Ritu Baral

Ritu Baral inquired about the desired characteristics of positive remlifanserin ADP data, specifically regarding the primary endpoint (SAPS-H+D at week six) and the exploratory NPI-C endpoint, including powering considerations.

Answer

Elizabeth Thompson, EVP and Head of Research and Development, explained that Acadia seeks a molecule aligned with their target product profile, emphasizing ease of use, a good safety profile similar to NUPLAZID, and no negative impact on motor or cognition. The study is powered for a moderate effect size (0.4) on SAPS-H+D, with NPI-C being an exploratory endpoint.

Ritu Baral inquired about the specific criteria for 'good' remlifanserin ADP data, focusing on the primary endpoint (SAPS-H+D at week 6), powering, and the significance of the exploratory NPI-C endpoint for the clinical story.

Answer

Elizabeth Thompson, EVP and Head of Research and Development, stated that ACADIA is looking for continued evidence of a molecule aligned with their targeted product profile, emphasizing ease of use, a good safety profile (similar to NUPLAZID), and no negative impact on motor or cognition. She confirmed the study is powered for a moderate effect size (0.4) on SAPS-H+D at week 6, noting NPI-C is exploratory and not powered.

Ritu Baral asked for specifics on Daybue's new momentum, including the percentage of new patients from the community setting and the proportion of new HCP writers from that segment. She also had a follow-up on the ACP101 trial regarding dropout rates and the finalization of the statistical analysis plan (SAP) with the FDA.

Answer

Chief Commercial Officer Thomas Garner revealed that referrals from non-Center of Excellence (COE) accounts grew to about 75% of the total, up from two-thirds in the prior quarter, with the vast majority of new prescribers coming from outside COEs. EVP, Head of R&D, Elizabeth Thompson, commented on the ACP101 trial, stating that it is unfolding acceptably and that a statistical analysis plan is in place, though it can be modified before unblinding.

Ritu Baral of TD Cowen inquired about the criteria for positive data from the ACP-101 (carbetocin) trial and the strategy for modeling DAYBUE's European pricing, considering potential 'most favored nation' drug pricing policies.

Answer

An executive, likely Head of R&D Elizabeth Thompson, stated that a statistically significant result on hyperphagia would constitute a positive outcome for the ACP-101 trial. CEO Catherine Owen Adams addressed European pricing, expressing confidence in achieving a strong price for DAYBUE that reflects its value and noting that the company will assess any future pricing policies as they are implemented, given the lengthy reimbursement timelines in Europe.

An analyst on behalf of Ritu Baral of TD Cowen asked about forward adoption rates for Daybue in community practices versus academic centers. The question also covered how comfortable community physicians are with titrating the drug and what learnings are being applied from the early launch.

Answer

Executive Brendan Teehan explained that the further from a Center of Excellence, the more education is required on both Rett syndrome and Daybue's clinical profile. To address this, Acadia is using clinical champions from the early launch phase to lead peer-to-peer programs. These programs pair experienced clinicians with caregivers to share real-world performance insights and expectations, which has been a successful strategy for engaging community physicians.

Ritu Baral sought further clarity on the $1 billion+ BRINSUPRI guidance, questioning if it implies a modest quarter-over-quarter growth given patient-finding initiatives, and asked if payer requirements for additional paperwork or documentation of two or more exacerbations were impacting uptake more than initially expected.

Answer

Will Lewis, Chair and CEO, clarified that the market access landscape is 'fantastic' and ahead of internal expectations, with documentation requirements being anticipated and not impacting the enthusiastic forecast. He emphasized that the $1 billion+ forecast, after only one full quarter, is an audacious goal that implies continued acceleration, not a slowdown, and that the company is very confident in the launch's trajectory.

Ritu Baral inquired about Insmed's thresholds for BRINSUPRI payer coverage, including covered lives or time to fill, and the target criteria for prior authorization and reauthorization.

Answer

Will Lewis, Chairman and CEO of Insmed, and Roger Adsett, Chief Operating Officer, stated their goal is a 'frictionless launch' with clear, non-burdensome criteria, ideally allowing physicians to attest to a confirmed bronchiectasis diagnosis and two or more exacerbations. They are engaging with payers representing 90% of targeted lives, focusing on ease of access rather than specific formulary targets.

