Yigal Nochomovitz

Yigal Nochomovitz asked whether the observed 40% combination use and 70% use in second line or higher for Revuforj are steadily growing percentages or if they are expected to remain stable until further clinical trial evidence is generated.

Answer

Michael Metzger, CEO, and Nick Botwood, Head of R&D and Chief Medical Officer, expect combination use to grow, driven by a desire for higher response rates and established tolerability. They anticipate that generating more real-world data and experience will further drive increased use due to better outcomes.

Yigal Nochomovitz asked if the real-world metrics, such as 40% combination use and 70% in second line or higher, are steadily growing or stable until further clinical trial evidence. He also asked if these metrics are similar across KMT2A and NPM1 patient populations.

Answer

Michael Metzger, Chief Executive Officer, and Nick Botwood, Head of R&D and Chief Medical Officer, expect combination use to grow, driven by the desire for higher response rates and tolerability, with more real-world data presentations throughout the year. Michael Metzger stated that combination use is roughly similar across KMT2A and NPM1, and maintenance use would be very high for KMT2A post-transplant.

Yigal Nochomovitz sought clarification on post-transplant maintenance, asking if the two-thirds of patients who haven't restarted are expected to do so. He also inquired about the reimbursement process for restarting therapy and requested more details on the upcoming real-world evidence presentation.

Answer

CEO Michael Metzger confirmed that the remaining two-thirds of transplant patients are expected to restart maintenance over time. CCO Steve Closter described the reimbursement process as 'seamless,' with no challenges expected. CMO Dr. Nick Botwood added that the company is collaborating with leading cancer centers to present real-world data on patient outcomes later in the year.

Yigal Nochomovitz from Citigroup Inc. asked for the rationale behind pursuing two separate frontline trials for fit NPM1 and KMT2A patients, and also inquired if commercial patients are achieving CR/CRh before proceeding to transplant.

Answer

CEO Michael Metzger explained that separate trials for the fit population are more efficient as they allow for trial designs optimized for the different characteristics and treatment goals of each patient group. Regarding transplant timing, he clarified that Syndax is not privy to the specific remission status of individual patients, as that is a physician's clinical decision.

Yigal Nochomovitz of Citigroup sought to confirm a patient count calculation, asked for a more specific definition of Tier 1 versus Tier 2 treatment centers, and inquired about the potential design of Phase III trials in the fit AML population.

Answer

CCO Steven Closter declined to confirm specific patient counts, citing limited visibility, but defined Tier 1/2 centers as the top ~200 accounts representing two-thirds of the patient opportunity. President and Head of R&D Dr. Neil Gallagher stated that while they are aggressively planning multiple trials in the fit setting, they are not disclosing specific trial designs due to the competitive landscape.

Yigal Nochomovitz asked how BeOne Medicines plans to avoid sacrificing long-duration revenues from continuous BRUKINSA if ZS (Sonrotoclax + BRUKINSA) becomes the fixed-duration standard of care in treatment-naive CLL.

Answer

Aaron Rosenberg, CFO, clarified that ZS targets the 50% of the market currently receiving fixed-dose treatment where BeOne has no presence, viewing it as market-expanding. John Oyler, Co-founder, Chairman, and CEO, added that ZS could fulfill the promise of fixed-duration therapy, positioning BeOne uniquely in that segment.

Yigal Nochomovitz sought clarification on how the potential emergence of ZS as a fixed-duration standard in treatment-naive CLL would impact long-duration revenues from continuous BRUKINSA.

Answer

Aaron Rosenberg, CFO, explained that the ZS combination targets the 50% of the market currently using fixed-duration treatments where BeOne has no presence, viewing it as market-expanding. John V. Oyler, Co-Founder, Chairman, and CEO, added that ZS could fulfill the promise of fixed duration, placing BeOne in a unique position.

Yigal Nochomovitz asked about the potential pricing strategy for the sonrotoclax plus zanubrutinib combination. He also inquired about long-range plans for establishing API supply in the United States and whether the redomiciling to Switzerland would shift more core R&D functions out of China.

Answer

CFO Aaron Rosenberg stated it was too early to discuss pricing but expressed confidence in the value the assets create. On supply chain, he affirmed the company is monitoring the environment and will act proactively to ensure supply. CEO John Oyler addressed the R&D question, describing the company as being in a constant state of global expansion, including recruiting for R&D in their San Carlos, California office, as part of a natural process to work globally.

Yigal Nochomovitz asked about the BRUKINSA patent settlement extending to 2037 and whether a future fixed-dose combination with sonrotoclax could provide further patent protection.

Answer

CFO Aaron Rosenberg confirmed the 2037 patent life for BRUKINSA as a starting point. He emphasized that the broader franchise strategy, which includes assets like sonrotoclax with patent protection well beyond 2037, is designed to create a durable, long-lived franchise that addresses the full patient journey.

Yigal Nochomovitz of Citigroup asked about the BRUKINSA patent settlement extending to 2037 and whether a fixed-dose combination with sonrotoclax could further protect the franchise from generics.

Answer

CFO Aaron Rosenberg confirmed the 2037 patent timeline as a starting point and emphasized that the broader strategy is to build a long-lived, durable franchise. He explained that combinations with assets like sonrotoclax, which have their own patent life, will extend protection well beyond BRUKINSA's exclusivity.

Yigal Nochomovitz of Citigroup asked about the BRUKINSA patent settlement extending to 2037 and whether a future fixed-dose oral combination with sonrotoclax could further extend the franchise's patent protection.

Answer

CFO Aaron Rosenberg confirmed the 2037 patent protection for BRUKINSA is a starting point. He emphasized that the broader franchise strategy relies on a combination of assets, including pipeline drugs with patent lives extending well beyond that date, to create a durable and long-lived franchise.

Yigal Nochomovitz from Citigroup sought clarification on Arcus Biosciences' frontline strategy, specifically whether the base case involves a casdatifan plus anti-PD-1/CTLA-4 triplet, or if a casdatifan plus anti-PD-1 (Zim) backbone could be a standalone option.

Answer

COO Jen Jarret confirmed the base case assumption is a casdatifan plus Ipi/Nivo triplet, with the casdatifan plus Zim combination serving as a backbone. CEO Terry Rosen added that while a casdatifan plus anti-PD-1 regimen would be highly beneficial for patients, the company is likely to pursue a three-arm Phase III study to evaluate the triplet against Ipi/Nivo, without getting 'too cute' based on early data.

Yigal Nochomovitz probed the frontline strategy, asking if the market research showing preference for a triplet (casdatifan plus anti-PD-1/CTLA-4) implies this is the base case, or if a doublet (casdatifan plus anti-PD-1) remains a reasonable potential.

Answer

Executive Director Jen Scott confirmed the base case assumption is casdatifan plus Ipi/Nivo (triplet), with casdatifan plus Zim (anti-PD-1) as a backbone. CEO Terry Rosen added that while a casdatifan plus anti-PD-1 doublet would be ideal for patients, they are likely to pursue a three-arm study including the triplet to avoid over-optimizing based on early data.

