Joseph Catanzaro

Joseph Catanzaro asked if Kymera considered using a skin immune challenge model (e.g., injecting a TLR agonist) in the KT-579 healthy volunteer study to assess cytokines, and if not, why. He also inquired what informs the 50%-80% target reductions in biomarkers, whether it's based on preclinical data or genetic insights.

Answer

Nello Mainolfi, Founder, President, and CEO, stated that Kymera philosophically believes the appropriate context for pathway questions is in patients. He argued that ex vivo blood stimulation is as effective as artificial skin activation, and since they can directly measure target engagement, a surrogate downstream biomarker from skin challenges is not necessary. Jared Gollob, Chief Medical Officer, explained that the 50%-80% inhibition target for multiple pathways (TLR 7, 8, 9) is based on preclinical data. He noted that impacting multiple pathways simultaneously means a lower individual inhibition percentage can still lead to significant synergistic activity, which is expected to translate to clinical impact in diseases like lupus.

Joseph Catanzaro asked if Kymera considered using a skin immune challenge model in the KT-579 healthy volunteer study and why they opted against it. He also inquired about the basis for the 50%-80% target reduction in biomarkers for IRF5, specifically whether it's informed by preclinical data or genetic insights.

Answer

CEO Nello Mainolfi explained that Kymera opted against skin immune challenge models for KT-579, preferring ex vivo blood stimulation for healthy volunteers as it provides similar insights into pathway activation without artificial complexity, especially given their ability to directly measure target engagement. CMO Jared Gollob clarified that the 50%-80% target reduction in IRF5 biomarkers is informed by preclinical data, recognizing that impacting multiple inflammatory pathways simultaneously can achieve significant activity within this range, which is expected to translate clinically.

Joseph Catanzaro asked about key data points the company is looking for in colorectal cancer (CRC) before committing to earlier line or later stage trials, and if any such data is expected in 2026.

Answer

Steve Kelsey, President of Research and Development, stated no timing guidance for CRC data disclosure. He emphasized that combination therapy is essential due to the biological complexity of RAS mutant CRC, and studies to determine the most efficacious combinations are ongoing. He noted multiple dimensions, including line of therapy and various biologically rational combinations, are being explored.

Joseph Catanzaro asked about key data points Revolution Medicines is looking for in colorectal cancer (CRC) before committing to earlier-line or later-stage trials, and if any such data is expected in 2026.

Answer

Steve Kelsey, President of Research and Development, stated that there is no specific timing to disclose for CRC data. He emphasized that combination therapy is essential for RAS mutant CRC due to its biological complexity, and ongoing studies are designed to identify the most efficacious combinations. He noted that CRC is a complex disease where mutant RAS may not be the sole oncogenic driver.

Joseph Catanzaro of Piper Sandler asked about the design of the frontline PDAC chemo-combination arm, questioning whether it would be continuous therapy or an induction-maintenance approach.

Answer

Chief Medical Officer Dr. Wei Lin noted the final design is pending regulatory feedback. CEO Dr. Mark Goldsmith added that a paradigm shift is needed, viewing the combination arm as 'the daraxonrasib arm to which we've added some chemotherapy.' This framing prioritizes the continuous benefit of the targeted therapy, which may not conform to traditional induction-maintenance nomenclature, especially since a separate monotherapy arm will also be included.

Inquired about the timeline for dose selection, its coordination with FDA discussions for the registrational trial, and how the response rate delta from Pfizer's BREAKWATER trial compares to their own.

Answer

The company aims to meet with the FDA as soon as possible to discuss dose selection and the registrational trial design, which is the gating factor for the next trial. The ORR delta from the BREAKWATER trial is consistent with what they have observed.

Joseph Catanzaro of Piper Sandler asked about the cadence for making the dose selection decision for onvansertib and its alignment with FDA discussions to potentially convert the CRDF-004 study into a registrational trial. He also asked if the response rate delta that supported accelerated approval for Pfizer's BREAKWATER trial was consistent with what Cardiff has observed.

