For an estimated 6.7 million Americans, the days are the same. Memory loss, poor judgment, difficulty completing simple tasks, and getting lost are a few of the many symptoms that constitute Mild Alzheimer’s disease. For those with moderate to severe disease, the symptoms are worse–problems recognizing family members, difficulty swallowing, and seizures.
According to the Alzheimer’s Association, an estimated 13 million Americans will suffer from Alzheimer’s by 2050. The continued progression of this disease disrupts families and will cost the U.S healthcare system an estimated $1 trillion by 2050.
However, there appears to be some light at the end of the tunnel. On July 17th, Eli Lilly published promising findings for Donanemab, its proprietary treatment for Alzheimer’s, in the Journal of the American Medical Association. Using a double-blind, placebo-controlled, 18-month phase 3 trial, Eli Lilly confirmed that Donanemab significantly slowed clinical progression of participants with early symptomatic Alzheimer’s disease at 76 weeks.
These findings suggest that pharma has made remarkable progress in treating a disease that was once thought to be incurable. In today’s blog post, I will provide a brief competitive landscape for the treatment of Alzheimer’s disease.
FDA Approved Treatments targeting the progression of disease
Eli Lilly’s Donanemab has yet to receive FDA approval, with the drug maker expecting a decision from the agency by the end of the year. Our focus then turns to the current FDA approved treatments for Alzheimer’s.
Clinicians divide Alzheimer’s treatments into two categories: medications that change disease progression and medications that target symptoms. Currently FDA approved Aducanumab and Lecanemab make up the former category. Truly innovative, these treatments are the focus of this blog.
Aducanumab, the first treatment to target the underlying progression of the disease, received FDA approval back in June of 2021. A monoclonal antibody, Aducanumab works by breaking down amyloid plaque build up present in Alzheimer’s patients. Although it occurs naturally in the body, amyloid protein binds together in a Alzheimer’s patient’s brain, triggering a variety of chemical reactions around neurons that damage and destroy them.
Despite the promise of Aducanumab, the drug is rife with controversy, originating from conflicting late-stage trial results. According to FiercePharma, “In a trial called Emerge, patients who got the highest dose of aducanumab experienced a 22% improvement on a clinical dementia scale over placebo after 78 weeks … Yet the same patient group in the Engage study did worse than placebo patients on that same measure, as well as on a test of cognitive function.”
Moreover, as a consequence of its high cost ($56,000) and suspect efficacy, the NCBI finds that many hospitals and insurers refused to cover the cost of the treatment. These factors contributed to disappointing sales for Biogen.
In response to the poor performance of Aducanumab, Biogen, along with Japanese partner Eisai, developed Lecanemab. Lecanemab, marketed under the brand name Leqembi, is a monoclonal antibody treatment that treats Alzheimer’s by binding to amyloid proteins when they form fibers in the brain.
In contrast to Aducanumab, Lecanemab’s efficacy appears slightly more convincing. The FDA granted traditional (full) approval for Lecanemab on July 6th of this year on the back of a confirmatory trial verifying clinical benefit. Clarity AD, a placebo-controlled, double-blind, parallel-group, randomized study, enrolling 1,795 patients, found that Leqembi reduced cognitive decline by 27% at 18 months compared to the placebo.
Despite all three of the above medications demonstrating progress towards Alzheimer’s, these treatments have significant and real side effects. Because these treatments target amyloid production, common side effects stem from ARIA (Amyloid-related imaging abnormalities).
ARIA can result in brain bleeding and swelling. Leqembi’s trial reported that 17% of patients had brain bleeding while 12% had brain swelling. In the placebo group, researchers reported 2% and 9% respectively. For most, these symptoms tend to subside and do not result in permanent health outcomes; However, in rare cases, they can be fatal.
In Eli Lilly’s Donemab phase 3 trial, researchers reported three deaths associated with the treatment.
Risks of side effects tend to increase if the patients are on blood-thinners or have the APOE4 gene, the Alzheimer’s linked gene mutation.
Ultimately, patients will have to weigh the benefits of the treatment against the corresponding costs of side effects. Medical improvement does not always result in an increase in quality of life.
Price, Other Costs, and Insurance Coverage Issues
The controversy surrounding Aducunamb secondarily stemmed from its price. Biogen originally priced the medication at $56,000 annually only to reduce it by 50%.
With Lecanemab, Biogen, understandably, has taken a more conservative approach, listing the drug for $26,500. However, Leqembi’s price does not include other costs associated with receiving the treatment. In order to receive Leqembi, patients must receive intravenous infusions in a doctor’s office bimonthly. Additionally, doctors must regularly scan the brains of patients to monitor for amyloid-related imaging abnormalities. These outside costs could push the total cost of taking Leqembi to close to $90,000 per year.
For Eli Lilly’s Donenmab, patients receive infusions once every four weeks, which may result in a cheaper price than that of Leqembi’s. Lacking full approval from the FDA, Eli Lilly has yet to price Donenmab.
In terms of coverage, Medicare refuses to cover Aducanamb unless patients are enrolled in a clinical trial. For Leqembi, the Centers for Medicare and Medicaid services posits that to receive coverage, patients must “1) be enrolled in Medicare, 2) be diagnosed with mild cognitive impairment or mild Alzheimer’s disease dementia, with documented evidence of beta-amyloid plaque on the brain, and 3) have a physician who participates in a qualifying registry with an appropriate clinical team and follow-up care.”
Medicare has affirmed that it will cover 80% of the costs associated with Leqembi. For Donanemab, Medicare will only cover the treatment once it has received full FDA approval.
Eligibility and Access
The issue of eligibility complicates the landscape of these innovative treatments. Principally, medical eligibility is a huge disqualifier. Because Leqembi and Donenmab have only demonstrated effectiveness against mild Alzheimer’s disease, 1.5 of the 6.7 million people can receive the treatment. The rest have Alzheimer’s disease that has progressed too far.
In today’s healthcare system, eligibility and access are not synonymous. A patient may be eligible for the treatment, but due to financial difficulties, he or she cannot afford it. According to the New York Times, despite Medicare covering 80% of the cost of Leqembi, a patient may still have to pay $18,000 in out-of-pocket costs.
Moreover, according to the Mayo Clinic, an estimated 5% to 6% of people with Alzheimer’s disease develop symptoms before the age of 65. Enrollment in Medicare begins at age 65. These two facts mean that between 75,000 and 90,000 patients will have significant difficulty receiving treatment despite being the group that is most likely to benefit.
We discuss the problem of Alzheimer’s and dementia market access in more depth here.
Standard of Care
Ultimately, the combination of efficacy, safety profile, and insurance coverage will determine which treatment is the standard of care.
While Biogen and Eisai have the benefit of being the first mover’s in this space, Eli Lilly appears to have a slightly more efficacious treatment with a smaller burden to administer.
Together, according to Datamonitor Healthcare, the two products could produce an estimated $9 billion in sales by 2030.
The stratospheric potential of treating Alzheimer’s disease should not be overlooked. As companies continue to improve upon the treatments discussed above, mergers and acquisitions activity will follow as smaller biotech companies, now seen as the source of innovation, seek capital to fund and develop their pipelines.