A series of treatments are in development for Alzheimer disease (AD) that target the amyloid beta protein in the brain, as existing treatments for AD may help slow memory decline but are not disease-modifying.

Clinicians should be aware of these emerging treatments as they are evaluated and tested since they could potentially be game changers in the treatment of this condition that affects so many patients.

 

A vast number of trials

As of December 2022, there were 488 ongoing clinical trials looking at improving quality of life in patients with AD. Why so many trials?

Since AD is believed to be the leading cause of dementia, this is a global public health crisis and priority.

Treatments for AD are targeting the amyloid beta protein in the brain, because its abnormal accumulation is believed to be the start of the AD process, according to research published by Nature Reviews Neurology.

Panza F, Lozupone M, Logroscino G, et al. A critical appraisal of amyloid-β-targeting therapies for Alzheimer disease. Nat Rev Neurol. 2019;15(2):73–88.

 

The accumulation begins at least 15 to 20 years before clinical symptoms develop, so removing the amyloid plaques is hypothesized to provide a disease-modifying clinical benefit if this accumulation can be slowed or stopped. However, there are safety and efficacy issues associated with each of the treatments that have to be weighed regarding risks and benefits for each patient.

According to MDLinx advisor Mohammad Kassem, MD, a neurologist practicing in Ohio, amyloid–targeting treatments that are FDA–approved or in development are lecanemab (Leqembi) from Eisai and Biogen, gantenerumab from Genentech and Roche, aducanumab (Aduhelm) from Biogen, and donanemab from Eli Lilly.

 

Donanemab

Another emerging drug targeting amyloid is donanemab, which is also for early-stage AD and given by IV. “Initial results show promising data, with final data being released Q2 of 2023,” Dr. Kassem said.

A phase 2 study published in 2021 in the New England Journal of Medicine found that donanemab resulted in a better composite score at 76 weeks compared to placebo for cognition and the ability to perform activities of daily living, although results for secondary outcomes were mixed.

Mintun MA, Lo AC, Duggan Evans C, et al. Donanemab in early Alzheimer’s disease. N Engl J Med. 2021;384(18):1691–1704.

 

A phase 3 trial (TRAILBLAZER-ALZ 4) is comparing the effectiveness of donanemab with aducanumab in early AD. Early data from this trial announced in November 2022, showed that 37.9% of donanemab-treated participants experienced brain amyloid clearance compared with 1.6% of Aduhelm-treated patients at 6 months.

Lilly shares positive donanemab data in first active comparator study in early symptomatic Alzheimer's disease. Eli Lilly and Company. November 30, 2022.

 

While Lilly had been pursuing an accelerated FDA approval for donanemab, the company announced in a January 2023 press release that the FDA had requested additional information, so Lilly will instead be pursuing traditional FDA approval in late 2023.

U.S. Food and Drug Administration issues complete response letter for accelerated approval of donanemab. Eli Lilly and Company. January 19, 2023.

 

Hopefully testing will confirm the efficacy of donanemab and the other amyloid-targeting treatments mentioned above. Physicians should stay apprised of updates on these promising therapies.

 

Lecanemab

The FDA approved lecanemab on January 6, 2023, using the Accelerated Approval pathway, which is utilized for serious conditions with unmet needs.

FDA grants accelerated approval for Alzheimer’s disease treatment. U.S. Food and Drug Administration. January 06, 2023.

 

A study published in the New England Journal of Medicine concluded that lecanemab reduced markers of amyloid in early AD and resulted in moderately less decline in measures of cognition and function than placebo at 18 months but was associated with adverse events.

van Dyck CH, Swanson CJ, Aisen P, et al. Lecanemab in early Alzheimer's disease. N Engl J Med. 2023;388(1):9–21.

 

Therefore, additional and longer trials are needed to confirm lecanemab’s efficacy and safety. While its results thus far are encouraging, there is a range of adverse effects that need to be considered.

Lecanemab is given by IV infusion for 1 hour every 2 weeks, so there is a considerable time commitment.

 

 

Gantenerumab

Gantenerumab is also for early-stage AD, and is given by IV, but this drug did not have as robust outcomes as expected and is currently being tweaked by the manufacturer to allow better [central nervous system] penetrance.

In addition, the Alzheimer’s Association issued a statement that it was disappointed in the topline phase 3 data from the GRADUATE study for gantenerumab.

Alzheimer’s Association statement on gantenerumab phase 3 topline data release. PR Newswire. November 14, 2022.

 

 

Aducanumab

Aducanumab was approved by the FDA, also under the Accelerated Approval pathway, for mild AD in July 2021. It is administered by IV infusion over time.

Highlights of prescribing information: Aduhelm. U.S. Food and Drug Administration. Updated June 2021.

However, there has been controversy about its data, approval process, cost, and side effects, and there have been numerous articles written that urge patients and HCPs to use caution.