Michael Schmidt

Michael Schmidt asked how Diraxonrasib's Phase I/II results are expected to translate to the global Phase III (Resolute 302), potential differences in patient characteristics, and commercial readiness regarding CMC, manufacturing capacity, and infrastructure.

Answer

Wei Lin, CMO, stated that Phase I patient populations are fairly similar to historical Phase III randomized studies and representative of expected Phase III enrollment, with predominant U.S. enrollment. Mark Goldsmith, Chairman and CEO, confirmed a strong manufacturing organization and supply chain are scaled appropriately. Anthony Mancini, Chief Global Commercialization Officer, detailed launch readiness plans, including experienced executives, market-shaping activities, and building field-based teams.

Michael Schmidt asked about the expected translation of Diraxonrasib's Phase 2 results to the global Phase 3 Resolute 302 study, including potential differences in patient characteristics, and the company's commercial readiness regarding CMC, manufacturing, and infrastructure.

Answer

Wei Lin, Chief Medical Officer, stated that patient populations in Phase 1 and Phase 3 are expected to be similar, with predominant enrollment in the U.S. for Resolute 302, providing reassurance for replicating results. Mark Goldsmith, Chairman and CEO, confirmed strong manufacturing and supply chain readiness. Anthony Mancini, Chief Global Commercialization Officer, detailed advancing launch readiness plans, including experienced executives, market-shaping activities, and talent acquisition across functions.

Michael Schmidt of Guggenheim Securities inquired about the enrollment progress for the RESOLUTE-302 study, specifically its ex-US status and geographic distribution. He also asked about the planned first-line pancreatic cancer (PDAC) trial, questioning the importance of clinical efficacy data from chemotherapy combinations in the decision to advance them.

Answer

CEO Mark Goldsmith confirmed that the RESOLUTE-302 trial is enrolling well, with US enrollment winding down to ensure a global geographic mix for registration, and expects a data readout in 2026. Regarding the first-line PDAC trial, President of R&D Steve Kelsey stated that while safety and tolerability are primary, supplementary efficacy data from first-line patients will be important and will be shared with the trial design later in the year.

Michael Schmidt of Guggenheim Securities inquired about Revolution Medicines' confidence in the tolerability of the proposed first-line NSCLC triplet therapy (elironrasib, daraxonrasib, and pembrolizumab), particularly concerning rash rates and dose reductions observed in doublet combinations.

Answer

Dr. Wei Lin, Chief Medical Officer, responded with optimism, clarifying that the company is still in the dose optimization phase for the triplet. He stated that observed safety signals, such as rash and QTc prolongation, are consistent with the known monotherapy profiles and are not showing new or enhanced concerns. Dr. Lin assured that more definitive data would be shared before the initiation of a Phase III trial.

Michael Schmidt of Guggenheim Securities asked for an update on the first-line metastatic PDAC strategy, including the status of the chemotherapy combination work and how zoldonrasib fits into the overall PDAC registration plan.

Answer

CEO Dr. Mark Goldsmith confirmed that more safety and tolerability data is needed for the daraxonrasib-chemotherapy combination to select the optimal regimen before initiating the planned three-arm trial in 2025. Chief Medical Officer Dr. Wei Lin explained that zoldonrasib, targeting the G12D mutation, is being considered for a separate, stand-alone registrational path and is also being evaluated in a doublet combination with daraxonrasib.

Michael Schmidt inquired about the patient population in the RAS(ON) inhibitor doublet combination study and asked for clarification on the slight delay of the planned Phase III lung cancer trial and the remaining steps for FDA alignment.

Answer

Dr. Mark Goldsmith, Chairman and CEO, stated that the doublet study includes patients with KRAS-G12C tumors across a mix of solid tumor types and prior treatment backgrounds, with more details to be shared with the data. Regarding the lung cancer trial, he clarified the timing adjustment to Q1 2025 was a practical decision due to the upcoming holidays, which made completing regulatory alignment and trial initiation before year-end unrealistic. He reaffirmed the company's commitment to launching the trial soon.

Michael Schmidt asked about the commercial opportunity size for Zanzalintinib in non-clear cell renal cell carcinoma (RCC), the current extent of Cabozantinib use in this segment, and whether the slight delay in STELLAR-304's top-line results to mid-2026 was due to a slowdown in event rates.

Answer

PJ Haley, Executive Vice President of Commercial, stated that non-clear cell RCC accounts for approximately 20%-25% of kidney cancer patients, where Cabozantinib already sees utilization. He expressed excitement for Zanza's potential to significantly impact this space with a positive phase III readout.

