Andrew Tsai

Andrew Tsai inquired about the hypothetical placebo-adjusted delta that would have triggered a trial upsizing during the Voyage interim analysis and confirmed no other interim stopping scenarios. He also asked about the potential for sharing Part B open-label extension data for DT120 ODT's durability by the early Q3 Voyage data readout.

Answer

Robert Barrow, CEO of Definium Therapeutics, clarified that the Voyage interim analysis was a blinded sample size re-estimation, preventing any unblinding or inferential testing, thus no information on placebo-adjusted delta was available. He confirmed no stopping for futility or success scenarios. Regarding Part B data, Mr. Barrow stated the company is focused on accruing sufficient data to confidently share insights on durability, but no firm commitment on the exact timing of presentation has been made.

Andrew Tsai inquired about the interim sample size re-estimation for the Voyage study, specifically asking about hypothetical scenarios like upsizing or stopping for futility/success. He also asked about the potential for piecemealing Part B open-label extension data to showcase durability and the timeline for sharing this information.

Answer

Robert Barrow, CEO of Definium Therapeutics, clarified that the Voyage interim analysis was a blinded sample size re-estimation, not involving unblinding or inferential testing, and confirmed no scenarios for stopping for futility or success. He expressed confidence in the study's power. Regarding Part B data, Mr. Barrow stated the focus is on durability and accruing sufficient representative data before committing to a specific presentation timeline.

Andrew Tsai inquired about Sarepta's siRNA readout strategy, specifically when the company plans to initiate pivotal studies for DM1 and FSHD, whether this would occur immediately after full MAD data or require further dose expansion, and the latest thinking on pursuing an accelerated approval pathway for these indications.

Answer

Louise Rodino-Klapac, Executive VP, Chief Scientific Officer, and Head of Research and Development, confirmed that Sarepta is working towards Phase III studies, with the ongoing MAD study informing the design, and manufacturing preparations are underway for commercial-ready material. She stated the company is pursuing the fastest possible approach, considering accelerated approval based on specific circumstances, and collecting appropriate functional data to support both accelerated and traditional approval pathways.

Andrew Tsai questioned Sarepta's siRNA readout strategy, specifically the timeline for initiating pivotal studies for DM1 and FSHD, whether dose expansion work is needed, and the company's current stance on pursuing an accelerated approval pathway for these indications.

Answer

Executive VP, Chief Scientific Officer, and Head of Research and Development Louise Rodino-Klapac confirmed work towards Phase 3, with MAD study data informing design and manufacturing readiness. She stated the company is pursuing the fastest approach, whether accelerated or traditional approval, collecting appropriate functional data for both.

Andrew Tsai asked about the potential worst-case scenario of ELEVIDYS being pulled from the market following the patient death, particularly in light of a recent FDA leadership appointment.

Answer

President and CEO Douglas Ingram expressed confidence that the FDA will remain a science-driven organization. He emphasized that the evidence for ELEVIDYS's approval was remarkable and has only grown stronger with new data. He stated there is no reason to believe the tragic but unique safety event, in the context of over 800 patients dosed and a laudable safety profile for an AAV gene therapy, would motivate such a drastic action.

Andrew Tsai asked about BridgeBio's expectations for Priority Review Vouchers (PRVs) as a source of non-dilutive capital, inquiring which pipeline drugs or indications are eligible and when they are expected to be received, given their current market value.

Answer

President and CFO Tom Trimarchi expressed enthusiasm for the reauthorized PRV program, noting its success in incentivizing rare disease investments. He confirmed three eligible programs: BBP-418 for limb-girdle, infigratinib for achondroplasia, and the Canavan gene therapy program, all expected to receive a PRV upon approval. He also mentioned potential for more PRV-eligible programs within the broader Bridge ecosystem (GondolaBio).

Andrew Tsai asked about BridgeBio's guidance and expectations for Priority Review Vouchers (PRVs) as a source of non-dilutive capital, identifying eligible pipeline drugs/indications and their expected receipt timelines.

