June 07, 2021

Deja Vu All Over Again?


The big news in geriatrics this week was the FDA  approval granted to a drug against Alzheimer's disease, the first new drug in 20 years. It reminded me of the day in 1986 when the initial report about what would be the very first FDA-approved drug against this disease appeared.

It was November 13, 1986 and I had been a practicing geriatrician for four years. My weekly copy of the New England Journal of Medicine had arrived right on time, as it did every Thursday. I scanned the table of contents and one article immediately jumped out at me. It had the suitably serious, scientific-sounding title “Oral tetrahydroaminoacridine in long-term treatment of senile dementia, Alzheimer type.”


During four years  of clinical practice—plus a year of geriatrics fellowship and three years doing an internal medicine residency—I had encountered patients with what we then called “SDAT,” (senile dementia of the Alzheimer’s type) and which we now simple call Alzheimer’s disease. The cognitive impairments of dementia were to me, to family members of the afflicted, and often to the affected themselves, among the saddest of the many disorders that develop among older individuals. Death, while also very sad, was part of the natural order of things, especially when it came after a long and rich life. But dementia in general and Alzheimer’s disease in particular was devastating because it attacked personality; some would say it assaulted personhood itself. While I would go on to spend much of my career thinking about how best to enable people with dementia (as well as those with physical frailty) to live meaningful lives despite their limitations, I recognized then and continue to believe today that the condition is a scourge that we should strive to prevent, eradicate, or at least ameliorate.


The medication described in the 1986 NEJM article would ultimately be approved by the FDA under the name of Tacrine for treatment of mild to moderate Alzheimer’s disease; it would be supplanted by its first cousin, the drug donepezil, brand name Aricept; and Aricept would top $2 billion in US sales by the time it came off patent in 2013. The story of the drug’s development says volumes about Americans’ desperation for a medical fix to Alzheimer’s, about big business, and about our regulatory system. Both the similarities and the differences between the Tacrine story and the tale of the new drug approved by the FDA for the treatment of Alzheimer’s are illuminating.

That 1986 study ostensibly showing that Tacrine led to improvements in cognition as well as to overall functioning was based on a whopping 17 patients, only 14 of whom actually completed the study. Its lead author was Dr. William Summers, a psychiatrist at UCLA medical center who had never before published anything of importance and had done very little research altogether. The scientific community immediately began questioning not only Summers’ credibility but also his methodology. Did the 17 patients actually have compelling evidence of an Alzheimer’s diagnosis? Did the “global assessment rating” used to measure outcomes translate into meaningful improvement?


After Summers filed for FDA approval for his drug,the FDA investigated Summers and his lab. The agency issued a rare “interim report” in 1991 in which it criticized Summers for the absence of documentation that the study was actually performed as  claimed in the NEJM  paper.  It questioned the randomization process and whether the physicians were, as asserted by Summers, blinded to what drug the patient was receiving. The best the FDA could say was that there was “no clear evidence of purposeful misrepresentation.”


In response, the public vilified the FDA, claiming the agency was “heartlessly impeding the relief of suffering.” David Kessler, the FDA director, received hate mail.


Approval of the drug came, but only after the release in 1992 of a larger more carefully conducted study by the “Tacrine Collaborative.” The trial lasted for 12 weeks and was carried out at 23 centers involving 468 patients. The results, published in the Journal of the American Medical Association, showed a statistically significant improvement in cognition and in overall function, whether measured by physicians or caregivers. And so, the first drug was approved for treatment of Alzheimer’s disease. Sales soared.  But questions continued to plague use of the drug—a subsequent study, for example, testing the effectiveness of a higher dose of the drug,  found that the higher dose was more effective than lower doses—but more than 2/3 of the patients dropped out of the study. Tacrine was soon effectively replaced by donepezil (Aricept), another cholinesterase inhibitor that differed only from Tacrine in that it is taken once a day rather than twice and has fewer gastrointestinal side effects. Patients and families demanded these drugs, which were soon followed by chemically slightly different but no more effective agents such as Excelon; the drug companies advertised them widely and made a small fortune on their  sales; but clinicians remained skeptical. I, for one, believe that the cholinesterase inhibitors are next to useless. None of the numerous studies of the drugs carried out since 1986 have persuaded me otherwise.


Fast forward to 2021 and the approval by the FDA of aducanumab under the brand name of Aduhelm. This is a completely different kind of treatment. Tacrine and Aricept are cholinesterase-inhibitors: they work by increasing the level of the neurotransmitter, acetylcholine, which is dramatically reduced in Alzheimer’s. They are given orally and were never terribly expensive, although Aricept got cheaper when the generic version became available. Side effects, particularly in the case of Aricept, are modest and consist of nausea and very rarely of liver enzyme abnormalities.  The new drug, by contrast, is a monoclonal antibody that works to mop up deposits of beta-amyloid from the brain, the chemical widely thought to cause Alzheimer’s disease. It must be given intravenously once a month. The average yearly cost will be set at $56,000. Two years ago, its manufacturer, Biogen, stopped an ongoing clinical trial of the drug after interim analysis failed to demonstrate efficacy. The drug company then re-analyzed the data and claimed it was effective after all, but an FDA Advisory Panel, convened in  November, 2020 unanimously concluded there was insufficient evidence of significant benefit to proceed. 


Multiple other monoclonal antibodies targeting beta amyloid have also failed, leading some to suggest that by the time these drugs are given to patients, it’s already too late. Or maybe beta amyloid is a marker for the disease and not the cause of the disease. It is in this setting, that the FDA approval of aducanumab is something of a surprise.

What is particularly striking about today’s FDA approval is that it is not based on the clinical effectiveness of the drug. Rather, it is based on its ability to clear the brain of amyloid deposits. There is a long tradition of requiring that drugs cause improvement in clinically meaningful outcomes, not just in “surrogate markers.” Cholesterol-lowering drugs were approved based on their ability to prevent heart attacks, not just on their ability to lower blood cholesterol levels. Antihypertensive drugs were approved based on their effectiveness in reducing strokes, not just on their capacity to lower blood pressure. To be sure, the FDA is holding off on full, unconditional approval until it sees the results of a yet to be performed large clinical trial demonstrating long-term benefit of amyloid plaque reduction. In the meantime, anxious patients and their families will submit to monthly injections of a drug that has been shown to cause symptomatic brain swelling, manifested by nausea, vomiting, visual problems, headaches and sometimes small strokes, in 40 percent of cases. 

We are a long way from the trials and tribulations of tacrine, but in the end, is the tale of aducanumab any less disturbing? In both cases, there was enormous pressure by the public to approve a drug that offered hope, some hope, however slim, of ameliorating this terrible disease. In both cases, the FDA, after seemingly acting based on scientific considerations alone, seemed to succumb to external pressures. And in both cases, the pharmaceutical industry stood to gain enormously by release of the drug. The FDA currently has an acting director: President Biden has yet to name a new, permanent head. Maybe it's time for the FDA director to become a civil servant, selected by the FDA members, rather than a political appointee. At the very least, the new director, when chosen, should take a long hard look at decision-making within the organization.

No comments: