Paul Matteis

Paul Matteis inquired about the integration of the Amicus business into BioMarin's commercial infrastructure, specifically how much existing reps and relationships can be leveraged, and sought clarification on Brian Mueller's earlier comment about updating models.

Answer

Alexander Hardy, Chief Executive Officer, explained that post-close, Amicus products will integrate directly into BioMarin's enzyme therapy business unit, leveraging the existing go-to-market model and driving significant synergies. Greg Friberg, Chief R&D Officer, clarified that Brian Mueller's comment about updating models was due to a mixed bag of analysts having or not having Amicus revenues included in their BioMarin models, not a specific modeling error.

Paul Matteis asked about the integration of the Amicus business into BioMarin's commercial infrastructure, specifically how much existing reps and units can be leveraged versus building new. He also sought clarification on Brian Mueller's earlier comment about not updating models for the Amicus deal yet.

Answer

Alexander Hardy, CEO, stated that post-close, Amicus products (Galafold, Pombiliti, Opfolda) will integrate directly into BioMarin's enzyme therapy business unit, fitting perfectly with the existing go-to-market model and offering tremendous top-line and operational synergies. He expects a Q2 close and more details then. Brian Mueller, Chief Financial Officer, clarified that his comment about not updating models was solely due to the mixed bag of analysts already including or not including Amicus revenues, not because anything was being missed.

Paul Matteis of Stifel Financial Corp. asked for confirmation that the competing program referenced for BMN 333 is TransCon CNP and inquired about the safety profile, specifically whether increased exposure raises the risk of hypotension.

Answer

Gregory Friberg, EVP and Chief R&D Officer, confirmed the competing agent was the one referenced in the cited publication. He stated that the safety profile in the healthy volunteer study was as expected, with no unexpected issues. He added that genetic data from individuals with naturally high CNP levels is reassuring, as they primarily exhibit increased height without other organ system complications.

Paul Matteis of Stifel asked for confirmation that BMN-333's competing program is TransCon CNP and inquired about the drug's safety profile, particularly the risk of hypotension with increased exposure.

Answer

Gregory Friberg, EVP and Chief R&D Officer, confirmed the competing agent was the one referenced in the cited pharmacology journal. He stated that BMN-333's safety profile in the healthy volunteer study showed nothing unexpected and highlighted that genetic data from individuals with naturally high CNP levels is reassuring, as they primarily exhibit increased height without other organ system issues.

Paul Matteis from Stifel asked for clarification on two points: whether VOXZOGO's global net price has changed recently and if the planned pivotal trial for BMN 333 is designed to show superiority or non-inferiority to VOXZOGO.

Answer

Brian Mueller, CFO, confirmed that recent VOXZOGO revenue trends are due to order timing, not pricing changes. Greg Friberg, Chief R&D Officer, provided a direct answer on the pipeline question, stating, 'Yes, we are looking for superiority' for BMN 333 in its comparative trial against VOXZOGO.

Paul Matteis asked if the reaffirmation of long-term guidance, despite increased competition in achondroplasia, implies the original guidance was conservative. He also asked what aspects of the long-term vision the Street might be missing.

Answer

EVP, Chief Financial Officer Brian Mueller stated the guidance was not conservative but that the company's model could absorb the new competitive data by adjusting assumptions. President and CEO Alexander Hardy added that the long-term outlook, including the mid-teen CAGR and $5 billion skeletal conditions opportunity, is based on modest penetration in new indications and excludes the potential impact of IP defense.

Paul Matteis asked about CRENESSITY's early 2026 performance, specifically inquiring about the first six weeks of sales and the observed slight decline in patient start forms from Q2 to Q4 2025, seeking insight into the near-to-midterm plateau for patient adoption.

Answer

CFO Matt Abernethy stated that while the company anticipates meaningful, steady new patient additions and strong growth for CRENESSITY in 2026, they are not providing specific guidance due to the early stage of the launch, similar to INGREZZA's initial years. He emphasized positive positioning for future years.