Answer

Tom Trimarchi, President and CFO, confirmed that the PRV program has been reauthorized and is a significant incentive. He identified three programs eligible for PRVs upon approval: BBP-418 for limb-girdle, infigratinib for achondroplasia, and the Canavan gene therapy program. He also noted the potential for more PRV-eligible programs within the broader Bridge ecosystem.

Andrew Tsai asked about BridgeBio's accumulation of real-world evidence suggesting Atrobi's better efficacy over Tafamidis, and the company's thoughts on conducting a head-to-head study to fully prove this, also considering its potential to mitigate risks from future Tafamidis generics.

Answer

Neil Kumar, CEO and Founder, BridgeBio Pharma, stated that Atrobi has already demonstrated superior stabilization across multiple in vitro assays and clinical measurements. He emphasized focusing on Atrobi's unique properties, such as its impact in the variant population, AFib, and the cardiorenal axis, rather than a costly head-to-head trial. He believes a double-blind head-to-head for serum TTR or anti-proBNP wouldn't significantly drive market share and that real-world evidence is more impactful for the prescribing community.

Andrew Tsai asked about BridgeBio's thoughts on conducting a head-to-head study for Attruby against Tafamidis, given accumulating real-world evidence suggesting better efficacy, and if such a study could mitigate the risk of future Tafamidis generics.

Answer

Neil Kumar, CEO and Founder, BridgeBio Pharma, stated that Attruby has already demonstrated superior stabilization across multiple in vitro and clinical metrics. He emphasized focusing on Attruby's unique properties, such as its impact in the variant population, AFib, and the cardiorenal axis, rather than a costly head-to-head trial that may not significantly drive market share. Kumar believes Attruby's competitive pricing and differentiated data would protect it against Tafamidis generics, stressing the increasing importance of real-world evidence for clinicians and regulators.

Andrew Tsai of Jefferies asked how BridgeBio operationally leverages new data to drive adoption, requested a summary of planned data generation for Atruvio over the next 1-2 years, and asked for quantification of inventory changes in Q2.

Answer

CEO Neil Kumar explained the strategy involves publications, medical affairs engagement, and real-world evidence studies to increase scientific share of voice, with a future focus on rapidity of response. CCO Matthew Outten addressed inventory, stating that days of inventory on hand declined from Q1 to Q2 as distributors grew confident in the company's 'just-in-time' supply model, which reduces their need to hold large stock.

Andrew Tsai asked about the enrollment progress for the TILVANCE-301 trial, the potential timing for first-line melanoma data with the AMTAGVI PD-1 combination, and the target objective response rate (ORR) and progression-free survival (PFS) compared to PD-1 monotherapy.

Answer

Frederick Vogt, Interim CEO and President, indicated an early interim ORR read is expected in the near term, but couldn't commit to 2026 for the large TILVANCE-301 study, noting that an announcement would imply a supplemental Biologics License Application. Friedrich Finckenstein, Chief Medical Officer, explained that the benchmark for ORR and PFS is pembrolizumab monotherapy data from KEYNOTE-006 (mid-30s ORR), and Iovance's C-02 Cohort 1A showed response rates up to 60%, providing confidence.

Andrew Tsai inquired about the potential timing for first-line melanoma data from the TILVANCE-301 trial, specifically regarding Amtagvi in combination with PD-1, and asked for benchmarks on objective response rate (ORR) and progression-free survival (PFS) compared to PD-1 monotherapy.

Answer

Dan Kirby, Chief Commercial Officer, indicated an early interim ORR read for TILVANCE-301 is near-term but couldn't commit to 2026 timing. Frederick Vogt, Interim CEO and President, explained that the benchmark for ORR and PFS is the KEYNOTE-006 trial (pembrolizumab monotherapy, mid-30s ORR), noting confidence from IOV-COM-202 Cohort 1A data showing ORR up to 60% for the combination.

Andrew Tsai of Jefferies questioned if the net cash burn guidance of less than $245 million for the next year implies a significant improvement in gross margins starting as early as Q3, and sought color on the drivers for this potential improvement.

Answer

Interim CEO Frederick Vogt confirmed the net cash burn guidance and affirmed that improving gross margins is a key objective of the recent strategic restructuring. He stated that margins are expected to increase through operational excellence initiatives, reduced cost of sales, and higher manufacturing capacity utilization at the company's internal facility as revenue volume grows.

