Myles Minter

Myles Minter asked about Axsome's approach to managing AXS-17's therapeutic window in epilepsy, specifically concerning potential sedation given its alpha-1 sparing properties and prior observations in generalized anxiety disorder, and whether dose adjustments would be explored.

Answer

Herriot Tabuteau, CEO, confirmed that Axsome is exploring dose ranges through PK/PD modeling to achieve the optimal risk-benefit profile. He acknowledged that while the drug has not been clinically studied in epilepsy patients, initial trials will provide crucial information, and the team is excited about the mechanism of action and receptor specificity.

Myles Minter asked about the therapeutic window for AXS-17 in epilepsy, specifically regarding its alpha-1 sparing properties for reduced sedation compared to benzodiazepines, and whether dose adjustments or the change in indication would make the observed sedation in generalized anxiety disorder acceptable.

Answer

Herriot Tabuteau (CEO, Axsome Therapeutics) stated that Axsome is exploring dose through PK/PD modeling, aiming to pick a dose with the best risk-benefit profile. He acknowledged that AXS-17 has not been studied in epilepsy patients clinically, so initial trials will provide more information, expressing excitement about the mechanism of action and receptor specificity.

Myles Minter questioned the rationale for a single pediatric and adolescent trial for Sunosi in ADHD being sufficient for approval, given FDA guidance often suggests two studies.

Answer

Chief Executive Officer Dr. Herriot Tabuteau explained that there are clinical trial strategies to include both children and adolescents in a single study to determine effective dosing. He suggested that this approach, combined with the existing adult efficacy data, could provide a streamlined path to potential approval.

Myles Minter of William Blair asked if Axsome has had any interaction with the 'Make America Healthy Again Commission' regarding its upcoming report. He also inquired whether the open-label extension for AXS-12 in narcolepsy will include Maintenance of Wakefulness Test (MWT) data.

Answer

Herriot Tabuteau, CEO, confirmed that Axsome has not had any interactions with the commission and is monitoring developments. Regarding AXS-12, he stated that the MWT was not incorporated into the open-label trial, though other measures of excessive sleepiness were used.

Myles Minter asked about any material impact from the Medicare Part D restructure on Auvelity revenues and inquired about the current patient access mix between Medicare and commercial payers.

Answer

Chief Financial Officer Nick Pizzie stated that the company does not expect a significant impact from the Part D changes, though it might slightly alter the evolution of GTN throughout the year. Executive Darren Opland added that Medicare currently represents about 15% of Auvelity's prescription volume and no significant changes to this mix are expected for the current indication.

Myles Minter of William Blair asked if the planned 300-rep sales force expansion for Auvelity anticipates securing a large GPO contract, and whether Axsome has begun payer discussions for AXS-14 (fibromyalgia), focusing on its potential fatigue benefit.

Answer

An executive, likely CCO Ari Maizel, clarified the expansion is based on current market access and primary care growth, not a future contract win. Regarding AXS-14, he confirmed general pipeline discussions with payers occur. COO Mark Jacobson added that the fatigue benefit is considered an important element of the AXS-14 product profile.

Myles Minter of William Blair inquired about the company's regulatory path forward for fasedienol, specifically asking about confidence in potential approval if PALISADE-4 is successful, and whether PALISADE-2 alone could support a regulatory path if PALISADE-4 misses its primary endpoint. He also asked if any blinded PALISADE-4 data provided confidence compared to PALISADE-3.

Answer

President and CEO Shawn K. Singh stated that regulatory outcomes depend on the totality of data, weight of evidence, risk-benefit, and unmet need, and they are mindful of AI's role at the FDA. He reiterated that the primary strategy is to complement PALISADE-2 with PALISADE-4 (if successful) and broader program data, emphasizing a weight-of-evidence approach regardless of PALISADE-4's outcome. He declined to comment on blinded PALISADE-4 data.

Myles Minter of William Blair & Company asked about the enrollment status of the PALISADE IV trial and whether its design could be altered based on PALISADE III results. In a follow-up, he inquired about the recent termination of a clinical trial site in Pennsylvania, asking if it was related to site conduct or enrollment issues.