Yigal Nochomovitz asked for the timing of the PEAK 1 trial's primary PFS readout compared to Merck's LITESPARK-11, and questioned Arcus's funding strategy for casdatifan following Gilead's decision not to opt-in.

Answer

President Juan Jaen stated it was too early to give specific guidance on PEAK 1 timing but noted the PFS endpoint and expected rapid enrollment could narrow the gap with Merck's trial, which was pushed to 2027. CEO Terry Rosen added that Arcus plans to execute the PEAK 1 trial on its own, citing a strong capital position, an experienced team, and significant investigator enthusiasm, though he did not rule out opportunistic collaborations.

In a follow-up, Yigal Nochomovitz of Citigroup sought clarification on CEO Terry Rosen's comment about potentially providing updates from the ARC-20 study "in the more near term," asking if this could mean new data before year-end.

Answer

CEO Terry Rosen clarified that with multiple cohorts from ARC-20 maturing, the company felt it was important to be transparent and would look for opportunities to release meaningful data as it emerges. However, he stated there are no specific plans for an update at this moment.

Yigal Nochomovitz inquired about the strategic rationale for the casdatifan plus cabozantinib expansion cohort, sought confirmation on early efficacy signals for the 50mg casdatifan dose, and asked about potential combination partners for the first-line metastatic study.

Answer

CMO Dimitry Nuyten explained the expansion cohort is primarily for establishing safety data before the larger Phase III trial, noting minimal expected overlapping toxicities. COO Jennifer Jarrett confirmed that the 50mg cohort showed a lower primary progressive disease rate than the LITESPARK-005 benchmark and that data would be presented separately. CEO Terry Rosen and COO Jennifer Jarrett added that the first-line combination partner will be disclosed soon, will be a differentiated approach from Merck, and involves a collaboration partner.

An analyst from Citigroup Inc. on behalf of Yigal Nochomovitz asked about the upcoming EDGE-Gastric data at ASCO. The questions focused on the necessary PFS benefit to derisk the Phase III STAR-221 study and the expected correlation between PFS and OS in this setting. A follow-up question concerned the status of Cohort A2 and its role in assessing domvanalimab's contribution.

Answer

CEO Terry Rosen noted the firm 7-8 month PFS benchmark for standard of care and expressed confidence that the upcoming data will be meaningful, despite a patient population with lower PD-L1 expression than in the CheckMate 649 study. COO Jennifer Jarrett added that in CheckMate 649, the PFS and OS benefits were highly correlative. Rosen explained that Cohort A2 enrolled sequentially and is about a year behind Cohort A1, but will provide another look at zimberelimab plus chemo versus historical controls.

Yigal Nochomovitz asked about the significance of the prefilled syringe (PFS) for Syfovre, its impact on retina practice efficiency, its role in driving renewed growth in 2027, and any advantages it offers for drug storage and practice dynamics.

Answer

Co-Founder, CEO, and President Cedric Francois stated that the PFS will be a significant practice-enabling innovation, offering convenience and efficiency to retina physicians. Chief Medical Officer Dr. Caroline Baumal added that it supports ease of clinical use and will be transformative for physicians and patients, with its design incorporating physician input for optimal fit in refrigerators. Both executives also mentioned Functional OCT as another key driver for future growth.

Yigal Nochomovitz inquired about the significance of the Syfovre prefilled syringe (PFS) for retina practices, its impact on workflow and efficiency, and whether it will be a key driver for renewed growth in 2027. He also asked about the practical dynamics of storing the drug with the new PFS presentation.

Answer

Chief Medical Officer Dr. Caroline Baumal stated that the prefilled syringe is a practice-enabling innovation offering convenience and efficiency, supporting ease of clinical use and being transformative for physicians and patients. She noted that retina physicians provided heavy input into its design, including packaging and refrigerator fit. Dr. Baumal also mentioned Functional OCT as another initiative supporting renewed growth.

Yigal Nochomovitz of Citigroup asked about the planned endpoints for the upcoming Phase 3 trial in FSGS and sought clarification on whether 'samples' are now included under the term 'free goods'.

Answer

CEO Dr. Cedric Francois confirmed the FSGS trial will align with the Parasol group's work on endpoints and is slated to begin enrollment in H2 2025. EVP of Commercial David Acheson clarified that 'free goods' is a new, broader term that now encompasses both traditional samples and the patient assistance program (PATH).

Yigal Nochomovitz from Citigroup inquired about the planned endpoints for the upcoming Phase III trial in FSGS and asked for clarification on whether 'free goods' is a new term that now includes what was previously called 'samples'.

Answer

Co-Founder and CEO Cedric Francois confirmed the FSGS trial is on track to start enrollment in the second half of the year. EVP & Head of Global Commercial David Acheson clarified that 'free goods' is a new, broader terminology that encompasses both traditional samples and the patient assistance program (PATH).

Yigal Nochomovitz of Citigroup asked about the planned endpoints for the upcoming Phase 3 trial in FSGS, referencing the Parasol working group's findings on proteinuria. He also requested clarification on whether 'free goods' now includes what was previously termed 'samples'.

Answer

Co-Founder and CEO Dr. Cedric Francois confirmed the FSGS trial plans are aligned with the Parasol group's work. EVP & Head of Global Commercial David Acheson clarified that 'free goods' is a new terminology that encompasses both traditional samples and the patient assistance program (PATH) to capture all non-commercial product usage.

Yigal Nochomovitz of Citigroup asked about the planned endpoints for the upcoming Phase 3 trial in FSGS and followed up with a request for clarification on the terminology change from 'samples' to 'free goods' for Cyfovri.

Answer

CEO Dr. Cedric Francois confirmed the FSGS trial would align with the Parasol group's work. EVP of Commercial, David Acheson, clarified that 'free goods' is a new, more inclusive term that encompasses both traditional samples and the patient assistance program (PATH) to capture all non-commercial product.

Yigal Nochomovitz asked about the company's visibility on the co-pay assistance funding situation being resolved and inquired about the pre-launch plans for EMPAVELI in C3G and IC-MPGN.

Answer

Executive David Acheson stated there is no predictability on the co-pay issue, and the company is operating as if it will not be resolved. For the EMPAVELI launch, he detailed that field teams are actively profiling accounts, medical affairs is educating on the data, and the key message is that EMPAVELI's superior efficacy will drive physician choice over route of administration. The teams have been in the field since April, preparing for a launch post-PDUFA date.

Yigal Nochomovitz from Citigroup inquired about the dosing strategy for the SYFOVRE and APL-3007 combination trial and asked about potential patent life extension for EMPAVELI.

Answer

CEO Dr. Cedric Francois explained the combo trial will synchronize subcutaneous and intravitreal injections for physician convenience. CFO Tim Sullivan addressed the patent question, stating that composition of matter for EMPAVELI extends to roughly 2035 with extensions, providing a significant runway for the new indications.

Yigal Nochomovitz of Citigroup sought more clarity on the Q3 gross-to-net impact, specifically regarding contracting and discounts, and asked for any available data on patient persistence and duration of therapy.

