A drug to effectively stop the advance of Alzheimer’s Disease (AD) in an affected person or actually cure one of it is one of the leading Holy Grails of modern medicine. It’s no wonder because AD is the most common cause of dementia — a continuous decline in thinking, behavioral and social skills that affects a person’s ability to function independently. The Mayo Clinic says approximately 5.8 million people in the U.S. age 65 and older live with AD, and of those 80% are age 75 or older.
According to the National Library of Medicine (NLM) at the National Institutes of Health, as of January 2022 there were 143 agents in 172 clinical trials in progress at one stage or another for treatment of AD. More than half of those trials had reached the Phase 2 milestone. About 80% of the studied therapies focused on modifying the disease, with approximately 10% targeted on “symptomatic cognitive enhancement.” Thirty-seven percent of the agents in the pipeline were repurposed drugs already approved for other indications. The NLM observed: “Advances in drug design, outcome measures, use of biomarkers, and trial conduct promise to accelerate the delivery of new and better treatments for patients with AD.”
Leqembi (lecanemab) is the latest entry for Alzheimer’s Drugs
Trials at any given time involve upwards of 50,000 participants. But amidst all the testing, significant breakthroughs have been slow in coming. In early 2023 came word that an AD drug from pharmaceutical manufacturers Eisai and Biogen had been approved by the Food and Drug Administration (FDA). Called Leqembi (generic name: lecanemab), it is intended to slow the progression of Alzheimer’s in people with mild cognitive impairment or early AD. The hope is that this drug might give people with AD more time to remain independent, make future health care choices, and be at or near their full abilities to participate in daily life.
Leqembi is said to be only the second AD drug approved in the U.S. that is aimed at attacking what is thought to be one of several underlying causes of AD—build-ups of plaques in the brain consisting of a protein called amyloid. The other approved drug, Aduhelm (generic name: aducanumab), also from Biogen, was greenlighted by the FDA in 2021 despite strong objections from its panel of outside advisers. (More on this below).
Pricing is controversial for Alzheimer’s Drugs
Among the contentious issues raised by both drugs is pricing, which as of this writing is $26,500 per year for Leqembi and $28,000 for Aduhelm. After initial approval, Aduhelm had a price tag of $56,000 per year before Biogen slashed the price in half, to $28,000. This was partly in response to widespread criticism, including how such pricing would bloat what Medicare would have to lay out to cover the drug. In fact, this initial Aduhelm pricing was a factor that led Medicare to increase its Part B monthly premium for beneficiaries from $148.50 to $170.10 for the year 2022.
According to an NBC News report, the $26,000 price for Leqembi is much higher than recommended by the Institute for Clinical and Economic Review, a Boston-based research group that helps determine fair prices for drugs. Dr. David Rind, the institute’s chief medical officer, reportedly said an appropriate cost for the drug is $8,500 to $20,600 a year. “Because of the high price tag,” NBC reported, “experts say the number of people who will be able to get the drug will be extremely limited.”
As a rule, Medicare restricts coverage for new Alzheimer’s treatments that target amyloid, including Leqembi, to only those patients participating in clinical trials. Those enrolled in clinical trials usually get the medications at no cost during the trial. It’s less certain that the drug would continue to be free once the trial ends, even if the person qualifies for Medicare. The Medicare standards for covering new Alzheimer’s treatments are higher than those for getting other new treatments on the market quickly.
A closer look at Leqembi for Alzheimer’s
Leqembi, which was initially developed as an amyloid vaccine by the Swedish scientist Lars Lannfelt, was approved under what’s called the FDA’s accelerated pathway, which allows early approval for new drugs that “fill an unmet medical need” and are found to be “safe and effective.” This pathway fast-tracks promising clinical treatments for diseases in which there are no other currently effective options. In its review for accelerated approval of Leqembi, the FDA looked at clinical trial data of more than 800 patients at the Phase 2 level of the trial. At that point Eisai and Biogen still needed to submit data from an additional Phase 3clinical trial that confirms the benefits of the drug to gain “full approval.”
