The biopharmaceutical firm Biogen announced yesterday that it will discontinue developing and marketing the Alzheimer’s disease drug Aduhelm. The rights to Aduhelm will now revert to the original developer of the medicine, the Swiss company Neurimmune. This ends the tortuous saga of a once promising treatment for the memory robbing disease.
Curiously, Aduhelm (aducanumab) was formerly heralded in the media as a metaphorical “game changer.” At the time of its accelerated approval in June 2021, for example, a Bloomberg article’s headline declared it “changes the game for Alzheimer’s treatment.”
Such pronouncements were questionable then in light of the extraordinarily controversial process by which the drug gained approval by the Food and Drug Administration. The agency ignored advice given by an independent advisory committee to not approve the therapeutic. Moreover, the FDA never gave a compelling justification for its decision.
Within days of Aduhelm’s approval the New York Times reported that three scientists resigned from the committee that advised the FDA on the treatment. They were troubled by the FDA overruling a near-unanimous vote of ten against and one uncertain.
This raises the question why some media reports still talked about a “major breakthrough.”
A detailed exposé in STAT revealed findings from a Congressional investigation in 2022 regarding Aduhelm in which it was noted that the drug’s sponsor, Biogen, spent $3 billion to “shape the narrative” by recruiting 50 journalists and connecting them with key opinion leaders. Maybe this contributed in part to the undeserved fanfare given Aduhelm?
In approving Aduhelm, the FDA acknowledged that there was insufficient evidence the drug would meaningfully improve outcomes in dementia patients, but granted it marketing authorization anyway under its “accelerated approval” program. This pathway allows authorization of unproven drugs for serious diseases if there are few if any treatment options available, and if the drug affects a biological mechanism or surrogate marker in a way considered “reasonably likely to predict clinical benefit.” In the case of Aduhelm, the drug decreases beta amyloid plaque in the brains of patients with Alzheimer’s disease. Such plaque accumulation is hypothesized to be a cause of Alzheimer’s disease.
In addition to lacking statistically significant efficacy, approximately 40% of patients who took Aduhelm suffered swelling or bleeding in the brain, according to the New York Times.
Prompted by the inconclusive evidence on safety and efficacy, very soon after the FDA approval the Centers for Medicare and Medicaid took the unusual step of commencing an analysis of the data regarding the entire class of monoclonal antibodies directed at beta amyloid plaque in Alzheimer’s disease patients. This included the approved drug Aduhelm, but also biologics in clinical development such as lecanemab, donanemab and gantenerumab.
Roughly a half year after Aduhelm’s accelerated approval, CMS posted a draft national coverage determination in which it stated that coverage in the Medicare program would be limited to beneficiaries who enroll in post-marketing clinical trials. The NCD was finalized in April of 2022.
Without a regular FDA approval in sight, which would have given Aduhelm a less restrictive set of conditions of reimbursement, the drug’s fate was sealed.
Aduhelm experienced extremely poor uptake in both the public and commercial markets. In the fourth quarter of 2021, for example, Aduhelm could only muster $1 million in sales. Since then, prospects for the biologic didn’t appreciably improve.
Biogen says it will now “reprioritize resources allocated to Aduhelm to advance Leqembi (lecanemab) and to develop new treatment modalities.” Similar to Aduhelm, Leqembi is a biologic that reduces plaque build-up in the brain thought to be a contributing factor in Alzheimer’s disease. Biogen and Eisai are co-sponsors of Leqembi which was granted accelerated and then full approval by the FDA in January and July 2023, respectively.
Phase 3 data for Leqembi demonstrated modest cognitive benefit in patients with early Alzheimer’s disease. At the Clinical Trials on Alzheimer’s Disease Congress in December 2022, trial investigators presented a full data analysis on Leqembi’s safety and efficacy. The findings published in the New England Journal of Medicine made experts both optimistic and cautious at the same time, which was reflected in the medical journal article’s conclusion that the drug should be studied further.
Leqembi offers some degree of hope to Alzheimer’s disease patients. Accordingly, there’s been rising demand for the drug since its July 2023 approval. Eisai said that the number of people on the infused drug reached 800 by the end of October.
However, there are lingering questions pertaining to this medication, some of which are related to safety risks while others concern whether the treatment provides clinically meaningfully improvement in health outcomes for patients. Among neurologists there’s an ongoing debate as to Leqembi’s clinical meaningfulness.
In turn, this challenges use of certain language to describe Leqembi. To illustrate, some in the Alzheimer’s community suggested the effects could be “seismic.” And results were hailed by the BBC as momentous.
The hyperbole doesn’t end with this particular beta amyloid plaque-busting antibody. When Eli Lilly announced last spring that its antibody, donanemab, had demonstrated positive results, publications boasted of the treatment’s “transformative” properties.
Subsequently, a neurologist specialized in Alzheimer’s disease critically pointed to the media hype regarding Phase 3 data on donanemab. He cited headlines from around the world which included phrases such as “beginning of the end,” “turning point” and “brink of wonder.” Given that in the Phase 3 trial the treatment group was merely three points better than placebo on a 144 point clinical dementia rating scale, he questioned the adoption of such superlatives.
Both Leqembi and donanemab do not improve cognitive function. They only modestly lessen its decline. To be sure, they’re considered better than Aduhelm and don’t have the same baggage. But it behooves the media and others to exercise caution when reporting on the attributes of all such antibodies.