Ritu Baral inquired about the company's thresholds for payer coverage for Brensupri, including targets for covered lives or time to fill, and the desired criteria for prior authorization and reauthorization.

Answer

Will Lewis, Chairman and CEO, stated the objective is a 'frictionless launch' with clear, non-burdensome criteria for approval, ideally allowing physicians to attest to diagnosis and exacerbations without extensive documentation. Roger Adsett, Chief Operating Officer, emphasized engaging with payers to establish easy criteria for patients and physician back offices, without specific formulary addition targets.

Ritu Baral sought clarification on payer feedback for brensocatib, asking about the specific aspects of Insmed's approach that payers found positive, potential prior authorization requirements, and whether free drug would be provided at launch.

Answer

COO Roger Adsett explained that payers have shown strong alignment on the appropriate patient profile: a CT scan diagnosis and two or more exacerbations in the past year. He stated the goal is a 'frictionless launch' with a simple physician attestation for prior authorization. Adsett confirmed that Insmed does not plan to offer direct sampling or free product, but will provide patient support programs, including co-pay assistance for commercial patients.

Ritu Baral asked if any FDA inspections for the Brensocatib review are still outstanding and questioned the clinical development path for TPIP if the PVR and 6-minute walk data were to diverge.

Answer

CEO William Lewis confirmed that while the FDA can inspect at any time, all scheduled inspections and the mid-cycle review have been completed without issue. Regarding TPIP, he stated that while data divergence is possible, it would be unexpected for a prostanoid, whose mechanism is well-established to benefit both measures.

Ritu Baral asked if there are any outstanding inspections for the Brensocatib regulatory review and about the potential Phase III design for TPIP in the event of divergent PVR and 6-minute walk data.

Answer

CEO William Lewis responded that while the FDA can inspect up until approval, all inspections to date and the mid-cycle review have proceeded on schedule with no surprises. Regarding TPIP, he expressed low concern about divergent data, given the well-established benefits of the prostanoid class on both measures, but noted the company will analyze any aberrations closely if they occur.

Ritu Baral questioned the impact of the IRA's manufacturer discount program on ARIKAYCE versus brensocatib, and asked if the upcoming TPIP data would include metrics on cough reduction.

Answer

CEO Will Lewis and CFO Sara Bonstein clarified that ARIKAYCE benefits from a phased-in discount as a 'specified small manufacturer,' while brensocatib will face the full 20% catastrophic coverage cost at launch. This is factored into gross-to-net guidance. Regarding TPIP, Lewis and CMO Martina Flammer explained its prodrug nature is designed to reduce cough, a hypothesis supported by low discontinuation rates in ongoing studies.

An analyst on behalf of Ritu Baral of TD Cowen inquired about the expected labeling language for brensocatib, specifically whether it would be broad or specify the reduction of exacerbations, and if adolescents would be included in the label.

Answer

CMO Martina Flammer stated that Insmed expects a broad label for non-CF bronchiectasis and will request the inclusion of adolescents, who were part of the clinical trial, pending FDA judgment. CEO Will Lewis added that while the FDA label may be broad, market access will likely initially focus on patients with two or more prior exacerbations, a requirement the company hopes to manage through physician attestation.

An analyst on for Ritu Baral asked about the expected labeling language for brensocatib, questioning if it would be broad or specific to exacerbation reduction, and whether adolescents would be included.

Answer

CMO Martina Flammer stated that Insmed expects a broad label for bronchiectasis and has requested the inclusion of adolescents, pending the FDA's final judgment. CEO Will Lewis added that while the FDA label may be broad, initial market access will likely focus on patients with two or more prior exacerbations, consistent with the trial population, which they hope to manage via physician attestation.

Ritu Baral (via Nicole) asked about the script growth needed in fiscal year 2026 to offset the increased gross-to-net impact and achieve revenue growth. She also inquired about the potential need for companion diagnostics to identify genetic predispositions for MASH if siRNA programs advance.