Answer

President and CEO Shawn Singh clarified that both PALISADE III and IV are actively enrolling and their protocols are locked, with no plans to adjust PALISADE IV. COO Joshua Prince added that the staggered start of the trials aids in training and oversight. Regarding the terminated site, Prince explained that it's part of a continuous evaluation process based on a multitude of factors, including enrollment, protocol execution, and personnel changes, and that sites are sometimes removed if they are not a good fit for the study.

Myles Minter of William Blair asked about the timeline for submitting the Phase IIb protocol for itruvone in Major Depressive Disorder (MDD), whether that study would use self-administration, and if the recent healthy subject data involved self-administration or physician administration.

Answer

CEO Shawn Singh indicated the Phase IIb MDD protocol is well advanced and targeted for submission by year-end or early January, and confirmed the study will involve outpatient self-administration. COO Joshua Prince clarified that the healthy subject studies with Dr. Monti require precise physician administration due to the sensitive equipment used to measure neurocircuitry.

Myles Minter inquired about the rationale for prioritizing the ACVR1C asset (ALN-2232) over inhibin in the obesity pipeline, and whether the target product profile aims for efficacy equivalent to or superior to competitors like Arrowhead.

Answer

Pushkal Garg, Chief Research and Development Officer, explained that ACVR1C was prioritized due to preclinical work, genetics, and emerging data suggesting it is a more potent target than inhibin for overweight and obesity. He noted questions about the monotherapy weight loss magnitude from competitor data and stated Alnylam aims to target unique patient segments or combinations for disproportionate benefit, with results expected by year-end.

Myles Minter inquired about the rationale for prioritizing the ACVR1C asset over inhibin in the obesity pipeline's Phase 1 trial, and whether the target product profile aims for efficacy equivalent to or superior to competitors like Arrowhead.

Answer

Chief Research and Development Officer Pushkal Garg explained that ACVR1C was prioritized due to preclinical work, genetics, and emerging data suggesting it is a more potent target than inhibin for addressing the unmet need in overweight/obesity and type 2 diabetes, complementing GLP-1s. He indicated an aim for superior efficacy, acknowledging questions about the monotherapy magnitude of weight loss from competitor data, and plans to explore unique patient segments and combinations. Phase 1 data is expected by year-end.

Myles Minter (represented by John) asked if there was any read-through from the CMV program miss to other latent vaccine studies in Moderna's pipeline, or if the CMV miss is viewed as an isolated event.

Answer

Stephen Hoge, President, clarified that the CMV program was unique in Moderna's pipeline as the only pivotal Phase 3 study targeting prevention of infection against a latent virus, which was the highest bar. He stated that there is no direct read-through to other programs in the late-stage or prioritized pipeline, as those are focused on preventing disease rather than infection. He noted that mRNA 1647 still has potential in indications like bone marrow transplant CMV reactivation, where the goal is disease prevention.

Myles Minter (William Blair & Company) asked about any potential read-through from the CMV trial miss to Moderna's other latent vaccine studies, or if the CMV miss is viewed as an isolated event.

Answer

President Stephen Hoge clarified that the CMV trial was unique as the only pivotal Phase 3 study against a latent virus targeting prevention of infection, which was the highest bar. He stated that other late-stage or prioritized pipeline programs do not have a similar read-through because they aim to prevent diseases, not infections. He noted that mRNA 1647 might still have an impact in bone marrow transplant patients by controlling CMV reactivation.

Myles Minter asked about the expected timing for an ACIP review of the RSV vaccine and whether the high end of the 2025 revenue guidance includes sales that would require a widened recommendation.

Answer

President Stephen Hoge stated that broader engagement with ACIP would follow FDA approval for the expanded 18-59 high-risk population. CFO Jamey Mock confirmed that while there is a small amount of RSV growth factored into the guidance, no revenue from new product approvals or expanded indications is included in the 2025 forecast.

Myles Minter asked about the Novartis Ianalumab data in Sjogren's disease, specifically if the 5.5-point change from baseline in SDI and the observed placebo responses were within expectations for argenx's UNITY study, and if this data would impact their powering assumptions.

