Biogen Submits Protocol for Phase 4 Aducanumab Study, FDA AdComm's Board Doesn't Recommend AMX0035 Approval, Intensive SBP Increases Cerebral Blood Flow

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Biogen has submitted the final study protocol to the FDA for the phase 4 ENVISION trial of aducanumab (Aduhelm) to be reviewed by the agency. The company noted in an announcement that it anticipates the first patient to be screened in May 2022.The trial will be conducted as part of the accelerated approval of aducanumab in June 2021, and will be global in scale, with a targeted enrollment of 1500 patients with Alzheimer disease (AD) and confirmed amyloid-ß pathology. The 100 mg/mL injection was approved for intravenous infusion in early AD, including those with mild cognitive impairment (MCI) because of AD and mild AD. ENVISION’s primary end point, which was originally detailed in an announcement from January 2022,2 will be cognitive decline at 18 months, measured by the Clinical Dementia Rating-Sum of Boxes (CDR-SB). Additionally, a long-term extension is planned to collect data for up to 48 months.

The FDA’s Peripheral and Central Nervous System Drugs Advisory Committee has voted not to recommend regulatory approval of AMX0035, Amylyx’s orally administered, fixed-dose coformulation of sodium phenylbutyrate-taurursodiol for the treatment of amyotrophic lateral sclerosis. The committee voted 6–4 (6 no; 4 yes; 0 abstain) that the data from the phase 2/3 CENTAUR trial (NCT03127514) and open-label extension study did not adequately establish AMX0035 as an effective treatment for ALS. AMX0035 has a PDUFA date of June 29, 2022. Several of the AdComm members who voted against the drug had concerns over the trial's conduct and robustness of the data. Additionally, some felt as though the ALS Functional Rating Scale-Revised (ALSFRS-R) scores for patients in the placebo arm were high, which may have altered the perception of the data. Notably, the FDA altered the wording of the key question it posed to the committee in the day before the meeting, changing the phrasing from asking whether the data from the trial "support" a conclusion to "establish" a conclusion, effectively removing a degree of uncertainty from the scenario.

A secondary analysis from the phase 3 SPRINT MIND randomized clinical trial showed that an intensive systolic blood pressure (SBP) target of less than 120 mm Hg was associated with a significantly larger increase in cerebral blood flow (CBF) compared with a standard blood pressure target of less than 140 mm Hg in adults with hypertension. Notably, this association was even more pronounced among those with a history of cardiovascular disease. After 4 years of follow-up, the mean whole brain (WB) CBF in the intensive treatment group increased by 1.46 mL/100 g/min (95% CI, 0.08-2.83) while WB CBF decreased in the standard treatment group, with mean change from baseline of –0.84 mL/100 g/min (95% CI, –2.30 to 0.61). Although the mechanistic reasons for this increase are uncertain, the investigators concluded that the findings suggest a complex relationship between BP and CBF that is "beyond simply static cerebral perfusion pressure and cerebrovascular autoregulation."

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