Andrew Tsai asked to identify the primary bottleneck for accelerating the commercial launch uptake, if it is not patient demand, manufacturing supply, or hospital bed availability.

Answer

Interim CEO Frederick Vogt identified the main factor as the time required for newer ATCs to gain operational proficiency, with each center having its own minor, resolvable bottlenecks. CCO Dan Kirby added that there is a natural learning curve for a first-in-class therapy, and the key growth lever is now driving community referrals to the increasingly experienced centers.

Andrew Tsai asked about the initial launch cadence for Auvelity in Alzheimer's agitation during the first year, comparing it to Rexulti's launch, and inquired about the expected trend for Auvelity's combined gross-to-net over time.

Answer

Ari Maizel (Chief Commercial Officer, Axsome Therapeutics) stated that Axsome does not guide on uptake but is actively preparing for launch, studying limited analogs like Rexulti and Auvelity's MDD launch. Nick Pizzie (CFO, Axsome Therapeutics) added that with over 70% of ADA scripts anticipated in the Medicare Part D channel, which has a more favorable gross-to-net (GTN) due to no copay card utilization, potential favorability for Auvelity's aggregate GTN is expected.

Andrew Tsai asked about the expected initial launch cadence for Auvelity in Alzheimer's disease agitation (ADA), comparing it to Rexulti's launch, and inquired about the potential long-term trend for Auvelity's combined gross-to-net (GTN) ratio.

Answer

Ari Maizel, Chief Commercial Officer, stated that Axsome does not guide on uptake but is actively preparing for launch, studying analogs like Rexulti and Auvelity's MDD launch. Nick Pizzie, CFO, added that with over 70% of ADA scripts expected from the Medicare Part D channel, which has a more favorable GTN due to less copay card utilization, Auvelity's aggregate GTN could see potential favorability.

Andrew Tsai asked about the EMERALD study for relutrigine in broader DEE, specifically regarding the number and diversity of enrolled patients and whether efficacy similar to or stronger than SCN2A is expected.

Answer

President and CEO Marcio Souza explained that EMERALD is phenotypically, not genotypically, defined, with a very diverse group of enrolled patients and no quotas for specific etiologies. He referenced overwhelming preclinical efficacy across various models (SCN2A, SCN8A, aldogenic) and expects good translation, noting the significant unmet need in the broader DEE population.

Andrew Tsai inquired about the EMERALD study for relutrigine, asking how many different DEE patients the FDA requires for a broad label, how many different DEEs have been enrolled so far, and if efficacy is expected to be similar or stronger than what was seen in SCN2A, with an explanation.

Answer

CEO Marcio Souza stated that the EMERALD study is phenotypically defined, not genotypically, with no quotas for different etiologies, and is enrolling a very diverse group of patients. He explained that the FDA's interpretation is to treat the disease, not just the cause, given the omnipresence of sodium channel participation in seizures. Based on overwhelming preclinical efficacy across various models and successful translation in SCN2A/SCN8A, he expects positive translation for EMERALD, noting that any significant benefit would be a fundamental change for DEE patients who currently have limited options.

Andrew Tsai from Jefferies questioned the 2026 Fanapt revenue guidance of $150-$170 million, asking if the implied 35-40% year-over-year growth at the midpoint suggests a 30% net price increase, and how much cannibalization from Bysanti's Q3 launch is factored into this guidance. He also inquired about Nereus's anticipated list and net price, and expected sales growth in its first four quarters post-launch. Lastly, he asked about the tradipitant GLP-1 phase III study design, expected efficacy, and the precedent for using a high upfront Wegovy dose.

Answer

Kevin Moran, CFO, clarified that the Fanapt revenue growth to $160 million at the midpoint is almost entirely volume-driven, as price increases are capped due to Medicaid and Medicare dynamics. He confirmed that the 2026 guidance includes $0 revenue contribution from Bysanti. For Nereus, Mr. Moran stated that pricing hasn't been communicated but noted NK-1 class doses range $200-$600, with Nereus expected to be at a premium to current motion sickness treatments. Dr. Mihael Polymeropoulos, CEO, added that the tradipitant GLP-1 phase III design will be similar to phase II, using a 1mg Wegovy challenge in naive patients, and while Wegovy's label suggests slower titration, the drug is expected to work effectively at lower challenges.