Answer

Mardi Dier, Chief Financial Officer, and Bill Sibold, Chief Executive Officer, reiterated expectations for robust revenue growth in 2026, despite the Q1 gross-to-net increase, driven by steadily adding patients and strong underlying business fundamentals. David Soergel, Chief Medical Officer, stated that while companion diagnostics are not currently foreseen for siRNA programs, the need could be evaluated as combination products advance, acknowledging the increasing commonality of genetic screening in general clinical care.

Ritu Baral asked how Madrigal reconciles its salesforce expansion and marketing to endocrinologists with its strategy for depth, inquiring about metrics and targets for depth and how GLP-1s factor in. She also asked for clarification on reconciling patient numbers with revenue, specifically regarding stocking or European contributions.

Answer

CEO Bill Sibold clarified that Q3 success was driven by U.S. demand, not inventory or Europe. He explained Madrigal can pursue both endocrinologist expansion (a dedicated, concentrated effort for a few thousand physicians) and deeper penetration within existing gastroenterologist/hepatologist prescribers simultaneously. He noted endocrinologists' interest in Rezdiffra despite GLP-1 availability suggests GLP-1s aren't a complete solution for MASH. CFO Mardi Dier confirmed Q3 revenue was primarily U.S. demand-driven, with no significant impact from inventory or Europe.

Ritu Baral asked Madrigal to reconcile its salesforce expansion and marketing efforts towards endocrinologists with its stated goal of achieving 'depth' in existing prescribers, seeking metrics for depth. She also asked for clarification on how patient numbers reconcile with revenue, specifically regarding stocking or European contributions.

Answer

Bill Sibold, Chief Executive Officer, clarified that Q3 revenue was driven purely by U.S. demand, with no impact from inventory or Europe. He explained that Madrigal can pursue both breadth (endocrinologists) and depth (existing GIs/hepatologists) simultaneously. A dedicated, smaller team targets endocrinologists as a long-term opportunity, acknowledging they are less familiar with NITs. He noted that endocrinologists' continued interest in Rezdiffra, despite using GLP-1s, suggests GLP-1s are not a complete solution for MASH.

Ritu Baral of TD Cowen asked about the strategy to maintain growth momentum with a potential Wegovy label expansion, inquiring about the next prescriber target after hitting 80% of the top tier and the plan for engaging endocrinologists.

Answer

CEO Bill Sibold responded that the focus is now shifting from prescriber breadth to depth, which is driven by positive real-world experience with ResDiffera. While hepatologists and gastroenterologists remain the primary focus, he confirmed they are expanding engagement with interested endocrinologists, who are particularly receptive to the drug's THR-beta mechanism of action.

Ritu Baral questioned the status of the European regulatory review, the reason for a clock stop extension, and how Europe's approach to non-invasive testing might impact Rezdiffra's label.

Answer

CEO William Sibold affirmed that the review is on track for a mid-year decision and the regulatory questions are expected for a first-in-class MASH therapy. He noted that Europe's physician community is well-prepared, with established EASL guidelines and a sufficient base of non-invasive testing (NIT) infrastructure to support a launch.

Ritu Baral from TD Cowen requested more detail on the data points that drive value in European health technology assessments (HTAs). She also asked for specifics on the safety profile in the F4 open-label cohort, particularly concerning events like hypoglycemia.

Answer

CEO William Sibold pointed to the formal value dossier process and the favorable U.S. ICER analysis as evidence of Rezdiffra's cost-effectiveness, which they will leverage in HTA discussions. Dr. Michael Charlton addressed safety, confirming that the adverse event profile in the F4c patients was comparable to that of non-cirrhotic patients in the study.

Ritu Baral questioned the utilization of the Medicare free drug program, citing physician feedback on logistical issues, and asked if the commercial co-pay program needs optimization due to its low utilization.

Answer

CEO William Sibold responded that free drug utilization has been very low, which he views as a positive indicator of strong insurance coverage. He stated he had not received the negative feedback but would monitor it. He expects co-pay assistance usage to increase over time as awareness grows. CFO Mardi Dier added that the time-to-fill for prescriptions has improved to 30 days, demonstrating system efficiency.