Answer

CFO Timothy Sullivan explained the Q3 gross-to-net increase was a 'perfect storm' resulting from three factors: strategic contracting decisions from late 2023, new rebates in Q3, and a true-up of prior quarter fees. COO Adam Townsend added that patient persistence and discontinuation rates are tracking similarly to established anti-VEGF therapies, supported by strong patient motivation and the flexibility of every-other-month dosing.

Yigal Nochomovitz inquired if specific HARMONi-3 event rates or new information, beyond HARMONi-2 and HARMONi-6 optimism, drove the Q2 interim PFS analysis. He also asked for details on alpha spend or event triggers and the scientific rationale for combining Ivonescimab and Ligufalimab, seeking evidence of synergy from ESMO 2024 data.

Answer

Dave Gancarz, Chief Business and Strategy Officer, and Allen Yang, Chief R&D Strategy Officer, confirmed the decision was primarily data-backed by HARMONi-2 and HARMONi-6, with no change to final PFS/interim OS timing or disclosure of statistical plan details. Regarding Ivonescimab and Ligufalimab, they cited encouraging ESMO 2024 data showing an uplift with the combination, and noted the ILLUMINE study's three-arm design will definitively assess contribution of components.

Yigal Nochomovitz pressed for details on the interim PFS analysis for HARMONi-3, asking if any specific HARMONi-3 event rate or new information, beyond HARMONi-2 and HARMONi-6 optimism, drove the decision. He also asked for details on alpha spend or event triggers and inquired about the contribution of components for ivonesimab and Ligufalimab from ESMO 2024 data.

Answer

Dave Gancarz, Chief Business and Strategy Officer, and Allen Yang, Chief R&D Strategy Officer, clarified that the interim PFS decision was primarily data-backed by HARMONi-2 and HARMONi-6, aiming to accelerate development, not due to specific HARMONi-3 event rates. No details on alpha spend or event triggers were provided. Regarding ivonesimab and Ligufalimab, Dave Gancarz noted ESMO 2024 data showed an uplift with the combination, and the new three-arm Phase III ILLUMINE study will definitively assess contribution of components. Allen Yang added that the combination showed a higher overall response rate than ivonesimab alone in ESMO data.

Yigal Nochomovitz inquired about the expected timing for the first overall survival (OS) data cut from the HARMONi-6 study, specifically if it would precede the HARMONi-3 squamous PFS readout. He also asked about the implications of HARMONi-6's stronger-than-expected hazard ratio (0.60 vs. 0.70) on the study's OS powering. Additionally, he questioned Summit Therapeutics' funding options and priorities for raising additional capital given the expanded phase III clinical development program.

Answer

Dave Gancarz, Chief Business and Strategy Officer, stated that specific details regarding the HARMONi-6 OS data cut would be deferred to their partners at Akeso, but indicated a likely review in 2026. Bob Duggan, Chairman of the Board and Co-CEO, and Maky Zanganeh, Co-CEO and President, addressed funding, mentioning an existing ATM facility, inbound interest for additional capital, and Bob Duggan's recent personal investment, emphasizing the significant opportunity and the team's control.

Yigal Nochomovitz inquired about the specifics of the upcoming HARMONi data release, asking if geographic breakdowns (China vs. ex-China) would be provided, about the data release timing relative to other trials, and whether statistically significant Overall Survival (OS) is necessary for a competitive U.S. filing. He also asked about the long-term strategy for ADC combinations beyond the Pfizer partnership.

Answer

Executive Dave Gancarz explained that top-line data would be more qualitative, with detailed geographic breakdowns likely presented in a forest plot at a major medical conference. He and Chief Medical Officer Dr. Allen Yang emphasized that HARMONi has two primary endpoints (PFS and OS) and the total data package will be considered for filing, noting that statistically significant OS has not been a precedent for approval in this specific setting. Regarding ADC strategy, Dr. Yang stated the company is open to other collaborations, and Dr. Jack West added that other combinations are being explored through ISTs and cooperative groups.

Yigal Nochomovitz inquired about the specificity of geographic data in the HARMONi readout, the timing of data releases, the necessity of statistically significant Overall Survival (OS) for a U.S. filing, and the long-term strategy for ADC combinations beyond the Pfizer deal.

Answer

Executive Dave Gancarz explained that top-line data would be qualitative, with detailed geographic breakdowns at a major medical conference. He and Chief Medical Officer Dr. Allen Yang emphasized that while OS is a primary endpoint, the totality of the data package is key, and precedent in this setting doesn't require stat-sig OS for approval. Dr. Yang and Dr. H. Jack West, VP, confirmed they are open to other ADC collaborations and are exploring combinations via ISTs.

Yigal Nochomovitz of Citigroup inquired about the expected timing for the HARMONi-2 overall survival (OS) data, whether a statistically significant OS is required for U.S. approval of the HARMONi trial, the timeline for the HARMONi-3 readout, and details on the new Pfizer collaboration.

Answer

Dave Gancarz, an executive, stated that the required events for the HARMONi-2 interim analysis are anticipated by the end of 2025. Dr. Allen Yang, Chief Medical Officer, explained that while statistically significant OS is the goal for the HARMONi trial, historical precedent suggests that progression-free survival (PFS) alone could be sufficient for approval. Manmeet Soni, COO & CFO, noted it was too early to provide a timeline for HARMONi-3's completion but confirmed the HARMONi-6 trial should read out in mid-to-late 2025. Dave Gancarz added that the Pfizer collaboration involves multiple ADCs in Phase Ib/II studies for solid tumors, with trials expected to start mid-2025.

Yigal Nochomovitz of Citigroup Inc. questioned the decision to amend the HARMONi-3 trial versus starting a new study for non-squamous patients and asked for the basis of management's confidence that the HARMONi-2 trial will ultimately demonstrate a statistically significant Overall Survival (OS) benefit.

Answer

CFO Manmeet Soni explained that amending the existing trial was faster and more efficient, leveraging existing sites and avoiding long lead times for a new study. CMO Dr. Allen Yang added that physicians were excited by the change. Regarding HARMONi-2's OS potential, Dr. Yang expressed unchanged confidence, citing the strong PFS hazard ratio and historical precedents where similar PFS benefits translated to OS benefits, noting the primary endpoint was PFS.

Yigal Nochomovitz asked about the read-through from HARMONi-2 to HARMONi-3, the patient TPS scores in HARMONi-3, potential interim readouts for HARMONi-3, and how the company's internal Phase II work will intersect with the new MD Anderson collaboration.

Answer

Chief Medical Officer Dr. Allen Yang expressed increased confidence in HARMONi-3 following the HARMONi-2 results, confirming it will enroll patients with all TPS scores. He could not disclose timelines for HARMONi-3 interim readouts. Chairman and CEO Robert Duggan explained that the MD Anderson collaboration will complement Akeso's Phase II work by exploring tumor types less prevalent in China and providing access to key scientific expertise.

Yigal Nochomovitz asked about the lag between strong Q4 patient start forms (up 24-25%) and Q4 revenue growth (up 13%) for FILSPARI. He also asked about the required homocysteine reduction for statistical significance in the pegtibatinase HARMONY study and if responder analyses are part of the analysis.