Michael Schmidt asked about the commercial opportunity size for Zanzalintinib in non-clear cell renal cell carcinoma (nccRCC), current Cabozantinib use in nccRCC, and the reason for the minor delay in Stellar-304 readout to mid-2026 from the first half.

Answer

PJ Haley, EVP of Commercial, stated that nccRCC accounts for approximately 20-25% of kidney cancer patients, and Cabozantinib already has utilization there. He believes a positive Phase 3 study for Zanzalintinib would significantly impact this space. The reason for the Stellar-304 readout delay was not explicitly stated in the answer.

Michael Schmidt of Guggenheim Securities asked about zanzalutinib's potential positioning in the colorectal cancer (CRC) market and the importance of the non-liver metastases (NLM) subset data for STELLAR-303 after the trial met its primary endpoint in the broader ITT population.

Answer

Amy Peterson, EVP & CMO, emphasized that achieving a statistically significant overall survival (OS) benefit in the ITT population against an active comparator is the 'gold standard' and makes the study positive. While the NLM endpoint is still being followed, hitting the ITT endpoint is sufficient for regulatory discussions.

Michael Schmidt inquired about the primary drivers of CABOMETYX's Q1 growth, any pre-approval sales contribution from the new neuroendocrine tumor (NET) indication, and the expected early launch trajectory for NET.

Answer

EVP of Commercial P.J. Haley attributed the strong performance primarily to the base renal cell carcinoma (RCC) business, particularly the frontline CABOMETYX/nivolumab combination, supported by recent 5-year follow-up data. He confirmed there was minimal NET utilization before the late-quarter approval on March 26 and stated that while early prescriber feedback is positive, it is too soon to project the launch trajectory.

Michael Schmidt inquired about the launch trajectory for cabozantinib in neuroendocrine tumors (NET), including the potential for an initial bolus, and also asked about the emerging safety profile of zanzalintinib.

Answer

EVP of Commercial P.J. Haley addressed the NET launch, stating the team is 'launch ready' for a market opportunity they estimate at $1 billion. He highlighted the broad applicability of the CABINET data and a significant 80% prescriber overlap with current indications, suggesting a rapid launch trajectory. He also noted a competitive advantage over existing generic therapies.

Michael Schmidt asked about the primary drivers for the reacceleration of CABOMETYX sales growth and how zanzalintinib is positioned in RCC relative to CABOMETYX and other competitors.

Answer

EVP of Commercial P.J. Haley attributed the strong CABOMETYX performance to record demand and new patient starts, particularly in first-line RCC. President and CEO Michael Morrissey added that while details of the zanzalintinib RCC trials with Merck are confidential, the partnership with the maker of the only approved HIF-2 inhibitor provides significant momentum.

Michael Schmidt of Guggenheim Securities, LLC inquired about the approximate patient split between Dose A and Dose B in the upcoming data, the planned venue for the data release, and the potential design of a Phase 3 study in TNBC, including whether it would be limited to topo-exposed patients and if it could include HER2-low patients.

Answer

President and CEO Dr. Martin Huber stated the data release venue is to be determined and did not provide a specific patient split, but assured a 'reasonable number' in both cohorts. Regarding a Phase 3 trial, he noted that most TNBC patients will be topo-exposed, making it a natural population. He highlighted the company's Fast Track designation for 'post-topo breast cancer,' which could allow for a broader population than classic TNBC, potentially including HER2-low patients in a randomized study.

Michael Schmidt asked for several clarifications: the tumor types of the two new patient responses, qualitative feedback on the effectiveness of the new proteinuria management protocols, and an update on enrollment progress for the 67mg cohort.

Answer

An executive, likely CEO Dr. Martin Huber, stated that the two new responses were in ACC1 (Adenoid Cystic Carcinoma) patients, with more detail to come at ASCO. Regarding proteinuria, he noted the goal is not elimination but management of consequences, and they are confident enough to proceed with the new, higher dose. On enrollment, he confirmed it has progressed sufficiently to guide for a data update with durability information in the second half of the year, indicating high investigator enthusiasm.

An associate for Michael Schmidt asked about the strategy for establishing the final B7-H4 biomarker cutoff and whether it would still capture about half of the TNBC population. He also requested expectations for the upcoming Phase I data update.

Answer

An executive stated they would be surprised if the final biomarker cutoff for B7-H4 high expression fell outside the 40-50% range of the TNBC population. Executive Jason Fredette added that while the next data update will include doses up to 95 mg/m², the company has not yet defined the amount of incremental data or specific timing beyond 'later this year'.

