William Pickering

William Pickering asked for clarification on whether the initial DM1 disclosure will include data from cohorts 3 and 4, the necessary follow-up duration to observe a splicing benefit, and if Avidity's hypothesis regarding biopsy timing (day 45 vs. day 90) influenced Sarepta's plan to delay sharing splicing data.

Answer

Louise Rodino-Klapac, Executive VP, Chief Scientific Officer, and Head of Research and Development, stated that the initial disclosure will include SAD cohort data and early MAD safety data. The CASI-22 splicing panel data for DM1 will be available in the second half of 2026, while early DEX target gene expression data will be part of the preliminary readout.

William Pickering inquired about the initial DM1 disclosure, specifically if it would include cohorts 3 and 4, the necessary follow-up duration to observe a splicing benefit, and if this informed the plan to share splicing data in the second half of the year.

Answer

Executive VP, Chief Scientific Officer, and Head of Research and Development Louise Rodino-Klapac clarified that the initial readout would include SAD cohort data and early MAD safety data. She stated that the CASI-22 splicing panel for DM1 would be available in the second half of the year, with early DEX target gene expression data in the preliminary readout.

William Pickering asked why a lower editing rate appears sufficient for PKU compared to sickle cell or AATD, and any risks associated with this translation to humans. He also inquired about the incremental OpEx for the PKU program over the next few years and how it scales with the number of unique mutations taken into the clinic.

Answer

CEO John Evans, Chief Scientific Officer Gopi Shanker, and CFO Sravan Emany explained that PKU, being a recessive loss-of-function disease, requires only modest restoration of enzyme activity, allowing for therapeutic benefit at lower editing levels. Sravan Emany confirmed that PKU is already factored into the company's runway guidance into mid-2029, and that the platform approach makes subsequent programs and additional mutations more efficient and less incrementally costly.

William Pickering asked why a lower editing rate appears sufficient for PKU compared to sickle cell or AATD, and any associated risks in humans. He also inquired about the incremental OpEx for the PKU program and how it scales with the number of unique mutations taken into the clinic.

Answer

CEO John Evans, CSO Gopi Shanker, and CFO Sravan Emany responded. Gopi Shanker explained that PKU is a recessive loss-of-function disease, requiring only modest restoration of enzyme activity for therapeutic benefit, as demonstrated in mouse models. Sravan Emany stated that PKU is already factored into the company's runway guidance, and while program-specific costs aren't disclosed, the platform approach makes subsequent programs and additional mutations more efficient.

William Pickering inquired about how baseline GFR might influence the observed effect size for povetacicept (pove), particularly if Phase III baseline GFR is lower than Phase II. He also asked about the larger standard error in RUBY-3 UPCR data compared to competitor studies and its potential causes.

Answer

Reshma Kewalramani, CEO and President, stated that within the studied proteinuria range (not end-stage kidney disease), baseline GFR should not significantly impact proteinuria. Regarding the standard error, she noted that it is influenced by sample size and the type of lab test used (e.g., 24-hour urine versus spot urine), but she had not reviewed the specific competitor data for comparison.

William Pickering asked how baseline GFR is expected to impact the observed effect size for povetacicept, noting that Phase 2 patients had a higher average GFR than competitor trials, and whether a lower Phase 3 baseline would influence effect size.

Answer

Reshma Kewalramani (CEO and President, Vertex Pharmaceuticals) clarified that within the studied range of proteinuria (not near end-stage renal disease), baseline GFR should not have a significant impact on proteinuria. She explained that only in cases of 'burnt-out kidney' might proteinuria seemingly decrease due to a lack of renal function, but this is not relevant to the current study population.

William Pickering of Bernstein questioned why Gernavix was not included in the draft rule for the NOPAIN Act and asked about the current cycle time for Casgevy treatment, from cell collection to infusion.

Answer

President and CEO Dr. Reshma Kewalramani explained the NOPAIN Act draft contained a misunderstanding about Gernavix's indication for postsurgical pain, which she expects to be resolved. She noted the Casgevy cycle time is roughly 4-5 months, with plans in place to improve it as the launch momentum accelerates.

William Pickering inquired about the specific assumptions for the placebo effect used in designing the Phase III study for suzetrigine in DPN and asked what magnitude of delta versus placebo would be considered clinically meaningful.

Answer

CEO Reshma Kewalramani explained that the Phase III trial design, which includes both placebo and active comparator (gabapentin) arms, was informed by extensive historical data from numerous DPN studies. She confirmed the study is appropriately powered to account for the known range of placebo effects seen in the literature.

William Pickering of Bernstein asked for details on the quantitative criteria for the interim analysis, such as minimum events or follow-up, and the sensitivity of the MRD conversion rate to these criteria.

