Biogen posts more Aduhelm biomarker data and a 'correlation' with Alzheimer's clinical benefit

Biogen has been in hot water lately thanks to the contentious FDA approval of Alzheimer’s disease therapy Aduhelm based on a debatable biomarker. Now, the Big Biotech has turned in data on another biomarker plus an analysis the company says suggests association with a slowing of disease progression.

Aduhelm, at the FDA-approved dose, significantly lowered blood levels of phosphorylated tau (p-tau) compared with placebo in the two phase 3 trials that supported its FDA nod, Biogen unveiled at the Clinical Trials on Alzheimer’s Disease conference. The FDA cleared Aduhelm in June with data on the drug’s ability to reduce amyloid beta plaque in the brain, which is a hallmark of Alzheimer’s.

More importantly, Biogen's p-tau data linked a greater reduction in the problematic protein to less cognitive and functional decline across four clinical outcome measures. But whether that correlation is strong enough may still be open to dispute.

Alzheimer’s is characterized by the toxic buildup of amyloid plaques and tau tangles in the brain. One theory holds that the aggregation of amyloid could drive up the plasma levels of soluble p-tau, which then leads to aggregation of tau, followed by cognitive decline, Maha Radhakrishnan, M.D., Biogen’s chief medical officer, explained in an interview ahead of the data presentation.

The new data showed that removing amyloid aggregation—with Aduhelm—could reduce soluble p-tau levels, thereby slowing the accumulation of the tau masses and hence clinical decline, Radhakrishnan said.

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To be specific, a type of p-tau called p-tau181 dropped 13% for Aduhelm takers in the phase 3 EMERGE trial, while patients on placebo saw their levels rise 8%. In the ENGAGE trial, p-tau decreased 16%, versus a 9% increase for placebo.

Although Aduhelm has proven the ability to pare back protein aggregates, its performance in improving Alzheimer’s symptoms is less clear, which is why the drug is getting heavy pushback from doctors.

On the more important results on Alzheimer’s symptoms, Radhakrishnan described a “robust correlation” between the lowering of plasma p-tau and less disease worsening in four clinical outcomes measures of cognition and function.

The four scores are the Clinical Dementia Rating Sum of Boxes Score, Mini-Mental State Examination, Alzheimer’s Disease Assessment Scale–Cognitive Subscale, and Alzheimer’s Disease Cooperative Study/Activities of Daily Living scale adapted for MCI. These scales are commonly used in Alzheimer's clinical trials to measure the severity of dementia, cognitive function, cognitive dysfunction and the patient's competency in performing daily tasks.

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The correlation values seen in Biogen's trial on the four markers only range between positive or negative 0.11 to 0.21 in the two trials. In statistics, the closer the value is to 1 or -1, the stronger the association. So Aduhelm’s data basically hover closer to 0, which would indicate no relationship.

But Radhakrishnan pointed to the analyses’ p-value to emphasize the statistical significance of the data, which basically means the findings didn’t happen by chance.

Besides the two phase 3 trials, Biogen also presented some baseline data for patients enrolled in a single-arm phase 3b trial dubbed EMBARK. That trial included past Aduhelm patients from previous clinical trials and is redosing them and following them for two years to evaluate the long-term safety and efficacy of the drug. The patients have undergone an average 1.7 years without Aduhelm treatment before joining the EMBARK trial.

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The study showed that compared with placebo, reductions in amyloid beta plaque observed in the previous trials were largely maintained in the FDA-approved Aduhelm dosing group despite the treatment gap. What’s more, the numerically slower decline in clinical function of Aduhelm over placebo was also still there.

The findings suggest that “impacting amyloid … may not be enough,” Radhakrishnan said. “We need to really think about, what are some of the other underlying pathological processes that we need to consider.”

Just as critics question Aduhelm’s benefit-risk profile, a death case related to the drug was recently reported to the FDA Adverse Event Reporting System; a 75-year-old female in Canada died after she was diagnosed with brain swelling, or amyloid-related imaging abnormality, a side effect seen with Aduhelm treatment.

Because the fatal case came from outside the U.S. and the drug is not currently approved in Canada, RBC Capital Markets analyst Brian Abrahams has speculated the patient was being treated through the EMBARK trial. Radhakrishnan declined to comment on whether the case is from EMBARK. Biogen is working with the treating physician and regulators to understand the case better, she said.