Michael Schmidt of Guggenheim Securities inquired about the potential market impact of Roche's recent complete response letter for glufitamab in second-line DLBCL and its effect on ADC Therapeutics' trials. He also asked about the maturity of the overall survival (OS) data for the LOTUS-5 trial, which is expected to have top-line PFS results by year-end.

Answer

Chief Medical Officer Mohamed Zaki stated that while the specifics of the CRL are unknown, ADC Therapeutics remains confident in the unmet need and the robust design of its LOTUS-5 and LOTUS-7 trials. He highlighted LOTUS-5's large, randomized design and noted it's difficult to speculate on OS data maturity at the time of the PFS analysis. CEO Ameet Mallik added that top-line PFS results will be announced after the database is locked, with full data to follow at a medical congress.

An analyst on behalf of Michael Schmidt from Guggenheim Securities asked for clarification on the LOTIS-5 trial timeline, questioning if the data readout would occur by year-end 2025 or be pushed to early 2026, and what the combination would need to demonstrate to be considered differentiated.

Answer

CEO Ameet Mallik stated that the timeline remains consistent with previous guidance, with top-line data expected in late 2025 or early 2026 following data cleaning and analysis. CMO Mohamed Zaki added that the key differentiating factor would be the study's primary endpoint result for Progression-Free Survival (PFS).

Michael Schmidt from Guggenheim inquired how the LOTIS-7 strategy might be impacted by LOTIS-5 results and asked about the significance of the upcoming AACR presentation for the Claudin-6 ADC.

Answer

CEO Ameet Mallik explained that the LOTIS-5 and LOTIS-7 trials are complementary. LOTIS-5 (ZYNLONTA + rituximab) targets patients not suitable for or progressing on CAR-T/bispecifics, while LOTIS-7 (ZYNLONTA + glofitamab) could become a preferred bispecific combination. Regarding the Claudin-6 ADC, Mallik stated the AACR presentation will reveal differentiating preclinical data, including a high therapeutic index, greater potency, and no observed ILD, showcasing its novel platform.

Michael Schmidt inquired about ZYNLONTA's commercial performance and potential for incremental growth in its approved indication, especially given the strong uptake of competing CD20 bispecific antibodies. He also asked what would be considered a positive outcome for the upcoming LOTIS-7 trial data.

Answer

CEO Ameet Mallik acknowledged that bispecifics have captured about a third of the third-line plus market but highlighted that ZYNLONTA's demand volume has remained stable, maintaining an $80+ million peak sales potential. For the LOTIS-7 data, he stated that a positive result would be competitive efficacy, with response rates in the 50-60% range, and a continued favorable safety profile, particularly a reduction in the rate and severity of Cytokine Release Syndrome (CRS).

Michael Schmidt from Guggenheim Securities, LLC questioned the company's readiness for a potential BLA submission for Tivesimig, focusing on CMC requirements. He also asked for more details on the CTX-8371 partial responses, including the dose levels and any other observed tumor shrinkage.

Answer

CEO Thomas Schuetz assured that the process performance qualification (PPQ) batches required for a BLA submission are underway and CMC should not be a limiting factor. For CTX-8371, he disclosed the responses occurred at the 0.3 mg/kg and 3.0 mg/kg dose levels but declined to release further clinical data, saving it for a scientific meeting later in the year.

Michael Schmidt from Guggenheim Securities, LLC questioned the company's CMC readiness for a potential Tivesimig BLA submission and sought more details on the CTX-8371 responses, including dose levels and patient treatment history.

Answer

CEO Thomas Schuetz confirmed that the process performance qualification (PPQ) batches required for a BLA submission are underway and CMC should not be a limiting factor. For CTX-8371, he disclosed the non-small cell lung cancer response was at the 0.3 mg/kg dose and the triple-negative breast cancer response was at 3.0 mg/kg, noting the patients were heavily pretreated, typical for a Phase 1 population.

Asked about the remaining requirements for a BLA submission, particularly CMC, and requested more details on the CTX-8371 responses, including dose levels and patient treatment history.

Answer

The company stated that the required CMC process performance qualification (PPQ) batches are underway and should not be a limiting factor for a BLA submission. For CTX-8371, the NSCLC response was at the 0.3 mg/kg dose and the TNBC response was at 3.0 mg/kg. The patients were heavily pretreated, with the TNBC patient having received three prior lines of therapy. Further clinical data will be presented at a future scientific meeting.

Paul Jeng, on behalf of Michael Schmidt, asked about the extent of off-label use of AvmapKefaxin Jakobak in the wild-type LGSOC population, reimbursement trends ahead of a potential NCCN guideline update, and the expected scope of the Q4 update for the KRAS G12D inhibitor program (VS7375).