Andrew Tsai of Jefferies questioned the rationale for filing Bisanti under a 505(b)(1) NDA instead of a 505(b)(2), the efficacy target for the Phase 3 MDD trial to be considered compelling, and the status and expected sales impact of the direct-to-consumer (DTC) campaigns for Fanapt and Ponvory.

Answer

President, CEO & Chairman Mihael Polymeropoulos clarified that the 505(b)(1) pathway for Bisanti was chosen at the FDA's direction because it is a new chemical entity, with bioequivalence serving as the required clinical evidence. For the MDD trial, he explained that the primary endpoint is statistical superiority over placebo, and the drug's competitiveness will be judged on its overall profile and tolerability rather than a specific efficacy delta. He also confirmed the DTC campaigns are ongoing, and their effectiveness is continuously being evaluated before any adjustments are made.

Andrew Tsai of Jefferies questioned the rationale for issuing 2030 revenue guidance, the breakdown of approved versus unapproved products in that forecast, the expected timing of the company's revenue and cash trough, and the sales contribution from HETLIOZ indications not facing generic competition.

Answer

Executive Kevin Moran explained the 2030 guidance reflects confidence driven by current commercial investments and a robust pipeline, noting the $750 million psychiatry target includes future approvals for Bysanti and Fanapt LAI. Moran asserted that the revenue trough year is "over the shoulder," citing 2024 growth and the 2025 forecast. However, he declined to provide a specific sales breakdown for HETLIOZ by indication or geography.

Andrew Tsai from Jefferies requested details on the data used to inform the Phase 3 EMPORER study's design, particularly the powering assumptions for the Vineland endpoint, and asked what would constitute a statistically significant result.

Answer

CMO Barry Ticho explained that powering was based on data from a patient group with a dosing regimen similar to Phase 3, which showed substantial Vineland score improvements versus a natural history cohort. The study was powered conservatively, assuming a 20% placebo effect. He stated that statistical significance is based on a clinically meaningful change of 1-3 raw score points, though the company anticipates potentially greater changes based on existing data.

Andrew Tsai from Jefferies asked about the bipolar depression study, focusing on the potential timing of its built-in interim analysis, the efficacy threshold required at that point, and whether the study is intended to be a pivotal trial.

Answer

President and CEO Ian Mortimer confirmed the program is designed to be registrational. Chief Medical Officer Christopher Kenney explained that the interim analysis timing depends on recruitment and is designed to assess if the study's power is sufficient at 400 patients or if an increase up to 470 patients is needed. This flexibility was included due to the lack of prior clinical data for Ezetucalner in this specific indication.

Andrew Tsai asked if Xenon would announce the completion of X-TOLE2 enrollment or simply narrow the data timing guidance. He also inquired about the baseline characteristics of enrolled X-TOLE2 patients, specifically the number of prior anti-epileptic drugs (AEDs), compared to the Phase II study.

Answer

President and CEO Ian Mortimer responded that the company will refine and narrow its data timing guidance as enrollment nears completion. Regarding patient characteristics, he did not provide specific numbers but stated that the overall patient population in Phase III is demonstrating 'consistency with the X-TOLE study,' suggesting a similar profile in terms of prior AEDs and other demographics.

Andrew Tsai from Jefferies asked about the specifics of the upcoming Q4 top-line data release for PALISADE III, including whether it would include efficacy kinetics and secondary endpoints like PGIC and LSAS. He also questioned if efficacy would be equivalent between genders and asked for a reminder of the baseline SUDS scores from PALISADE I and II.

Answer

President and CEO Shawn Singh stated the data release will be similar to that of PALISADE II, focusing on primary and secondary endpoints, with PGIC now being a secondary endpoint. COO Joshua Prince noted they expect similar efficacy between males and females, consistent with PALISADE II results. Prince also projected the baseline SUDS score for PALISADE III to be around 80-85, similar to past trials, while Singh highlighted the stricter randomization criteria for the current trials.