Paul Matteis asked about CRENESSITY's commercial performance, specifically inquiring about early 2026 trends, the potential plateau of the patient adoption rate in the near to midterm, and how the fourth-quarter revenue compared to STAR forms.

Answer

Matt Abernethy, Chief Financial Officer, stated that 2025 was a tremendous year for CRENESSITY, exceeding $300 million in sales. He anticipates meaningful, steady new patient additions leading to strong growth in 2026, though specific guidance is not yet provided due to the learning nature of the launch. Eric Benevich, Chief Commercial Officer, added that CRENESSITY's guidance might not take as long as INGREZZA's due to it being a rare disease with a more focused prescriber base, noting better-than-expected adoption, reimbursement, and persistency.

Paul Matteis inquired about the implications of the upcoming Oscado price under the IRA for Neurocrine Biosciences, specifically how INGREZZA's gross-to-net, which is approaching mid-to-high 30%, might be affected by the small biotech exemption.

Answer

Matt Abernethy, Chief Financial Officer, explained that CMS's Oscado pricing announcement is expected in late November. He noted that health plans and PBMs would likely use varied strategies for IRA-affected and non-IRA medicines. Abernethy emphasized INGREZZA's patient stickiness and the company's strategy to maximize new patient starts before its IRA year. Eric Benevich, Chief Commercial Officer, added that there is room on formularies for MFP-adjacent products and that maximizing patient share is crucial, which is a rationale for the INGREZZA sales force expansion.

Paul Matteis inquired about the implications of the Inflation Reduction Act (IRA) for Neurocrine Biosciences, specifically regarding the upcoming Oscado price and how INGREZZA's increasing gross-to-net discount, now in the mid-to-high 30%, might change the worst-case scenario given the small biotech exemption.

Answer

Matt Abernethy, Chief Financial Officer, explained that the company expects to learn Oscado's pricing in November and anticipates health plans and PBMs will use varied strategies. He emphasized INGREZZA's patient stickiness and the focus on maximizing new patient starts before 2027. Eric Benevich, Chief Commercial Officer, added that there's room for MFP-adjacent products on formularies and that maximizing patient share is a key rationale for the INGREZZA sales force expansion.

Paul Matteis from Stifel Financial Corp. asked about the concentration of Crinesity prescribing, questioning whether it's mainly from academic centers of excellence or more broadly distributed in the community.

Answer

CEO Kyle Gano and CCO Eric Benevich explained that the CAH patient population is not highly concentrated. While Centers of Excellence are important, many patients are treated by pediatric and community endocrinologists who may only have one or two CAH patients. They noted most prescribers to date have initiated one or two patients, and the new patient additions have been very steady week-over-week, indicating broad, consistent adoption rather than a concentrated bolus.

Paul Matteis inquired about INGREZZA's growth outlook for the second quarter and beyond, and asked whether the strong initial number of CRENESSITY prescriptions represented a one-time bolus or a sustainable trend.

Answer

CEO Kyle Gano confirmed that while Q1 had challenges, a record number of new patient starts for INGREZZA provides strong momentum for growth acceleration in Q2 and the rest of 2025. Chief Commercial Officer Eric Benevich added that for CRENESSITY, it is too early to define a trend after one quarter, but the initial adoption exceeded the company's expectations.

Paul Matteis questioned the INGREZZA sales guidance, highlighting the significant deceleration from 26% growth in 2024 to a guided sub-10% sequential growth, asking if this signals a fundamental change in the market.

Answer

Chief Commercial Officer Eric Benevich reiterated the record growth of INGREZZA in 2024 and stated the 2025 guidance reflects continued VMAT2 category growth while accounting for an increasingly complex payer environment and competitive dynamics. CEO Kyle Gano added that the Q4 sales force expansion caused some disruption but is expected to drive growth in the second half of 2025 and beyond, emphasizing the product's differentiated profile and the large untreated patient population.