Ritu Baral questioned the gross-to-net pattern for 2026, asking if the mid-single-digit adjustment would be stepwise or gradual, if access discussions for the full year are complete, and how potential longer-term competitive dynamics are factored into the gross-to-net outlook.

Answer

Chief Financial Officer Jeff Poulton clarified that the mid-single-digit net price decrease for the U.S. market in 2026 is expected to be gradual throughout the year. Chief Commercial Officer Tolga Tanguler added that while 2027 outlook is too soon, the company is well-positioned to manage growth, and the 2030 CAGR of 25% incorporates competitive thinking to preserve and increase category value.

Ritu Baral inquired about the gross-to-net pattern for 2026, specifically if the mid-single-digit adjustment would be stepwise or gradual, whether all access discussions for the full year are complete, and how potential longer-term competitive dynamics are factored into the gross-to-net outlook.

Answer

Jeff Poulton, CFO, clarified that the mid-single-digit net price decrease for the U.S. market in 2026 is expected to be gradual throughout the year. Tolga Tanguler, Chief Commercial Officer, added that while it's too soon to comment on 2027, the company is well-positioned to manage growth, and the 2030 CAGR of 25% incorporates competitive considerations to preserve and increase category value.

Ritu Baral at TD Cowen asked about the degree of commercial investment required in Europe to expand AMVUTTRA beyond the PN indication to ATTR cardiomyopathy, balancing this against potential lower costs. She also inquired about how center type impacts first-line AMVUTTRA use, distinguishing between commercial hospital systems and patient characteristics.

Answer

Tolga Tanguler, Chief Commercial Officer, explained that Europe's market, largely managed by centers of excellence (except Germany), allows for effective commercial teams with limited field activity, meaning no significant expansion of European business is expected for ATTR CM. Japan, being more fragmented, requires continued investment. He did not directly address the impact of center type on first-line use but emphasized the strong ecosystem and recognition of AMVUTTRA's value in key European centers.

Ritu Baral asked about the commercial investment required in Europe to expand beyond the polyneuropathy indication and how center type impacts first-line use.

Answer

Tolga Tanguler, Chief Commercial Officer, explained that Europe's market, largely managed by centers of excellence, requires limited significant expansion of the existing European business for cardiomyopathy. He noted that cardiomyopathy patients are also primarily treated in these centers, with Japan being a more fragmented market requiring continued investment.

Ritu Baral from TD Cowen asked about prescribing trends in the V122I variant population and sought clarification on payer terminology like 'step-through' versus 'prior authorizations'.

Answer

CCO Tolga Tanguler clarified that payer policies generally do not restrict access based on hereditary status like V122I. CMO Pushkal Garg added that HELIOS-B data showed Amvuttra works equally well in both wild-type and V122I patients, supporting its use as a first-line agent across the board.

Ritu Baral asked for the profile of patients receiving AMVUTTRA as a first-line therapy and sought clarification on whether health system formulary inclusion also establishes prior authorization requirements.

Answer

Chief Commercial Officer Tolga Tanguler clarified that health system formulary inclusion is about the institution's ability to purchase and administer the drug, separate from payer-level prior authorizations. Regarding first-line use, he explained that physicians who understand AMVUTTRA's differentiated profile are using it broadly for both newly diagnosed patients and those progressing on stabilizers, rather than for a specific patient subtype.

Ritu Baral followed up on the label topic, asking about the potential commercial advantage of having mortality data included in the clinical data section of the label for detailing and payer discussions.

Answer

Chief Commercial Officer Tolga Tanguler expressed confidence in their ability to communicate the product's benefits, given significant results on all prespecified endpoints. Chief Medical Officer Pushkal Garg added that they expect the label to reflect the clinical trial results, enabling the commercial and medical teams to educate providers on all attributes of the HELIOS-B study.

Ritu Baral inquired about Alnylam's current payer discussions for AMVUTTRA ahead of a potential label expansion, focusing on negotiation levers and the possibility of volume-based discounts.

