Jonathan Wolleben

Jonathan Wolleben inquired about Mirum Pharmaceuticals' discussions with the FDA regarding safety database requirements for volixibat, specifically for PSC, including necessary follow-up data and the implications for the timing of a potential NDA submission.

Answer

CEO Chris Peetz stated that based on pre-IND interactions and subsequent confirmations with the FDA, the current VISTA PSC study is expected to provide a sufficient safety database. Mirum plans to interact with the FDA after top-line data to finalize the submission plan, targeting an NDA submission in the second half of the year.

Jonathan Wolleben asked about the potential label for LIVMARLI if the EXPAND study succeeds and how Mirum determined the 1,000-patient prevalence estimate for this group of indications.

Answer

CEO Chris Peetz described the potential label as a 'definition of exclusion' for rare cholestasis causes. He clarified the 1,000-patient estimate for the U.S. and Europe is a tangible figure, comparable to the PFIC opportunity, derived from analyzing compassionate use requests and physician interest rather than a formal epidemiology study.

Jonathan Wolleben inquired about the long-term growth trajectory of the F2, F3 target population over the next five years, given current market dynamics, and whether similar growth is expected for the F4 population as patients progress.

Answer

CEO Bill Sibold projected double-digit growth for the F2, F3 population for the foreseeable future, including the next five years, attributing it to an effective therapy, increased awareness, and competitor activity. He also indicated that the F4c population is expected to grow, with more detailed updates to be provided closer to its potential launch.

Jonathan Wolleben asked for insights into the projected growth of the F2/F3 target population over the next five years, given the recent market expansion from 315,000 to 460,000 patients. He also inquired about expected growth in the F4 (compensated cirrhosis) population as patients advance.

Answer

Bill Sibold, Chief Executive Officer, stated that double-digit growth is expected for the F2/F3 target population for the foreseeable future, including the next five years, driven by increased awareness and competitor activity. He also indicated that the F4c population is expected to grow as the overall MASH market expands, with more detailed updates to follow closer to launch.

Jonathan Wolleben of Citizens JMP asked about insights from blinded baseline data, specifically concerning efficacy in larger individuals or Hispanic populations. He also inquired about the management of discontinuations and dose adjustments for semaglutide in the combination arm.

Answer

Dr. Puneet Arora stated that while the company remains blinded, the trial has recruited a representative population, including Hispanic participants and a broad weight range, which will allow for sub-analysis later. He explained that the rollover gap for the combination arm is kept minimal to avoid extended time off semaglutide, with minor dose re-adjustments permitted for the few patients who experience a gap, noting they have already proven tolerance to the effective dose.

Jonathan Wolleben asked about the drivers of rapid enrollment, the importance of optimizing for monthly dosing, and the potential clinical path for nimacimab in patients with diabetes.

Answer

President and CEO Punit Dhillon attributed rapid enrollment to high patient interest in obesity trials, an alternative mechanism of action, and strong execution by the operations team and investigators. COO Tu Diep noted that while monthly dosing would improve convenience and cost of goods, weekly dosing is considered acceptable by KOLs. Executive Puneet Arora added that the company is very excited about testing in diabetics due to the drug's mechanism impacting insulin sensitivity, with plans to design a study for this population after proof of mechanism is established.

Catherine, on behalf of Jonathan Wolleben, asked for context on how to compare Skye's preclinical mouse model data with data from other compounds, like Novo's, and whether relative potency could be gleaned from these early results.

Answer

President and CEO Punit Dhillon emphasized nimacimab's clear pharmacokinetic advantage, with sustained peripheral exposure and minimal brain penetration, avoiding CNS side effects. Executive Christopher Twitty added that while nimacimab's potency is similar to small molecules in classic assays, direct cross-trial comparisons are difficult. He suggested benchmarking against the semaglutide arm in their study, where nimacimab performed significantly better at its highest dose, and noted that head-to-head studies would be the most definitive way to compare.

Jonathan Wolleben of JMP Securities inquired about the reasons for patient discontinuations among nonresponders in the hypothalamic obesity (HO) trial and asked about real-world patient persistence and adverse event experiences compared to clinical trial data.