Answer

COO Matthew Ros stated that while not promoted, the company has seen utilization in the wild-type population and reimbursement has not been an issue to date. President and CEO Dan Paterson added that the VS7375 update would be of a similar magnitude to the data presented by their partner Genfleet at ASCO, and that Genfleet itself would provide two additional updates later in the year.

Michael Schmidt from Guggenheim Securities asked for details on RINA S development outside of ovarian cancer, specifically the rationale and supporting data for the new Phase II study in non-small cell lung cancer (NSCLC).

Answer

Chief Medical Officer Tahamtan Ahmadi explained that RINA S's efficacy in tumors with low folate receptor alpha (FRα) expression prompted the expansion. The NSCLC study will initially target EGFR-mutated tumors, which have higher FRα expression, and is supported by encouraging signals from a small existing patient cohort.

Michael Schmidt from Guggenheim Securities asked for details on the development of RINA S outside ovarian cancer, specifically the new Phase II study in non-small cell lung cancer (NSCLC), including the supporting data and knowledge of folate receptor alpha expression in that cancer.

Answer

Tahamtan Ahmadi, EVP & Chief Medical Officer, explained that RINA S's efficacy in tumors with lower folate receptor alpha expression prompted the expansion. He noted that EGFR-mutated NSCLC has increased folate receptor alpha expression, making it a rational target. He confirmed that an initial small cohort has already shown encouraging signals, supporting the new, dedicated Phase II study to strategically explore the opportunity.

Paul Jeng on for Michael Schmidt of Guggenheim Partners questioned the confidence in EPKINLY's approval in follicular lymphoma based on ORR and asked how it would compete against a CD19 R2 regimen.

Answer

CMO Tahamtan Ahmadi expressed high confidence in approval, citing the breakthrough therapy designation and positive FDA engagement based on the totality of the data. Regarding competition, he stated that once Genmab's data is public, its competitive position will be clear, but declined to preview the results.

Michael Schmidt from Guggenheim Securities, LLC asked about the early reimbursement process using miscellaneous codes, the commercial synergies from the Jelmyto launch, and the regulatory path and potential differentiation for UGN-103.

Answer

CCO David Lin stated it's too early for paid claims data but noted UroGen provides 'white glove service' to educate offices on the manual J-code process. CEO Liz Barrett and CMO Mark Schoenberg highlighted significant commercial synergies, with the key difference being Zasturi's much larger patient population. Regarding UGN-103, Barrett explained the Utopia trial is designed to replicate ENVISION data to ensure a clean regulatory path, with plans to engage the FDA later in the year.

Michael Schmidt of Guggenheim inquired about the expected initial launch trajectory for UGN-102, potential pricing relative to JELMYTO, and whether to anticipate a significant channel inventory build.

Answer

Chief Commercial Officer David Lin stated that the launch curve for UGN-102 is expected to be similar in shape to JELMYTO's, but with larger absolute numbers due to the larger patient population. He noted that pricing is currently being evaluated in the $18,000 to $19,000 per dose range, with ongoing payer research to refine this figure.

Sarah, on for Michael Schmidt, asked for more details on Arvinas's oral pan-KRAS program and how the company expects to differentiate it from later-stage pan-KRAS and pan-RAS inhibitors.

Answer

CSO Angela Cacace explained that the pan-KRAS program aims for the same potency and differentiation as ARV-806. A key advantage is that as a degrader, it avoids the KRAS upregulation seen as a major resistance mechanism to clinical inhibitors. She also highlighted its potential for superior combinability with immuno-oncology agents like KEYTRUDA because it is not expected to inhibit T-cell receptor activity, a potential advantage over pan-RAF molecules.

Michael Schmidt asked about the rationale for discontinuing the CDK4/6 inhibitor combination trials for vepdegestrant, its competitive positioning in the second-line setting, and the required investment in commercial infrastructure.

Answer

CEO John Houston explained the decision was driven by emerging class data suggesting ER therapies will be restricted to ESR1 mutant patients in the second-line setting, making the planned ITT trial design unsuitable. He stated a belief that vepdegestrant has a best-in-class profile for this population. For commercialization, he described a prudent, data-driven build-out for the 50-50 co-commercialization with Pfizer, with ongoing discussions about the optimal approach.

Michael Schmidt asked if Arvinas plans to present data from the VERITAC-3 lead-in cohort with palbociclib this year and if any learnings could be applied to the new Phase III study with atirmociclib. He also asked for the company's base case assumption for PFS in the fulvestrant control arm of the VERITAC-2 study.

