I probably should have added 20-25 MM to my cash burn estimate for an OLE for AD.
Doc, could you help us understand why you think PDD/PD P3 is less likely to succeed compared with AD/Schizo/Rett?
The AChEI's like donepezil and rivastigmine did better at AD than PDD so success likelihood is probably a little lower for PDD. The indication may just be harder to prove benefit - or study might just need to be longer. The P2 did not meet the primary endpoint (pre-specified CDR Battery subscales (not the sub-subscales they tried to pass off as the actual endpoint)) and the study was short at 12 weeks, so it is too insignificant to serve as a 2b/3. PD looked potentially interesting with significant changes noted on the MDS-UPDRS. However, they needed to use the less vigorous Wilcoxan rank statistics implying data was skewed or many outliers. Who knows what was in the SAP. The study would be a little chea;er than AD as less complex and could be shorter. If only looking at PD (i.e MDS-UPDRS endpoint), could be 6 months plus OLE. If company can get AD approval, they may be able to get by with a single PDD phase 3. But without AD approval, they may need to do 2. They just don't have the funds without excessive dilution. Hence I doubt they do PDD trial start in next couple years unless they drop AD.
PR says they’ll be “providing relevant biomarker data” for the re-exam
I'll do a separate post for this
The one clean precedent I can find is panitumumab (Vectibix) in mCRC:
Nice example that is somewhat relevant - the exception that proves the rule?. I researched this further. There are important factors that prevent a perfect correlation with A273. - caveat: cancer drugs are often looked at differently and this is from 15 years ago. This drug had multiple studies. - Most tumors are KRAS WT. - FDA:It was actually first approved by FDA in 2006 with accelerated approval using PFS as a surrogate marker (OS was primary endpoint). The company quickly started 2 P3 trials. As these were enrolling, further analysis of the P2 showed that KRAS WT tumors showed benefit but the KRAS variant tumors did not. The 2 P3 were already enrolling (ultimately > 1100 patients). The SAPs were amended to reflect KRAS startus before the readout (so post-hoc for the P2 and amended SAP for the P3's). So all 3 studies enrolled 'all-comers' with the P3's evaluating (and publishing in 2009) reflecting booth the all comers and the variants. The label was modified in 2009 to reflect the KRAS status based on this amended SAP analysis of the P3's and approval was changed from accelerated (all-comers) to full (KRAS WT) a couple years later. . - The EMA, usually slower than FDA, granted initial/conditional authorization in 2007, The P2 genetic analysis came out during the MAA evaluation. Therefore the initial conditional authorization was for KRAS WT and then updated to reflect KRAS status later after the P3 trials confirmed the KRAS subset finding. - I do not know if they needed to do an oral argument but it was approved without a re-examination-- as A273 will apparently need. . - A273 had the S1R WT/Q2P data, and the limited biomarker data and MRI data at the time of the MAA (November 2024). The drug is not already approved in the US. There are no additional studies already in progress.
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