Answer

Chief Commercial Officer Tolga Tanguler stated that payer discussions are centered on the strong value proposition and compelling clinical outcomes from the HELIOS-B study. He mentioned that their patient access strategy includes value-based agreements and rebates, with more specific details to be shared closer to the PDUFA date.

Ritu Baral of TD Cowen inquired about the implications of the 25% over-enrollment in the Phase III SELVA study, questioning its effect on statistical power, patient heterogeneity, market size perception, and the specific data points to be released at top-line.

Answer

President and CEO Wes Kaupinen stated the over-enrollment was driven by high investigator interest and provides a larger dataset for the NDA. Chief Scientific Officer Jeff Martini added that the study was already 99% powered, and strict screening criteria manage heterogeneity. Wes Kaupinen confirmed the top-line release will include the primary endpoint, safety, and tolerability, with guidance on other endpoints to be provided later.

Ritu Baral from TD Cowen asked about the biological mechanism driving the increasing efficacy of vormatrogene over time, the exposure-response analysis supporting the addition of a 40mg dose in the POWER-2 study, and sought more specific details on the POWER-1 enrollment timeline.

Answer

President & CEO Marcio Souza explained that while steady state is reached quickly, the efficacy deepens over time, a concept he described as "less seizures leads to less seizures." He noted that exposure-response modeling indicated potential for even greater efficacy at higher doses, justifying the 40mg arm. Chief Scientific Officer Steven Petrou added that this effect is likely due to resetting neuronal activity levels, a process that takes time. Regarding POWER-1, Souza confirmed strong enrollment and enthusiasm from investigators, driven in part by positive mood effects, and reiterated the goal to finish by year-end.

Ritu Baral inquired about the registrational potential of the expanded 80-patient cohort for relutrigine, including any changes to enrollment criteria, and sought specifics on the regulatory alignment timeline for the EMERALD study.

Answer

CEO Marcio Souza explained that the main change for the relutrigine cohort is a higher starting dose (1mg/kg/day) to achieve a faster, deeper effect, with no major changes to inclusion criteria. For the EMERALD study, he noted they are finalizing the protocol for a parallel group study, with alignment expected by year-end for a 2025 start, focusing on defining patient inclusion based on genotype and mechanism sensitivity.

Ritu Baral asked about FDA requirements for the initial responder rate in the Essential3 withdrawal study. For PRAX-628, she asked for confirmation on placebo control in the RADIANT and POWER studies, the doses being used, any targets for the generalized epilepsy patient mix in RADIANT, and major differences between POWER1 and POWER2.

Answer

Executive Marcio Souza clarified that in the Essential3 withdrawal study, only patients meeting a pre-defined response criteria after 8 weeks are randomized to stay on drug or switch to placebo. He confirmed RADIANT is not placebo-controlled, while POWER1 and POWER2 are. Doses are 30mg in RADIANT and a 20mg to 30mg step-up in POWER1/2. He expects about 30% of RADIANT patients to have generalized epilepsy, reflecting the clinical mix and investigator excitement, and noted the staggered start of POWER1 and POWER2 is for operational efficiency.

Ritu Baral asked about FDA requirements for the Essential3 withdrawal study's responder rate, whether the PRAX-628 studies are placebo-controlled, the doses being used, the target for generalized epilepsy patients in RADIANT, and design differences between POWER1 and POWER2.

Answer

CEO Marcio Souza explained the withdrawal study uses a specific response criteria after 8 weeks to randomize patients, while non-responders move to a long-term extension. He confirmed RADIANT is open-label while POWER1 and 2 are placebo-controlled. Doses will be 30mg in RADIANT and a 20mg-to-30mg titration in POWER. He expects about 30% of RADIANT patients to have generalized epilepsy, reflecting clinical practice. POWER1 and 2 are similar but staggered to optimize enrollment.

Ritu Baral inquired about the strategy to direct patients to sites with more capacity, asking if these are community sites and why they are not already at capacity, and if the company plans to open more sites.