Answer

David Meeker, Chairman, CEO, and President, explained that discontinuations were varied, including patients unable to manage the trial burden and some due to adverse events. He noted that the data imputation method for dropouts is conservative. For real-world persistence, he stated that while the global discontinuation rate is around 30%, he expects the rate for the HO population to be better, citing the low discontinuation rate in the trial and high patient motivation.

Jonathan Wolleben asked if the Phase III HO trial protocol allows for dose reductions similar to Phase II and requested a comparison of the MC4 receptor activity between setmelanotide and the next-gen candidates.

Answer

CEO David Meeker confirmed the Phase III protocol allows for dose titration to manage tolerance. Regarding receptor activity, he stated that RM-718 and setmelanotide have highly similar potency, while a head-to-head assay for bivamelagon is underway. However, preclinical models suggest bivamelagon achieves similar results at the doses being studied.

Jonathan Wolleben asked for a summary of the preclinical toxicology work for the Netherton syndrome program (BCX17725) and the specific clinical metrics that will be used to assess efficacy and guide dosing decisions. He also followed up on trial logistics, including cohort sizes and the expected timing of clinical improvements.

Answer

Chief R&D Officer Dr. Helen Thackray stated that the program has a standard safety profile for a protein therapeutic, which is supported by the open INDs in the U.S. and Australia. The key clinical efficacy metric is skin normalization, assessed by patient-reported itch and physician assessment of redness and scaling. She explained that Part 3 of the trial will have fewer than 10 patients, with Part 4 being slightly larger, and that clinical signs of improvement could appear within 4 to 8 weeks.

Jonathan Wolleben inquired about historical trends in ORLADEYO patient reauthorizations during the first quarter and how the current season is tracking. He also asked about the market opportunity for the pediatric indication and if it's included in long-term forecasts.

Answer

Chief Commercial Officer Charlie Gayer noted that about half of all patients undergo reauthorization in Q1 and early Q2, and the process is proceeding as expected. He clarified that the pediatric opportunity, estimated at around 500 U.S. patients, is not yet included in the $1 billion peak global revenue forecast and may represent upside, especially given new data on early disease onset. CEO Jon Stonehouse reiterated that Q1 revenue would likely be flat to slightly down due to seasonal dynamics.

Jonathan Wolleben inquired about how the planned Phase 3 trial design amendments might improve upon Phase 2 results, the estimated enrollment timeline for the treatment-naive population, and whether the FDA requires a minimum number of patients in each dosing interval.

Answer

Dr. Victor Chong, Chief Medical Officer, explained that the Phase 3 design reduces patient variability by targeting a more general population compared to the difficult-to-treat patients in Phase 2, which should improve results. He anticipates enrollment will take just under 12 months. Dr. Chong also clarified that the FDA agreed to view the different dosing cohorts as a single arm for safety and efficacy assessment, consistent with recent approvals for EYLEA high dose and VABYSMO.

Jonathan Wolleben asked for a comparison of CLS-AX against other TKIs in development and inquired about the most important endpoints for investors to focus on in the upcoming Q3 data readout, particularly concerning durability and visual acuity.

Answer

Dr. Victor Chong, Chief Medical Officer, explained that Clearside's TKI is more potent than competitors, as indicated by a lower IC50. He emphasized that for the upcoming data, visual acuity (BCVA) is the most critical endpoint. Dr. Chong also highlighted that the trial's 9-month duration and mandatory retreatment protocol will provide valuable data for the Phase III design.

Jonathan Wolleben inquired about the change in statistical powering for the smaller SOL-R trial. He also asked how management weighs the value of accelerating the regulatory filing against securing 12-month durability data on the label, considering physicians already use treat-and-extend strategies.

Answer

President and CEO Dr. Pravin Dugel responded that the statistical powering for SOL-R remains robust and unchanged, as the original patient number was dictated by safety requirements, not statistics. He stressed the high value of the label, stating that a superiority label with 6-to-12-month flexibility would be a first-of-its-kind, providing critical scientific data for physicians and a significant commercial advantage with payers.

Jonathan Wolleben from Citizens JMP asked about the potential for different weight loss results in NASH patients versus other populations and how Altimmune plans to address the real-world adherence challenges seen with other incretins.

