By Kyo Jin Hwang
Published: 12:45 PM GMT+9, June 4, 2024
(Seoul, June 4) Cancer, cardiovascular, and brain diseases are the top three hard-to-treat and deadly diseases in Korea. Cancer and cardiovascular diseases have been well studied and have treatments. However, brain diseases, including Alzheimer's Disease (AD), are difficult to recover from and expensive to treat, causing a wide range and depth of suffering. There are constant news stories of patients and their families giving up on their lives, and they are vulnerable to exploitation and criminalization by caregivers who are motivated by money. Without money, the families of brain disease patients suffer even more.
On May 24, a new drug for AD was approved by the Ministry of Food and Drug Safety. It is an injectable drug called lecanemab (Leqembi), which we have covered many times in <Dementia News> and expected to be approved for market in the second half of this year, but we did not expect it to be approved and ready for market so soon. South Korea is the fourth country to be approved after the US, Japan, and China. It would be a mistake to think that we should rush to approve the drug because the first three countries have approved it. As pharmaceutical companies are global big pharma companies such as Esai and Biogen, we should review the history of lecanemab.
The U.S. Food and Drug Administration (FDA) Advisory Committee granted Accelerated Approval to lecanemab on January 6, 2023, followed by full approval in July. Japan followed in September 2023, and China was the third country to approve the drug on January 10 of this year, putting it on the market. The European Medicines Agency (EMA) received the request for approval in January 2023, but has yet to approve it and has deferred it.
On June 10 last year, the FDA's Peripheral and Central Nervous System Drugs Advisory Committee evaluated the results of a Phase 3 trial (CLARITY AD) involving 1,795 patients with dementia. The trial showed that the lecanemab treatment group experienced slower progression of memory, judgment, and other cognitive decline than the placebo control group. Participants' Clinical Dementia Rating-Sum of Boxes (CDR-SB [1-18], Clinical Dementia Rating-Sum of Boxes) scores averaged 3.2 at the start of the study. At the end of the trial, 18 months later, scores were 1.21 points worse in the experimental group compared to 1.66 points worse in the control group, a difference of 0.45 points. This translates to a five-month slowdown in progression.
While the differences between the treatment and placebo groups were statistically significant, the results of these phase 3 trials “did not meet the criteria for a minimum clinically important difference in mild cognitive impairment (MCI) and early AD,” said Esther Oh, MD, co-director of the Center for Memory and Alzheimer's Care at Johns Hopkins University, adding, “Clinicians should weigh the benefits of lecanemab against the risks and contraindications.” But lecanemab was marketed as a new drug that would save the world from AD.
Much of what has been said about lecanemab is well known, but it bears repeating. Here are five red flags to keep in mind.
First, it's not a cure-all. Lecanemab is the first drug approved by the FDA to slow the progression of AD. What does a 27% slowdown mean? The Phase 3 trial of lecanemab had a primary endpoint of change in CDR-SB score over 18 months. At baseline, the mean CDR-SB score in the lecanemab treatment and control groups was 3.2 points (3.17 vs. 3.22 in the treatment group), and after 18 months, the CDR-SB score increased by 1.66 points in the control group and 1.21 points in the treatment group, representing a 27% benefit in the treatment group compared to the control group. This is slightly better than 23% for aducanumab(Aduhelm).
However, when comparing the CDR-SB score itself at 18 months (4.38 in the treatment arm vs. 4.88 in the control arm) instead of the change in CDR-SB score over 18 months, the difference in CDR-SB score between the two arms is 0.5 points, which plummets the efficacy from 27% to 11%. I'm curious to see how this 11% difference will translate to the clinic.