Answer

President and CEO Douglas Ingram explained that it's a focus issue, not a site number issue. The company initially prioritized large, high-experience sites which are now fully booked. The strategy is now to increase educational outreach and engagement with secondary sites that have available capacity to make them more productive. He clarified they cannot redirect start forms but can drive awareness to balance the network.

Ritu Baral of TD Cowen asked about the potential for a splicing biomarker-based accelerated approval for the FSHD and DM1 programs and requested a description of the planned manufacturing bridging study.

Answer

CEO Douglas Ingram described the bridging study as a relatively small, fast-moving trial empirically comparing expression and safety between the suspension and adherent manufacturing processes. Regarding accelerated approval, Dr. Louise Rodino-Klapac noted that for FSHD, the ability to quantify DUX4 knockdown provides a unique biomarker opportunity. She stated that while splicing is one of many biomarkers being evaluated for DM1, it's too early to say if it could be a sole basis for approval.

Ritu Baral from TD Cowen inquired about Sarepta's approach to forward guidance, asking if the company would continue to provide granular forecasts given its 3-to-5-month visibility into the patient pipeline, and what swing factors to consider.

Answer

President and CEO Doug Ingram affirmed that the company's goal is to provide reasonable and accurate guidance that it is comfortable with, even if it appears conservative. He acknowledged that deep insight into the patient pipeline provides significant confidence but stated they would not update guidance at this time and would likely discuss 2025 at the January JPMorgan conference.

Ritu Baral asked if the previously guided ~$4 billion peak sales figure for ELEVIDYS still holds and what factors explain the tight range of the 2025 revenue guidance.

Answer

CEO Douglas Ingram confirmed that the company has no basis to amend its prior long-term peak sales guidance for ELEVIDYS. He explained that the confidence in the 2025 guidance comes from extensive experience, algorithmic modeling of launch curves, and granular data on start forms, which indicate the current launch is exceeding their optimistic expectations.

Ritu Baral questioned the specifics of the sales force expansion, including headcount and roles, and asked if the initiative was driven by the rising proportion of DDEB patients or potential competition.

Answer

Jennifer McDonough, SVP of Patient Access, confirmed the field force was enhanced in Q1 to support deeper community outreach. Krish Krishnan, Chairman and CEO, clarified the expansion is not related to competition but is a response to the longer education cycle required for physicians and patients in the community, particularly as the mix of DDEB patients increases. He stressed it's about shortening the time to get a patient start form.

Ritu Baral asked for details on the upcoming European launch, including the breakdown of the 1,000 identified patients in Germany and France, the role of centers of excellence, expected pricing frameworks, and the potential for home dosing.

Answer

Chairman and CEO Krish Krishnan detailed that the patient split is approximately 600 in Germany and 400 in France, with France being more concentrated in centers of excellence. He outlined that Germany allows launching at the U.S. price for six months before a negotiated price is set, while France's access program requires accruing for rebates from day one. He also confirmed that home dosing is expected in Europe.

Ritu Baral focused on the European launch, asking about the status of the EMA's 180-day questions, expectations for the label's breadth (from birth, dominant vs. recessive), and how investors should model European pricing relative to the U.S.

Answer

An executive, likely President of R&D Suma Krishnan, confirmed that responses to the 180-day questions were submitted and no oral arguments are currently expected. The anticipated label includes patients from birth with both dominant and recessive DEB, with home dosing also on track. Chairman and CEO Krish Krishnan stated that while they will aim for the highest price, a conservative blended European price would be around 50% of the U.S. price, with a goal to land between 50% and the full U.S. price.

Ritu Baral of TD Cowen asked about the DMX-200 trial, specifically what eGFR benefit the FDA requires, the timeline for the next interim analysis, and what evidence supports the expected acceleration of U.S. switches to Pombiliti/Opfolda.

Answer

Chief Development Officer Dr. Jeff Castelli clarified the FDA agreed to proteinuria for full approval, requiring only supportive, not statistically significant, eGFR data. He estimated the next interim analysis could be in roughly 9 months. President and CEO Bradley Campbell addressed the Pombiliti/Opfolda question, citing a significant acceleration in U.S. switches already seen in April, driven by more Nexviazyme patients reaching the two-year switch window and growing real-world evidence.

