Three opinion pieces published Wednesday in the New England Journal of Medicine may end up in business school classes as a case study in how one set of facts, about which no one disagrees, can generate starkly different interpretations. These pieces concern aducanumab (Aduhelm), the recently approved drug for Alzheimer's disease, which has been controversial ever since developer Biogen announced plans to seek FDA authorization despite two phase III trials being stopped for futility -- and wasn't quickly shot down by the agency. Many observers thought the drug was finally dead when an FDA advisory panel voted unanimously against it last November. So the Alzheimer's community was flabbergasted when the agency gave it a qualified OK in June, though opinion varied as to whether it was the correct decision. Three of the advisory panel's 11 members quit in protest, while the Alzheimer's Association and other advocacy groups rejoiced. Harsh rhetoric broke out on Twitter and media op-ed pages, including on MedPage Today. Now the principals are duking it out in the New England Journal's Perspectives section. In one corner, the top brass at FDA's Center for Drug Evaluation and Research (CDER); in the other, seven members of the advisory panel that voted the drug down, including the three who then resigned; and serving as referee, Gil Rabinovici, MD, of the University of California San Francisco, an Alzheimer's biomarker researcher. Biomarkers -- specifically, amyloid plaque burden as measured with PET scans or cerebrospinal fluid (CSF) assays -- were a key part of the FDA's rationale for authorizing aducanumab through the agency's "accelerated approval" pathway. As CDER officials led by director Patrizia Cavazzoni, MD, explained in their NEJM piece, that pathway provides market access for drugs to treat serious conditions without effective alternatives, when clinical benefit hasn't yet been proven directly, but studies do show an effect on a biomarker predictive of benefit. It's been used (though critics say it's been abused as well) for many HIV and oncology drugs. Ultimately, drug sponsors are required to conduct follow-up trials to confirm clinical effectiveness, though follow-through has been spotty. For aducanumab, secondary analysis of the placebo-controlled trial data showed substantial reductions in plaque burden, a point that all parties accept as true. So the question then became, is it "reasonably likely" (the standard set in previous FDA guidance) that the drug will produce a slowing, if not reversal, of clinical dementia progression? Cavazzoni and colleagues said unequivocally yes. Subgroup analysis in the trials showed that patients assigned to a higher aducanumab dose did show less progression (the primary endpoint covered both doses tested in the trials), "and one of the two phase III trials was strongly positive, showing statistically significant effects on all four endpoints assessing mental and daily life function -- standard endpoints in Alzheimer's trials," the group wrote. The officials also cited data on other, as yet unapproved anti-amyloid biologics connecting reduced plaque burden with clinical outcomes. For their part, the advisory panel members and ex-members, led by G. Caleb Alexander, MD, of Johns Hopkins University in Baltimore, argued that the evidence supporting amyloid plaque as a valid surrogate is too weak to support the accelerated approval. "To date, clinical trials provide no substantial evidence that lowered beta-amyloid predicts clinical benefit," they argued, noting that all previous trials of anti-amyloid drugs have failed to meet symptom-based endpoints, and "some have worsened cognition." A considerable literature has accumulated that suggests that beta-amyloid plaques are more of an epiphenomenon, lying atop an underlying disease process, than a causative factor. The group also complained that the advisory panel "was never consulted about beta-amyloid's suitability as a surrogate," and that an FDA scientist had assured them that it was not being considered. And FDA staff's own review of the Biogen data concluded that "it is not clear that there is any linkage between reduction in plaque and long-term clinical change." Alexander and colleagues scoffed at the FDA's requirement for the confirmatory study, noting that it gave Biogen "at least 9 years" to complete it. They also were incensed that, even when top officials decided that amyloid burden was indeed a valid surrogate outcome, the FDA did not stipulate that patients undergo plaque measurements before receiving aducanumab. "p to half of people with mild cognitive impairment, and many people with a presumptive diagnosis of Alzheimer's disease, do not have elevated [amyloid] levels," the group observed. Rabinovici agreed with many of the critics' points, though with a more measured tone. He cited his own study from 2019 showing that only 64% of patients with Alzheimer's diagnoses had positive amyloid PET results. He also suggested that Alexander et al. were correct in calling the aducanumab label overly broad, leaving insurers and clinicians with the accountability to "set responsible guidelines for clinical use of aducanumab." In particular, "a positive beta-amyloid test (PET scan or CSF assay) should be a prerequisite for therapy," Rabinovici wrote. Other recommendations were offered this week by researchers and clinicians at the virtual Alzheimer's Association International Conference, covering patient selection, dosages, and monitoring for side effects and clinical response. But Rabinovici stopped short of condemning the drug's approval, declining to dispute the FDA's ultimate determination that amyloid burden is a valid surrogate. The previous "failed trials" on which Alexander and colleagues built much of their case "preceded the biomarker-based era of Alzheimer's drug development," he pointed out, and he agreed with the FDA officials that subsequent data with other amyloid-targeting agents support predictions of clinical benefit. Finally, Rabinovici offered the hope that, even though aducanumab's clinical effect will probably be no more than modest for most patients, it "should encourage development of drugs targeting other elements of Alzheimer's pathophysiology (e.g., tau or neuroinflammation), which in combination with amyloid-based therapies might affect the disease trajectory more profoundly." Source
