Promising Phase 3 Results for Alzheimer's Drug Donanemab

The monoclonal antibody donanemab (Eli Lilly) significantly slows cognitive and functional decline for patients with early, symptomatic Alzheimer's disease (AD) in comparison with placebo, results of a phase 3 study show.

"This trial demonstrates that an anti-amyloid drug significantly slows the disease and provides meaningful benefit to patients, and we're hoping that with approval, we will be able to make that drug available," Mark Mintun, MD, VP, Pain and Neurodegeneration Research, Eli Lilly, told Medscape Medical News.

At a press briefing highlighting the new results, Maria Carrillo, PhD, chief science officer, Alzheimer's Association, noted the "palpable excitement" surrounding this new study, which follows on the heels of other promising anti-amyloid research. "This is the decade of Alzheimer's disease, and it will get better from here," she said.

The findings were presented at the Alzheimer's Association International Conference (AAIC) 2023 and were published online July 17 in the Journal of the American Medical Association.

Primary, Secondary Endpoints Met

The TRAILBLAZER-ALZ 2 study included 1736 patients with mild cognitive impairment (MCI) or mild dementia for whom positron-emission tomography (PET) showed evidence of amyloid and tau pathology. The mean age of the participants was 73 years, and most of the participants were White patients.

Participants were randomly assigned to receive either placebo or donanemab, an investigational immunoglobulin G1 monoclonal antibody directed against an insoluble, modified, N-terminal, truncated form of β-amyloid. Donanemab was administered at a dose of 700 mg for the first three doses and 1400 mg thereafter. The drug was administered intravenously every 4 weeks for up to 72 weeks.

Researchers stratified patients on the basis of the amount of tau, a biomarker for AD progression, into a low/medium tau group and a combined tau group (low/medium and high tau).

The primary endpoint was change from baseline to 76 weeks on the integrated Alzheimer's Disease Rating Scale (iADRS), which measures cognition and activities of daily living.

In those with low/medium tau levels, the least squares mean (LSM) change in iADRS score was −6.02 (95% CI, −7.01 to −5.03) in the donanemab group and −9.27 (95% CI, −10.23 to −8.31) in the placebo group (difference, 3.25; 95% CI, 1.88 – 4.62; P < .001), representing a 35.1% slowing of disease progression.

In the combined (tau) population, LSM change in iADRS was −10.19 (95% CI, −11.22 to −9.16) in the donanemab group and −13.11 (95% CI, −14.10 to −12.13) in the placebo group (difference, 2.92; 95% CI, 1.51 – 4.33; P < .001), representing a 22.3% slowing of disease progression.

The study also met all secondary endpoints regarding measurements of cognitive and functional decline, including the Clinical Dementia Rating–Sum of Boxes (CDR-SB), which showed 36% slowing of decline (P < .0001) over 18 months.

The authors noted that the changes on these scales were clinically meaningful (considered to be >20% slowing of clinical progression) for both the low/medium tau and combined populations.

Greater Benefit With Lower Tau

However, patients with low/medium tau generally demonstrated effect size estimates that were larger than those of the overall population, which suggests there's greater benefit when amyloid-lowering therapies are initiated at an earlier disease stage, the investigators note.

Additional support for clinical relevance was a 38.6% risk reduction of disease progression, as measured on the Clinical Dementia Rating Global Score (CDR-G).

In addition, participants who received the active drug benefited in terms of activities of daily living, as demonstrated by 40% less decline (P < .0001) on the Alzheimer's Disease Cooperative Study – Instrumental Activities of Daily Living Inventory.

Donanemab significantly reduced brain amyloid plaque: 80% (low/medium tau population) and 76% (combined population) of participants achieved amyloid clearance at 76 weeks. The intervention was also associated with a greater decrease in whole-brain volume.

The treatment effect continued to widen after patients were switched to placebo, as evidenced on PET scan at 6 or 12 months, said Mintun.

The effects of the drug were similar among men and women but were especially pronounced among younger participants, with a 48% slowing on iADRS and a 45% slowing on CDR-SB in those younger than 75 years.

Safety Issues

However, the drug is not without some safety concerns. Amyloid-related imaging abnormalities (ARIAs) occurred in 36.8% of the treatment group, vs 14.9% of the placebo group, and in 40.6% of patients who were homozygous for APOE ε4 and received the drug. Microhemorrhage occurred in 26.8% in the donanemab group, vs 12.5% in the placebo group.

Most ARIA cases were mild to moderate and resolved or stabilized with appropriate management. However, three deaths were determined to be drug related among participants who developed serious ARIAs or brain bleeding and swelling.

An important study limitation was that it enrolled primarily White patients (91.5%), which may limit generalizability to other populations, and the age limit was 85 years, which some believe is an inadequate representation of older adults. In addition, the 18-month treatment window limits the long-term understanding of donanemab's benefits and side effects.

Eli Lilly has filed a submission to the US Food and Drug Administration (FDA). If approved, donanemab will be the third anti-amyloid monoclonal antibody to receive this status, following aducanumab (Aduhelm) and lecanemab (Leqembi).

Strongest Data Yet

Commenting for Medscape Medical News, Percy Griffin, PhD, director of scientific engagement, Alzheimer's Association, said these new results are "very, very exciting" and represent "the strongest data to-date" for anti-amyloid monoclonal antibodies in AD.

"A good percentage of individuals on the drug actually saw a complete clearance of amyloid, and some had to be taken off the drug, because if you're on an anti-amyloid drug and there's no amyloid, what are you going for?"

He noted that the study had some unique aspects, including using tau-PET "to see whether or not the drug is more effective in subpopulations."

Access to this and other anti-amyloid therapies should be a priority, said Griffin. "We have to make sure people who have the potential to benefit from these treatments do."

The Alzheimer's Association is calling for Medicare beneficiaries who are living with the disease to receive the same coverage afforded to those with other diseases.

"The Centers for Medicare & Medicaid Services (CMS) policy to block Medicare access to Food and Drug Administration (FDA)-approved Alzheimer's treatments is in stark contrast to scientific evidence, is unprecedented and must be reversed immediately," Joanne Pike, DrPH, president and CEO of the Alzheimer's Association, said in a press release.

Also important is tracking the longitudinal performance of these drugs outside of clinical trials, said Griffin. "Not everyone is going to be in that Goldilocks zone of being able to see a doctor whenever they want and have access to these PET and MRI tools and other things used in clinical trials."

He noted that the Alzheimer's Association is leading a network for diagnostics and therapeutics (ALZ-NET) that will track the performance of novel FDA-approved AD therapies "in the real world."

While these are exciting findings for anti-amyloid therapy, "we can't take our foot off the gas, we need more therapies that target different aspects of the disease biology," said Griffin.

Alzheimer's Association International Conference (AAIC) 2023: Presented July 17, 2023.

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