Answer

Peter Heerma (Chief Commercial Officer) explained that there's always a time lag between patient start form generation and revenue recognition, noting December was the strongest month and Q4 had higher gross-to-net discounts. Jula Inrig (Chief Medical Officer) stated that Travere hasn't externally disclosed the exact treatment effect for statistical significance but pointed to the COMPOSE study's 67% reduction in total homocysteine. She confirmed the HARMONY study is well-powered for 70 patients and will look at clinically meaningful thresholds.

Yigal Nochomovitz asked about the lag between the strong quarter-over-quarter growth in patient start forms and revenue from Q3 to Q4. He also inquired about the required homocysteine reduction for statistical significance in the pegtibatinase HARMONY study and if responder analyses are part of the plan.

Answer

Peter Heerma, Chief Commercial Officer, explained the time lag between patient start form generation and revenue recognition, noting strong December PSFs carrying into Q1 and higher Q4 gross-to-net. Jula Inrig, Chief Medical Officer, stated they haven't disclosed the exact treatment effect for statistical significance but referenced COMPOSE's 67% reduction, confirming the HARMONY study is well-powered for 70 patients and will include clinically meaningful thresholds, with all patients in prior studies showing homocysteine reduction.

Yigal Nochomovitz of Citigroup asked for clarification on the meaning of 'sustained complete remission' (CR) as referenced in a recent publication on FSGS endpoints, and whether the DUPLEX study results are consistent with this definition.

Answer

Dr. Jula Inrig, Chief Medical Officer and a co-author of the cited paper, explained that while the paper didn't define a specific duration, 85% of DUPLEX patients who achieved CR stayed below their baseline proteinuria, showing durability. President & CEO Dr. Eric Dube added that the Parasol analysis, which is more recent and robust, is the key focus and that the treatment effect in DUPLEX was sustained at both nine months and two years.

Yigal Nochomovitz inquired if a REMS modification would apply to a future FSGS label, what the next step after quarterly monitoring would be, and whether FSGS pricing would be double the IgAN price due to the higher dose.

Answer

CEO Eric Dube confirmed that any REMS in place at the time of a potential FSGS approval would apply to the new indication, and that the next step after modification is full removal. CCO Peter Heerma addressed pricing, stating that while the dose is doubled, the pricing strategy is based on the value proposition, which is higher in the more progressive FSGS. He noted they are refreshing their value assessment and did not commit to a specific price.

Yigal Nochomovitz requested more detailed information on the 90 patients prescribed VYJUVEK in Europe, specifically how this number splits across Germany, France, and Japan, and the month-over-month cadence of patient additions in the recent quarter. He also asked about the reimbursement process in Italy, comparing it to the accrual and negotiation setups in Germany and France.

Answer

Krish Krishnan, Chairman and CEO, Krystal Biotech, explained that the 90-patient estimate for Europe is an approximation due to differing laws between the U.S. and Europe, making further segmentation into specific countries less relevant at this time. He reiterated that the company will provide a clearer breakdown of U.S. versus rest-of-world revenue starting in Q1. For Italy, Krishnan stated that the company expects to launch only after pricing is finalized, meaning no accrual-type situation is anticipated.

Yigal Nochomovitz asked for a detailed breakdown of the 90 VYJUVEK patients across Germany, France, and Japan, including month-over-month patient add cadence. He also inquired about the reimbursement process in Italy, comparing it to the accrual and negotiation setups in Germany and France.

Answer

Krish Krishnan, Chairman and CEO, stated that the 90-patient estimate is an approximation due to differing laws and supply chain complexities, making further segmentation difficult and less relevant. He indicated that Q1 revenue reporting would provide clearer insights. For Italy, Krishnan clarified that the launch would occur only after pricing is finalized, meaning no accrual-type situation is expected.

Yigal Nochomovitz of Citigroup asked about the timeline to capture the remaining 40% of the U.S. market beyond the initial 720-patient target and requested more detail on the early access program (EAP) continuity in France.

Answer

Chairman & CEO Krish Krishnan stated the company is targeting the full 1,200 identified patient base, calling the 720 number a benchmark for launch speed. SVP & GM for Europe Laurent Goux explained the EAP comment relates to a formal transition from a pre- to post-authorization access program, in which they are confident.

Yigal Nochomovitz inquired about the potential revenue contribution from the Japanese market, the number of identified patients there, and the outcome of the recent manufacturing inspection for Japan.

Answer

Krish Krishnan, Chairman and CEO, described Japan as an attractive market with a prevalence of around 500 patients, over 200 of whom are identified. He expects pricing between U.S. and EU levels and a launch in late 2025 or early 2026. Both Krish and Suma Krishnan, President of R&D, confirmed the pre-approval manufacturing inspection for Japan was completed successfully with no findings.

Speaking on behalf of Yigal Nochomovitz, an analyst asked for more detail on the AATD program, including expectations for upcoming data from expanded cohorts, the definition of 'comprehensive molecular assessments,' and whether plasma AATD levels are a relevant endpoint.

Answer

CEO Krish Krishnan and President of R&D Suma Krishnan clarified that the goal is to confirm prior findings and establish a dose response. They explained that while AAT levels in the lung are the primary focus, establishing a clear correlation with plasma levels could provide a less invasive biomarker pathway for regulatory purposes, potentially avoiding the need for future bronchoscopies.

Yigal Nochomovitz asked about the effectiveness of the broad social media campaign in identifying new patients and driving new starts, and requested an update on the previously mentioned market expansion beyond the initial 1,200 identified patients.

Answer

Christine Wilson, SVP and Head of U.S. Sales and Marketing, confirmed that social media outreach is successfully engaging patients not previously connected to the healthcare system. Chairman and CEO Krish Krishnan added that the trend of market expansion continues as awareness grows, and the company will report on significant milestones as they are achieved.

Yigal Nochomovitz asked for more details on the OTC (DTX-301) study, inquiring about its prominence in the company's expectations for success and what would be needed for the study to hit its endpoints. He also asked if the UX111 IRL requests, which would typically occur during an inspection, imply that the inspection would be limited or different.

Answer

CEO Emil Kakkis explained that while OTC is an important program with a serious unmet need, it's not the top priority among Ultragenyx's many programs. He detailed that the Phase 3 trial (around 37 patients) will primarily look at the change in ammonia between treated and control groups, followed by an assessment of patients getting off standard of care. Kakkis confirmed that the FDA will still conduct an inspection for UX111, but providing the extensive supportive documentation upfront is intended to give them greater confidence that all requests regarding quality manufacturing have been addressed.

Yigal Nochomovitz asked for clarification on the revised submission order for UX111 and DTX401, and then followed up by asking about the progress towards the cap of the initial $145 million OMERS transaction from 2022.

Answer

Eric Crombez, Chief Medical Officer, explained that DTX401's rolling BLA submission is now ahead of UX111 due to specific report requirements for UX111. Howard Horn, Chief Financial Officer, clarified that the company does not disclose tracking to the cap for the 2020 OMERS deal, but confirmed it has its own cap, and once hit, will flow into the new agreement, which has a combined cap of 1.55 times the $400 million raised.