Answer

Tim Van Hauwermeiren, Chief Executive Officer, acknowledged the need for better endpoints in Sjogren's, noting that regulators currently mandate the use of 'cleanest dye' endpoints. He stated that the observed placebo effect was consistent with historical trials and within the expected ballpark when designing and powering their clinical trial.

Myles Minter from William Blair referred to the ianalumab data and placebo responses in Sjögren's disease, asking if the observed 5-5.5 point change from baseline in SDI was within expectations for argenx's UNITY study and if it would alter powering assumptions.

Answer

Tim Van Hauwermeiren, Chief Executive Officer, emphasized the need for better endpoints in Sjögren's, noting that the placebo effect observed in the ianalumab study was consistent with historical trials and within the expected ballpark when designing and powering argenx's clinical trial.

Myles Minter from William Blair followed up on the CIDP safety topic, asking for an updated worsening rate now that over 2,500 patients are on therapy, and inquired if the Phase IV IVIG-to-efgartigimod switch study data is still expected this year.

Answer

CEO Tim Van Hauwermeiren stated that the rate of severe CIDP worsening is not increasing and remains a very small number, emphasizing that therapeutic switches inherently carry this risk in CIDP. He highlighted the transformative functional benefits seen in patients. He also confirmed the IVIG-to-efgartigimod switch study is enrolling well and on track, with data to be presented at a future clinical conference.

Myles Minter asked about the real-world incidence of CIDP disease worsening when patients switch from IVIg to VYVGART Hytrulo.

Answer

Chief Executive Officer Tim Van Hauwermeiren explained that some risk of relapse exists with any treatment switch in CIDP. He noted that the symptom worsening seen with VYVGART is in line with historical switch studies and is a relatively small phenomenon in the real world, with low single-digit reporting. He added that switching one week after the last IVIg dose appears to be a successful strategy, which is being formally documented in a Phase IV switch study.

Myles Minter asked for comments on the hepatic fat fraction data from the Olzarsen CORE studies, given robust serum triglyceride reductions, and whether there were concerns about shunting too much fat to the liver, referencing Waylivra's data showing reductions in hepatic fat fraction.

Answer

Brett Monia, CEO, stated that hepatic fat fraction is a secondary endpoint and will be covered in the detailed AHA presentation and subsequent publication, declining to elaborate further ahead of the official data release.

Myles Minter asked for comments on hepatic fat fraction data from the olzarsen CORE studies, inquiring if it would be presented and addressing concerns about potential shunting of triglycerides to the liver given robust serum triglyceride reductions.

Answer

Brett Monia, CEO, Ionis, stated that hepatic fat fraction is a secondary endpoint and will be covered in the upcoming AHA presentation and publication. He declined to elaborate further ahead of the official data release, noting that the presentation would include a deep dive into primary and secondary endpoints.

Myles Minter asked about CRENESSITY's new patient starts, noting the decrease from 664 in Q2 to 540 in Q3, and inquired if there was a 'warehousing effect,' the expected trajectory for the next quarter, and a return to growth with the sales force expansion.

Answer

Eric Benevich, Chief Commercial Officer, characterized Q3 adoption as consistent and steady, noting that the overall adoption rate has been quicker than anticipated. He explained that Q2 benefited from patients transitioning from an adult open-label study, which slightly boosted numbers. Kyle Gano, Chief Executive Officer, added that the launch continues to exceed expectations across enrollment, persistence, and compliance, with steady adoption and persistency expected to stack volume over time.

Myles Minter asked about CRENESSITY's new patient starts, noting a decrease from 664 in Q2 to 540 in Q3, inquiring if there was a 'warehousing effect' and what trajectory to expect for the next quarter, including a return to growth with the sales force expansion.

Answer

Eric Benevich, Chief Commercial Officer, characterized Q3 adoption as consistent and steady, noting that the overall adoption rate since launch has been quicker than anticipated. He explained that Q2 benefited from patients transitioning from an adult open-label study, which slightly boosted numbers. Kyle Gano, Chief Executive Officer, added that the launch continues to exceed expectations across enrollment, persistence, and compliance, with steady adoption and persistency expected to stack volume over time.

Myles Minter from William Blair & Company asked for the discontinuation rate for Crinesity in its one-year open-label extension studies, as a potential proxy for real-world patient retention.