Andrew Tsai from Jefferies asked what operational factors provide confidence that the current fasedienol Phase III studies will succeed, focusing on site operations, protocol rigor, and public speaking challenge execution. He also asked if PALISADE-4 would proceed if PALISADE-3 were to fail.

Answer

CEO Shawn Singh stated that the ability to conduct in-person training and site visits, unlike during the pandemic, has fundamentally improved protocol adherence and reduced staff attrition. He also confirmed that both PALISADE-3 and PALISADE-4 are fully funded and will be run to completion regardless of the outcome of the other. COO Joshua Prince added that in-person site initiation visits and immediate interventions for any protocol deviations are now standard practice, increasing confidence in data quality.

Andrew Tsai of Jefferies questioned the implied moderation in Q3/Q4 growth following the full-year guidance raise, asking about conservatism and seasonality. He also sought data on new patient initiations in Q2 to assess dropout rates and future persistency trends.

Answer

CEO Gregory Divis stated the guidance assumes continued growth and sustained improvements in patient metrics like persistency and reimbursement rates. CFO Tom McHugh noted the Q1 to Q2 lift is partly due to gross-to-net improvements. Regarding persistency, Divis confirmed that positive trends from Q1 continued into Q2 and are expected to be durable, driven by execution rather than patient mix.

John, on behalf of Andrew Tsai from Jefferies, requested additional details on Q1 patient trends and guidance on how to model gross-to-net adjustments and inventory levels for the first quarter.

Answer

Executive Gregory Divis stated that key patient demand metrics, including enrollments and patient starts, were tracking at or above internal expectations for Q1, with the revenue impact expected to become more apparent in Q2. Executive Thomas McHugh explained that gross-to-net is seasonally highest in Q1 due to insurance deductible resets and confirmed that inventory levels in the channel have remained consistent with the end of 2024.

Andrew Tsai of Jefferies asked for the company's latest perspective on the peak sales opportunity for Zareve's three current indications and whether that view has evolved. He also inquired about a potential timeline for initial data from the investigator-sponsored studies in vitiligo and HS.

Answer

President and CEO Frank Watanabe reiterated previous guidance, suggesting each of the three main indications could represent a $700 million to $1.2 billion opportunity, and stated that achieving 10% of the total topical market is a very achievable goal. He noted that the company is just scratching the surface of the commercial opportunity. Regarding the clinical trials, he stated that no specific timeline for data from the collaborative vitiligo and HS studies is being provided at this time.

Andrew Tsai from Jefferies asked how Lexicon could leverage the political momentum for non-opioid pain drugs and questioned what the 'worst-case scenario' might be from the upcoming end-of-Phase 2 FDA meeting for pilavapitan.

Answer

CEO Mike Exton stated that Lexicon is actively engaged with legislative efforts like the 'Alternatives to Pain Act' and sees bipartisan support as a positive tailwind for pilavapitan's development and future market access. SVP & Chief Medical Officer Dr. Craig Granowitz clarified that the expected outcome from the FDA meeting is a requirement for two parallel Phase 3 trials for the DPNP indication, which is standard for the space and has been affirmed by their advisory board.

Asked about the potential for the pilavapadin Phase IIb study to be considered a pivotal trial by the FDA and how the upcoming Phase III trials will be powered.

Answer

The company views the Phase IIb study as a strong supportive trial, but their base case is that it will not be a pivotal trial. They anticipate needing two pivotal trials of 300-400 patients each. The trials would be powered for a 0.6-point placebo-adjusted drop in pain score, with confidence that the effect will be maintained or increased over a 12-week duration.

Andrew Tsai asked for confirmation on an inferred 2025 revenue range for Qelbree, inquired about the key growth levers for the drug, and questioned how the company's business development appetite and M&A firepower have changed following the SPN-820 trial data.

Answer

CEO Jack Khattar confirmed the inferred Qelbree revenue range is fair and identified continued prescription growth as the primary lever, citing high patient satisfaction and market outperformance. He stated that business development remains a top priority, focusing on revenue-generating products and late-stage assets, and noted the company has significant financial flexibility for deals ranging from $500 million to $1.5 billion, depending on the target's cash flow.

