Elemer Piros

Elemer Piros asked if the December 17th announcement had any impact on the enrollment patterns for PALISADE-4. He also sought conceptual clarification on how amending the SAP, potentially by including covariates identified through AI/ML analysis of PALISADE-3 and other studies, could influence the separation between treatment arms in PALISADE-4, and the process for FDA approval of such changes. Finally, he asked for clarification on the difference between shares outstanding at quarter-end and the weighted average for the quarter.

Answer

Joshua Prince, Chief Operating Officer, confirmed that enrollment for PALISADE-4 has continued as planned without impact from the December 17th announcement. Shawn K. Singh, President and Chief Executive Officer, explained that AI and machine learning are being used to identify potential covariates that could have a fixed effect on ANCOVA, which, if appropriate and impactful, could lead to an SAP modification requiring FDA review and approval before database lock. Joshua Prince added that they are looking across all PALISADE studies (1, 2, and 3) for these insights. Nick Tressler, Chief Financial Officer, clarified that the weighted average shares outstanding for the quarter includes pre-funded warrants, which accounts for the difference from the shares outstanding at quarter-end.

Elemer Piros from Lucid asked if the December 17th announcement regarding PALISADE-3 results had impacted PALISADE-4 enrollment patterns. He also sought conceptual clarification on how amending the Statistical Analysis Plan (SAP) for PALISADE-4, potentially by including covariates identified from PALISADE-3 and PALISADE-2 data using AI/ML, could influence the separation between treatment arms, and the process for FDA approval of such changes. Additionally, he asked a housekeeping question about the discrepancy between shares outstanding and weighted average shares for the quarter.

Answer

Chief Operating Officer Josh Prince confirmed no impact on PALISADE-4 enrollment, which continued as planned. President and CEO Shawn K. Singh explained that AI/ML is being used to identify potential covariates that could have a fixed effect on ANCOVA, and if appropriate, any SAP modification would require FDA approval before database lock. Chief Financial Officer Nick Tressler clarified that shares outstanding at quarter-end are used for EPS, and Shawn K. Singh added that the weighted average includes pre-funded warrants.

Elemer Piros sought clarification on the timeline for completing the necessary CMC (Chemistry, Manufacturing, and Controls) work for the CORDStrom RDEB program ahead of a potential BLA filing in the U.S. and U.K.

Answer

Dr. Mark Lowdell, Chief Scientific Officer, confirmed that the CMC work will take until the end of the year to complete. He stated the company is targeting a BLA filing in the first quarter of 2025, noting that the manufacturing team is now fully dedicated to CORDStrom and an external review is planned to ensure regulatory readiness.

Sought clarification on whether pain and functional improvements are co-primary endpoints and if a patient must demonstrate improvement in both to be classified as a responder.

Answer

Management confirmed that under the current protocol, improvement in both pain (VAS) and function (ODI) is required for a patient to be considered a responder, and that the 7 out of 10 responders met this co-primary endpoint. They also noted they are strategically considering the possibility of amending the protocol to focus only on pain, given recent FDA precedents, and plan to strengthen their case with radiographic data.

Elemer Piros sought clarification on the trial's primary endpoints, asking if pain and functional improvements are co-primary and whether a patient must demonstrate at least a 30% improvement on both scales (VAS and ODI) to be classified as a responder.

Answer

VP of R&D Francisco Silva confirmed that, per the current protocol, patients must show improvement in both pain (VAS) and function (ODI) to be considered a responder. CEO Lance Alstodt added that while the 7 of 10 responders met this dual requirement, the company is aware of a shift at the FDA that might allow for a single endpoint like pain. Alstodt noted they are strategically considering this for the future but are pleased to be clearing the higher bar for now.

Elemer Piros sought to verify if the statistical analysis plan (SAP) was locked with the FDA, whether both co-primary endpoints must be met for success, the status of the integrated ADAS endpoint, the existence of a preset analysis for mild AD patients, the rationale for focusing on pTau 217, and the progress of the data cleanup.