Answer

Executive Mark Erlander explained that Cardiff's goal is to meet with the FDA as soon as possible to discuss both the dose selection (20mg vs. 30mg) and the final design for the registrational CRDF-005 trial. He noted this meeting could occur before data from all 90 patients is available. Erlander also confirmed that the ORR delta in the BREAKWATER trial (61% vs 40%) was consistent with the efficacy signal Cardiff has observed so far.

Joseph Catanzaro of Piper Sandler & Co. asked if Cardiff Oncology might release another data update from the ONSEMBLE cohort before the CRDF-004 readout. He also inquired about the preclinical data in RAS wild-type CRC and the potential for future clinical exploration in that patient population.

Answer

Executive Mark Erlander stated that there are no current plans to provide a further follow-up on the ONSEMBLE data, as the company feels the data released in February was robust. Regarding RAS wild-type CRC, Erlander acknowledged the biology is distinct from RAS-mutant tumors and that the preclinical findings with cetuximab are interesting. However, he emphasized that the company's primary focus remains on the ongoing CRDF-004 trial in RAS-mutated mCRC and no moves have been made to start a trial in the wild-type setting.

Inquired about a potential Progression-Free Survival (PFS) signal in the ONSEMBLE data and asked detailed questions about the upcoming frontline trial, including the safety run-in for the FOLFOX backbone, historical neutropenia comparisons, and the expected chemotherapy backbone split.

Answer

The company acknowledged an emerging PFS signal in the ONSEMBLE data but has not performed a rigorous analysis yet due to the small patient numbers. For the frontline trial, they confirmed a safety run-in for the first 10 patients on the FOLFOX arm. They do not expect major toxicity issues, noting that preclinical data shows synergy with both FOLFOX and FOLFIRI backbones.

Joseph Catanzaro asked for more detail on the 'queuing effect' impacting AGAMREE adoption in the DMD space and what led to the decision to split the salesforce. He also followed up on FYCOMPA, asking if 2025 guidance reflects market resiliency to generics and what efforts will be made to slow erosion.

Answer

CCO Jeffrey Del Carmen explained the 'queuing effect' is due to patients being evaluated for other new therapies like ELEVIDYS, which delays changes to their steroid regimen. He expects this to resolve by mid-2025. He also noted the salesforce split allows for a more focused approach in the crowded DMD market and deeper relationship-building for LEMS. CEO Richard Daly addressed FYCOMPA, stating that while the epilepsy market is 'sticky,' the guidance accounts for both price and volume erosion post-patent expiry as they contract with payers and some patients switch to generics, though the decline will be more gradual than typical retail products.

Joseph Catanzaro asked if promoting second-line OJEMDA use is seen as a near-term benefit by expanding the patient pool or a long-term one via longer treatment duration. He also asked about the gating factors for releasing initial data from the DAY301 program.

Answer

Chief Commercial Officer Lauren Merendino described the benefit of earlier use as 'a little of both,' as healthier patients may have improved duration and the patient pool is larger. CEO Jeremy Bender addressed DAY301, stating that the company will wait for a sufficient data set, likely including dose escalation and potentially some dose expansion data, before public disclosure to properly contextualize the development plan.

Joseph Catanzaro of Piper Sandler inquired about the cadence of new patient starts for OJEMDA in Q3, its sustainability, and whether a total prescription (TRx) equates to a one-month supply.

Answer

CEO Jeremy Bender confirmed that new patient additions were steady and consistent with the launch quarter, a pattern they expect to continue. CCO Lauren Merendino added that a TRx represents a 28-day supply, with minimal exceptions.

Joseph Catanzaro of Piper Sandler inquired about the clinical validation of the PRMT5 target from competitor data and how Schrodinger's program aims to differentiate.

Answer

President of R&D Karen Akinsanya acknowledged that competitor data shows PRMT5 is an exciting mechanism with broad monotherapy activity. She stated Schrodinger's program aims for a best-in-class profile by focusing on brain penetrance to target tumors like glioblastoma, an improved DDI profile for combinations, and a novel angle to maximize synergy between PRMT5 and MTA for deeper responses.

Joseph Catanzaro inquired about the criteria for determining the optimal dose for CX-904 and the timing of the Phase Ib decision. He also asked where the fifth dose level of CX-2051 falls within the expected therapeutic window.