Andrew Tsai inquired about the level of detail to expect from the upcoming interim analysis release for the Reliance II study, and sought clarification on the statistical thresholds for futility.

Answer

CEO Sergio Traversa explained that the detail of the release will depend on the outcome, but the company will share the Data Monitoring Committee's (DMC) recommendation. He clarified that the futility threshold is a drug-placebo delta of approximately 2.0 points, not 2.2, below which a clinically meaningful result would be highly unlikely.

Asked about the specific timing of the supplemental New Drug Application (sNDA) filing for MDD (Q3 vs. Q4 2024) and the filing strategy if the second dataset (Study 502) yields different results from the first.

Answer

The readout for Study 502 is expected late in Q2 (likely June). A Q3 filing is considered aggressive but possible, making a Q4 filing more probable. The company believes in the robustness of its overall data package and is working towards a submission in the second half of 2024, pending the results of the second study.

The analyst asked an open-ended question about the top concerns or potential execution challenges regarding the Phase III RSE study, and whether the company would provide an update if the trial's stopping criteria are not met.

Answer

The company confirmed they will provide an update regardless of the interim analysis outcome. The main past concern was the complexity of patient data and ensuring data integrity. However, the clinical team has implemented robust data cleaning and computer-generated checkpoints, giving management confidence in the data set. They feel the trial has enrolled the right highly-refractory patients and are excited to see the results.

Asked about the expected impact of the holiday season on RSE trial enrollment, the enrollment target for year-end 2023, and the timing of the next enrollment update.

Answer

The company does not expect the holiday season to significantly impact enrollment for the RSE trial, as it's an acute care study. The next formal update on enrollment will likely be at the J.P. Morgan Healthcare Conference in January. They are conservatively projecting 3-4 patients per month to reach their goal by the end of Q1 2024.

Andrew Tsai of Jefferies asked what drove the FDA's decision to accept the NDA filing for roluperidone, whether the lack of a planned AdCom was surprising, and about the company's commercialization strategy.

Answer

Executive Chairman and CEO Dr. Remy Luthringer explained that no new data was provided, but a detailed briefing book and a face-to-face meeting led the FDA to agree an in-depth review was warranted. He added that while an AdCom isn't currently planned, that could change. SVP and CFO Fred Ahlholm stated that a drug of this scale would likely require a partner for launch, and the company is currently evaluating its needs.

Andrew Tsai from Jefferies asked what drove the FDA's favorable decision to file the roluperidone NDA, whether the lack of a planned advisory committee was surprising, and about the company's commercialization strategy for a potential 2024 launch.

Answer

Executive Chairman and CEO Dr. Remy Luthringer explained that no new data was submitted, but a detailed re-explanation during a face-to-face meeting led the FDA to grant an in-depth review. He added that the absence of a planned Adcom at this stage is not surprising. SVP and CFO Fred Ahlholm stated that a launch would likely require a partner and the company is currently evaluating its needs.

Andrew Tsai of Jefferies asked for clarification on the FDA's outstanding issues with the roluperidone NDA, the specific reasons for the Refuse to File (RTF) letter, the potential timeline for a resolution, and the impact of Dr. Billy Dunn's departure from the FDA.

Answer

CEO Remy Luthringer explained the FDA's two main concerns: the applicability of the European Phase 2b study data to the U.S. population and a technical issue with the statistical correction method used in the Phase 3 study. He stated that Minerva is providing additional data to address these points and believes the current data package warrants a full review. While unable to provide a specific timeline, Luthringer indicated that dialogue is ongoing and expects updates in the coming months. He expressed confidence that Dr. Dunn's departure would not be a problem, as his successors are also knowledgeable and open to innovation.

Andrew Tsai of Jefferies LLC inquired whether Minerva could infer if the FDA was now comfortable with previously raised issues—such as formulations, U.S. vs. ex-U.S. data, and roluperidone as a monotherapy—despite the Refusal to File (RTF) letter. He also asked about the circumstances under which the company would consider a new clinical study and questioned the status of other pipeline assets as a contingency.