Answer

Strategic Advisor Eiry Roberts stated that discontinuation rates have been very low, noting that over 95% of patients from the pivotal trials rolled over into the open-label extensions, and many have now been on therapy for over three years with continued low discontinuation. CCO Eric Benevich added that strong insurance coverage and affordability programs should also support high persistency in the real world.

Myles Minter questioned the powering assumptions for the osavampator Phase III studies, given their relatively small size, and asked for clarification on which Phase III studies the company had initiated.

Answer

Chief Medical Officer Dr. Eiry Roberts clarified that the osavampator program includes three key studies. She defended the study size by explaining that extensive research suggests larger MDD trials can increase placebo response and the risk of failure. She affirmed the trials are appropriately powered based on Phase II results.

Myles Minter questioned the decision to advance the M1/M4 agonist NBI-570 into schizophrenia/acute psychosis first, rather than Alzheimer's disease psychosis, and whether this was related to a tolerability signal.

Answer

Chief Medical Officer Eiry Roberts explained that testing NBI-570 in the same adult acute psychosis population as their selective M4 agonist (NBI-568) is a straightforward initial step, while remaining open to other indications later. CEO Kyle Gano added that this approach allows for a valuable comparison between a dual and a selective agonist in the same patient population, which will help the company learn more about this target class.

Myles Minter of William Blair referenced a New England Journal of Medicine correspondence questioning the glucocorticoid dosing threshold used in the Crinecerfont trials and asked if payers were requesting other surrogate metrics.

Answer

CMO Eiry Roberts responded that the trial's definitions were negotiated closely with the FDA for what was a first-of-its-kind study in a heterogeneous population. She expressed strong confidence that the data shows the vast majority of CAH patients can benefit from Crinecerfont and that real-world experience will be important to observe post-launch. The question on payer metrics was not directly addressed.

Myles Minter of William Blair & Company questioned the FDA's rationale for requesting plasma progranulin as a co-primary endpoint and whether this implies it's predictive of functional benefit. He also asked Dr. Ryan Darby if a 25% slowing of cognitive decline would be clinically meaningful and attractive to prescribers.

Answer

CMO Giacomo Salvadore stated the FDA's input underlines progranulin's importance as a biological marker and noted a strong correlation between CSF and plasma levels. Dr. Ryan Darby confirmed a 25% reduction would be meaningful given the lack of other treatments, especially if the safety profile is favorable. CEO Arnon Rosenthal added that latozinemab appears well-tolerated.

Asked if all INVOKE-2 doses are therapeutic, how the trial is powered, how the patient population compares to other AD trials, and if the study duration is sufficient to show a treatment effect.

Answer

All doses in INVOKE-2 are considered potentially therapeutic based on Phase 1 data, and the analysis will pool data. The patient baseline characteristics are comparable to other recent AD trials. The common close design with follow-up to 96 weeks and a blinded LTE is intended to capture treatment effects that may emerge over different timeframes, as the full benefit of the novel mechanism may take longer to manifest.

Sarah, on behalf of Myles Minter from William Blair & Company, asked if all doses in the INVOKE-2 trial are considered therapeutic, how the baseline patient characteristics compare to other AD trials, and if the 48-week study duration is sufficient to observe a clinical effect.

Answer

Dr. Gary Romano, Chief Medical Officer, confirmed that all doses showed target engagement in Phase 1 and are considered potentially therapeutic, with plans to analyze doses both individually and pooled. He described the patient population as comparable to other recent AD trials. He also noted that while a signal is hoped for at 48 weeks, the common close design provides data out to 96 weeks, which is crucial for a novel mechanism.

Myles Minter of William Blair asked two questions: First, whether Neumora expects NMRA-215 to show greater than 15% weight loss in its preclinical model given its superior brain exposure compared to a peer. Second, he asked if confidence in the COASTal program has changed following recent competitor data.

Answer

Joshua Pinto, President, and Bill Aurora, Chief Operating & Development Officer, responded. On NMRA-215, Pinto noted that competitor NLRP3 inhibitors have shown 10-15% weight loss, which is compelling, but declined to give a specific numerical target for NMRA-215, emphasizing that its best-in-class brain exposure gives it a chance to show compelling data. On the COASTal program, Pinto stated confidence has not changed. Aurora added that Navacoprant's selectivity and monotherapy setting differentiate it from competitors, and the enhanced trial measures are proving helpful.