Answer

CEO John Houston stated that the VERITAC-3 lead-in data would be shared at some point but was a lower-ranking factor in the decision to proceed with atirmociclib, which was based on the totality of evidence. He reiterated the company's policy of not answering any questions related to the VERITAC-2 trial due to the imminent data readout.

Michael Schmidt from Guggenheim asked how investors should interpret the upcoming Phase 1 data for ARV-102 in healthy volunteers and whether any predictive biomarkers beyond LRRK2 degradation are being assessed.

Answer

CMO Noah Berkowitz explained that the primary goal of the healthy volunteer study is to understand the drug's PK/PD relationship and confirm CNS penetration by measuring LRRK2 in cerebrospinal fluid (CSF). He stated that success would be the validation of their preclinical modeling in humans, which would de-risk dose selection for future patient trials, but downstream disease biomarkers are not expected to change in healthy volunteers.

Michael Schmidt of Guggenheim Securities, LLC posed a big-picture question about R&D productivity and capital allocation, asking if there are areas where Incyte is underinvested, and also asked about the importance of povorcitinib data in asthma.

Answer

President and Head of R&D Pablo Cagnoni addressed R&D strategy, highlighting an increased focus on novel biology and platforms through collaborations. He also confirmed that asthma remains an important potential indication for povorcitinib, particularly in non-type two asthma, with key data expected by year-end.

Michael Schmidt asked if the HiSCR 75 endpoint for povorcitinib showed a similar increasing efficacy trend to week 18 and inquired about the differentiation strategy for Incyte's KRAS G12D inhibitor.

Answer

Executive Steven Stein confirmed the HiSCR 75 trend was similar to the HiSCR 50 data. Executive Pablo Cagnoni added that while the KRAS space is competitive, Incyte is optimistic its G12D inhibitor will have a very competitive profile based on progress in both single-agent and combination studies, with data to be shared later in the year.

Michael Schmidt of Schmidt & Co. AG inquired about the efficacy targets for povorcitinib in hidradenitis suppurativa (HS) to be competitive against Humira and other biologics, asking about a specific placebo-adjusted effect size.

Answer

Steven Stein, an executive at Incyte, responded that replicating the strong Phase II data, which included a HiSCR 100 response of up to 29%, would establish an extremely favorable and differentiated efficacy profile. He highlighted that demonstrating pain relief would further enhance its competitiveness and noted that strong enrollment in the Phase III studies reflects investigator confidence based on the Phase II results.

Michael Schmidt asked about the market opportunity for BRUKINSA in first-line mantle cell lymphoma based on the MANGROVE trial and whether filings would follow the interim data. He also questioned BRUKINSA's long-term positioning in CLL against Lilly's pirtobrutinib, especially with its upcoming first-line data.

Answer

Wang Lai, Global Head of R&D, highlighted that the MANGROVE trial evaluates a chemo-free regimen (zanubrutinib + rituximab) against BR, which could be a preferred option for patients. He expressed confidence in BRUKINSA's position against pirtobrutinib, noting pirtobrutinib's frontline trial comparator is not BRUKINSA. Matt Shaulis, GM of North America, added that the company expects to maintain and expand market share, believing continuous BTK therapy will remain the best option in earlier lines.

An analyst on behalf of Michael Schmidt at Guggenheim Partners followed up on the CDK4 inhibitor, asking about expectations for the upcoming ASCO data and what efficacy signals would support further development and differentiation.

Answer

Management expressed excitement, stating that early dose-escalation data is already showing signs of translating the drug's superior selectivity and potency into clinical benefits, including less hematological toxicity and better target inhibition. They will use incoming data to decide on initiating a pivotal trial later in the year or early next.

An analyst on behalf of Michael Schmidt at Guggenheim Partners followed up on the CDK4 inhibitor, asking about expectations for the upcoming ASCO data and what efficacy signals would be needed to support further development and differentiation.

Answer

CEO John Oyler responded that early data is already showing less hematological toxicity and better target inhibition, consistent with the drug's selective profile. He stated the company will analyze incoming data to inform a decision on initiating a pivotal trial in late 2025 or early 2026.

Michael Schmidt inquired about the first-line mantle cell lymphoma opportunity for BRUKINSA from the MANGROVE trial, including its market size and potential for regulatory filing based on interim data. He also asked about BRUKINSA's long-term competitive positioning in CLL against pirtobrutinib.

Answer

Lai Wang, Global Head of R&D, highlighted that the MANGROVE trial's chemo-free regimen could be a preferred option. He and Matt Shaulis, GM of North America, expressed confidence in BRUKINSA's position, noting that pirtobrutinib's frontline trial comparator is not BRUKINSA, and they do not expect significant shifts in earlier lines of therapy.

