Dementia affects about 4.6 million people in Japan (not all of which is due to Alzheimer's disease).
Irish poet Oscar Wilde stated that a cynic is someone "who knows the price of everything, and the value of nothing." Deep reflection on value is needed in particular when the issue is approving new medicine for widespread use. Inevitably in such circumstances, the questions arise: How does society define what is important for its own well-being and cohesion? What are our values?
Values Today, Subject to Change Tomorrow?
Japan-based pharmaceutical company Eisai's January 7, 2023 press release, reported on by The Sankei Shimbun, explained how it will price its new Alzheimer's disease drug, lecanemab (Leqembi).
News of a new Alzheimer's drug is bound to attract much attention. However, the fine print footnote at the bottom of every corporate press release escaped mention:
"Materials and information provided in this announcement may contain so-called 'forward-looking statements' … [which are] based on current expectations, forecasts, and assumptions that are subject to risks and uncertainties that could cause actual outcomes and results to differ materially from these statements."
This means that Eisai could change its mind tomorrow. Whatever was in the press release is conditional at best.
This is important for many reasons, not least because of the interplay of price and values. Further details on how Eisai defined lecanemab's "societal value" and "value-based price," in both American dollars and Japanese yen can be found in Eisai-sponsored publications.
Some medications are available inexpensively at the corner drug store. Others come with a staggering price tag. Some drugs for intractable, even inevitably lethal, diseases are priced in the five to six-figure range. Many of these need to be taken several times a year, perhaps for the rest of the patient's life.
Potential gene editing treatments, in which patients are essentially free, albeit temporarily, of disease, will cost several million dollars per treatment.
Price and Values Are Not Always in Cooperation
The Eisai press release provided a good opportunity to think about what medicines do, and what they can cost. There indeed needs to be a greater discussion on the economic impact of hugely expensive treatments. The economic burden is borne by patients, and also by the public. It is the public which funds social health care programs, after all. And the reality is that such programs are supporting ever-increasing numbers of elderly and sick people.
Taking care of the sick and the elderly constitutes good social values. We must remember, though, that drug companies, while harping on "societal values," ultimately answer to investors. It is good that The Sankei Shimbun raises this issue as well.
However, the Sankei article missed an opportunity to give readers more information on lecanemab. Readers must be informed to make a "value" judgment and to determine if this drug is worth the "price" that Eisai will be asking.
To put it another way, it may be that our values will further drive up the price of new treatments like lecanemab, or else bring them crashing down. Price and values can sometimes work in opposite directions.
Painting a Fuller Picture
Some information that the Sankei did not include must be shared widely with the public. For example, in 1996, Eisai had already developed donepezil (Aricept), which received the approval of the United States Food and Drug Administration (FDA) for the "treatment of dementia of the Alzheimer's type." Donepezil was approved for use in Japan in 1999.
Unfortunately, donepezil does not address the underlying pathology of Alzheimer's disease: the gradual death of brain neurons. Animal and human clinical studies showed that a crucial neurotransmitter, acetylcholine, is involved in brain functioning. This includes cognition and memory.
Acetylcholine is naturally cleared from the brain by the enzyme acetylcholinesterase. Decreased acetylcholine production has been observed in Alzheimer's patients. Donepezil blocks acetylcholinesterase, thereby sustaining brain levels of acetylcholine. The medicine, therefore, treats a symptom of Alzheimer's disease but does not cure it.
Lecanemab, by contrast, was developed to clear a protein from the brain associated with Alzheimer's disease, amyloid-beta. The theory is that if brain levels of amyloid-beta were reduced in Alzheimer's disease patients, then the death of neurons could be slowed or even halted. So, several drug companies have developed amyloid-beta-clearing drugs to preserve cognitive functioning or at least slow its decline.
A Small Effect
It is important to consider not only how a potential drug works, but whether it works. The way to do that is through clinical trials.
In the clinical trials for the drugs discussed above, key measures of efficacy included preserving cognitive functioning and evidence of reduced brain levels of amyloid-beta in treated patients compared to those treated with a placebo.
At the end of its clinical trial, Eisai's new product did not overwhelm. Mildly impaired Alzheimer's disease patients treated with lecanemab demonstrated slightly better cognitive functioning compared to patients treated with a placebo.
One assessment tool was a standardized 18-point scale that measures a wide range of functions, from memory and problem-solving to personal care. After 18 months of treatment, lecanemab-treated patients were not as impaired as placebo-treated patients — by a difference of 0.45 points. Some have wondered if this small difference is meaningful at all on an 18-point scale. The threshold should be at least 1 point.
