Mixed Readthrough From BIIB‘s ASO Tau Data @AAIC to ARWR‘s MAPT Program

Research evidence excerpt

Mixed Readthrough From BIIB‘s ASO Tau Data @AAIC to ARWR‘s MAPT Program

tive benefit does not scale w/ more drug or more frequent dosing;

however, we wonder if IT ASO biodistribution and KD depth reach a ceiling in BIIB's data before

disease-relevant deep brain regions are fully modulated.

BIIB biomarker evaluations confirmed that CSF total tau and phosphorylated tau reductions were

dose-dependent w/ the higher doses achieving deeper reductions than the low dose. However,

this did not translate to a dose-response on clinical efficacy, even though pre-specified analyses of

cognitive endpts suggested a slowing of clin decline across all 3 active doses vs PBO.

BIIB's paradoxical dose-response relationship leads to a bear debate on whether tau lowering

plateaus for reasons unrelated to biodistribution; if this is the case, then more drug in the

'right' places (i.e., deeper brain) may not translate into better clin benefit. ARWR has their own

translation risks as TfR1 delivery may hit its own limits (unproven clinically w/ SC delivery platform).

Overall BIIB's safety profile was good, notably w/ absence of ARIA typically seen w/ Aβ Abs. It

is reassuring to see long-term KD safety is looking favorable, helping derisk the class-wide safety

profile of intracellular tau-lowering drugs. Also, ARWR's preclin tox data in rodents and NHPs have

demonstrated a safety margin of at least 10-fold over the anticipated clin active dose. Maury Raycroft, Ph.D. * | Equity Analyst

(212) 323-3990 | mraycroft@jefferies.com

ARWR will have early 'MAPT HV data in 3Q that is necessary to validate ARWR's SC BBB delivery Farzin Haque, Ph.D. * | Equity Analyst

platform. Co is aiming for CSF tau KD of 50-60% as a base case along w/ good tolerability in HVs. +1 (212) 778-8349 | fhaque@jefferies.com