Michael Schmidt inquired about the first-line mantle cell lymphoma opportunity for BRUKINSA from the MANGROVE trial, asking about market size and filing plans. He also asked about BRUKINSA's long-term positioning in the CLL market against Lilly's pirtobrutinib.

Answer

Lai Wang, Global Head of R&D, highlighted MANGROVE's chemo-free regimen as a potential preferred option. He expressed confidence against pirtobrutinib, noting its pivotal trials use comparators other than BRUKINSA. Matt Shaulis, GM of North America, added that he sees a reasonably sized MCL opportunity and does not expect pirtobrutinib to significantly shift to earlier therapy lines.

Michael Schmidt from Guggenheim asked about the extent of off-label use in NPM1 patients for Revuforj in Q1 and questioned how the change to include a CR endpoint in the EVOLVE-2 study might affect trial timelines.

Answer

CEO Michael Metzger stated that anecdotal feedback suggests the vast majority of Q1 Revuforj sales were for on-label KMT2A use. Regarding the EVOLVE-2 trial, he clarified that adding complete remission (CR) as a dual primary endpoint does not impact the overall trial timeline but creates a path for potential accelerated approval. He noted positive progress on the planned studies in the fit population but did not disclose specific FDA feedback.

Michael Schmidt of Guggenheim asked for commentary on early gross-to-net trends for Revuforj, the extent of the free drug program's use, and any early feedback from the market regarding patient transplant dynamics.

Answer

CFO Keith Goldan stated that gross-to-net is "very tight" due to the limited distribution model and no foreseen need for rebates. CCO Steven Closter added that the patient assistance program use is in the low single digits. CEO Michael Metzger noted that physicians are successfully getting patients to transplant, with the expectation that many will resume Revuforj as maintenance therapy post-transplant.

Michael Schmidt of Guggenheim Securities questioned if the 13-month duration of response in KMT2A could be expected for NPM1 and asked about any emerging competitive advantages for Revumenib from combination data.

Answer

CEO Michael Metzger found the 13-month KMT2A duration encouraging but refrained from speculating on NPM1 outcomes. He highlighted the SAVE trial's combination data, with a 58% CR/CRh rate in heavily pretreated patients, as evidence of Revumenib's distinguished and well-tolerated profile, noting Syndax is furthest advanced in venetoclax/aza combinations.

Michael Schmidt of Guggenheim Securities posed a long-term strategic question about internal R&D initiatives beyond NBTXR3 that could create value, given the program's transition to J&J. He also asked for the expected R&D spending allocation between NBTXR3 and other programs in 2025 and 2026.

Answer

Co-Founder and CEO Laurent Levy clarified that while J&J is taking the lead, Nanobiotix remains involved with NBTXR3 in areas like manufacturing and registration support. He noted the shift frees up resources for the Curadigm platform, which is a key focus for future value creation through partnerships and an internal pipeline. CFO and CBO Bart Van Rhijn added that remaining NBTXR3 and Curadigm costs are in the 'single-digit millions' each, meaning the overall R&D burn will decrease significantly as the major Phase III study costs are removed.

Representing Michael Schmidt of Guggenheim Partners, an analyst questioned KIMMTRAK's commercial performance, noting the U.S. penetration rate of around 65% and asking about the potential for further headroom, where the market share might plateau, and the long-term outlook for treatment duration.

Answer

Ralph Torbay, Head of Commercial, stated that the 65% penetration reflects significant growth and that the company will continue its expansion into the community setting. Regarding treatment duration, he noted it is already trending beyond clinical trial experience, making it difficult to predict a final plateau. CEO Bahija Jallal added that this extended duration is unusual and highlights KIMMTRAK's impact.

Michael Schmidt from Guggenheim Partners requested an updated view on the lung cancer opportunity for the PRAME program, asking about specific patient subsets, genotype focus, and the expected scope of the data readout later in the year.

Answer

David Berman, Head of R&D, described lung cancer as highly heterogeneous and noted they are exploring subsets like those with actionable gene mutations. The initial monotherapy data will be in PRAME-positive patients, but the dataset will be smaller than for melanoma or ovarian. The readout will include both monotherapy and chemotherapy combination data, with future plans for docetaxel and osimertinib combinations.

Asked for an update on the PRAME program in lung cancer, including target patient subsets and the scope of the upcoming data release.

Answer

The company is exploring subsets like those with actionable mutations. The upcoming data will be a smaller set than prior readouts, focusing on PRAME-positive patients for monotherapy and also including chemo combinations. The plan is to move to earlier lines with docetaxel and osimertinib combinations next year.