Paul Matteis from Stifel asked about Neurocrine's business development philosophy, specifically its capacity and strategic appetite for larger, transformative deals versus its historical strategy of smaller acquisitions.

Answer

CEO Kyle Gano responded that the company feels no immediate pressure to pursue deals of any size due to its deep and diversified internal pipeline, with a current focus on executing late-stage programs. CFO Matt Abernethy added that Neurocrine maintains strong financial flexibility, with significant cash and a clean balance sheet, providing capacity for future opportunities.

Julian, on behalf of Paul Matteis, asked about the potential for additive benefit with setmelanotide for Prader-Willi Syndrome (PWS) patients who may also be on background GLP-1 therapy, based on the mechanism of action.

Answer

David Meeker, Chairman, CEO and President, Rhythm Pharmaceuticals, noted that patients on stable diazoxide doses are allowed in the trial. He explained that setmelanotide (MC4R agonists) and diazoxide likely work through different, non-redundant mechanisms, suggesting a possibility for complementary effects. He also highlighted that there are no overlapping toxicities, so they can be used together safely, and the trial aims to provide insights into this combination.

Julian, on behalf of Paul Matteis, asked about the potential for additive benefit with setmelanotide for PWS study patients who may also be on background GLP-1 therapy, based on the mechanism.

Answer

David Meeker, Chairman, CEO and President, clarified that patients on diazoxide (not GLP-1, but a similar concept of background therapy) are allowed in the PWS trial if stable. He believes setmelanotide and diazoxide are not redundant and could be complementary, with no overlapping toxicities, expressing interest in learning from the trial's insights.

Paul Matteis of Stifel Financial Corp. asked about the RM-718 study, focusing on the expected patient mix and key factors for comparing its efficacy to other drugs. He also questioned whether the MC4R agonist mechanism's efficacy has been maximized.

Answer

David Meeker, Chairman, President & CEO, stated that the RM-718 trial will enroll patients aged 12 and older, and the key question is identifying the right dose for the weekly formulation, not its efficacy as an MC4 agonist. He affirmed his belief that the mechanism's efficacy has likely been maxed out, with dose adjustments potentially mattering only on the margins for patients with very different body weights.

Paul Matteis from Stifel asked about any safety signals, particularly idiosyncratic ones like liver issues, from the ongoing bivamelagon study and sought clarification on the 10% efficacy bar for the shorter Phase II trial.

Answer

David Meeker, CEO, confirmed that based on a blinded view, there are no significant safety signals of concern in the bivamelagon study, including no serious adverse events related to liver function tests. Regarding the efficacy bar, he explained that while 10% is a reasonable target based on setmelanotide's Phase II data, the full context of the data will be important, and he is more interested in individual patient responses than the mean value alone.

Paul Matteis asked about the anticipated evolution of launch metrics, specifically if the company would report actual doses prescribed versus start forms. He also sought confirmation on the insurance process, including initial and subsequent paid doses, and its implications for launch kinetics.

Answer

Nicole Sweeny, Chief Commercial Officer, reiterated the Quick Start program's function, confirming immediate access and the process for paid shipments. She stated that initial prescriptions typically include two boxes, with refills dependent on physician discretion. She also indicated that future KPIs would evolve to include repeat prescribers, refills, and product utilization.

Paul Matteis inquired about the expected evolution of launch metrics, specifically if actual doses prescribed would be reported later in the year, and sought confirmation on the insurance process regarding initial and subsequent paid doses, and how this informs launch kinetics.

Answer

Nicole Sweeny, Chief Commercial Officer, confirmed that future KPIs would evolve to include repeat prescribers, refills, and product utilization per patient. She reiterated that the quick start program provides immediate access, with KalVista facilitating paid access. Sweeny confirmed that patients typically receive two boxes for their initial prescription, and refills are often written 'as needed' to allow physicians flexibility based on disease burden.