Answer

CEO Remy Luthringer stated that while progress is made in each FDA discussion, he would not comment on specific resolutions ahead of the upcoming Type A meeting. He explained that the decision to conduct another study would be made after that meeting. Regarding the pipeline, Luthringer confirmed the primary focus remains on the late-stage asset roluperidone, but the early-stage pipeline is advancing, with potential updates in the next year.

Andrew Tsai of Jefferies inquired about the expected timeline for the Type C meeting outcome and questioned the FDA's rationale for suggesting a Type C meeting over a pre-NDA meeting, asking if it implied unresolved issues.

Answer

CEO Remy Luthringer acknowledged the official 75-day timeline for a Type C meeting but noted past interactions have been faster, suggesting a 2-3 month timeframe is a reasonable estimate. He explained the FDA's preference likely stems from the need for a focused discussion on the use of roluperidone as a monotherapy, which he views as a fair and critical point. Luthringer expressed confidence in Minerva's data package, including open-label extension results, to support the monotherapy approach.

Andrew Tsai from Jefferies focused on PCN-101's efficacy, questioning the rationale for the 5-point placebo separation bar, the comparability to SPRAVATO, and the thresholds for advancing the program. He also inquired about Compass Pathways' Phase 3 trial design, the role of digital therapeutics, and whether Biogen's recent CIAS trial failure impacts Atai's confidence in its RL-007 program.

Answer

CSO Srini Rao explained the 5-point efficacy bar for PCN-101 was derived by backtracking from the ultimate goal of a 4-point change in pivotal studies and by triangulating with similar trials. He cautioned against direct comparison to SPRAVATO's early Phase 2a data due to differences in study size and functional unblinding. CEO Florian Brand stated that efficacy below a clinically meaningful level would trigger a reassessment. Regarding digital tools, Rao emphasized their importance for scalability and standardizing therapy, aligning with Atai's vision for combination therapies.

Andrew Tsai asked about Atai's strategy for later-stage trials relative to industry peer COMPASS, the planned integration of digital therapeutics into clinical studies, and the potential for COMPASS's Phase 2b study to be considered pivotal. He also questioned the market's efficacy expectations for PCN-101 versus S-ketamine, the translatability of inpatient data to an at-home setting, and the key gating items for the next PCN-101 study.

Answer

CSO Srini Rao and CEO Florian Brand provided answers. Srini Rao confirmed Atai is following a similar development path to COMPASS with dose-ranging studies but expressed skepticism about a Phase 2b being accepted as pivotal. For PCN-101, he stated that rapid onset and an at-home use profile are key differentiators, potentially justifying a different efficacy bar than S-ketamine. Florian Brand elaborated on the strategic importance of Atai's digital therapeutics pillar, confirming that early data from their use in trials would be available in the coming months.

Andrew Tsai of Jefferies LLC asked about potential deal-breakers for the GRX-917 Phase I data and whether the PCN-101 program could be completely free of dissociative side effects, seeking precedents for at-home drugs with such properties.

Answer

CEO Florian Brand responded that for GRX-917, a significant safety or tolerability concern would be a 'no-go' factor. Regarding PCN-101, he explained that the selected doses showed minimal to no dissociative effects in Phase I, a finding that the Phase II trial aims to confirm. He cited lorcaserin (Belviq) as a precedent for an approved at-home drug with potential psychedelic effects at higher doses, underscoring the importance of the therapeutic index.

Andrew Tsai inquired about the specifics of the upcoming Q2 topline data release for the ACT-AD study, including which endpoints and efficacy curves would be shared. He also asked for historical context on the performance of approved Alzheimer's drugs at six months and questioned how the high percentage of patients on combo therapy might affect the study's outcomes.

Answer

President & CEO Mark Litton confirmed they will release data for the primary endpoint (P300) and ADAS-Cog11 but will likely not show full efficacy curves, saving more detail for a scientific conference. Chief Medical Officer Hans Moebius added that historically, approved drugs showed a 2-3 point benefit on ADAS-Cog at six months, and noted that having 60% of patients on concomitant cholinergic medication is viewed as a potential advantage for the trial.