Michael Schmidt from Guggenheim Partners requested an updated view on the PRAME program's opportunity in lung cancer, asking about specific patient subsets and the expected scope of the data readout later in the year.

Answer

David Berman, Head of R&D, explained they are focusing on subsets like gene mutation-positive patients and have enriched for PRAME-positive patients in the monotherapy cohort. He noted the upcoming data set will be smaller than prior readouts. Mohammed Dar, an executive, added that combinations with docetaxel and osimertinib are planned for next year.

Asked about the registrational strategy for PRAME in late-line cutaneous melanoma and for more details on the specific patient subsets being targeted in the PRAME lung cancer trial.

Answer

David Berman stated the company is focusing PRAME on first-line melanoma due to the larger opportunity, while KIMMTRAK is positioned for the late-line setting. Mohammed Dar added that for lung cancer, they are exploring distinct and well-described molecular subsets.

Paul Jeng, on behalf of Michael Schmidt, asked about the conversion rate of double-positive patients to treatment, whether any have opted out, and if more patients have been apheresed in the fourth quarter.

Answer

CEO Adrian Rawcliffe responded that it is too early to provide metrics on patient conversion rates but expects the majority of the 15 identified double-positive patients to be treated in the first half of 2025. He emphasized that the high efficacy of Tecelra compared to the standard of care suggests most eligible patients will eventually opt for treatment. He confirmed that as of the call, one patient had been apheresed.

Michael Schmidt of Guggenheim Securities inquired about potential adverse events for KT-621 based on its mechanism and preclinical data, and how the company plans to prioritize indications for later-stage development.

Answer

CEO Nello Mainolfi highlighted KT-621's excellent preclinical safety profile and selectivity, noting that human genetics also support STAT6 as a clean target. He stated they do not expect safety flags. For future development, he described KT-621 as a broad 'Th2 drug' and said the company will prioritize large indications like AD, asthma, and COPD.

Michael Schmidt asked about the upcoming KT-621 (STAT6) data, questioning the interpretability of PD markers in healthy volunteers and what the company aims to learn from the Phase 1b patient study. He also asked if a loading dose, similar to Dupixent, is being considered.

Answer

President and CEO Nello Mainolfi stated that for both studies, the expectation is for KT-621 to perform like dupilumab, which showed clear effects on biomarkers and clinical scores. The key addition from Kymera will be data on the actual level of STAT6 protein degradation. Regarding dosing, he noted that preclinically, KT-621 achieves full degradation rapidly, so a loading dose is not anticipated to be necessary.

Michael Schmidt asked about potential on- or off-target adverse events for the STAT6 degrader (KT61) based on preclinical and knockout model data, and how the company will prioritize indications for later-stage studies.

Answer

Founder, President, and CEO Nellie Monofi highlighted the program's strong safety profile, noting the compound is highly selective and that STAT6 knockout models are normal, suggesting a wide therapeutic window. She stated that KT61 is viewed as a broad TH2 drug, with plans to prioritize large indications like AD, asthma, and COPD while aiming for broad impact across all relevant diseases.

Paul, on behalf of Michael Schmidt at Guggenheim, asked how to interpret the upcoming STAT6 healthy volunteer biomarker data (IgE, TARC) and whether this data could guide future indication prioritization.

Answer

CEO Nello Manalfi stated the Phase 1 goal is to confirm that robust preclinical pharmacology translates to humans. The biomarker data will serve as confirmation of target engagement, referencing Dupixent's data as a benchmark. He clarified this early data will not be used for indication selection; that will be determined by later proof-of-concept studies in patients.

Asked about AYVAKIT treatment duration, specifically regarding continuous versus intermittent use by patients, and what the company is observing in terms of refill rates and long-term compliance.

Answer

The real-world data mirrors the PIONEER trial, with patients trending towards a multi-year duration of therapy with very few discontinuations. Patient compliance and refill rates are very high, at the upper end of analogs, which is expected to be an increasingly important growth driver.

Michael Schmidt from Guggenheim asked if the MANTRA trial would have sufficient follow-up for mature Overall Survival (OS) data at the primary analysis and requested information on potential pricing analogs for milademetan upon success.

Answer

CMO Richard Bryce stated that the OS data will be an interim look and will be immature at the time of the primary PFS analysis. CEO Avanish Vellanki identified ripretinib in the GIST space and a therapy for PEComa as relevant pricing comparables.

Michael Schmidt of Guggenheim Partners inquired about the enrollment progress in the MANTRA-2 study since the MDM2 amplification cutoff was lowered and the number of patients needed to determine next steps. He also asked if the MANTRA trial has reached its required number of progression events.