Yigal Nochomovitz asked for clarification on the submission timing for UX111 and DTX401, noting a perceived change in the order of BLA filings, and inquired about the reasons behind this adjustment. He also asked about the progress towards the cap of the initial OMERS Crysvita royalty transaction from 2022.

Answer

Eric Crombez, Chief Medical Officer, explained that while the filings were always close, specific full reports required for UX111 took slightly longer, causing DTX401 to proceed first. Howard Horn, Chief Financial Officer, stated that the company does not disclose tracking to the cap of the prior OMERS deal but clarified that the 2020 agreement has its own cap, and once reached, it will flow into the new deal, which has a combined cap of 1.55 times the $400 million raised.

Yigal Nochomovitz from Citigroup sought clarification on two topics: whether the GSD1a filing delay was due to a specific CMC issue from UX-111 or general precaution, and for any updated thoughts on the expected placebo fracture rate and statistical variance in the OI trial.

Answer

Eric Crombez, Chief Medical Officer, explained that the GSD1a filing is being carefully managed because both it and UX-111 are produced at the same manufacturing facility, so any facility-related findings could have implications for both. He also noted that for OI, the Phase III ORBIT study enrolled a higher proportion of severe Type 3 and 4 patients compared to Phase II, which influences baseline characteristics.

Yigal Nochomovitz asked about the distribution of OI types (1, 3, and 4) in the Phase III Orbit trial compared to Phase II, and also questioned the precise tolerance for the interim analysis p-value (e.g., if 0.011 would be a fail).

Answer

CEO Emil Kakkis explained that following strong Phase II results, physicians enrolled more severe Type 3 and 4 patients into the Phase III study, resulting in about half the population being Type 3 or 4. On the p-value, he confirmed that a result like 0.015 would not meet the <0.01 threshold and would be considered a miss. He also reiterated that the company was not provided the p-value from the first interim analysis.

An analyst on behalf of Yigal Nochomovitz asked if Ultragenyx would retrospectively share data on how close the OI study was to succeeding at previous interim analyses.

Answer

CEO Emil Kakkis was non-committal about releasing past interim data, emphasizing that the final result is what matters. He pointed to the Phase II data, where the p-value improved from 0.04 at 6 months to 0.0014 at 14 months, as a reasonable model for the expected progression in the Phase III study.

Yigal Nochomovitz asked for the specific cornstarch reduction data for the original DTX401 treatment group and questioned the company's cash position and revised timeline to profitability.

Answer

CEO Emil Kakkis explained the original group had a 41% reduction in the blinded phase and is now improving further. CFO Howard Horn reiterated the path to profitability, stating that with recent financing and expected PRV monetizations, the company has the cash to fund its plan to reach a GAAP profitable quarter by the end of 2026, driven by revenue growth and leveling expenses.

Yigal Nochomovitz probed further on CRENESSITY's 10% market share in CAH, asking if it's exclusively from endocrinologists and if any early share is observed from other categories like PCPs or OB/GYNs, also inquiring about the use of AI/database inferencing for identifying best candidate prescribers.

Answer

Chief Commercial Officer Eric Benevich clarified that virtually all new patient starts for CRENESSITY have originated within endocrinology. He explained that Neurocrine is leveraging technology platforms and datasets to identify potential patients and prescribers beyond endocrinology, allowing the field sales organization to follow up and improve targeting in this rare disease market.

Yigal Nochomovitz probed further on CRENESSITY's 10% market share in CAH, asking if it was exclusively from endocrinologists, if there was any early share from PCPs or OB/GYNs, and the extent to which AI database inferencing is used for targeting.

Answer

Eric Benevich, Chief Commercial Officer, clarified that the estimated 10% of the prevalent CAH population on treatment (out of ~20,000 in the U.S.) has virtually all originated from endocrinology. He stated that to expand further, Neurocrine needs to reach beyond the current prescriber base and is leveraging technology platforms and datasets to identify similar patients for field sales follow-up, as Classic CAH lacks a specific diagnosis code, making technology and team crucial for growth.

Yigal Nochomovitz asked about Neurocrine Biosciences' capital management strategy, specifically the continuation and pace of the share buyback program given the announced increase in SG&A expenses.

Answer

Matt Abernethy, Chief Financial Officer, highlighted the company's strong financial position with $2.1 billion in cash and no debt. He stated that capital allocation priorities are driving revenue growth, advancing R&D (targeting 35%), and enabling business development. While flexibility for share buybacks exists, the bias is towards utilizing capital for internal initiatives and potential business development activities.

Yigal Nochomovitz of Citigroup asked about the timing of the end-of-Phase 2 meeting for the CF program, the reason for disclosing specific dose levels now, and the latest thinking on proceeding with a higher dose cohort for the OTC program.

Answer

President and CEO Joseph Payne guided for an end-of-Phase 2 meeting in the first half of 2026, stating no further trials are expected before a pivotal study. He said doses were disclosed to highlight the high, well-tolerated cumulative dose being administered (280mg). For OTC, he indicated it is a "conservative expectation" that they will test the 0.7 mg/kg dose, but a final decision is pending.

Yigal Nochomovitz of Citigroup asked about the specific FEV1 improvement thresholds that would be considered strong enough to advance the CF program and inquired if biomarkers like orotic acid and alanine were also being measured in the OTC study.

Answer

President and CEO Joseph Payne detailed that a 3% FEV improvement would likely necessitate a large Phase 3 trial, whereas a 5% improvement could reduce the trial size to under 100 participants. For the OTC program, he confirmed that orotic acid and other amino acids are being tracked, but emphasized that glutamine is a more common and well-understood biomarker in the clinical community for monitoring hyperammonemia.

Yigal Nochomovitz asked whether the $25 million milestone was cash or accounts receivable, and inquired about ARCALIS's manufacturing capacity for CF and OTC programs, including its fill/finish capabilities for a nebulized product. He also asked about the branding of KOSTAIVE doses made in different locations.

Answer

CFO Andrew Sassine clarified the $25 million milestone is an accounts receivable with 60-day payment terms. CSO Padmanabh Chivukula confirmed ARCALIS is building out fill/finish capabilities and that a tech transfer is required for the CF product. Management indicated OTC manufacturing will remain with current partners due to its smaller scale, while Sassine confirmed all KOSTAIVE doses will have uniform labeling.

Yigal Nochomovitz from Citigroup posed questions on operational strategy, asking about Zymeworks' supply chain planning, particularly concerning domestic manufacturing, and the extent to which the company is utilizing AI for early-stage drug discovery.

Answer

CEO Kenneth Galbraith confirmed that partners Jazz and B1 are managing the zanidatumab supply chain and are prepared for domestic manufacturing if needed. He and CSO Paul Moore added that Zymeworks has deep roots in computational biology and actively uses AI and machine learning in protein engineering and the design of complex biologics like multi-specific antibodies.