Answer

CEO Sean McCarthy explained that for CX-904, the company believes it is critical to continue dose escalation to maximize potential efficacy, which extends the timeline for a Phase Ib decision. For CX-2051, he noted that the trial is now at dose levels where an unmasked version would likely show toxicity, suggesting the masking technology is performing as designed, though it remains early.

Joseph Catanzaro asked about the newly clinical XL-495 program, inquiring about the strategy for tumor type selection, biomarker use, and potential cytotoxic combinations.

Answer

Chief Scientific Officer Dana Aftab explained that the PM1 inhibitor targets tumors with increased cyclin E levels, driven by biomarkers like CCNE amplification. He noted they are exploring these and other undisclosed biomarkers in the Phase 1 study, as well as evaluating data from preclinical combination studies with cytotoxics and other agents.

Inquired about potential changes to the PRECISION1 trial design following the second interim analysis and the growth prospects for FYARRO.

Answer

The company stated that the PRECISION1 trial is fully enrolled and no changes are currently anticipated. For FYARRO, they saw a strong rebound in Q2 demand after a low Q1 and expect continued incremental growth.

Asked about the pretreatment level of patients in the remainder of the PRECISION 1 trial, any changes in enrollment since the interim data, the timeline for data from the endometrial and NET studies, and any updates on the adagrasib combo trial post-BMS acquisition.

Answer

The company anticipates continuing to enroll later-line patients in PRECISION 1 but will not comment on the final patient mix until the next readout. Initial data from the endometrial and NET studies are expected later in the year, with both trials actively enrolling. The adagrasib combination trial with BMS (formerly Mirati) is ongoing and enrolling with no further updates.

For PRECISION 1: 1) How many post-baseline scans are guaranteed with the 4.5-month follow-up for the first interim? 2) Was the second interim analysis always planned? 3) What modifications could be made after the second interim if the trial is already fully enrolled?

Answer

The 4.5-month follow-up ensures at least two post-baseline scans. The second interim analysis was always part of the adaptive statistical plan. It allows for assessing whether the sample size is sufficient to file early or if resizing is needed, as additional follow-up on the full cohort will still be ongoing even after enrollment is complete.

Joseph Catanzaro from Piper Sandler asked for the company's perspective on the implications of recent zolbetuximab data for Claudin18.2 as a therapeutic target and how I-Mab's givastomig is positioned within the increasingly competitive landscape.

Answer

Andrew Zhu, Acting CEO, stated that recent Phase 3 data for zolbetuximab validates Claudin18.2 as a target but noted it's for a select population (about 30% of patients) with high expression. He positioned givastomig as unique due to its potential to target a broader population, including those with lower Claudin18.2 expression. Dr. Zhu also highlighted givastomig's favorable safety profile, with localized 4-1BB activation avoiding systemic toxicities and causing less GI toxicity than other agents in the class.

Joseph Catanzaro from Piper Sandler asked about the expected timeline for database lock and analysis for the MANTRA trial after reaching the event threshold. He also questioned if the MANTRA-4 trial design accounts for patients' prior exposure to immune checkpoint inhibitors.

Answer

Chief Medical Officer Richard Bryce stated that the data cleaning and analysis process for the MANTRA trial will take several weeks due to its complexity and the involvement of multiple vendors. He also confirmed that the MANTRA-4 study is specifically designed for patients who are resistant or refractory to prior IO therapy.

Joseph Catanzaro of Piper Sandler inquired about the expected disclosures from the six-patient safety lead-in for the MT-401 trial and whether the optimized manufacturing process could enable higher T cell doses in the main Phase II study.

Answer

Chief Medical Officer Dr. Mythili Koneru stated that the primary objective of the safety lead-in is to monitor for dose-limiting toxicities, with a potential announcement upon completion and the start of the main trial. Chief Development Officer Dr. Juan Vera and Dr. Koneru confirmed that the improved manufacturing process yields a superior product and opens the opportunity to explore higher, safe cell doses in the main Phase II portion, based on data from the Baylor Phase I trial.