely. We would not be anticipating doing a randomized study in, in a disease that is devastating and quickly moving as GM1 gangliosidosis. As you know, we're in the process of gathering comparator data from our ongoing natural history study at Penn and from other natural history study sources. We're looking forward to sharing that data as a comparator as it becomes available.
Outside of survival, are there very specific milestones that would be acceptable to the agency, given the recent progress that Orchard has made with LIBMELDY's BLA? I'm just wondering what your, how your thought process has evolved.
Sure. Of course, there are many significant, potentially significant milestones that we could use as binary endpoints, and when we have that full discussion with the FDA, we look forward to sharing it.
Good luck. Thank you.
Sure.
I'm not showing any further questions at this time, so this does conclude today's presentation. You may now disconnect and have a wonderful day.