In January, 2023, the Food and Drug Administration (FDA) approved a drug, lecanemab [aka, Leqembi] developed by the Japanese pharmaceutical manufacturer Eisai and distributed by the American drug firm Biogen. The approval was specified as ‘accelerated,’ a designation with specific conditions attached which require further information from the drug companies marketing the drug and which also temporarily excludes the cost of the drug from being covered by government programs, such as Medicare and Medicaid. This was the second drug approved by the FDA for the treatment of the dementing illness Alzheimer’s disease that involved an antibody to a material called beta amyloid that accumulates in the brains of people with Alzheimer’s disease. It was the second approval of a type of medication that probably provides no benefit for people with Alzheimer’s disease.
Beta amyloid increases over time in the brains of individuals suffering from Alzheimer’s disease. Because the amount of beta amyloid found in the brain appeared to correlate with the severity of the dementia that developed, most investigators assumed that it was beta amyloid that caused the progressive loss of brain function. Consequently, numerous Alzheimer’s disease drug trials involved agents intended to reduce or eliminate the beta amyloid in the brain. One of several approaches that looked promising was the development of antibodies targeting the presumably toxic beta amyloid.
Antibodies are a class of proteins that can target exceedingly small and highly specific bits of organic material and label them for destruction. The first such antibody-type agent shown to consistently reduce the amount of beta amyloid in the human brain was aducanumab (aka, Aduhelm), a treatment for Alzheimer’s disease developed by Biogen and approved for use in people by the FDA in June, 2021. Biogen had previously developed an entirely different treatment for Alzheimer’s disease called donepezil (aka, Aricept). Biogen partnered with Eisai to develop Leqembi in an effort to dominate the market for Alzheimer’s disease drugs by promoting Aricept, Aduhelm, and Leqembi. Unfortunately, these three medications were minimally, if at all, effective.
Aricept was prescribed for lack of an alternative treatment and appeared to slow the decline of some of the people with Alzheimer’s disease. It did not affect the accumulation of beta amyloid in the brain, but it did not appear to have any serious toxicity. Some patients complained of stomach or intestinal problems, but none had inflammation or swelling of the brain. Many of the antibody-type treatments in trials for several years produced an unacceptable level of brain swelling, fluid collection, inflammation, or bleeding. Aduhelm clearly reduced the amount of beta amyloid accumulating in affected patients and was associated with minimal brain swelling or fluid collection or bleeding inside the head, but it did not appear to have any substantial impact on the disease it was supposed to treat.
The FDA has a panel of experts review drug applications and decide if the candidate drug is safe and effective enough for the disease it is supposed to treat. The panel reviewing Aduhelm did not recommend it for approval. It was safe enough, considering the grim outlook for people with Alzheimer’s disease, but it did not have much, if any, impact on the course of the disease. Breaking with its longstanding tradition of following the recommendations of its expert panels, the FDA approved Aduhelm for the treatment of early phase Alzheimer’s disease. I shall not speculate on what forces or considerations were brought to bear of the FDA’a decision.
Another surprise associated with Aduhelm was its initial price: $50,000 annually for each person getting the medication. The ‘shock and awe’ this price elicited convinced Biogen it should drop the price to $26,500 per patient per year. Since it was approved for “early phase” Alzheimer’s disease, it was likely that many individuals would receive this treatment for more than a decade. With most of the affected individuals being elderly, the assumption was that Medicare would eventually, if not immediately, be covering the cost of this treatment. More than 6 million Americans are currently diagnosed with Alzheimer’s disease. If just 10 percent of these patients are prescribed this treatment, the projected annual cost to Medicare exceeds $17 billion. These projected costs to Medicare prompted a 15 percent increase in Medicare Part B premiums between 2021 and 2022.
The negative press associated with the FDA approval of Aduhelm and the excessive cost of the treatment convinced many physicians to forego prescribing it. Consequently, Biogen sales of Aduhelm in 2022 were less than $5 million, an appalling return on its enormous investment in this treatment.
Drug trials take several years to complete, and once they are in the final phase of development, pharmaceutical companies are unlikely to halt a study or even change course. Consequently, a second treatment, Leqembi, developed on the basis of the same logic that led to the development of Aduhelm, was brought before the FDA for review and approval. Leqembi had fewer negative effects than Aduhelm and the assessment of efficacy was tweaked slightly on the basis of the disappointing Aduhelm results. Consequently, the statisticians hired to find a benefit from Leqembi succeeded, but even still the benefit was slight or negligible. The benefits of eliminating beta amyloid from the brain again proved minimal, and again the manufacturer and distributor attached a $26,500 price tag for each person treated for each year he or she was treated.
As the ultimate purchaser of these ‘biologic agents’ [that being their official designation as a drug class], you would expect the U.S. government would have considerable clout in negotiating the price of these therapies when Medicare starts paying the bills. You would be wrong. The pharmaceutical lobby blocked the government’s ability to negotiate drug prices thanks to its ‘education’ of our Congressmen and Congresswomen. With the Inflation Reduction Act of 2022, the agency responsible for Medicare reimbursements was allowed to negotiate the cost of some drugs but biologic agents were specifically excluded from this option. Consequently, the price demanded by the manufacturers of these beta amyloid depleting drugs will be their actual costs for at least 13 years from the date of their full licensure by the FDA. You should expect to see relentless advertising promoting the adoption of these biologic agents for the treatment of Alzheimer’s disease. If patients demand it, physicians will prescribe it.
Dr. Lechtenberg is an Easton resident who graduated from Tufts University and Tufts Medical School in Massachusetts and subsequently trained at The Mount Sinai Hospital and Columbia-Presbyterian Medical Center in Manhattan. He worked as a neurologist at several New York Hospitals, including Kings County and The Long Island College Hospital, while maintaining a private practice, teaching at SUNY Downstate Medical School, and publishing 15 books on a variety of medical topics. He worked in drug development in the USA, as well as in England, Germany, and France.