Yigal Nochomovitz of Citigroup inquired if Zymeworks had compared its DLL3 T-cell engager, ZW209, against DLL3-targeting ADCs. He also asked for the company's general strategic view on pursuing a T-cell engager versus an ADC for this specific target.

Answer

Chief Scientific Officer Dr. Paul Moore explained that they have not conducted direct head-to-head comparisons with ADCs, as they typically benchmark against similar modalities. He stated that the T-cell engager approach was chosen for DLL3 due to the clinical proof-of-concept from tarlatamab and the opportunity to leverage Zymeworks' proprietary co-stimulatory (TriTCE) platform, which preclinical data strongly supported for this target.

Yigal Nochomovitz followed up on the ZW251 prioritization, asking if a specific standout preclinical result prompted the recent decision, and questioned the future development path for ZW220 (NaPi2b), whether internal or partnered.

Answer

Chair and CEO Kenneth Galbraith reiterated the decision was about accelerating a high-potential program. CSO Dr. Paul Moore added that maturing preclinical data from HCC PDX models continued to look very exciting, supporting the decision. Galbraith stated that no guidance has been given on the timing or method for reinitiating the IND-ready ZW220 program.

On behalf of Yigal Nochomovitz, Ashiq Mubarack asked about the company's philosophy on data sharing for its wholly-owned pipeline and its plans for the remaining $30 million of its stock repurchase program.

Answer

CEO Kenneth Galbraith stated that data will be shared at peer-reviewed medical meetings only after a substantial and conclusive dataset is available, not via preliminary press releases. Regarding the share repurchase, he confirmed the first $30 million tranche is complete and the decision to initiate the second tranche will depend on a careful evaluation of market conditions, though he reiterated the company still feels undervalued.

Yigal Nochomovitz of Citigroup Inc. posed several detailed questions on bemarituzumab, asking for perspective on the expected overall survival delta in the FORTITUDE-101 study and the subsequent trial with nivolumab. He also inquired about the DLL3 ADC combo dose with atezolizumab and asked for an updated view on the total peak sales potential for efgartigimod given its expanding pipeline of indications.

Answer

Rafael Amado, President and Head of Global R&D, stated he could not comment on the specific OS delta for bemarituzumab due to data embargo but reiterated the results were clinically meaningful. For the DLL3 ADC, he expressed confidence that the 1.6 mg/kg dose would be combinable with atezolizumab due to non-overlapping toxicities. Josh Smiley, President & COO, addressed efgartigimod's potential, noting that new indications could expand the addressable patient population in China from ~170,000 to over 500,000, reinforcing the company's view of a greater than $1 billion peak sales opportunity.

Yigal Nochomovitz asked about the NRDL negotiation process for VYVGART's different formulations, the competitive positioning of bemarituzumab against other gastric cancer therapies, and the engineering specifics of the company's ADC assets.

Answer

Jonathan Wang, CBO, explained that VYVGART's IV and subcutaneous formulations are treated as separate products, allowing pricing flexibility, and expects a 'modest discount.' Dr. Rafael Amado, President and Head of Global R&D, highlighted bemarituzumab's targeted approach for the distinct FGFR2b patient population and confirmed the ADCs feature a linker system allowing for both intracellular and extracellular payload release.

Rena, on behalf of Yigal Nochomovitz, inquired about Zai Lab's strategy for ZL-1310 in the first-line small cell lung cancer setting and asked for specifics on the data expected at the upcoming medical congress, such as patient numbers and efficacy points.

Answer

Dr. Rafael Amado, President and Head of Global R&D, detailed that the upcoming data presentation will include about 75 patients from dose escalation and optimization cohorts. For the first-line setting, the strategy involves combination studies with PD-L1 inhibitors and chemotherapy, with the goal of potentially supplanting the current standard of care. Data from this first-line dose optimization is expected later in the year.

Yigal Nochomovitz from Citigroup inquired about the market dynamics between VYVGART's IV and upcoming subcutaneous (subcu) formulations, including whether patients are waiting for the subcu version. He also asked about the CIDP market opportunity in China.

Answer

President and COO Josh Smiley stated that patients are not waiting for the subcu version for GMG, as the IV formulation is suitable for the current hospital-based treatment setting. Dr. Harald Reinhart, President and Head of Global Development, added that for CIDP, there are no approved treatments, creating a significant unmet need where VYVGART can have a major impact.

Yigal Nochomovitz asked for commentary on the use of a blended primary endpoint versus a single time point and whether EyePoint would launch immediately upon approval or after a delay.

Answer

CEO Dr. Jay Duker explained that the blended endpoint was a strong suggestion from the FDA to reduce data variability and de-risk the trials, noting it has been used in other recent studies. He affirmed that EyePoint is working diligently towards an immediate launch of DuraVu following a potential FDA approval.

Yigal Nochomovitz of Citigroup inquired about the use of a blended primary endpoint versus a single time point and whether the company could launch immediately upon potential FDA approval.

Answer

CEO Jay Duker explained that the blended endpoint was a 'strong suggestion' from the FDA that the company adopted to decrease variability and de-risk the trial. He noted this approach is not new and has been used in other recent studies. Regarding a potential launch, Duker stated that EyePoint is 'working diligently towards an immediate launch after approval,' assuming successful trial outcomes and a positive NDA review.

Yigal Nochomovitz asked for the company's view on being first to file an NDA for a long-acting TKI given the rapid enrollment, and requested a review of its supply chain and IP positioning.

Answer

President and CEO Dr. Jay Duker expressed high confidence in being first-to-file, citing rapid enrollment and trial design, which could lead to a first-to-market advantage. He also highlighted a secure, U.S.-based supply chain, with the API and in-house manufacturing located in the U.S., and a new facility ready to meet global demand.

Yigal Nochomovitz of Citigroup asked for the company's thinking on being first-to-file an NDA for long-acting TKIs and requested a review of EyePoint's supply chain and IP positioning.

Answer

President and CEO Dr. Jay Duker expressed high confidence in being first-to-file, citing rapid enrollment, a 56-week trial duration, and no run-in period before randomization. He detailed the supply chain, noting the API is U.S.-sourced and the inserts are manufactured in-house in Massachusetts at a facility capable of meeting global demand. This vertical integration and the small molecule nature of vorolanib provide a secure and cost-effective supply chain, mitigating tariff risks.

Yigal Nochomovitz asked for commentary on the VERONA trial's subgroup analysis, specifically the performance of the 1.3mg dose versus the 2.7mg dose, and requested more specific timing for the Phase III top-line data release in 2026.

Answer

President and CEO Dr. Jay Duker attributed the difference in dose performance to a clear dose-response, emphasizing the strength of the 2.7mg go-to-market dose. He also indicated that EyePoint expects to provide more granular timing on the Phase III data readout in the second half of 2025.

Julian Kim, on for Yigal Nochomovitz, asked whether Artificial Intelligence (AI) was used in compiling the Vepdeq NDA submission and inquired about the broader potential for AI utilization in Arvinas's drug development pipeline.