Not long after Leqembi was approved by the FDA, Yahoo News interviewed James E. Galvin, a neurologist from the University of Miami School of Medicine who specializes in the study of Alzheimer’s disease and Lewy body dementia. Yahoo asked Dr. Galvin, to explain the drug’s clinical potential. Here are key points Dr. Galvin offered:
- Leqembi is a monoclonal antibody that targets beta-amyloid, a naturally occurring protein that becomes toxic when it clumps together to form the plaques in the brains of those with AD. The Leqembi antibodies circulate in the blood and neutralize substances seen as foreign—in this case, the particular beta-amyloid proteins that are most likely to aggregate into plaques that play a role in the development of Alzheimer’s Disease. “Earlier trials of other monoclonal antibodies failed to demonstrate a benefit and had more side effects,” Dr. Galvin said, “possibly because they targeted forms of beta-amyloid either too early or too late in the aggregation process.”
- Dr. Galvin said Leqembi might be a game-changer for people with early-stage Alzheimer’s Disease. In one study published in early January 2023, that included 1,795 participants, half of whom received Leqembi and the half who didn’t, treatment with Leqembi not only met all its clinical outcomes and safety requirements, but it also reduced the amounts of beta-amyloid measured in imaging tests and in the blood.
- Researchers also saw reductions in the levels of tau—the protein responsible for the “tangles” that accumulate inside the neurons in patients with Alzheimer’s. And they found reduced levels of other proteins that measure brain injury and degeneration. “This suggests that lecanemab [i.e., Leqembi] could potentially address the disease by targeting it through both direct and indirect pathways,” said Dr. Galvin.
- In one Phase 3 study, Leqembi slowed disease progression by 27% compared with the control group and also showed 26% less decline on cognitive testing and a 36% slower loss of function in everyday activities. The study also found a marked reduction in the amount of beta-amyloid deposits in the brains of those who received the treatment.
- “While not cures, [these outcomes] provide hope that by significantly slowing physical, cognitive and functional decline while also removing amyloid, the course of disease might be altered in a way to give patients improved quality of life,” Dr. Galvin observed. “[But] it is important to remember that we do not fully know the long-term benefits of lecanemab.” It is also important to note that Leqembi was not studied in and was not approved for individuals with moderate or severe stages of Alzheimer’s disease.
Dr. Galvin cautioned that Leqembi comes with potential adverse effects that need to be considered. In trials, these included swelling of the brain and small bleeds of the brain in up to 30% of the participants, especially prominent in the patients with a familial form of Alzheimer’s disease. “While few participants experienced complications, at least three deaths due to brain hemorrhage have been reported in individuals enrolled in an ongoing long-term study. But notably, each of these people appear to have had additional risk factors.”
Dr. Galvin added that Leqembi differs significantly from currently available Alzheimer’s treatments such as donepezil, rivastigmine, galantamine and memantine. Those drugs primarily treat symptoms, he said, and do not address the underlying disease processes. So they have modest clinical benefits. The one other medication currently that does treat the disease is Aduhelm (aducanumab). But Dr. Galvin notes that drug, while FDA-approved, has not become widely used due to controversy over its efficacy, severe side effects and pricing.
Its FDA approval notwithstanding, it will likely be several months before it is available for clinical use. Medicare will not cover it at this time except for individuals who are enrolled in clinical trials funded by the National Institutes of Health. Commercial insurance companies generally follow Medicare guidance.
The Aduhelm story used to treat Alzheimer’s
What about Aduhelm, the brand name for the drug aducanumab? Because the FDA approved it faster than usual and against the recommendation of its own advisory panel, some medical experts question whether more research is needed about the drug’s safety and effectiveness. There has also been criticism that the FDA worked too closely with Biogen, the drugmaker, in the evaluating process, leading to questions about impartiality that should govern FDA actions. Of note, many patients in the clinical trials of Aducanumab suffered severe side effects, including swelling of the brain (35% of treated patients) and cerebral bleedings (21% of treated patients). Several members of the FDA committee approving this drug later stepped down from the committee in response to wide criticism for the approval decision.
