(+) BIIB080 Phase II Tau Data De-risks, Has Favorable Readacross to DNL628

Research evidence excerpt

(+) BIIB080 Phase II Tau Data De-risks, Has Favorable Readacross to DNL628

ar to -50-60% at Week 24

in the prior Phase Ib (vs marginal for pbo), sustaining out to Week 74. Pre-specified analyses of

cognitive endpoints (including CDR-sb) suggest a slowing clinical decline across all three doses

(over pbo), with the strongest signal with the 60mg Q6M (lowest dose). (c) Technically, achieving

stat-sig was predicated on high-dose performing better than low-dose. Instead, low-dose was most

pronounced. (d) We surmise CDR-sb could be -0.5-1.0 pbo-adj (vs -0.4-0.7 pbo-adj for abeta drugs

at Week 76). Our understanding is placebo behavior was normal, supporting a ''real'' drug effect. (e)

Also, safety is also consistent with Phase Ib. No fundamental ARIA risk either (a key differentiation

over abeta therapies).

Taken together, BIIB080's data clinically validates the intracellular tau approach partially de-

risks DNL628 (also targets intracellular tau), and even potentially leaves room for '628 to

differentiate on efficacy. (a) In H1:27, IV DNL628 (MAPT tau) has 24-week Phase Ib data

(NCT07328451) in actual Alz patients (N=68). Mgmt is hoping for a -40-50% tau reduction

(preclinical data achieves >50% tau knockdown after >8 weeks). Seeing (+) cognition trends would

be ideal, but the Phase Ib is only 24 weeks long. (b) Ultimately, DNL628 could be differentiated

due to superior BBB penetration (TfR brain shuttle) for improved brain biodistribution (engaging in

the deepest brain regions) and dosing convenience (IV vs IT). The molecule has been optimized to

improve peripheral exposure and safety. (c) In mice that express human tau, '628 knocks down both

Andrew Tsai * | Equity AnalystMAPT RNA, as well as quantifiable tau biomarker up to 12 weeks after dosing. As such, knockdown