Paul Matteis asked about the anticipated evolution of launch metrics, specifically if future reporting would include actual doses prescribed rather than just start forms. He also sought confirmation on the insurance process regarding initial and subsequent paid doses and how this informs launch kinetics.

Answer

Nicole Sweeny, Chief Commercial Officer, stated that future KPIs would evolve to include repeat prescribers, refills, and product utilization/consumption per patient. She clarified that the quick start program provides immediate no-charge access, with KalVista staff working to secure paid access, and a second shipment provided if the exception process takes longer. Initial prescriptions typically involve two boxes, with refills dependent on the physician's p.r.n. prescription and the patient's burden of disease.

An analyst on behalf of Paul Matteis questioned the company's confidence in the safety profile of the M4 PAM NMRA-861, specifically in contrast to the previously halted NMRA-266 molecule from the same Vanderbilt deal.

Answer

Joshua Pinto, President, and Nicholas Brandon, Chief Scientific Officer, addressed the question. Pinto emphasized that all M4 PAM compounds (NMRA-861, NMRA-898, and the prior NMRA-266) are structurally distinct. Brandon added that the key safety hurdle was the unexpected convulsions seen in rabbits with NMRA-266. He stated that both NMRA-861 and NMRA-898 have been tested in rabbits at doses and exposures exceeding where issues occurred with NMRA-266, with no convulsions observed, thereby de-risking the new molecules.

Paul Matteis questioned why management seemed confident in the conduct of KOASTAL-1 before its failure and what was missed in hindsight. He also raised concerns about the cash runway appearing tight relative to the upcoming trial readouts.

Answer

Chief Operating and Development Officer Daljit Aurora acknowledged the outsized placebo response and highlighted the new, enhanced monitoring measures. Chief Financial Officer Michael Milligan addressed financials, stating the current cash runway extends into mid-2026 and that the company is always opportunistically evaluating funding options, including debt, BD, and equity. President Joshua Pinto added that the team is now applying even more diligent oversight.

Julian, on behalf of Paul Matteis at Stifel, asked for logistical details on how subcutaneous Leqembi initiation would work in practice, including the administration setting and its value proposition given ARIA concerns.

Answer

Priya Singhal, EVP & Head of Development, stated that trials were designed to allow for self-administration and that human factors studies were positive. Alisha Alaimo, President & Head of North America, explained the approach will be flexible and tailored to the patient and physician. Experienced prescribers may be comfortable with at-home initiation, while others may prefer in-office settings, with Biogen exploring home support options.

Julian, on behalf of Paul Matteis from Stifel, asked about the practical logistics of subcutaneous Leqembi initiation, specifically how it would be administered (in-center vs. at-home) given concerns over ARIA.

Answer

Priya Singhal, EVP & Head of Development, explained that trial data supports flexible administration options, including self-administration. Alisha Alaimo, President & Head of North America, elaborated that the choice will be tailored to the patient and physician's comfort level. Experienced prescribers may be comfortable with at-home initiation, while others may prefer an in-office start, ensuring flexibility based on individual patient needs.

Paul Matteis asked whether Biogen can achieve sustainable revenue growth with its current portfolio or if it requires a major pipeline success or external business development.

Answer

President and CEO Christopher Viehbacher stated that while the declining MS franchise is a headwind, the combination of growth from new launches, led by LEQEMBI, and the maturing pipeline can return the company to growth. He noted that for Biogen, a '$1 billion product really moves the needle,' suggesting that a combination of internal execution and potential BD will drive the future.

Paul Matteis asked whether Biogen is strategically shifting away from high-risk neuroscience towards immunology and if its business development focus reflects this change.

Answer

CEO Christopher Viehbacher clarified that Biogen remains heavily invested in neuroscience (Alzheimer's, Parkinson's) but is expanding into adjacent areas to diversify. He views immunology as a natural extension of their MS expertise and a key R&D growth area. The strategy is to leverage existing capabilities, like their rare disease commercial model, rather than making a wholesale shift away from neuroscience.