Answer

CMO Dr. Scott Harris addressed the questions by explaining that the higher 2.4mg dose of pemvidutide could be used in Phase III to achieve significant weight loss. He expressed confidence in achieving strong adherence, citing the very low discontinuation rates due to adverse events observed in prior pemvidutide trials, which he believes will carry over to the IMPACT trial.

Jonathan Wolleben of JMP Securities inquired about the specifics of the 'label-in, label-out' concept for Viaskin Peanut, seeking clarification on the term 'patch wear-time experience.' He also asked for quantification of what constitutes a 'robust' efficacy response, the patient split between the two groups in the EPITOPE trial, and an update on the COMFORT Children study.

Answer

CEO Daniel Tassé and CMO Dr. Pharis Mohideen explained that 'patch wear-time experience' is a holistic measure including not just wear duration but also day-to-day variability and tolerability, which helps identify patients likely to have a robust response. Dr. Mohideen noted that while specific percentages for 'label-in' vs. 'label-out' groups cannot be shared due to ongoing FDA discussions, the separation is clear. Mr. Tassé added that the 'label-in' response rate would be higher than the 67% overall rate seen in the EPITOPE trial and clarified that resolving the COMFORT Toddlers protocol is the priority before addressing the COMFORT Children study.

Jonathan Wolleben inquired about the specifics of the 'label-in, label-out' criteria for the Viaskin Peanut patch, asking for clarification on 'patch wear-time experience,' the definition of a 'robust' clinical response, and the patient split in the EPITOPE trial. He also asked for an update on the COMFORT Children study and its relation to the COMFORT Toddlers study.

Answer

CEO Daniel Tassé and Chief Medical Officer Dr. Pharis Mohideen explained that 'patch wear-time experience' is a holistic measure including hours worn, day-to-day variability, and tolerability. While declining to provide specific percentages for the 'label-in' group pending FDA alignment, Mr. Tassé noted the overall EPITOPE response rate was 67%, implying the 'label-in' group's response would be higher. He also confirmed that resolving the COMFORT Toddlers protocol with the FDA is the priority before addressing the related COMFORT Children study.

Jonathan Wolleben asked for clarification on the 'label-in, label-out' criteria for Viaskin Peanut, including the definition of 'patch wear-time experience' and 'robust clinical efficacy.' He also requested the patient percentage breakdown from the EPITOPE trial using this new criteria and an update on the COMFORT Children study.

Answer

CEO Daniel Tassé and Chief Medical Officer Dr. Pharis Mohideen clarified that 'patch wear-time experience' is a holistic measure combining wear duration, day-to-day variability, and overall tolerability. They explained that while specific efficacy numbers for the 'label-in' group are pending FDA alignment, the response rate would exceed the 67% overall rate from the EPITOPE trial. Mr. Tassé also noted that resolving the COMFORT Toddlers protocol is the priority before advancing discussions on the COMFORT Children study.

Jonathan Wolleben of JMP Securities LLC asked for clarification on the 'label-in, label-out' concept for Viaskin Peanut, specifically inquiring about the definition of 'patch wear-time experience,' the parameters for a 'robust clinical efficacy response,' the percentage of EPITOPE patients in each category, and an update on the COMFORT Children study.

Answer

CEO Daniel Tassé and Chief Medical Officer Dr. Pharis Mohideen explained that 'patch wear-time experience' is a holistic measure of a patient's experience over the first 90 days, including wear-time variability and tolerability, not just adhesion. They stated that while specific efficacy numbers for the 'label-in' group could not be shared during ongoing FDA discussions, the response rate would be higher than the 67% overall rate seen in the EPITOPE trial. Mr. Tassé added that the COMFORT Children and Toddlers studies are intertwined, and the company is prioritizing alignment with the FDA on the toddler protocol before advancing the children's study.

Jonathan Wolleben of JMP Securities asked about differences in baseline characteristics for patients who previously participated in Phase I, clarification on achieving steady state by day 14, and whether the FDA had provided any specific safety guidelines for dose escalation.

Answer

Dr. Carole Ben-Maimon, President and CEO, stated that the demographics between the Phase I and Phase II trials were very similar, encompassing a broad population of both ambulatory and non-ambulatory patients. She confirmed that the drug, CTI-1601, reached pharmacokinetic steady state by day 14. Dr. Ben-Maimon also noted that the FDA had not set any a priori safety criteria for moving forward with the next cohort.