Second Alzheimer’s Drug to Slow Disease’s Progression

After Leqembi, another drug that might hit the market by the end of this year for Alzheimer’s disease is Donanemab, and it’s being developed by Eli Lilly. In a recent study, donanemab showed promise in slowing the progression of the disease.

The Phase 3 clinical trial results were shared at the Alzheimer’s Association International Conference, making this a significant step forward. Lilly has already completed its submission to the US Food and Drug Administration for this drug and hopes for regulatory approval before the year ends.

Prevalence of Alzheimer’s disease and efficacy of drugs

Over 6 million Americans are believed to be living with Alzheimer’s disease, and around 1 million of them are in the early stages where the drugs Leqembi and Donanemab have shown positive effects. However, experts have raised some questions about how much these drugs really benefit patients.

In a series of editorials published in the Journal of the American Medical Association, alongside the data on Donanemab, some concerns were expressed.

Both Leqembi and Donanemab function by clearing a protein called amyloid in the brain, which is a key characteristic of Alzheimer’s disease. While Donanemab proved highly effective in removing this amyloid target, the clinical impact was comparatively modest, as mentioned in an editorial written by Jennifer Manly from Columbia University Irving Medical Center and Kacie Deters from the University of California, Los Angeles.

Despite these concerns, the fact that these drugs have shown some positive outcomes in slowing down the disease’s progression is encouraging news for those affected by Alzheimer’s.

Slower progression of the disease

In a trial involving over 1,700 participants, those taking the Donanemab medicine experienced a 35% slower progression of Alzheimer’s disease compared to those on a placebo. The measure used to gauge this effect was called the integrated Alzheimer’s Disease Rating Scale (iADRS), which is a 144-point scale.

Patients on the drug lost six points on this scale over a year and a half, while those on the placebo lost nine points.

Researchers found that patients on Donanemab had a reduced risk of transitioning from mild cognitive impairment or independence in daily activities to mild dementia, which would require some assistance with daily activities. Similarly, there was a lower risk of progressing from mild to moderate dementia, requiring assistance with basic self-care.

Impact of Donanemab on different groups

To better understand the impact of Donanemab on different groups of patients, Lilly assessed them based on their levels of another Alzheimer’s-related protein called tau.

The 35% slowing of disease progression was observed in individuals with low to medium levels of tau, indicating that the drug’s effect was more prominent in those in the early stages of the disease. When patients with higher tau levels were included, the benefit decreased to 22% compared to the placebo.

For patients in the low/medium tau category, the trial’s researchers highlighted that Donanemab slowed the decline on the iADRS scale by approximately 4.4 months over the 18-month study period.

On another scale called Clinical Dementia Rating-Sum of Boxes (CDR-SB), the drug’s impact resulted in a delay of approximately 7.5 months in disease progression.

Despite these positive findings, the authors of the editorial, Dr. Gil Rabinovici and Renaud La Joie from the University of California, San Francisco, emphasized that while this trial represents a promising start, more effective and safer treatments are still needed to combat Alzheimer’s disease.

Course of therapy

In the trial, the company planned for patients to discontinue the drug if a sufficient amount of amyloid was cleared from their brains. About half of the patients switched to the placebo based on this measure at either six or 12 months, as mentioned by Skovronsky. Surprisingly, even for those who stopped taking the drug, the benefits of the treatment continued to increase over time.

Skovronsky expressed delight in this discovery, explaining that once the plaques were removed, the Alzheimer’s trajectory changed in a positive direction. This meant that patients didn’t need to continue the therapy to maintain those benefits.

The trial also sought to address the question of whether there were greater benefits for individuals in the early stages of the disease. It has been a hypothesis that treating Alzheimer’s at an early stage with amyloid-clearing drugs would yield better outcomes, and the Donanemab trial supported this notion.

The world really is on the cusp of treating Alzheimer’s disease. #Donanemab is the second drug in just twelve months showing promising signs of slowing early-stage Alzheimer’s. These new drugs have only been possible thanks to decades of #dementia research. pic.twitter.com/5E57ZleXeM

— BRACE Dementia Research (@AlzheimersBRACE) May 4, 2023

The researchers examined different groups of patients, including those with mild cognitive impairment (MCI), which is the earliest stage of the disease, as well as those with mild and moderate Alzheimer’s. Donanemab demonstrated positive effects in all three groups, but its impact was most significant in the MCI patients, who were in the earliest stages of the disease.

Age also played a role in the drug’s effectiveness. Patients under 75 years old in the low/medium tau category experienced a greater slowing of the disease (48% on the iADRS scale) compared to those 75 or older (25% on the same scale).

Prevention study of the disease

Lilly is currently conducting a trial with patients who do not yet show symptoms of Alzheimer’s disease to investigate if the results could be even more robust. Skovronsky expressed confidence that these positive outcomes could lead to even better results in this prevention study.

The hope is that this trial could potentially slow disease progression by 40 to 50% in the early stages of the disease, and if successful, it could lead to studies at even earlier stages to try and halt the progression of the disease entirely. This exciting prospect has the researchers looking forward to the potential impact on Alzheimer’s prevention.

Leqembi is also being studied for its preventive effects in individuals at higher risk of developing Alzheimer’s.

Method of administration of Alzheimer’s drugs

One significant issue is the administration method, as both Leqembi and donanemab require intravenous infusion. Leqembi is administered every two weeks, while donanemab is given every four weeks.

The main safety concerns lie in brain swelling or bleed seen on MRI scans, known as amyloid-related imaging abnormalities (ARIA). Donanemab had a 37% ARIA rate, which included both types of abnormalities, compared to 15% for patients on the placebo.

While most of the cases were mild to moderate, a few were severe, and there were three patient deaths in the Donanemab group, and one in the placebo group, considered related to the treatment.

These safety concerns underscore the need for further investigation and understanding of the potential risks associated with these drugs, alongside their benefits, to ensure the well-being of patients with Alzheimer’s disease.