To be sure, brain amyloid-beta in lecanemab-treated patients in these trials were cleared such that levels were well below detectable levels. Even with clearance of amyloid-beta from the brain, however, lecanemab-treated patients still showed decreasing cognitive function, albeit at a slightly slower pace than placebo-treated patients.
Perhaps there are other disease mechanisms that need to be addressed to effectively treat Alzheimer's disease.
Will the Japanese People Benefit from This New Drug?
Even more troubling than the lackluster performance of lecanemab in clinical testing is the potential harm from taking it. There are serious adverse side effects associated with this class of drug. One side effect is amyloid-related imaging abnormality (ARIA), which includes brain edema and hemorrhages. Strokes have been observed more frequently in lecanemab-treated patients than in placebo-treated patients. Brain atrophy, one of the neuroanatomical hallmarks of advanced Alzheimer's disease, has also been observed in patients treated with amyloid-beta-blocking drugs. The recent lecanemab clinical trial has yet to report on changes in brain volume following treatment, but this is also obviously a concern.
Despite the potential risks, an FDA committee decided that patient benefits outweighed risks. The FDA committee unanimously granted lecanemab approval on July 6, 2023, for the treatment of mild cognitive impairment and mild stage of Alzheimer's disease.
Dementia affects about 4.6 million people in Japan (not all of which is due to Alzheimer's disease). A new Alzheimer's drug would therefore be potentially very welcome.
However, it is likely that only a fraction of these patients will have access to lecanemab. The drug is expensive, and its treatment regime (bi-weekly intravenous infusions) is not easy to endure. Also, close post-treatment follow-ups with very sophisticated neuroimaging equipment and Alzheimer's disease specialists will be necessary. These are not readily accessible to all Japanese.
In addition, patients may be excluded from treatment, for example, if they are taking anticoagulants, which help to prevent strokes and heart attacks.
Past Red Flags Must Be Taken Into Consideration
There is one other relevant insight not mentioned in the Sankei article about lecanemab. Namely, Eisai and its developmental partner Biogen, a US biotech company, have been down this murky road in the past with a drug called aducanumab (Aduhelm).
Aducanumab, like lecanemab, reduces brain amyloid-beta. However, results from two clinical trials (that were terminated early) showed conflicting effects on cognitive functioning, though there was robust clearance of brain amyloid-beta.
Members of an FDA advisory committee that reviewed the results of the clinical trials for aducanumab withheld their support. Despite this, the risk of brain hemorrhaging from taking the drug, and an approval process that was politely called "unusual," on June 7, 2021, the FDA granted aducanumab "accelerated" approval. The FDA requested additional clinical data, but Biogen and Eisai were allowed to market the drug in the meantime.
A congressional investigation, published in December 2022, called the FDA review process for aducanumab "irregular." Congress noted that the FDA had not followed its own guidelines. It also called interactions between the sponsor, Biogen, and the FDA "inappropriate" and "atypical."
The congressional investigation also uncovered that Biogen anticipated peak revenue of $18 billion USD per year from the sale of aducanumab, and developed "aggressive" launch and marketing plans. (By contrast, Comirnaty, Pfizer's mRNA covid vaccine, brought in $37.8 billion USD in 2022. Others have pointed out that the non-transparent, "irregular" FDA approval process for new drugs such as aducanumab is business as usual.
One Can't Put a Price on Good Health
Eisai and Biogen initially agreed on profit sharing for aducanumab. However, in March 2022 Eisai backed out, agreeing to leave Biogen solely responsible for marketing. Eisai would get a single-digit percent in royalties.
This brings us back to the new Alzheimer's drug, lecanemab, that Eisai is touting in Japan. Perhaps Eisai's current efforts to define lecanemab in terms of "societal values" and "value-based pricing" is to move away from Biogen's shadow. Or perhaps there is money to be recouped from a previous business deal that did not pan out.
In all of this, it must be noted that heated debates over pharmaceutical economics and hosannas for new drugs for incurable illnesses have drowned out sagely advice. That advice is simple and time-tested. Individuals should take control over their own health.
The editors of The Lancet, one of the oldest medical journals in publication, stated on December 3, 2022, that while lecanemab "might" be the next "welcomed" step, one should not forget that maintaining brain health is also important. One does this, The Lancet went on, by reducing risk factors such as smoking, diabetes, and obesity, and by increasing social contact and physical activity.
These are measures that one can do today. We can work to be healthy now. We do not need to sit forlornly, waiting for the next miracle drug that may never arrive.
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Author: Dr Aldric Hama
Find other reports and analyses by Dr Hama on JAPAN Forward.
