Biogen sacrificed a clean endpoint and proved something bigger. The market will grade the tau question. The delivery question is the one that reprices the field.
Certainly much to unpack here. First off I would have liked to have seen the comparative P2 data for the approved amyloid mabs. Secondly, my company has not yet put forward a plausible explanation for the lack of dose-response (AFAIK). Thirdly, beyond superior safety (not trivial) and MOA advantages, I'd like to see some initiatives on patient segmentation (we may see this in the P3 trial design). If, ultimately combination therapy is the way to go, then we're going to need to see significantly larger changes on CDR-SB. Finally, as you stated there is clearly potential utility to use this approach in rare diseases such as PSP/CBD. However I can envisage potentially major pricing challenges (assuming clinical success-a big assumption) using the same drug both for rare and common neurodegenerative disease.
Sharpest response the piece has gotten, thank you. Quickly, on each:
On the comparative data, fair hit. Figure 1 puts our Phase 2 against the mAbs' Phase 3, which isn't clean. Trouble is the amyloid antibodies' Phase 2 record is a weak comparator too, aducanumab's PRIME, the EMERGE/ENGAGE split, mostly cross-era and underpowered. The comparison we'd both want is Phase 3 against Phase 3, and it doesn't exist yet. I should have flagged the stage mismatch harder.
On the dose-response, you'd know better than I would whether there's an internal read, so I'll hold mine as hypotheses: either the target has a floor, tau does normal work and stripping too much costs you, or the harm is exposure-driven, since the serious-event and confusional-state signals tracked cumulative intrathecal dose. Can't separate those on this data. If the program has a third read, I'd like to hear its shape.
On segmentation, agreed, and it's the strongest move the Phase 3 could make. TRAILBLAZER enriched on tau PET and saw benefit concentrate in the low-to-medium arm, and blood-based staging makes that practical now.
On combination needing bigger CDR-SB movement, agreed, that's the real hurdle. 0.54 points is thin, and the combo has to clear a bar neither drug clears alone, which nobody's shown.
Fair point in pricing. The likely path is orphan-first then broaden, but it runs through net price and indication-based contracting, not a list-price cut, since WAC is easy to raise and hard to lower. Workable, and also exactly where it gets messy. Deserves its own piece.
Certainly much to unpack here. First off I would have liked to have seen the comparative P2 data for the approved amyloid mabs. Secondly, my company has not yet put forward a plausible explanation for the lack of dose-response (AFAIK). Thirdly, beyond superior safety (not trivial) and MOA advantages, I'd like to see some initiatives on patient segmentation (we may see this in the P3 trial design). If, ultimately combination therapy is the way to go, then we're going to need to see significantly larger changes on CDR-SB. Finally, as you stated there is clearly potential utility to use this approach in rare diseases such as PSP/CBD. However I can envisage potentially major pricing challenges (assuming clinical success-a big assumption) using the same drug both for rare and common neurodegenerative disease.
Sharpest response the piece has gotten, thank you. Quickly, on each:
On the comparative data, fair hit. Figure 1 puts our Phase 2 against the mAbs' Phase 3, which isn't clean. Trouble is the amyloid antibodies' Phase 2 record is a weak comparator too, aducanumab's PRIME, the EMERGE/ENGAGE split, mostly cross-era and underpowered. The comparison we'd both want is Phase 3 against Phase 3, and it doesn't exist yet. I should have flagged the stage mismatch harder.
On the dose-response, you'd know better than I would whether there's an internal read, so I'll hold mine as hypotheses: either the target has a floor, tau does normal work and stripping too much costs you, or the harm is exposure-driven, since the serious-event and confusional-state signals tracked cumulative intrathecal dose. Can't separate those on this data. If the program has a third read, I'd like to hear its shape.
On segmentation, agreed, and it's the strongest move the Phase 3 could make. TRAILBLAZER enriched on tau PET and saw benefit concentrate in the low-to-medium arm, and blood-based staging makes that practical now.
On combination needing bigger CDR-SB movement, agreed, that's the real hurdle. 0.54 points is thin, and the combo has to clear a bar neither drug clears alone, which nobody's shown.
Fair point in pricing. The likely path is orphan-first then broaden, but it runs through net price and indication-based contracting, not a list-price cut, since WAC is easy to raise and hard to lower. Workable, and also exactly where it gets messy. Deserves its own piece.
This may be of interest Robert (https://substack.com/home/post/p-207794465)