An analyst on behalf of Myles Minter asked for updates on the pharmacokinetic (PK) data from KOASTAL-1, particularly regarding site performance or sex-based differences. He also asked if the option to increase trial enrollment by 25% is still available and included in the timeline guidance.

Answer

Chief Operating and Development Officer Daljit Aurora confirmed that PK exposures in KOASTAL-1 were consistent with the Phase II study and that the 80mg dose is considered efficacious. President Joshua Pinto affirmed that the flexibility to increase the sample size by up to 25% remains for KOASTAL-2 and 3 and has been factored into the updated timeline guidance.

Myles Minter from William Blair asked about Navacaprant's benign safety profile, the 80mg dose selection rationale, and target receptor occupancy. He also inquired about the IP scope of the Vanderbilt Muscarinic franchise beyond M4 PAMs.

Answer

Robert Lenz, Head of R&D, confirmed the 80mg dose achieves ~90% receptor occupancy, based on human PET studies, and attributed the favorable safety profile to high selectivity. Joshua Pinto, CFO, added that the Vanderbilt partnership has focused on M4 PAMs and expressed confidence in the franchise's potential.

Jake, on behalf of Myles Minter from William Blair, asked about felzartamab for antibody-mediated rejection (AMR), inquiring how Biogen is modeling the market and how competitor data has influenced expectations.

Answer

CEO Christopher Viehbacher estimated the addressable AMR market at approximately $1.5 billion annually and expressed confidence that Biogen's asset will be first-to-market. Priya Singhal, EVP & Head of Development, added that the company is expanding into a fourth indication, late microvascular inflammation (MVI), a newly classified rejection phenotype that could add another 5,000-6,000 patients to the potential opportunity.

Myles Minter asked about the powering of the X-TOLE2 study, questioning if the company assumes any erosion in effect size from Phase II to Phase III and whether they might increase enrollment beyond the 360-patient target as a mitigation strategy.

Answer

Chief Medical Officer Dr. Chris Kenney confirmed the study is highly powered (over 99% for the 25mg dose) for the primary endpoint and key secondaries. He noted that while effect size can vary, there is generally good consistency between Phase II and III in epilepsy. Given the robust Phase II data, the company believes the study is appropriately powered and does not plan to increase enrollment.

Myles Minter asked if a specific dose and frequency for the zerlasiran Phase III trial were proposed to regulators. He also questioned how divesiran achieves its efficacy with a modest increase in hepcidin compared to the much higher levels seen with mimetics like Rusfertide.

Answer

Steven Romano, Chief R&D Officer, confirmed that an optimal dose and frequency for zerlasiran were discussed with regulators but are not being disclosed publicly due to the competitive environment. Regarding divesiran, he explained that it works by manipulating endogenous physiology, and the resulting hepcidin increase, while within the physiological range, is 20-40 fold higher than the low baseline in PV patients and clearly correlates with robust clinical outcomes and a favorable safety profile.

Myles Minter asked if a specific dose and frequency for zerlasiran's Phase III trial was proposed to regulators. He also asked for clarification on divesiran's mechanism, specifically how a modest increase in hepcidin can drive efficacy compared to larger increases from mimetics like Rusfertide, and the related safety implications.

Answer

Steven Romano, Chief R&D Officer, confirmed that an optimal dose and frequency for zerlasiran were discussed with regulators but are not being disclosed publicly due to the competitive environment. Regarding divesiran, he explained that its mechanism manipulates the body's own physiology, leading to an increase in hepcidin within the physiological range that is sufficient to correlate with robust clinical outcomes, such as reducing phlebotomy needs. He contrasted this with administering an exogenous hormone and highlighted divesiran's favorable safety profile seen to date.

Questioned if a specific dose and frequency for the zerlasiran Phase III trial were proposed to regulators, and asked for an explanation of divesiran's efficacy mechanism via a modest hepcidin increase compared to the higher levels from mimetics like Rusfertide, including safety implications.

