… For a minute there I almost forgot what I wanted to write about.
To be serious, dementia is a disease that will touch all of us, hopefully not directly, but invariably when family members, friends and neighbours suffer its ravages.
On June 7, the United States Food and Drug Administration (FDA) granted marketing approval for aducanumab (brand name: Aduhelm™); an approval that has been met with mixed reactions.
The FDA employed its Accelerated Approval pathway, under which an approval may be granted for a drug “for a serious or life-threatening illness that may provide meaningful therapeutic benefit over existing treatments when the drug is shown to have an effect on a surrogate endpoint that is reasonably likely to predict a clinical benefit to patients and there remains some uncertainty about the drug’s clinical benefit.”
In this case the “surrogate endpoint” was the drug’s ability to reduce or remove amyloid plaques in the brain that are thought to be the root cause of Alzheimer’s disease. I will share more about this later.
It is not unusual for the FDA to approve a drug through this mechanism. But the list of “Accelerated Approvals” is dominated by drugs used for the treatment of a multitude of cancers.
To quote from the FDA website, “The late-stage development program for Aduhelm consisted of two phase 3 clinical trials. One study met the primary endpoint, showing reduction in clinical decline. The second trial did not meet the primary endpoint. In all studies in which it was evaluated, however, Aduhelm consistently and very convincingly reduced the level of amyloid plaques in the brain in a dose- and time-dependent fashion. It is expected that the reduction in amyloid plaque will result in a reduction in clinical decline.”
For the FDA, this is a giant leap of faith, for as a rule the agency requires the successful completion of two “pivotal” phase 3 clinical studies to qualify for marketing approval. In reviewing drug approval submissions, the FDA convenes an advisory committee meeting of outside experts (in this case the Peripheral and Central Nervous System Drugs Advisory Committee) to review the data provided by the sponsor(s), which were the pharmaceutical firms Biogen and Eisai). This advisory committee provided little to no support for the application, yet the FDA (as we read above) granted approval. While the FDA generally follows the recommendations of its expert committees, in this case it did not. Three advisory committee members resigned in protest.
The FDA decision was driven by a number of factors. On the one hand, it has been almost two decades since the last marketing approval was granted for a drug to treat Alzheimer’s disease. Six million Americans suffer from the disease, and that number will rapidly grow as the population ages. This approval marks the first time that a disease modifying drug will enter the market, and to quote the FDA’s director of the Center for Drug Evaluation and Research, “Although the Aduhelm data are complicated with respect to its clinical benefits, FDA has determined that there is substantial evidence that Aduhelm reduces amyloid beta plaques in the brain and that the reduction in these plaques is reasonably likely to predict important benefits to patients.” A reproduction of amyloid beta protein molecule is featured below.
The Amyloid Hypothesis
Scientists have identified hundreds of families globally in which genetic mutations practically guarantee the development of Alzheimer’s. The mutations occur in three genes, each of which is associated with amyloid production. Then there are mice, genetically engineered by scientists to carry these gene mutations, and which develop amyloid plaques. These little guys have trouble finding their way through mazes, together with other symptoms that resemble Alzheimer’s symptoms in humans. And finally there is the presence of amyloid plaques in adults with Down syndrome. Down syndrome patients who live past 65 (of whom there are few) will invariably develop Alzheimer’s.
Opposite of the debate about the importance of amyloid is the belief, held by many in the neuroscience community, that there are other processes at play apart from those involving amyloid. Years ago, when I was working for a company developing a treatment for stroke, one of our consultants, acknowledging the complexities of the brain, commented that each stroke is different, and that, “Once you’ve seen one stroke, you’ve seen one stroke.” The same may well apply to Alzheimer’s and that Aduhelm may not be the silver bullet.
The FDA approved Aduhelm for all patients with Alzheimer’s, despite the drug not being studied in patients with moderate to severe disease. And the approval process used by the FDA requires Biogen to conduct post-approval studies to confirm clinical effectiveness. The FDA retains the right to demand withdrawal of the drug from the market, should those studies disappoint.
In the meantime, Aduhelm will be sold with a $56,000 annual price tag — which seems quite a lot for a drug with questionable efficacy. Adding to the cost of treatment is the requirement that patients undergo an MRI twice during the course of a year’s treatment. Plus the drug has to be administered intravenously once a month; bringing access and burden of care issues into the equation.
Despite its constituency, the American Association of Retired Persons (AARP), seems less than enamoured with the approval; and puts the cost issue into a different perspective. AARP estimates that the annual cost to Medicare with 500,000 of its beneficiaries on the drug will run to $29 billion. Ouch!
In the meantime, I will continue to do my memory exercises — doing the weekly crossword, recording accurate scores on the golf course, and reading as much as possible. If I could only find my glasses.