Answer

CMO Dr. Zachary Roberts stated that the MRD conversion rate is not expected to be highly sensitive to those factors. He explained that the protocol specifies an MRD assessment at a particular time point, and the company will simply analyze and report the binary positive or negative result from that test.

William Pickering requested more detail on the conversion rate from patient consent to randomization in the ALPHA3 trial and any factors that might cause patients not to convert.

Answer

EVP of R&D and CMO Dr. Zachary Roberts stated that patient uptake is very high when the trial is explained at the appropriate time. He noted the vast majority of MRD-positive patients agree to proceed to the main study, and screen-fail rates are low in this healthier frontline population. He deferred providing specific conversion metrics, citing the early stage of the trial.

William Pickering noted that multiple dose-limiting toxicities (DLTs) occurred at the dose level selected for the ALLO-316 expansion cohort and asked about the acceptability of this safety profile going forward.

Answer

Dr. Zachary Roberts, EVP of R&D and CMO, clarified that the DLTs occurred at that cell dose but specifically in the arm that received the more intensive FCA lymphodepletion regimen (including ALLO-647). The expansion cohort is proceeding with the FC-only regimen, where DLTs were not encountered and efficacy appeared most promising. Dr. David Chang, President and CEO, added context on the two specific DLTs, one of which was previously disclosed.

William Pickering questioned an apparent change in the maximum dose for the ARO-DM1 program, from a previously mentioned 12 mg/kg to a current protocol of 6 mg/kg.

Answer

CEO Christopher Anzalone provided a direct clarification, stating, 'We still can go up to twelve mgs per kg in the current study, the DM1 study.'

William Pickering asked for color on the ~$50 million sequential increase in R&D spending this quarter and for expectations on the R&D expense line over the next few quarters.

Answer

CFO Ken Myszkowski attributed the R&D increase to the company's pipeline candidates advancing into later, more costly stages of development. He anticipates that R&D expenses will continue to increase into next year and noted that more specific guidance will be provided on the next earnings call following the completion of the budgeting process.

William Pickering asked about enrollment rate expectations for the MAGNITUDE-2 study in ATTR polyneuropathy (PN) and whether competitor studies are reasonable benchmarks, given the evolving treatment landscape.

Answer

Chief Medical Officer David Lebwohl explained that while the trial must enroll in countries where modern therapies like Vutrisiran are not yet available, this has led to very high investigator interest. He expects brisk enrollment through 2026, enabling a potential BLA submission in 2028. He also noted the trial could stop early based on an interim analysis due to the high efficacy seen in PN.

William Pickering asked about the long-term observation period in the HAE Phase III trial, its importance for demonstrating a functional cure, and how long the company would wait before submitting a supplemental filing with that data.

Answer

CMO David Lebwohl acknowledged that the full 104-week data would not be available at the initial BLA filing. However, he noted they would be close to having the full data set by the time of approval and would consider filing a supplemental BLA 'fairly soon after the initial approval' to include it.

William Pickering asked if there are plans to expand the AATD program study beyond the initial New Zealand site and whether it is reasonable to expect initial data in 2025.

Answer

CMO David Lebwohl confirmed that other trial sites will be added and listed on clinicaltrials.gov as they become active. He also stated that it is 'reasonable to think we have data in 2025.'

William Pickering of AllianceBernstein inquired about the EYLEA HD monthly dosing submission, asking about the amount of safety data included from the recently completed trial and whether the FDA was aligned on its sufficiency.

Answer

President and CEO Dr. Leonard Schleifer declined to provide specific enrollment data but emphasized that the FDA's acceptance of the submission for review signifies that it met the threshold for sufficiency. He stated the focus is now on the agency's review process.

William Pickering of AllianceBernstein asked about the company's complement programs, specifically how the antibody-siRNA combo might fit into the Myasthenia Gravis (MG) and Geographic Atrophy (GA) treatment landscapes.

Answer

President and CSO, Dr. George Yancopoulos, explained the combo's efficacy benefit is in driving more patients' LDH levels to the normal range, with a safety profile consistent with the class. For GA, he positioned their systemic approach as an alternative to intravitreal treatments, allowing physicians to weigh the different risk profiles of class-specific infections versus potential immediate vision loss.

William Pickering of Bernstein asked if the biosimilar erosion curve for Lucentis is a good proxy for EYLEA and what key commercial differences should be considered.

Answer

EVP of Commercial Marion McCourt stated it was too early to comment on erosion for a product not yet used in the real world. President and CSO Dr. George Yancopoulos added a key difference: unlike with Lucentis, EYLEA patients have the option to switch to a differentiated, superior product in EYLEA HD, not just a biosimilar, creating a very different market dynamic.