Downstream Impacts of Lecanemab on Alzheimer Disease, Future Drug Development

David Bates, PhD

The pathophysiology of Alzheimer disease (AD) is complex, and it is unlikely that any one drug or other intervention will successfully treat it in all people living with the disease. Despite this, researchers have made significant progress in better understanding the disease and in developing and testing new treatments. Most recently, after receiving accelerated approval in January, the FDA granted traditional approval to Eisai’s antiamyloid agent, lecanemab (Leqembi), as therapy for patients with early-stage AD who show amyloid positivity.

Lecanemab’s efficacy was confirmed in the phase 3 Clarity AD trial (NCT03887455), a large scale study of nearly 1800 patients with AD who were followed for an 18-month treatment period. At the conclusion of the analysis, the agent met its primary end point of change in Clinical Dementia Rating-Sum of Boxes score, with treated patients demonstrating a statistically significant 27% reduction.

Although lecanemab stands as the second antiamyloid in its class, it became the first to receive traditional approval. The next steps involve efficiently and effectively identifying individuals who may be best candidates for the therapy, specifically in their earliest stages. Tools like the Linus Health Digital Clock and Recall may have a more pronounced role in primary care settings as a screening tool for potential patients. NeurologyLive® reached out to David Bates, PhD, chief executive officer and cofounder of Linus Health, to provide perspective on the next steps following lecanemab’s approval. Bates talked specifically about how to effectively implement the therapeutic, its impacts on future drug development, and the questions that still remain.

NeurologyLive®: What is the significance of granting traditional approval for lecanemab?

David Bates, PhD: AD has had few treatment options historically, worsening an already extremely tough diagnosis. The approval of Leqembi puts a powerful new tool against AD in providers’ hands and offers hope to millions of current and future AD patients and their families—a need that is becoming increasingly urgent as our population ages. While not a silver bullet, the approval of a new drug to treat AD with a demonstrated clinical impact—a 27% slowing of cognitive decline—is a major milestone in the fight against this terrible disease. It is also the first disease-modifying drug ever approved for dementia - Leqembi changes the course of the disease, slowing down the progressive cognitive decline.

More holistically, this approval is also significant due to its potential to accelerate an overdue shift in the status quo when it comes to brain health. The historical absence of many pharmaceutical treatment options for AD has played no small role in the perpetuation of a status quo that doesn’t put sufficient focus on prevention of disease and disability through early detection in brain health—in stark contrast to cancer, heart disease etc. where proactive testing is the standard of care. Leqembi’s approval not only strengthens the case for early detection by expanding treatment options, but also shines a spotlight on the need for it given that the drug is only approved to treat patients in the early stages of AD (mild cognitive impairment or mild dementia). If providers and health systems continue to wait until patients or their families raise a concern to react, the disease in most patients will be too advanced to really benefit from Leqembi. Therefore, proactive evaluation of brain health and cognitive function to detect impairment as soon as it develops needs to be promoted, which requires empowering primary care providers with the right tools.

How can we effectively use this therapy now that it's in the market?

Traditional FDA approval is a fundamental step in getting this drug to the people who can benefit from it, but there is a lot of work that still needs to happen to ensure timely and equitable access to it in the US healthcare system. Amid questions related to administration, reimbursement, registries, physical access to infusion centers, and more, one thing remains clear: primary care will have an increasingly essential role. As noted above, Leqembi’s impact relies on early detection and, with today’s reliance on specialists with limited supply and long wait times, the industry must innovate quickly to better empower primary care providers to assess and triage patients’ efficiently and appropriately. Put another way, Leqembi is a monoclonal antibody that targets amyloid plaques in the brain, which are neurotoxic. By removing amyloid plaques, irreplaceable neurons are preserved. Neuron preservation equates to preservation of cognition and quality of life. Conversely, neurons lost equals increased cost.

It’s not an exaggeration to say that lives depend on this innovation, as models have shown the potential for neurologist wait times to more than double in the wake of new drug approvals. Correspondingly, patient survey data shows that demand for testing and potential access to this new drug is set to cause a surge in requests for cognitive care services: in a Linus Health survey of 1000 older adults (65+ years) earlier this year, 6 in 10 people said that they would contact a provider for information and/or testing upon learning of a new drug being approved for AD. Primary care providers will need to be prepared for this surge in requests and healthcare organizations will need to rapidly implement new care paths to route patients effectively. This will require implementing more advanced cognitive assessment tools, putting infrastructure in place for widespread cognitive testing, and promoting primary care-specialist collaboration around new protocols to identify patients who are the best candidates for the drug and streamline their access to it before their AD progresses too far.

How will this decision impact future drug development?

The investment in development of new drugs has been enormous in past decades, but the lack of successful new drugs has been disappointing for the public and led to understandable reduction in the budgets of many pharmaceutical companies in dementia and neuroscience portfolios, despite the enormous need. The positive results of the Lecanemab phase 3 trial and the resulting FDA approval signals the potential for success, further supported by early positive results of other drugs in the pipeline, for example Lilly’s donanemab.

At the same time, it is also clear that amyloid monoclonal antibodies, like Leqembi, even if effective in modifying the course of the disease, are not a cure. This further emphasizes the potential of combination therapeutics. AD is a complex disorder and targeting different mechanisms of its pathophysiology is likely more effective than expecting that one target alone will resolve all problems. Thus, multipronged approaches that combine different pharmacologic agents with distinct mechanisms of action, along with lifestyle and behavioral modification programs, are likely going to be increasingly explored.

Finally, this approval is a source of great hope to patients and their families. Dementia is the most feared disease as we age. The availability of a medication that has been shown to slow down the progression of the disease is a welcomed source of encouragement and hope.

What questions remain unanswered about lecanemab?

There are a lot of questions to still clarify regarding Leqembi. One important issue to remember is that what we know to-date comes from a controlled randomized clinical trial. However, real-world experience with any treatment can be different than the experience in a research trial. Therefore, we need to gather insights from real-world clinical use of the drug.

Ultimately, most important is the question of how to weigh the risk-benefit ratio for a given individual. What we have to-date are results at the population level; what do they mean for each individual? This includes important open questions that the phase 3 clinical trial raised. For example, in the subgroup analysis of the study results, women did not show a significant benefit, while men did. On the other hand the risk of side effects was equally high in women and men. This suggests the risk-benefit balance may be different for women and men. Since dementia is more common in women, this is a particularly important issue to clarify.

Another important issue relates to side effects and complications, and the potential impact of other medications and treatments on such side effects. The most feared complication of Leqembi is bleeding in the brain and in patients who are on blood-thinning medications this can become so severe as to cause death. We need more data on what medications to avoid and how to minimize the risk of complications.

Also of note, the data we have to-date reflects treatment over 18 months. If treatment continues, does the benefit continue to grow? Longer follow-up of patients is thus critical to understand how much benefit can be gained.

In addition, there are many open questions related to access to the drug, particularly given that it needs to be given as an intravenous infusion every two weeks. However, perhaps it may possible to administer the medication in different ways down the road, or the frequency of infusions may be changed over time. For now, the infusion-based administration raises questions around where and how patients will get Leqembi, as well as how equitable access to it will be when the cost is so high ($26,500 per year). While Medicare has agreed to cover it, the required use of a registry also brings logistical and administrative questions for providers and healthcare organizations on top of core clinical questions—how to determine if patients are eligible, ensure they get an accurate diagnosis in time to catch the treatment window, weigh the benefits and risks for each patient, monitor patients for side effects over time etc.

Aside from amyloid agents, how will the community need to tackle Alzheimer disease?

It’s important to recognize that, while the approval of Leqembi provides new hope for many, it is not a cure or silver bullet—even for those who are eligible for it. There are two fundamental needs that it’s approval shines a spotlight on when it comes to tackling AD: 1) the need to increase people’s chances of obtaining a diagnosis early, while they are are still in the Leqembi treatment window and 2) the need to improve care for the many people who won’t be eligible for Leqembi to begin with, have had their AD diagnosed too late, or are not good candidates for the drug due to the risk/benefit evaluation.

New primary care-centered tools approaches and tools for assessing patients and prioritizing referrals is key to both of these. However, these will only go so far if testing continues to occur reactively, after a patient presents with symptoms. To tackle AD, the community must not only push for broader cognitive testing—using digital alternatives in place of outdated paper methods—but also a more holistic approach to brain health. This must combine pharmaceutical and non-pharmaceutical options whenever possible and also put a greater focus on preventing and delaying cognitive issues. Lifestyle interventions, such as the multidomain set in the Worldwide FINGERS program, have been proven to slow cognitive decline, yet they are severely underutilized (only 16% of Linus Health survey respondents said they’d had coaching from PCPs on lifestyle changes to promote brain health).

Such evidence-based lifestyle interventions have a powerful role to play in protecting cognitive function for all patients, and for some, they will be one of very few options currently available. In fact, early cognitive impairment should be considered similarly to other chronic illnesses like hypertension and diabetes in that care is managed using both medications and lifestyle interventions, which can be optimized through chronic care management platforms. Ultimately, we need better approaches to test patients, route them to the right care for their unique needs, and put them in the best position to employ all of the tools available—early—to protect their brain health.

Transcript edited for clarity.