Second, the patient criteria are challenging. Patients with MCI or mild Alzheimer's Dementia, the earliest stages of AD, are the primary target population. Prescribing requires the presence of accumulation of the target substance, beta amyloid protein. Specifically, the following criteria must be met: positive amyloid PET, age in the range of 50 to 90 years, although effects have been observed in older age groups, MMSE 22 to 30, other cognitive modulators can be used, accompanied by a caregiver, both patient and caregiver understand the potential risks, no history of stroke in the last 12 months, no psychiatric illness, depression and suicidal ideation resolved, no immunosuppressive medications, no bleeding disorders, no anticoagulants, no unstable medical conditions, and good economic status. All of these must be met. In short, lecanemab is a weird drug of pride that's gotten a lot of attention for being both ineffective and obnoxious. You've probably walked into a blood donation box wanting to donate blood, only to walk out because you're not eligible due to a number of restrictions. Just as not everyone can easily donate blood, not everyone can easily receive lecanemab treatment.
Third, there are side effects. Lecanemab has serious side effects, including cerebral edema and cerebral hemorrhage. Two patients died in clinical trials after suffering a brain hemorrhage. However, the FDA advisory panel noted that it was unclear whether the deaths were caused by lecanemab itself or by other underlying factors in the patients, such as taking anticoagulants, which can cause brain bleeding. “There are side effects. But they can be monitored,” he said, emphasizing the effectiveness aspect of lecanemab. It's like saying, “There's alcohol on the table. But you can control it so you're not as drunk as you were before.”
Fourth, discomfort. The dose depends on your weight and is injected into a vein once every two weeks. You have to go to the doctor every time, which is uncomfortable. If you're taking the injections and your condition worsens, such as if you notice side effects, you'll have to stop taking them. All of these situations need to be considered. Currently, the Korean Dementia Association (KDA) is hoping to raise the severity level of patients with MCI or early AD to facilitate medication in the injection room of a high-level hospital.
Fifth, the price of the drug. In the United States, it costs $26,500 (about 36 million KRW) per year, and in Japan it is slightly lower but similar. In Korea, the price is expected to be in the mid-30 million won range. In the U.S., the cost of amyloid brain positron emission tomography (A-PET) scans, brain magnetic resonance imaging (MRI) scans, and cerebrospinal fluid (CSF) tests can be as high as $85,600 (about 117 million KRW) per year.
Lecanemab needs to be studied further to provide clear clinical results on its effectiveness. Currently, the consensus is “little or no benefit,” and it's a case of “we're going to market it without solving the puzzle. And it's expensive. I'd like to ask why Adduhelm's voluntary withdrawal was used as a cautionary tale. It's like defense contractor corruption. If patients and families with high expectations for healing cannot make their own judgments, doctors should play this role, but when I interviewed the KDA, there were many voices cheering and expecting the approval of lecanemab in Korea.
There is a big difference in perception between the haste of the KDA and related pharmaceutical companies and the lack of efficacy and safety based on the results of lecanemab. In the past, the KDA hoped that Aduhelm, which was expelled from the organization due to problems, would also be approved in Korea. The implication is that something has to give in order to fight the great enemy of AD. It's a logic that makes sense to approve a weapon and hope that it will be developed gradually, but what will be the explanation to patients who are harmed by a shoddy weapon? It's not something that can be overlooked with proper precaution.
In the middle of Netflix's <The Eight Show>, the ruling class is divided by capital after being invited to play the same game. Those at the top, who earn more money per hour, control the power and pamper the lower class. The lower class has no choice but to follow. In the real world, those with money and those without money are divided into two groups, and the drama shows how they are in opposition to each other. People who don't have money but want to get something will only be unhappy. But what kind of copy would be appropriate for an ineffective drug like lecanemab that delays the progression of early AD for people with money at the top? Instead of hailing the new dementia drug as “finally approved,” the question should be, “Approved for whom?”
<Dementia News> will continue to uncover the true efficacy of lecanemab. In short, don't get your hopes up. It's best to remember that this is just the first drug approved on the long road to a cure. It's not about approval, it's about effectiveness and safety. So, what can we do? I'd be more than happy to see a drug that addresses the current limitations of lecanemab and shows promise. The reality of the dementia treatment market is that we have to keep saying the obvious.