Paul Matteis from Stifel Financial Corp. asked about the clinical criteria physicians are using to identify 'stabilizer progressors' and the potential percentage of stabilizer patients who could be candidates for Amvuttra.

Answer

CCO Tolga Tanguler cited research suggesting a third to half of patients on stabilizers eventually progress. CMO Pushkal Garg explained that physicians assess a constellation of factors, much like in general heart failure management—including biomarkers, echo data, and symptoms—rather than a single indicator, and expects formal guidelines to evolve over time.

Paul Matteis asked about the percentage of prescribers who can administer AMVUTTRA without a P&T committee review and the uptake from that group. He also questioned if Medicare fee-for-service patients could eventually receive their first dose on the same day of prescription.

Answer

Chief Commercial Officer Tolga Tanguler explained that same-day administration is not feasible due to the coordination required for a buy-and-bill, HCP-administered product. He did not provide a specific metric on P&T committees but emphasized that the process for getting patients on therapy is effective across all payer types, thanks to the drug's profile for a severe disease and the company's value-based agreements.

Paul Matteis asked if Alnylam expects insurers to cross-manage formularies between Part B and Part D drugs, and whether Part D stabilizers could be used as a step-edit for Part B AMVUTTRA.

Answer

Chief Commercial Officer Tolga Tanguler responded that despite noise, Alnylam expects payers to cover the product for this rare, devastating condition. He anticipates payer mix dynamics will be similar to what was seen with polyneuropathy and that AMVUTTRA's favorable patient affordability profile will be a key driver of uptake.

Paul Matteis asked for clarification on current prescribing dynamics, specifically the prior authorization hurdles a cardiologist might face when prescribing AMVUTTRA for a mixed-phenotype patient.

Answer

Chief Commercial Officer Tolga Tanguler explained that the primary difference lies in the diagnostic pathway, not payer access. Polyneuropathy requires genetic testing and a neurological workup, whereas cardiomyopathy often relies on scintigraphy. He emphasized that most patients ultimately secure reimbursement, making the diagnostic process the main distinguishing factor.

Paul Matteis of Stifel Financial Corp. inquired about Compass's engagement with the FDA post-data, potential scenarios for an accelerated filing path for COMP360, and whether they would engage with senior FDA or HHS officials.

Answer

CEO Kabir Nath confirmed a Q3 meeting is requested with the FDA to discuss accelerated pathways, citing two positive late-stage studies. While not predicting the outcome, he noted supportive signals from the administration and confirmed engagement with senior officials. CCO Lori Englebert added that they are educating receptive members of Congress. Nath also revealed they have applied for the commissioner's national priority review voucher.

Paul Matteis of Stifel inquired about the company's base case for the placebo effect in the Phase III trial and how the Data and Safety Monitoring Board (DSMB) would differentiate a true suicidality signal from statistical noise.

Answer

Dr. Guy Goodwin, Chief Medical Officer, responded that the placebo effect estimate is based on previous studies and their own Phase IIb data, noting that a MADRS score difference over 3 would be clinically significant. Regarding suicidality, he clarified that the DSMB's assessment is a nuanced medical judgment based on the severity, timing, and evolution of each event, not just on raw numbers.

Paul Matteis of Stifel Financial Corp. asked about the rationale for using a propensity-matched versus propensity-weighted analysis for AMT-130, whether this was an FDA request, and how investors should think about the clinical bar for a meaningful slowing of disease progression.

Answer

Chief Medical Officer Walid Abi-Saab explained the shift to propensity score matching aligns with the FDA's stated preference, but assured that both matched and weighted analyses will be submitted and are expected to yield similar results. He noted that KOLs consider a 25-30% reduction in disease progression to be significant, and uniQure aims for a result that is both clinically meaningful and sufficient for regulatory approval.

