Biotech Values

[jq1234]

I am generally no longer interested in discussing SRPT AA much ever since I saw individual patient dataset. AA is immaterial to me longer term.

There will never be 1:1 correlation in any surrogate endpoints, even in well established surrogate endpoints of ORR, PFS in oncology, GL3 in Fabry for example. For genetic disorder, you have to understand natural disease history which is much more predictable than other disease. Those two patients' status are quite easily explained - I know many people think that's cherry picking, I thought that too initially without seeing full dataset if you look back my old postings on this subject, I changed my position gradually with more data coming in - they were the oldest, and had lowest 6MWT around 250m at entry, which are major predicting factors to becoming non-ambulatory quickly, and they did.

I never predicted FDA would approve based on the dataset, I thought they would likely accept AA filing based on the limited dataset because of reasonable likelihood of dystrophin predicting clinical outcome. The long term stabilization of DMD patients in this age group provides strong evidence of that. Whether they approve based on dystrophin surrogate endpoint or find other way to approve it or reject it after review is more difficult to predict - there are many more factors involved. Approve based on surrogate endpoint in this case has consequences which means they'll have to approve similar drugs for this indication in the future, thus they'll need to ensure the methodology etc are sound and replicable. The closest case I can think of is Fabrazyme/Replagal for Fabry - datasets were larger, but they still convened adcom due to surrogate endpoint. On the other hand, if they reject it, then one year later, ph3 meets endpoint, they'll face strong criticism of delaying the approval of a major milestone drug in extremely unmet medical need area. Based on my experience in this area, I think they know that. This is similar to ERT for genetic disorder, efficacy can be established based on small set of patients, the issues usually are long term safety, thus larger trials are needed. In this case, there isn't any safety signal yet.