Ritu Baral inquired about the specifics of Pombiliti's prescribing trends, including the drivers for physicians and patients to switch therapies in the U.S., and requested a quantification of the Pompe market opportunity in Japan.

Answer

President and CEO Bradley Campbell and Chief Development Officer Dr. Jeff Castelli explained that prescribing trends show growth in both new prescribers (breadth) and repeat prescriptions (depth). They noted physicians typically monitor patients for 12-24 months on a new therapy before considering a switch, often prompted by signs of clinical decline. Chief Business Officer Sebastien Martel added that the Japanese Pompe market is relatively small, with approximately 100 patients currently on treatment.

Ritu Baral asked about Amicus's counter-messaging to competitive claims from Genzyme and also questioned the reimbursement process, citing anecdotes of coverage issues for the Opfolda component.

Answer

President and CEO Bradley Campbell and Chief Development Officer Dr. Jeff Castelli addressed the competitive dynamic by highlighting Pombiliti and Opfolda's unique Phase 3 data showing improvement versus an active comparator, allowing them to message that 'improvement is possible.' Regarding reimbursement, Campbell stated they have not seen denials for either component and that the time from prescription to infusion is shortening as expected, now down to ~65 days.

An analyst on behalf of Ritu Baral from TD Cowen asked for an update on the potential future development paths for SPR720 and the expected timing for a decision following the recent interim analysis results.

Answer

Executive Esther Rajavelu stated that the immediate next step is to complete the data analysis for all 25 patients in the trial. She indicated that an oral treatment path for NTM-PD is now considered unlikely due to dose-limiting toxicity observed at the 1,000 mg dose. A final decision on the program's future, which may include a reformulation strategy, will be made after the full data review is complete.

Asked for clarification on the patient mix (treatment-naive vs. experienced) in the SPR720 trial, its potential impact, and for details on the 'time to positivity' secondary endpoint.

Answer

The executive confirmed the trial includes both naive and non-refractory experienced patients but the specific mix is blinded. They explained that 'time to positivity' is a measure of bacterial growth time, where a longer duration indicates efficacy, and it's expected to correlate with the primary endpoint.

Ritu Baral asked if the top-line data release would include secondary analyses like remission or response rates, inquired about patient disposition and background SSRI use, and questioned if the study's statistical powering would be disclosed.

Answer

CEO Kabir Nath stated clearly that the 6-week data will not include secondary analyses, remission, or response rates, focusing only on the MADRS effect size difference. He mentioned that patient characteristics appear similar to Phase IIb but could not provide precise statistics mid-trial. He confirmed the company would be willing to share the study's powering details with the data release.

Ritu Baral asked about Biogen's commitment to the expanded marketing efforts for ZURZUVAE, questioning if Biogen has matched Sage's personnel and program investments, and requested more detail on the expanded commercial initiatives.

Answer

CEO Barry Greene confirmed a fully aligned and integrated 50-50 commercialization plan with Biogen for 2025, covering sales force expansion and other investments. COO Chris Benecchi elaborated on the initiatives, which include social media campaigns on TikTok and Instagram, connected TV, broader digital efforts, and peer-to-peer education to drive both brand and disease state awareness.

Ritu Baral sought clarification on the 600-unit gap between prescriptions written and shipped for ZURZUVAE, the role of free drug in that gap, and specifics on the planned sales force expansion.

Answer

CEO Barry Greene explained the gap is largely due to timing differences at quarter-end and that the free goods program is used strategically to ensure rapid access for patients, with its use expected to decline as payer coverage solidifies. CFO Kimi Iguchi clarified the distinction between patient shipments and revenue recognition. Greene confirmed a sales force expansion is planned for Q4 but did not provide specific numbers.

Ritu Baral questioned if the FDA is requiring a specific proportion of data from female Fabry patients or those with cardiac variants, given the renal-focused endpoint. She also asked about plans to collect prospective data on these subgroups for potential commercial use.

