Yue-Wen Zhu

Yue-Wen Zhu asked how the recent and upcoming results from the ASCENT-3 and ASCENT-4 trials could alter the standard of care for TNBC and potentially impact Mersana's clinical development plans in the post-topo-1 ADC setting.

Answer

CEO Dr. Martin Huber responded that these developments are viewed as very positive. He explained that Mersana's expansion cohort is exclusively focused on post-topo-1 ADC patients. As drugs like Trodelvy move into earlier lines of therapy, the patient pool for the post-topo-1 setting, a high unmet need, will expand significantly. He emphasized that Mersana has deliberately studied this population and has shown unique activity, positioning the company well to address this growing market opportunity.

Yue-Wen Zhu asked about the expected distribution of patients in the Emi-Le dose expansion based on their number of prior therapies and whether the selection of a second dose is dependent on the success of proteinuria mitigation strategies.

Answer

An executive responded that it is too early to predict the patient distribution by prior lines of therapy but confirmed the protocol limits it to a maximum of four. Regarding the second dose, the company is currently exploring doses up to 95 mg/m² and is not investigating higher levels at this time.

Yue-Wen Zhu of LifeSci Capital asked about the expected prior lines of therapy for Phase I patients, differences seen between TOPO-experienced versus naive patients, the rationale for high dose escalation, and if escalation could continue alongside expansion.

Answer

CEO Martin Huber described the population as heavily pretreated but emphasized the type of prior therapy (e.g., TOPO ADCs) is more critical than the number of lines. He suggested investigators are preferentially enrolling post-TOPO patients due to the need for a non-TOPO payload. Dr. Huber attributed the ability to dose escalate to the Dolasynthen platform's design avoiding key toxicities. He confirmed that dose expansion can begin even if dose escalation continues, with plans to take at least two doses into expansion.

Yue-Wen Zhu inquired about Zymeworks' capital allocation strategy, asking how potential milestone and royalty revenues from partnered assets like zanidatamab are factored into pipeline prioritization. He also asked for details on the cytokine induction profile of the DLL3 T-cell engager, ZW209, and its implications for safety.

Answer

CEO Kenneth Galbraith affirmed a commitment to disciplined capital allocation, stating that future capital from milestones, such as those from zanidatamab or the J&J partnership, will be deployed based on clinical data and shareholder value, potentially including returns to shareholders. Chief Scientific Officer Dr. Paul Moore explained that ZW209's design limits cytokine release by making CD28 co-stimulation conditional on CD3 engagement, which is expected to improve its therapeutic index and has shown a favorable safety profile in preclinical models.

Yue-Wen Zhu of LifeSci Capital inquired about the long-term development strategy for the farnesyl transferase inhibitor KO-2806 in renal cell carcinoma (RCC), given the evolving treatment landscape that includes next-gen TKIs and checkpoint inhibitors.

Answer

Executive Mollie Leoni explained that Kura sees a significant opportunity for KO-2806 to be used with standard-of-care agents like cabozantinib. The goal is to leverage a therapy physicians are already comfortable with and potentially deliver deeper, more durable responses, thereby augmenting the current treatment paradigm.

Yue-Wen (Charles) Zhu of LifeSci Capital asked about the proportion of 'adverse risk' AML patients, enrollment speed in broader cohorts, the apparent inverse dose response, and the assay used for detecting menin resistance mutations.

Answer

EVP of Clinical Development, Dr. Mollie Leoni, estimated adverse risk patients at ~30% and noted brisk enrollment in Phase Ib. She attributed the apparent inverse dose response to small numbers and varying patient characteristics, confirming the 600mg dose is supported by the totality of data. She also affirmed their resistance mutation assay is reliable and findings are consistent with previous reports.