Long delayed publication of data on Alzheimer’s drug Aduhelm leaves questions unanswered

Trial data on Biogen’s Alzheimer’s disease drug aducanumab (Aduhelm), which was published nearly a year after it was approved by the US Food and Drug Administration (FDA), fails to answer critical questions raised in a review by the FDA’s own statistician, specialists have said.

The paper was published in a respectable but small publication, the Journal of Prevention of Alzheimer’s Disease (JPAD), which has an impact factor of 4.5.1 Trial data on such a major new drug typically appears in top journals such as the Journal of American Medical Association (JAMA), which has an impact factor of 56, or the New England Journal of Medicine, with a factor of 91.

The editor of JPAD, Paul Aisen, is one of the authors of the paper and has worked as a paid consultant for Biogen. The company submitted the paper to JAMA last year, but withdrew it “to pursue other publication opportunities,” according to the news website Axios.2 Biogen declined to comment on its reasons for withdrawing the paper from JAMA.

Aduhelm has been the subject of fierce debate since the FDA gave it accelerated approval last June. The agency’s own expert advisory committee had recommended against allowing Aduhelm onto the market by 10 votes to zero, with one abstention, but after hosting a meeting of patient groups, the regulator gave an unexpected assent.

Two phase 3 trials of the drug, called Emerge and Engage, were stopped early after a futility analysis suggested that they were unlikely to produce positive results. Only 55% of the intended patients ever completed the trials. But after reviewing the data, Biogen announced that the futility analysis had been based on false assumptions, and that the final data from the Emerge trial, but not from Engage, had shown evidence of treatment benefit measured by patients’ cognitive test scores.

Reporting in JPAD, the researchers found that for the primary outcome measure—increase from baseline to week 78 on a clinical dementia rating scale that assesses both function and cognition—Emerge reported 39% less increase in high dose aducanumab compared with placebo, with lower score signalling milder dementia (−0.39, 95% confidence interval, −0.69 to−0.09; P=.012; 22% decrease from baseline). But in Engage, there was no improvement from baseline and no significant difference between the scores of high dose aducanumab subjects and those on placebo, with the treated subjects’ scores rising by an extra 3% (0.03, 95% CI, −0.26 to 0.33; P=.833; 2% increase from baseline).

Examining the cause of such sharply divergent results in nearly identical trials, the FDA’s statistician found that the apparent clinical benefit in Emerge was largely based on a greater than expected cognitive decline in the placebo group, rather than a slowing of cognitive decline in the treatment group. This was one of the factors that led the expert panel to recommend against approval.4

Another factor, said Rob Howard, old age psychiatrist at University College London, was the likely unblinding of trial subjects. A common adverse effect of Aduhelm is amyloid related imaging abnormalities (ARIA) such as brain oedema, which may be serious or asymptomatic. Finding an ARIA in the trial triggered a series of magnetic resonance imaging exams, but since the ARIAs were mostly limited to those taking high dose Aduhelm and rare in those taking placebo, such screenings could unmask the patients in the treatment group.

Biogen did not respond to The BMJ’s requests for comment. The company claimed in a press release last week that new, unpublished data show Aduhelm continuing after 128 weeks to lower two biomarkers, amyloid β plaque and plasma p-tau181, which it called “key Alzheimer’s disease pathologies.”3 But the link between reducing these biomarkers and clinical, symptomatic benefit has never been established.