Answer

CEO Sandy Macrae clarified that the regulatory discussions have encompassed the entire Fabry population, not specific subgroups, and the filing will be based on the totality of data from all 32 patients. He emphasized that improvements are seen across multiple measures, suggesting a systemic benefit. Chief Development Officer Nathalie Dubois-Stringfellow added that recent patient feedback underscores a significant unmet need and broad quality-of-life improvements with the therapy, reinforcing its potential across the patient population.

Ritu Baral from Cowen inquired about Atai's recent progress, the target clinical profile for PCN-101, the strategic balance between efficacy and tolerability for at-home use, and the specifics of the safety risk ratio. She also asked about dose selection and the subcutaneous bridging strategy for PCN-101, as well as endpoint selection and dosing for the RL-007 trial in CIAS.

Answer

CEO Florian Brand provided a pipeline overview, explaining that PCN-101 aims for unsupervised at-home use with rapid onset, prioritizing a safety profile that allows this over superior efficacy. CSO Srini Rao detailed the risk ratio calculation, comparing it to SPRAVATO's approval basis, and discussed the PK/PD targets for the subcutaneous formulation. For RL-007, Brand stated the MCCB endpoint has FDA support for CIAS and that doses were selected based on positive biomarker data from a prior study.

Ritu Baral of Cowen and Company asked about the funding flexibility for atai's digital therapeutics initiative relative to its cash runway. She also questioned the commercial lessons learned from SPRAVATO's launch for the PCN-101 program, the potential Phase 3 design for PCN-101, and the unique mechanism and expected sedation profile of the GABAergic candidate GRX-917 for anxiety.

Answer

CEO Florian Brand affirmed that digital therapeutics are an integral and fully funded part of atai's strategy, essential for achieving sustained outcomes with psychedelic-assisted therapies. He explained that for PCN-101, atai can leverage the clinical infrastructure of over 1,000 clinics established for SPRAVATO, viewing it as an advantage not to be the first mover. CSO Srini Rao added that the PCN-101 Phase 3 design will be informed by Phase 2 data and likely modeled on other at-home therapies. For GRX-917, Rao detailed its unique mechanism of increasing endogenous neurosteroids, which is expected to result in a superior safety profile with minimal sedation compared to benzodiazepines or PAMs, based on historical data for etifoxine.

Ritu Baral from Cowen and Company asked about the types of biomarkers being investigated, how to interpret the qEEG beta band shift for GRX-917 versus other GABA PAMs, and whether PCN-101 is being monitored for hemodynamic effects similar to Spravato.

Answer

CEO Florian Brand outlined a strategy using both biological (metabolomic) and digital biomarkers. CSO Dr. Srini Rao added that for GRX-917, they don't necessarily expect a qEEG shift of the same magnitude as direct agonists due to its unique mechanism. He confirmed that PCN-101's hemodynamic effects are being monitored, but it's too early to compare with S-ketamine, with the upcoming subcutaneous study being critical for this assessment.

Ritu Baral of Cowen questioned the statistical powering assumptions for the 8-patient, 1-to-1 randomized AT132 pivotal cohort and asked for an outline of the planned clinical study for the Pompe program.

Answer

Chairman and CEO Matt Patterson expressed high confidence that the 8-patient cohort is adequately powered, based on the expectation of no change in ventilator use in the control group as seen in prior data. For the Pompe program, he indicated the initial study will likely start in adults and include both biopsy and clinical endpoints, with plans to expand to infantile patients later.

Ritu Baral from Cowen Inc. sought clarification on the preclinical studies for the Pompe program (AT845), including the difference between non-GLP and GLP studies, and inquired about the manufacturing scale-up strategy for the Pompe commercial product.

Answer

Matt Patterson, Chairman and CEO, clarified that a recent non-GLP primate study for AT845 demonstrated a clean safety profile, which is a significant de-risking step given a prior construct had safety issues in primates. This provides high confidence for the final, ongoing GLP toxicology studies in primates and mice required for the IND. For manufacturing, he stated current capacity covers near-term clinical needs, and the company has the flexibility to add capacity for commercial Pompe demand by expanding its current site or adding a new one, potentially by simply adding more 500L bioreactors to avoid comparability work.