Answer

CEO John Houston, CMO Noah Berkowitz, and CSO Angela Cacace all contributed. They confirmed AI is used through vendors for NDA submissions and more broadly in development for medical writing, clinical operations contract management, and statistical programming. In research, AI and machine learning are heavily used for PROTAC design optimization, identifying new drug targets, and mining biomarker data from public datasets to inform clinical strategy for diseases like Parkinson's.

Yigal Nochomovitz asked for the preclinical rationale for the vepdegestrant-KAT6 combo, details on the vepdegestrant supply chain and IP domicile, and whether the complexity of a novel-novel combo influenced the decision to stop the first-line trial.

Answer

CEO John Houston and CMO Noah Berkowitz clarified the KAT6 combo rationale is based on Pfizer's data and attractive results with fulvestrant, not specific Arvinas preclinical work. Houston confirmed Pfizer manages manufacturing in Ireland while Arvinas holds the IP in the U.S. He also acknowledged that the challenges of a novel-novel combination likely factored into Pfizer's decision to await more mature data.

Yigal Nochomovitz of Citigroup asked about the potential first-line trial design for an atirmociclib/vepdegestrant combo, specifically regarding the comparator arm and addressing the 'contribution of components' issue. He also inquired about data supporting a lack of drug-drug interaction (DDI).

Answer

CMO Noah Berkowitz indicated the comparator would likely be an AI combination, but the final design is not set. CEO John Houston addressed the DDI concern, stating that upcoming data will demonstrate that vepdegestrant is broadly combinable and that any potential interaction is a 'non-issue from a clinical perspective.'

Yigal Nochomovitz inquired if the new, higher growth trajectory of 45-52% is sustainable beyond 2025 and asked for details on the Phase 2 study design for elutacitinib in glioma and the regulatory path for the CONNECT trial data.

Answer

President & CEO Raul Rodriguez noted the strong start was due to specific 2025 dynamics but expressed confidence in continued growth without giving guidance beyond the year. EVP & Chief Medical Officer Lisa Rojkjaer stated that details on the glioma study design would be shared later in the year and that the regulatory path for the CONNECT study data requires further discussion with partners and the FDA.

Ashik, on behalf of Yigal Nochomovitz, inquired about the extent of any stocking benefit in GAVRETO's initial sales and the expected growth trajectory for the product under Rigel's management.

Answer

Chief Commercial Officer David Santos stated that the initial stocking occurred at the end of Q2, and the vast majority of Q3 sales represented true patient and account demand. He noted that shipment volume increased throughout Q3 as the transition progressed, suggesting continued demand growth. CFO Dean Schorno added that the Q2 inventory build was 228 bottles, with a much smaller incremental build in Q3.

Yigal Nochomovitz inquired about the rationale for adding new twice-daily dosing cohorts to the IRAK1/4 inhibitor trial, the competitive efficacy goals for the olutasidenib combination study with MD Anderson, and whether the company plans to provide revenue guidance in the future.

Answer

Chief Medical Officer Lisa Rojkjaer explained that the new IRAK1/4 dosing cohorts aim to thoroughly explore all options to determine the optimal dose for Phase II. Regarding the MD Anderson trial, she noted olutasidenib is a distinct molecule from competitors and that a key goal is to develop a novel all-oral triplet therapy. President and CEO Raul Rodriguez addressed guidance, stating that while the business is strengthening, the newness of REZLIDHIA and GAVRETO makes forecasting complex, but providing guidance is something the company regularly evaluates for the future.

Yigal Nochomovitz from Citigroup sought clarification on the SONATA trial design, asking if obstructive and nonobstructive HCM were co-primary endpoints and about enrollment stratification. He also questioned the rationale for choosing KCCQ as the primary endpoint over a physiological measure like peak VO2.

Answer

Dr. Craig Granowitz, SVP and Chief Medical Officer, explained that SONATA is powered for the overall KCCQ endpoint, with the FDA looking for consistency across subgroups, not two independently powered arms. Enrollment is stratified 1-to-1. He noted KCCQ was chosen because sotagliflozin has established outcomes data, unlike newer agents needing surrogates. CEO Michael Exton added that KCCQ directly measures symptomatic benefit, which is the primary need for HCM patients.

Yigal Nochomovitz asked about the expected sales trajectory for INPEFA into 2025, the appropriate level of investment for the launch, and details on the types of patients receiving the drug, including prior SGLT2 use.

Answer

Tom Garner, SVP & Chief Commercial Officer, reported encouraging Q3 volume growth despite a gross-to-net true-up affecting net revenue. He noted heavy Medicare Part D exposure and that most patients require step-throughs. He anticipates modest quarter-over-quarter growth moving forward. CEO Dr. Mike Exton added that the future investment level for INPEFA is part of ongoing scenario planning that depends on the ZYNQUISTA PDUFA outcome.

Yigal Nochomovitz asked for early thoughts on the pricing strategy for the sonrotoclax plus zanubrutinib combination. He also inquired about long-range plans for U.S.-based API manufacturing and whether the company's redomiciling to Switzerland would shift core R&D operations out of China.

Answer

CFO Aaron Rosenberg stated it was too early to discuss specific pricing but that it would reflect the value created for patients. On supply chain, he confirmed the company is proactively ensuring global supply resilience. CEO John Oyler described the company's geographic footprint as being in 'inevitable expansion mode' globally, including active R&D recruitment in the U.S.

Yigal Nochomovitz asked about early pricing thoughts for the sonrotoclax plus zanubrutinib combination. He also inquired about long-range plans for U.S.-based API manufacturing and whether the redomiciling to Switzerland would shift more core R&D out of China.

Answer

CFO Aaron Rosenberg stated it was too early to discuss pricing but that it would reflect the value created for patients. He affirmed the company is monitoring the supply chain environment. CEO John Oyler described the company's geographic footprint as being in 'inevitable expansion mode,' highlighting R&D recruiting in California as part of its global growth.

Inquired about the specifics of the FDA approval for the UDENYCA supplier, the basis for the specific timing on the CCR8 data, and if there was a recent price increase for LOQTORZI.

Answer

The company explained the FDA needs to review manufacturing validation data without a facility visit. The specific timing for the CCR8 data is based on strong patient enrollment, good site engagement, and a close relationship with their CRO. They also confirmed a LOQTORZI price increase of approximately 2.46%.

Inquired about the UDENYCA supply situation, asking for a timeline for commercial availability and inventory restocking, and how customer accounts managed during the shortage.

Answer

Sales are expected to resume in late November/early December. A robust replenishment of the supply chain is planned through December and beyond. The company is confident customers will return to UDENYCA, citing the product's strong value proposition. During the shortage, accounts used existing channel inventory or switched to competitor products but have indicated they will switch back upon resupply.

Yigal Nochomovitz of Citigroup questioned the conservative nature of the 2025 IBSRELA guidance, the timeline for XPHOZAH's peak sales target, and the potential for a business development deal in 2025.

Answer

President and CEO Michael Raab explained the IBSRELA guidance reflects typical Q1 market contraction and the company's practice of providing achievable targets. He confirmed the XPHOZAH peak sales timeline includes the Hatch-Waxman extension and stated that any potential business development deal is to be determined based on finding the right opportunity.

