Final Response to Shareholder Inquiry (as of 23.05.25)“primary endpoint of reduced iron in substantia nigra was not statistically significant (SS) and so were the nfl values which were not SS”
Thank you for your inquiry. As CEO, I wanted to personally address your statements, which explains the delay in our response. We appreciate your patience.I’ve prepared a comprehensive explanation below that should clarify your statement regarding both iron as the primary endpoint and NfL.Iron as the primary endpoint:As the first Phase 2 study of ATH434 for any indication, we evaluated several efficacy and biomarker endpoints. This is typical for an initial Phase 2 study, which is exploratory in nature. Also, one note about statistical significance as it relates to Phase 2 trials: In an initial Phase 2 study, where true powering is not possible, it is more important to focus on the treatment effect rather than a P-value. As we reported, the treatment effect from ATH434 observed at both dose levels in the Phase 2 study is clinically meaningful.We selected the primary endpoint of iron content because of the large amount of preclinical data we had accumulated over the years. In these studies, ATH434 achieved efficacy and reduced iron content in animal models of both Parkinson’s disease and MSA. We designed the Phase 2 studies based on thisinformation. In the 201 study, ATH434 demonstrated target engagement in MSA by reducing iron at both dose levels in the globus pallidus (GP) and at 50 mg in the putamen (PT) and substantia nigra (SN). The lower impact on reducing iron at 75 mg in certain regionsmay be based on differences in disease severity between the dose groups. Additionally, it is harder to measure iron in the SN because of its size and location in the brain.Regarding NfL levels, we are running additional analyses on these data and will report our findings when these analyses are completed. Why clinical endpoints are most important:We have discussed clinical endpoints with the FDA and it is clear that the UMSARS Part I (UMSARS I) outcome is most relevant to them given it is a clinical endpoint that looks at patients’ function in daily life. Therefore, we prespecified UMSARS I as our key secondary endpoint. Importantly, we observed efficacy at both dose levels on the UMSARS I along with efficacy on important secondary endpoints such as the CGI-S, OHSA and wearable movement sensors. We also showed a favorable safety profile with no safety signals. As efficacy data, in particular UMSARS I, and safety data will provide the basis for approval, we are thrilled with our results and look forward to discussing them with FDA in our end-of-Phase 2 meeting. I hope this clarifies matters. We value your continued interest in our company. Kind regards,David Stamler, MD
Hi Scotty
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