Patients treated with the drug (aducanumab-avwa) saw reduction in amyloid beta plaques and p-tau181; while clinical decline was reduced in participants who had plasma p-tau181 reduction at 78 weeks, according to the company.
Reduction in pathologies
Biogen’s Aduhelm has followed a rocky road to date. It was approved by the US FDA in June last year; although the agency asked for further data on the drug’s clinical benefits.
In January, the US Centers for Medicare & Medicaid Services (CMS) announced that – under its draft policy - Aduhelm (and any other monoclonal antibodies targeting amyloid for the treatment of Alzheimer’s) would only be covered for patients in qualifying clinical trials. The final policy is expected in April.
In Europe, the EMA rejected the drug's application: saying that, although Aduhelm had been shown to reduce amyloid beta in the brain, the link between this effect and clinical improvement had not been established.
Presenting its findings at the International Conference on Alzheimer’s and Parkinson’s Diseases in Barcelona this week, Biogen says the latest data are part of its ongoing commitment to provide additional clinical data to further characterize and understand Aduhelm’s profile.
It adds that these data help inform the scientific evidence for amyloid as a surrogate biomarker and the importance of continuation in treatment.
Long-term Phase 3 data
The new data released by Biogen this week come from the long-term extension phase of the Phase 3 trials. Patients treated for 128 weeks with Aduhelm injection 100 mg/mL for intravenous use ‘continued to experience significant reduction in two key Alzheimer’s disease pathologies, amyloid beta plaques and plasma p-tau181.’
The data also showed that, at 78 weeks, patients with reduced levels of plasma p-tau181 ‘had less clinical decline than those whose plasma p-tau181 levels were not reduced.’
Aduhelm also ‘significantly reduced’ amyloid beta plaque levels out to week 132. The drug also continued to decrease plasma p-tau181 levels at 128 weeks. Patients with more effective amyloid beta clearance (SUVR lower than 1.1 by 78 weeks) also had greater decreases in p-tau181 at week 128. Biogen says these findings point to the potential of continued benefit of treatment in the longer term with continued reduction of amyloid beta plaques.
“These are meaningful findings, which further our understanding of amyloid and downstream biomarkers, such as p-tau 181, in Alzheimer’s disease and can help inform how long patients may benefit from treatment to reduce amyloid beta plaque,” said Samantha Budd Haeberlein, Ph.D., SVP, Head of Neurodegeneration Development at Biogen.
With the uptake of the drug far less than expected, Biogen started the process of laying off some US staff earlier this month.
Yesterday, Aduhelm partner Eisai amended its previous deal with Biogen, changing from sharing in global profits and losses to a simple global tiered royalty model, in which it will not participate in Aduhelm’s economics beyond these royalties (effective as of 2023).
Biogen’s existing final decision-making rights on Aduhelm have been converted to sole decision making and commercialization rights worldwide.
“These data demonstrate that long-term treatment with Aduhelm continues to reduce the underlying pathologies of Alzheimer’s disease beyond two years."
Patients with a reduction in plasma p-tau181, an exploratory endpoint, had less clinical progression across all four clinical endpoints (CDR-SB, MMSE, ADAS-Cog13, and ADCS-ADL-MCI) measuring cognition and function in both Phase 3 trials at Week 78.
Part of the controversy around Aduhelm's approval has been questions over the risk/benefit analysis: with the EMA and CMS both holding back over questions of safety with 'brain scans of some patients showing abnormalities suggestive of swelling or bleeding, which could potentially cause harm' (EMA).
Biogen's long-term study is assessing cases of ARIA (amyloid-related imaging abnormalities): already documented in Phase 3 trials and included as a warning in prescribing information for Aduhelm in the US.
"In the placebo-controlled period of the Phase 3 trials, the incidence of ARIA-E in the 10 mg/kg group was 35.2%. The incidence was higher among APOE ε4 carriers (43.0%) than non-carriers (20.3%)," says the company.
"While the majority of ARIA is asymptomatic, serious symptoms in the setting of ARIA can occur (0.3% of participants in the 10 mg/kg group of the Phase 3 trials. Most events (98.2%) of ARIA-E resolved on study, with the majority resolving within 12-16 weeks.
“Biogen is committed to continuing to work with the aim that ARIA is further characterized and that the risk of ARIA is well understood."
Publication of Phase 3 data
Meanwhile, a peer-reviewed manuscript detailing data from the Phase 3 Emerge and Engage trials was published yesterday in The Journal of Prevention of Alzheimer’s Disease (JPAD).
The publication includes results from the primary, secondary and tertiary endpoints in the trials, as well as safety data and biomarker sub-studies.