Paul Matteis asked about uniQure's approach in its recent meeting with the FDA regarding the statistical analysis plan (SAP), the rationale for using 3-year versus 2-year natural history data, and whether waiting for meeting minutes was standard procedure or indicated a need for clarification.

Answer

CEO Matthew Kapusta clarified that waiting for meeting minutes is simply 'good housekeeping' and best practice. CMO Dr. Walid Abi-Saab explained that the primary analysis will focus on 3-year data because the majority of patients will have reached that timepoint, making it the most relevant dataset to demonstrate a continued effect, though all data (2-year, 4-year) will be considered.

Paul Matteis of Stifel Financial Corp. asked about the focus on visual adverse events (AEs) with the Orexin program, questioning if the attention is warranted and how to differentiate between a benign versus a clinically significant signal for regulatory and commercial purposes.

Answer

Richard Pops, Chairman & CEO, stated the focus on visual AEs is primarily from Wall Street, not clinicians, and highlighted that the VIBRANCE-one study's rigorous ophthalmic exams showed no changes. Marcus Yountz, VP of Clinical Development, added that mild AEs not interfering with daily activity are not overly concerning. Craig Hopkinson, EVP and Chief Medical Officer, noted the Data Safety Monitoring Board's approval to proceed. Pops also clarified the full safety database is not yet closed and will be presented at World Sleep.

James Condulis, on behalf of Paul Matteis, asked for an update on the safety profile of the orexin program on a blinded basis, with a specific focus on the instances of visual disturbances observed in prior data.

Answer

CEO Richard Pops stated it was inappropriate to comment on blinded data but confirmed that an independent Data Safety Monitoring Board (DSMB) is actively overseeing safety. He noted the DSMB has met regularly and has consistently recommended the study continue without any modifications.

Paul Matteis inquired about the orexin program, ALKS 2680, asking how Alkermes is monitoring adverse events and retention in the blinded NT2 study and about the company's confidence in the drug's therapeutic index.

Answer

CEO Richard Pops explained that while the studies are blinded, safety is continuously monitored by an internal team and an independent Data Safety Monitoring Board (DSMB). He stated that the company expects high retention and has seen no data to suggest otherwise, expressing confidence in the therapeutic index based on a clear dose response observed in the Phase Ib program.

Paul Matteis followed up on the 2025 EBITDA guidance, asking for the biggest mismatch versus consensus beyond royalty revenues, and inquired about the biggest perceived risk in translating early ALKS 2680 data to Phase 2 success in NT2 and IH.

Answer

COO Blair Jackson reiterated that the primary mismatch in Street models is the misunderstanding of the manufacturing and royalty revenue transition, along with increased R&D spend for ALKS 2680. CEO Richard Pops identified the biggest risk for ALKS 2680's Phase 2 studies as the inherent variability of the NT2 and IH patient populations, though he noted the drug has already shown a meaningful, dose-dependent effect on the MWT endpoint.

Paul Matteis asked about the potential timeline from receiving top-line epilepsy data for azetukalner to filing an NDA, and requested color on the key metrics being tracked in the X-TOLE2 study.

Answer

President and CEO Ian Mortimer stated that the timeline from top-line data to an NDA filing is approximately six months, with the clinical data being the critical path item. He explained that key metrics tracked for study quality include patient baseline characteristics, diary compliance, and rollover rates into the open-label extension, all of which are showing consistency with the successful Phase IIb X-TOLE study.

Paul Matteis asked about the enrollment status and timing for the first Phase III epilepsy data readout and whether potential negative results from a competitor's Kv7 trial in bipolar mania would affect Xenon's plans for bipolar depression.

