Alzheimer’s drug donanemab Phase 3 data announced

Alzheimer’s Society hails Eli Lilly’s drug as ‘a turning point in the fight against Alzheimer’s’.

Pharma giant Eli Lilly announced data from its TRAILBLAZER-ALZ 2 clinical trial of donanemab at the world’s largest forum for the dementia research community.

The full Phase 3 data was reported at the Alzheimer’s Association International Conference 2023, in Amsterdam, Netherlands, and were simultaneously published in the Journal of the American Medical Association.

The randomized clinical trial included 1736 participants with early symptomatic Alzheimer’s disease and amyloid and tau pathology. The results showed that among participants with early symptomatic Alzheimer’s disease, donanemab treatment significantly slowed clinical progression at 76 weeks [1], an outcome that the Alzheimer’s Association called “an important advancement in Alzheimer’s research and treatment [2].”

Longevity.Technology: The Phase 3 results showed that donanemab significantly slowed cognitive and functional decline in people with early symptomatic Alzheimer’s disease – an outcome that confirms Eli Lilly’s topline data release in May. While donanemab’s trial results seem to indicate it might well be more effective than Biogen and Eisai’s recently-approved drug Leqembi, it is not all plain sailing ahead, as the Eli Lilly drug may also come with higher rates of worrying side effects which include brain swelling and brain bleeds.

“The positive TRAILBLAZER-ALZ 2 data bring hope to people with Alzheimer’s disease who urgently need new treatment options. This is the first Phase 3 study of a disease-modifying therapy to replicate the positive clinical results observed in a previous study,” said Anne White, executive vice president of Eli Lilly and Company and president of Lilly Neuroscience.

“If approved, we believe donanemab can provide clinically meaningful benefits for people with this disease and the possibility of completing their course of treatment as early as 6 months once their amyloid plaque is cleared. We must continue to remove any barriers in access to amyloid-targeting therapies and diagnostics in an already complex healthcare ecosystem for Alzheimer’s disease [3].”

Lilly previously announced that donanemab met the primary and all cognitive and functional secondary endpoints in the Phase 3 study, and today it confirmed submission to the US FDA for traditional approval had been completed last quarter with regulatory action expected by the end of the year. Submissions to other global regulators are currently underway, and the majority will be completed by year end.

Donanemab specifically targets deposited amyloid plaque and has been shown to lead to plaque clearance in treated patients. Treatment with donanemab significantly reduced amyloid plaque levels regardless of baseline pathological stage of disease. Among all participants, treatment with donanemab reduced amyloid plaque on average by 84% at 18 months, compared with a 1% decrease for participants on placebo [3].

Study participants at the earliest stage of disease had greater benefit, with 60% slowing of decline compared to placebo. Significant benefits were also seen in more advanced patients. Nearly half (47%) of study participants at the earliest stage of disease who received donanemab had no clinical progression at one year [2].

“With this fuller picture, there is additional, convincing scientific evidence that thoroughly removing beta amyloid from the brain is associated with significant slowing of disease progression in people living with early Alzheimer’s,” said Maria C Carrillo, PhD, Alzheimer’s Association chief science officer.

“The results illustrate that initiating treatment as early as possible enables the possibility of a bigger beneficial effect, but also that there is potential for slowing of disease progression even when treatment is started later in the disease progression,” Carrillo said. “These benefits are real and meaningful, giving people more time to participate in daily life, remain independent and make future health care decisions [2].”

Noting that dementia is the biggest killer in the UK, Dr Richard Oakley, Associate Director of Research and Innovation at Alzheimer’s Society, said of today’s announcement: “This is truly a turning point in the fight against Alzheimer’s and science is proving that it is possible to slow down the disease [4].”

Participants in TRAILBLAZER-ALZ 2 were assessed over 18 months using scales that measure both cognition and function. A pre-specified analysis of low-medium tau participants based on clinical stage showed greater benefit of donanemab in those at earlier stages of disease.

It is interesting to note that donanemab clinical trial testing differs from that conducted on the two FDA-approved Alzheimer’s anti-amyloid treatments; in the donanemab study, participants go off treatment once they achieve a predetermined level of amyloid clearance from the brain. Once below a certain threshold, patients were removed from treatment and added to the placebo group. Half (52%) of study participants who received the drug finished the course of treatment in less than 12 months; 72% completed by 18 months. Given how expensive this drug is likely to be, it is encouraging to see that patients may not need to receive this treatment on an ongoing basis for the rest of their lives.

The potential side effects remain a concern, however. Approximately 37% of patients who received donanemab in the trial developed either brain swelling or a brain bleed, and three patients died as a result.

There was more good news for Alzheimer’s therapies today as Alnylam reported updated positive interim Phase 1 results for ALN-APP, its investigational RNAi therapeutic targeting amyloid precursor protein (APP) which is in development for the treatment of Alzheimer’s disease and cerebral amyloid angiopathy (CAA).

ALN-APP, which is being developed in collaboration with Regeneron Pharmaceuticals, is the first investigational RNAi therapeutic to demonstrate gene silencing in the human brain.

“We’ve known for decades that mutations that increase APP production, or alter its proteolysis, cause early-onset Alzheimer’s disease, early-onset CAA or both,” said Sharon Cohen, MD, FRCPC, Neurologist and Medical Director, Toronto Memory Program. “These Phase 1 results show that a single dose of ALN-APP can rapidly reduce APP production and that this effect is sustained at 6 months. Given the critical need for new and better treatments for AD and CAA, these results are promising, and the approach warrants further study [5].”