(Footnote: It is generally believed that the biopharmaceutical industry sponsors about half of all clinical trials,and funds an even greater percentage of trials that reach Phase 2 and 3. This is not surprising since trials are indispensable to eventually getting a drug to market. But because industry operatives have a vested interest in what trial results will show, this system routinely raises questions as to how unbiased the drug trials will be.)
There are additional allegations—such as in a finding by a congressional investigation—that particularly in its initial pricing for Aduhelm ($56,000/year) Biogen chose to maximize profits at the expense of patients and taxpayers. The controversy resulted in widespread skepticism about the drug and wild fluctuations in Biogen’s stock price.
Similar to Leqembi, Aduhelm targets the accumulation of plaques that contain a toxic protein called amyloid-beta, which builds up in the brain and represents one mechanism for the widespread death of neurons seen during the disease progression. With Aduhelm, the body’s immune defense responds to this “vaccine” by getting rid of the amyloid build-up. Two large studies looked into Aduhelm’s effectiveness. Both studies showed lowered numbers of beta-amyloid plaques. One study reportedly found that high doses of the drug slightly slowed (but did not stop) troubles with thinking, memory, and the ability to function. The other study didn’t show a benefit and was stopped early. One problem with the two drugs is that they specifically target amyloid plaques, and this is not the only thing going wrong in the brain of those with Alzheimer’s disease. Many other factors contribute to the widespread loss of neurons in the disease.
Questions and controversy over Aduhelm
That one successful study wasn’t enough to win over the FDA advisory panel, but the agency nonetheless gave a conditional approval with the condition that Biogen confirm the drug’s possible benefit in a “post-approval” study. The drugmaker was to be allowed nine years to do so.
Among the questions about the drug’s safety are its side effects, which include temporary brain swelling, brain bleeds, headaches, falling, and confusion. (Some of the same side effects have also been reported for Leqembi, where up to 30% of the participants reported brain swelling).
A CNBC report in early 2022 said the initial excitement over Aduhelm had diminished. The business news channel quoted a former broadcaster, Dick Novik, who helped care for his wife following her Alzheimer’s diagnosis. Said Novik: “In terms of this new drug, we are keeping an open mind. If only there were a way of being more certain in our minds that it works.” This is important in light of recent research in the Alzheimer field showing that many other pathological processes in the brain contribute to the concerted loss of nerve cells and ensuing inflammation during progression of the disease. The “amyloid hypothesis” of Alzheimer’s disease has recently been put to significant test, with other players considered equally important. These include tangle pathology and neuroinflammation.
The British newspaper The Guardian in late 2022 cited a U.S. congressional report that found the FDA’s approval process for Aduhelm “rife with irregularities” and the price point (at the time) of $56,000 per year “unjustifiably high.” There were also concerns about demonstrated clinical benefit. The Guardian quoted this statement from the congressional report: “The findings in this report raise serious concerns about FDA’s lapses in protocol and Biogen’s disregard of efficacy and access in the approval process for Aduhelm.”
Focus on profits cited
The congressional report also faulted Biogen for what it considered its overemphasis on the revenue potentials of the drug and its wide-ranging billions-dollar marketing plans focused on having a “blockbuster” drug. After the chairman of the House Energy and Commerce Committee also criticized the FDA’s approval process for Aduhelm, the FDA said it would “fully cooperate with the committees’ evaluation.” For its part, Biogen said in a formal statement that it stood by “the integrity of the actions we have taken,” noting that Alzheimer’s is “a highly complex disease,” and the company has learned from the development of Aduhelm.
Recommendations in the congressional report included that the FDA maintain documentation of its interactions with drug companies, that companies communicate safety and efficacy concerns to the FDA, and that the actual value of a drug be considered when setting prices.
“The American people rely on the FDA for assurance on the safety and efficacy of the medications they take, and it is incumbent upon drug companies such as Biogen to ensure that the wellbeing and safety of patients are prioritized,” the report said.
So clearly the Alzheimer’s drug picture is far from settled and severe side effects in 20-30% of the participants may not be acceptable. Early efforts show some tentative promise but not, as referenced in the opening of this article, a definitive Holy Grail to defeat AD. Still, with as many agents as are being looked at and tested, it is also clear that the quest for successfully defeating this disease that wracks the lives of so many seniors will go in in earnest.