Answer

President and CEO Ian Mortimer confirmed the guidance for Phase III epilepsy data remains in the second half of 2025 and will be narrowed closer to the date. He stated that competitor results in bipolar mania will not impact their plans, as Xenon believes the scientific rationale for Azetukalner is stronger in bipolar depression. Chief Medical Officer Dr. Chris Kenney added that genetic links between Kv7 and bipolar disorder appear even stronger than for MDD, and prior data for other Kv7 drugs in mania was unconvincing, making depression a more compelling target.

Julian, on behalf of Paul Matteis from Stifel, asked about the primary risks associated with the European approval and reimbursement for trofinetide, and inquired about the role of business development in the company's current priorities.

Answer

CEO Catherine Owen Adams expressed high confidence in the EMA approval process, stating it is proceeding as expected. Regarding business development, she confirmed that Acadia is 'very interested in transacting' for assets in high-unmet-need areas, including rare diseases beyond neurology. CFO Mark Schneyer added that the company is well-positioned to act on strategic deals that offer good financial value.

An analyst on behalf of Paul Mattis of Stifel asked about the expected return on investment (ROI) for the NUPLAZID direct-to-consumer (DTC) campaign in 2025, given the strong execution in 2024.

Answer

Executive Brendan Teehan stated that since the campaign began in mid-August, the vast majority of its benefits will be realized starting in 2025. He emphasized that the lifetime value of a NUPLAZID patient extends beyond 2025, so the full ROI will not be realized in a single year. While enthusiastic about early indicators like website visits, the primary impact on new patient starts and their continuing value will be seen in 2025 and beyond.

Speaking on behalf of Paul Matteis, Julian asked for more color on what gives Acumen confidence it has enrolled the 'right patients' in the ALTITUDE trial, given the rapid enrollment. He also requested further details on the subcutaneous study results and whether they met expectations.

Answer

Dr. James Doherty, President and Chief Development Officer, expressed high confidence in the patient population due to robust entry criteria and the use of high-quality clinical sites. Regarding the subcutaneous data, he stated the results were positive, with no new safety signals and pharmacokinetic exposure levels that support continued development. Dr. Eric Siemers, CMO, added that the ALTITUDE patient baseline characteristics appear very similar to the lecanemab studies and Acumen's own Phase I trial.

Paul Matteis questioned the strategic rationale for focusing the pipeline on high-risk areas like neurodevelopmental disorders (NDDs) and developmental and epileptic encephalopathies (DEEs), and asked about the timeline for proof-of-concept data.

Answer

CEO Barry Greene explained the new focus leverages key learnings and molecules with specific pharmacology, targeting well-validated mechanisms like NMDA NAMs. CMO Laura Gault added that for DEEs, there is strong preclinical and clinical validation for GABA PAMs. For NDDs, the strategy is to target associated behavioral symptoms like anxiety and sleep, not the core symptoms of the disorder. For SAGE-319, results from the MAD study are expected by late 2025, which will provide data on its profile and therapeutic index.

Paul Matteis asked for the rationale behind changing the primary endpoint for the dalzanemdor study in Huntington's disease and whether the new endpoint would be acceptable to the FDA.

Answer

CEO Barry Greene positioned the change as an application of learnings from the SURVEYOR study. CMO Laura Gault elaborated that while the original composite endpoint showed small differences, the Symbol Digit Modalities Test (SDMT) showed directionally positive signals. She described the SDMT as a reliable and widely used measure of executive function, making it a suitable new primary endpoint.

Paul Matteis sought clarification on the LIFT-AD study's path to registration, asking if both cognitive and functional endpoints are required and about the flexibility in selecting the functional scale. He also inquired if the company had observed any correlation between baseline disease severity and baseline P300 latency in the ACT-AD data.

Answer

Chief Medical Officer Hans Moebius explained that they have ample time to select the co-key secondary endpoint for LIFT-AD, as the unblinded ACT-AD results will inform the statistical analysis plan before unblinding LIFT-AD. He noted they have not specifically analyzed P300 latency by baseline disease severity. President & CEO Mark Litton reiterated that the 77-patient ACT-AD study is exploratory for secondary endpoints.