 Atacanamab, sold as annual helm, is the first new drug approved for Alzheimer's treatment in nearly 20 years. It involves getting IV infusions of an antibody that targets the amyloid plaque protein, which represents a core brain pathology of the disease. After a phase one study found no change in the placebo group, but a dramatic reduction in amyloid plaque burden at different doses of the drug, they jumped straight to phase three. Two randomized controlled trials to put it to the test on thousands of Alzheimer's patients. Unfortunately, both trials were stopped early after a futility analysis deemed them failures, as cognition and function continued to decline in the treatment groups. That shouldn't be surprising, since over the last 20 years there have been more than 20 amyloid targeting therapies that have universally failed to offer meaningful cognitive benefit for people with Alzheimer's disease. In fact, a 2022 investigation into a seminal paper implicating amyloid as a causal factor in Alzheimer's alleged shockingly blatant data fraud, which has further tarnished the reputation of the amyloid theory. So, no surprise, ADU-HELM flopped. But what happened next was surprising indeed. Just when the drug's prospects seemed dead, Biogen, the drug company that developed it, launched a secret campaign codename Project Onyx to use back channels to convince the Food and Drug Administration to approve it anyway. They went back to the data and found a subset of patients in one of the trials that had a 0.39 increase on an 18-point scale of cognitive function. This was well below the minimal standard for clinical significance, judged to be at least one or two full points. And the same subset at the same dose in the other study they funded failed to even find that effect. This kind of post-hoc after-the-fact data dredging is like firing a shotgun at a barn and then painting a target around the bullet holes, as one FDA committee statistician put it. FDA reviewers thoroughly demolished Biogen's re-analysis, concluding there is no compelling substantial evidence of treatment effect or disease slowing. The American Academy of Neurology noted that 35% of those getting adacatamab suffered swelling or bleeding in the brain within the first four months of treatment, one in three, 10 times more than those in the placebo group. So, not surprisingly, not a single member of the FDA expert advisory panel voted in favor of approval. 10 out of 11 voted against, with one quote unquote uncertain. Yet FDA ignored its own advisory panel, and in 2021 approved the drug anyway. The FDA admitted the submitted data left residual uncertainties regarding clinical benefit and so couldn't give it the standard approval, which involves a designation that the drug is safe and effective. Instead they used an accelerated approval pathway that allows drugs to be accepted on the basis of surrogate markers, in this case amyloid clearance. But more than two dozen other amyloid targeting treatments flopped and despite convincing plaque reduction, there was no clinical improvements or even worsening of the disease. The FDA approval of adacatamab proved to be one of the most controversial in recent memory. The approval despite mere unanimous opposition by its own expert committee is virtually unprecedented, leading three of the committee members to resign in protest, one of whom called it probably the worst drug approval decision in recent US history. The response from the scientific community may best be summed up by a commentary written by the head of the American Geriatric Society entitled, My Head Just Exploded. The FDA did stipulate the biogen wouldn't have to run a post-marketing trial proving that the drug actually has some benefit, but has until 2030 to report the results. Meanwhile, biogen is charging $56,000 per person per year for the drug, without a pocket expense estimated at up to $11,000 annually. And this doesn't include the cost of IV administration or the sequential $4,000 to $7,000 MRI scans need to monitor for the rain bleeds and swelling. Yeah, the risks far exceed any likely benefits, but shouldn't patients and their families be able to make up their own minds? The problem is that the FDA's stamp of approval implies that a can of effective when at the current time, it appears to be neither. The official position statement of the American Medical Directors Association, which specializes in long-term care facilities, is that the drug is likely to have extraordinarily negative consequences for the millions living with dementia in this country. The European equivalent of the FDA does not seem as easily swayed by big pharma, recommending refusal of the drug. I mean, that's the whole point of drug regulation, as one of the former FDA committee members who resigned put it, a responsibility to help vulnerable patients and their families, not just from sketchy drugs, but also from false hopes. A congressional investigation concluded FDA approval of that account of member was rife with irregularities, raising serious concerns about FDA's lapses in protocol and biogen's disregard of efficacy. Of course, that didn't stop the FDA from their 2023 accelerated approval of a similar antibody, lekinomabs, sold as lekinby, of similar questionable efficacy and safety.