Key Findings
Arrowhead Pharmaceuticals has released early Phase 1/2a data for ARO-MAPT, an investigational gene silencer designed to lower tau protein levels. The study in healthy volunteers demonstrated significant reductions in cerebrospinal fluid (CSF) tau, providing clinical validation for Arrowhead’s platform for targeting the central nervous system through subcutaneous administration.
Technical Details
The magnitude of tau reduction varied by dose and schedule at day 105:
- Low dose (2.1-mg/kg): Administered on days 1, 8, and 15, resulting in an average CSF tau reduction of 40%.
- Medium dose (6.4-mg/kg): Administered on days 1, 8, and 15, resulting in an average reduction of 69%.
- High dose (12.8-mg/kg): Administered on days 1 and 15, resulting in a mean reduction of 73%, with a maximum reduction of 85% in this cohort.
Regarding safety, the treatment was generally well tolerated. Adverse events were largely mild, with no deaths, serious side effects, or dropouts due to toxicities.
Background & Context
Stifel analysts noted that these results appear more compelling than other blood-brain barrier (BBB) platforms, specifically comparing ARO-MAPT to Biogen’s BIIB080 (diranersen). While BIIB080 requires direct injection into the spine, ARO-MAPT is delivered subcutaneously. Biogen’s Phase 1b data for diranersen showed average CSF tau declines of 30% to 49% at eight weeks post-final dose, reaching up to 56% at 24 weeks. However, Jefferies cautioned that direct comparisons are limited due to differences in dose strengths and study populations.
Significance & Outlook
The Phase 1/2a trial is currently enrolling up to 112 participants, including healthy volunteers and patients with early Alzheimer’s disease. While Biogen’s Phase 2 CELIA study failed to meet its primary goal regarding cognitive and functional outcomes, Biogen intends to move diranersen into registrational development. Arrowhead expects further data on Alzheimer’s disease and healthy volunteers next year and is discussing studies for progressive supranuclear palsy and MAPT-associated frontotemporal dementia with regulators.
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