Answer

Executive Richard Barry clarified that the company incorporated the FDA's minor comments into the SAP, which was signed before the database was locked. He confirmed that per the SPA with the FDA, both co-primary endpoints (ADAS-Cog12 and ADL) must be met for success. The integrated ADAS endpoint is a secondary one. Barry also confirmed a preset analysis for mild patients, who make up about 70% of the trial, and noted the field has shifted focus to pTau 217 as the more prominent biomarker. He declined to quantify the data cleanup progress but reiterated the year-end timeline for results.

Inquired about the statistical analysis plan's status with the FDA, the requirements for the co-primary endpoints, the role of secondary endpoints, subgroup analysis for mild patients, the shift from pTau 181 to pTau 217 as a key biomarker, and the progress of the data cleanup.

Answer

The statistical analysis plan is finalized and signed. Both primary endpoints must be met for success. An integrated ADAS score is a secondary endpoint. A subgroup analysis for mild patients is planned. The company is focusing on pTau 217 as it has become the more prominent biomarker in the field. The executive did not comment on the data cleanup progress but confirmed results are expected by year-end.

Asked about the statistical analysis plan for the co-primary endpoints, the basis for the $40M SEC reserve, the reason for expanding the open-label study, and potential partnership dynamics.

Answer

The statistical analysis plan is written and currently with the FDA for commentary; it requires both co-primary endpoints to meet a p-value of less than 0.05 for success. The company cannot provide more details on the ongoing SEC discussions. The open-label extension was expanded due to strong demand from clinical sites and patients. A partnership is considered unlikely before Phase III data is released, as potential partners are typically risk-averse.

Elemer Piros of Rodman & Renshaw sought clarification on the statistical analysis plan for the co-primary endpoints, asking if it was finalized with the FDA. He also inquired about the methodology for arriving at the $40 million SEC settlement figure, the reasons for expanding the open-label access program, and the company's outlook on potential partnerships.

Answer

CMO Dr. James Kupiec confirmed the statistical plan is written and under review by the FDA before being locked, and that success requires both co-primary endpoints to meet a p-value of less than 0.05. General Counsel Chris Cook declined to elaborate on the $40 million reserve due to ongoing discussions. Executive Chair Richard Barry explained the open-label extension was driven by requests from clinical sites and patients' families, calling it 'the right thing to do.' Regarding partnerships, Barry stated a deal is unlikely before Phase III data is available.

Elemer Piros of Rodman & Renshaw asked about the specifics of the retreatment protocol in the trials, including how relapse is defined and whether patients who resume taking antidepressants must undergo another washout period before retreatment with COMP360.

Answer

Guy Goodwin (Executive) clarified the retreatment criteria. He explained that patients who go back on antidepressants can remain on them during retreatment, which provides useful co-administration data. He stated that the criteria for retreatment, which is based on a MADRS score threshold, is the same for patients who did not respond initially and for those who relapsed after responding.

Elemer Piros of ROTH Capital Partners sought clarification on CYB004's formulation, the compound used in the frontline worker study, and whether Cybin's therapeutic protocol would be more robust than that of the recent Compass 360 trial.

Answer

CEO Doug Drysdale confirmed CYB004 is a deuterated tryptamine intended for future inhaled delivery. He clarified the frontline worker study uses psilocybin, with findings expected to be relevant to the CYB003 program. He emphasized Cybin's belief in robust psychotherapy, highlighting that their EMBARK program includes three preparation sessions, contrasting with the single session used in the Compass trial.

Elemer Piros of Roth Capital Partners questioned the reason for not having an open-label extension in the cystic fibrosis trial and asked for clarification on how missing data would be handled differently between the event-driven CF trial and the 52-week SSc trial.

Answer

Dr. Barbara White, CMO, explained that the decision to forgo an open-label extension for the CF trial was made following guidance from the Cystic Fibrosis Foundation. Regarding missing data, she stated that the CF trial had very little missing data for its primary endpoint. For the SSc trial, the few patients with missing data due to COVID-19 will be handled using LOCF (last observation carried forward), with additional standard sensitivity analyses performed.