An analyst on behalf of Yigal Nochomovitz from Citi asked what triggered the decision to pause the vobra duo and lorigerlimab combination study now, rather than earlier, and requested details on patient numbers and safety.

Answer

Dr. Scott Koenig, President and CEO, clarified that the decision was made to await the final TAMARACK data to determine the optimal vobra duo dose before proceeding with combination expansions. He explained this ensures they use the best possible dose in future combination studies, making it a matter of prudent sequencing.

Yigal Nochomovitz asked how the upcoming Mycosis Fungoides (MF) data would impact the filing strategy and potential label for Lacutamab, the timelines for FDA discussions, and whether expected milestones from partners could extend the cash runway beyond 2025.

Answer

Chief Medical Officer Sonia Quaratino stated the goal is to maximize Lacutamab's value across the entire CTCL space and that progressing the regulatory strategy with the FDA is a priority post-ASCO. She noted a randomized registrational trial is likely required. Interim CEO Hervé Brailly clarified that the current cash runway projection through the end of 2025 does not include any potential future milestones from partnerships.

Yigal Nochomovitz of Citigroup asked if tissue biopsies were used to confirm FT819's tissue trafficking and questioned the efficacy expectations for FT522 in autoimmunity, specifically whether the goal is to match CAR-T efficacy or prioritize a better preconditioning profile.

Answer

Dr. Bob Valamehr, Chief Research and Development Officer, clarified that tissue activity is confirmed through various methods, including flow cytometry for bone marrow and biopsies for lymphoid tissues. CEO Scott Wolchko addressed efficacy, stating that while competitiveness is essential, the autoimmune setting prioritizes safety, accessibility, and avoiding harsh conditioning, which are key differentiators for an off-the-shelf therapy.

Inquired about evidence for FT819's tissue penetration, the strategic plan for expanding into other autoimmune indications beyond the competitive lupus space, and the rationale for the selected starting dose in the autoimmune trial.

Answer

The company cited evidence of tissue trafficking from responses seen in their B-cell lymphoma trial. They confirmed they are actively looking to expand FT819 into additional autoimmune indications. The starting dose of 360 million cells was based on the dose level cleared for safety in the oncology study at the time of the IND submission.

Yigal Nochomovitz of Citigroup inquired about the early signs of tumor reductions in the MANTRA-2 MDM2 amplified basket trial, asking for specifics on the tumor types, any correlation with MDM2 copy number, and the p53 status of the patients.

Answer

CSO Robert Doebele clarified that no new data was available beyond the 2022 update. He reiterated that tumor reductions were observed in lung, pancreatic, breast, and biliary cancers, all in p53 wild-type patients, and that there was no observed correlation with copy number beyond the fact that all were amplified.

Yigal Nochomovitz of Citigroup asked about potential combination partners for MANTRA-2 if it were to pursue a combination strategy, the key lessons learned from the terminated RAD52 program, and the frequency of checking for MANTRA trial events.

Answer

CEO Avanish Vellanki noted that potential MANTRA-2 combinations could include partners like MEK inhibitors, not just IO agents. CSO Robert Doebele explained the RAD52 program was halted because the biochemical assays failed to predict cellular potency and selectivity. CMO Richard Bryce added that MANTRA events are checked every two weeks, and it's possible to exceed the 105-event minimum at analysis.

Yigal Nochomovitz from Citi asked about the approximate cost savings from discontinuing the MANTRA-3 trial and whether lowering the MANTRA-2 copy number cutoff to 8 meaningfully expands the long-term market opportunity. He also posed a strategic question about the potential for a future first-line trial in Dedifferentiated liposarcoma.

Answer

CEO Avanish Vellanki estimated the cost savings from stopping MANTRA-3 to be slightly less than one quarter's historical cash burn. Chief Scientific Officer Robert Doebele added that lowering the MDM2 copy number cutoff increases the potential market size by over 40%. Mr. Vellanki also clarified that the current MANTRA trial design already allows for enrollment of first-line metastatic patients who previously received anthracyclines.

Yigal Nochomovitz from Citigroup asked for an update on the partnering discussions for Reproxalap for dry eye disease and inquired about the strategic thinking regarding the second Phase 3 trial for allergic conjunctivitis.

Answer

President and CEO Dr. Todd Brady described the partnering discussions for Reproxalap as 'robust' and involving multiple parties, noting that potential partners would likely want to engage before label negotiations in the fall. Regarding allergic conjunctivitis, he emphasized its importance as a market differentiator and stated that a decision on filing a new drug application would be made following the results of the INVIGORATE II trial and the outcome of partnership talks.

Yigal Nochomovitz asked about the nature of the upcoming pre-NDA meeting for reproxalap in dry eye disease, specifically questioning the balance between administrative tasks and seeking substantive FDA guidance on filing strategy.

Answer

President & CEO Dr. Todd Brady clarified that while the pre-NDA meeting is officially for discussing format and submission details, Aldeyra will use the opportunity to ask key questions. The primary question for the FDA is how they view the unprecedented breadth of the submission package, which includes data on symptomatic improvement plus three different objective signs, to fulfill efficacy requirements. He highlighted the agency's familiarity with the Schirmer test responder analysis, which they view favorably as it correlates with symptoms.

Yigal Nochomovitz of Citigroup Inc. asked for a ranking of the four new indications for ADX-629 based on probability of success, sought clarification on the finalization of analytical plans for TRANQUILITY-2, and confirmed the safety data requirements for the NDA filing.

Answer

CEO Dr. Todd Brady stated that while optimistic about all four ADX-629 indications, diseases directly linked to aldehydes like Sjogren-Larsson syndrome and ethanol toxicity are likely to show strong pharmacodynamic activity. He clarified that 'finalizing analytical plans' for TRANQUILITY-2 refers to determining the precise alpha allocation between the redness and Schirmer test endpoints. He also detailed that the NDA can be submitted with 6 months of safety data, with the full 12-month data due by the 120-day update.

Speaking on behalf of Yigal Nochomovitz from Citigroup, Asha Mubarak asked for more detail on the secondary resistance pathways that may have impacted ORIC-101's efficacy and inquired about enrollment timelines for the new clinical programs.

Answer

CEO Jacob Chacko explained that resistance pathways such as AR-V7, P-10 loss, and TP53 loss, which were screened for at baseline, were observed to develop in patients while on the study. Regarding timelines for the new programs, he stated it was too early to provide guidance on enrollment completion for the trial that had just initiated in the current quarter.

Yigal Nochomovitz from Citigroup sought clarification on the most relevant of the 17 secondary endpoints in the STARS trial, how results for key domains like behavior and sleep would be presented, and confirmation of the company's cash runway.

Answer

CEO Jeremy Levin directed the question to Executive Amit Rakhit, who explained it was premature to rank endpoints but that behavior, motor function, and sleep are all considered important. He assured a robust data set would be released in Q3. Executive Yaron Werber confirmed the company has 'more than 12 months of cash,' ending the year with $87 million after a quarterly cash use of just over $9 million.