Answer

The company confirmed they discussed the optimal dose and frequency for zerlasiran with regulators but are not disclosing details publicly. For divesiran, they explained that their approach of manipulating endogenous physiology leads to a hepcidin increase within the physiological range that correlates with robust clinical outcomes. They emphasized the drug's favorable safety profile seen so far.

Myles Minter asked if a specific dose and frequency for zerlasiran's Phase III trial were proposed to regulators. He also requested an explanation of divesiran's efficacy mechanism, particularly how a modest hepcidin increase confers benefit, and the related safety implications compared to a hepcidin mimetic.

Answer

Steven Romano, Chief R&D Officer, confirmed that an optimal dose and frequency for zerlasiran were discussed with regulators but are not being disclosed publicly due to the competitive landscape. Regarding divesiran, he explained that it works by increasing the body's own hepcidin production. This increase, while within the physiological range, is significantly above the low baseline in PV patients and correlates with robust clinical outcomes. He highlighted divesiran's favorable safety profile seen so far but was cautious about making direct comparisons to other drugs.

Myles Minter sought clarification on the cystic fibrosis (CF) program, asking whether the 3% FEV1 improvement bar is on an absolute or percent-predicted basis, and if the use of albuterol in the open-label study could impact the readouts.

Answer

President and CEO Joseph Payne clarified that the 3% improvement benchmark is an absolute FEV1 change, consistent with historical precedents in the CF modulator field. He also explained that the pre-treatment with albuterol, a short-acting drug, will not affect the FEV1 analysis as measurements are timed appropriately before the next dose administration.

Myles Minter asked for clarification on the EMA approval timeline for KOSTAIVE, whether keeping the ARCALIS stake allows Arcturus to report on manufacturing orders, and if moving CF manufacturing to ARCALIS for a U.S. trial necessitates an FDA inspection.

Answer

CEO Joseph Payne confirmed a CHMP opinion is expected in December, preceding a Q1 approval. Both Payne and CFO Andrew Sassine stated they cannot report on Meiji's manufacturing orders, as that is up to Meiji and CSL. Sassine emphasized the strategic importance of ARCALIS for the large-scale manufacturing required for the CF program, noting its efficiency and the need for a global supply base.

An analyst on behalf of Myles Minter asked for an update on how the usage of tafamidis (stabilizer) in the MAGNITUDE study is tracking against the original projection of approximately 50%.

Answer

CMO David Lebwohl confirmed that they are seeing 'greater usage' of tafamidis than originally projected, particularly as access expands globally. He framed this as a positive development, as it provides an opportunity to demonstrate a significant benefit on top of tafamidis, which could be a key driver of future use.

A representative for Myles Minter asked about the NTLA-3001 program, specifically how many patients would be dosed before an initial data release and the target serum AAT levels for the lower dose cohorts.

Answer

CEO John Leonard stated that the company will report data when it is 'meaningful, consistent, and interpretable.' He reiterated that the primary objective of the program is to normalize the levels of the wild-type protein, which will be the key measure of success.

Myles Minter from William Blair inquired about the regulatory process, specifically when the FDA requested unblinded frataxin data. He also asked for the lower limit of quantification on the frataxin assay and whether the patient with the allergic reaction had received a single dose or multiple doses.

Answer

President and CEO Dr. Carole Ben-Maimon confirmed the FDA requested unblinded data but did not elaborate on the timing or motivation behind the request. She explained that frataxin levels in early-onset FA patients can be very low, sometimes falling below the assay's limit of quantification. Dr. Ben-Maimon clarified that the patient who experienced the allergic reaction had participated in prior trials and received more than a single dose.

Myles Minter of William Blair & Company sought clarification on whether the FDA had formally proposed the Type A meeting as a recommendation in its letter. He also asked for insight into the specific questions Minerva submitted to the FDA for that meeting, as the company is required to provide them in its request.

Answer

CEO Remy Luthringer confirmed that the FDA did propose the Type A meeting. He explained that the list of questions Minerva submitted for the meeting is very limited and focuses exclusively on the specific points the FDA raised in its Refusal to File letter, in line with the standard procedure for a Type A meeting.