Answer

CEO Avanish Vellanki explained that determining the next steps for MANTRA-2 is data-dependent and that while enrollment has accelerated since the November update, specific numbers are not being disclosed. Regarding the MANTRA trial, Vellanki stated that the company is not disclosing whether the event threshold has been met and does not plan to do so publicly.

Michael Schmidt of Guggenheim inquired about the MANTRA-2 trial's MDM2 amplification cutoff, specifically asking about observed activity in patients with a copy number below 12 and the impact of lowering the cutoff to 8 on the total market size. He also asked for insights on the effect of co-mutations, such as KRAS, on milademetan's efficacy.

Answer

Chief Scientific Officer Robert Doebele explained that the decision to lower the MDM2 copy number cutoff from 12 to 8 was based on observed clinical activity in that range, which is expected to increase the addressable market. Regarding co-mutations, Dr. Doebele stated the company's belief that these are independent pathways that may not significantly impact the effect of milademetan on the MDM2-p53 pathway, and they are continuing to gather data to understand these relationships.

Michael Schmidt of Guggenheim Securities inquired about the patient populations likely to respond to the IGM-8444 plus birinapant combination and how the strategic shift for imvotamab to autoimmune diseases affects partnership considerations.

Answer

Chief Medical Officer Dr. Chris Takimoto and Chief Scientific Officer Dr. Bruce Keyt explained that the birinapant combination could be broadly applicable across solid tumors by targeting both intrinsic and extrinsic apoptotic pathways. CEO Fred Schwarzer stated that given the vast opportunity in autoimmune diseases, securing a strategic partner for the T-cell engager franchise, including imvotamab, would be highly beneficial for the company long-term.

Michael Schmidt sought clarification on the total number of patients treated with IGM-2323, the timing of the Grade 3 CRS case relative to the ASH update, the process for determining the recommended Phase II dose given the planned 1000mg top dose, the hypothesis for CRS in post-CAR-T patients, and potential predictive biomarkers for IGM-8444.

Answer

Chief Medical Officer Daniel Chen clarified that 25 patients have been treated, with expansion cohorts contributing to the increase. President and CEO Fred Schwarzer confirmed the 50mg CRS case occurred after ASH. Dr. Chen explained the Phase II dose decision will be based on efficacy, kinetics, safety, and biomarker data, noting they may not reach a maximum tolerated dose. He also discussed the hypothesis that IGM-2323's physiologic stimulation might reactivate residual CAR-T cells. For IGM-8444, he stated the focus is on broad applicability and sensitization via combinations rather than a narrow biomarker-driven approach.

Michael Schmidt of Guggenheim sought to understand the dose level at which clinical activity for IGM-2323 is expected based on animal models, the possibility of opening expansion cohorts before reaching a maximum tolerated dose (MTD), and the patient selection strategy for the upcoming Phase 1 trial of the DR5 agonist, IGM-8444.

Answer

Chief Medical Officer Dan Chen explained that biologic effect was observed throughout the entire dose range in preclinical models, starting with the 500 microgram MABEL (minimally active biologic effect level) dose. He confirmed the trial protocol allows for cohort expansion at any dose level. For the IGM-8444 trial, Chen stated the initial Phase 1 study will enroll patients with all solid tumors to assess signals broadly, with plans to add hematologic malignancies after dose escalation.

Michael Schmidt from Guggenheim Partners asked which tumor types are expected to be most frequently enrolled in the Phase 1 study and where early clinical activity might first be observed.

Answer

President and CEO Benjamin Zeskind stated that while enrollment is open to any solid tumor with a RAS mutation, clinical sites were selected for their expertise in key areas like pancreatic cancer, melanoma, lung cancer, and colorectal cancer. Chief Medical Officer Scott Barrett added that investigators are aware of the preclinical data and are actively looking to enroll patients from these high-priority tumor types.

On behalf of Michael Schmidt from Guggenheim, Yige Guo asked about the market opportunity for the new PLK4 program, specifically related to TRIM37 amplification, and inquired how CNS activity for ORIC-114 will be measured in the Phase 1 study.

Answer

CEO Jacob Chacko deferred specific questions on the PLK4 market size to an upcoming AACR poster but emphasized it is a potential first-in-class, single-agent opportunity in breast cancer. Chief Medical Officer Pratik Multani addressed the ORIC-114 question, stating that the Phase 1 trial has liberal eligibility criteria that allow for the enrollment of patients with untreated, asymptomatic active brain metastases, in addition to those with treated, stable brain metastases.