AAIC: Lilly’s Donanemab Data, Analyses Show Additional Benefit for Younger Patients

Pictured: A physician studies a brain scan/iStock,

Pictured: A physician studies a brain scan/iStock,

sudok1/Getty Images/iStockphoto

Full data for Eli Lilly’s Phase III TRAILBLAZER-ALZ 2 study, presented Monday at the 2023 Alzheimer’s Association International Conference, confirm positive results announced in May.

Pictured: A medical professional looks at an EEG/iStock, sudok1

The wait is over as Eli Lilly presented full results Monday from the Phase III TRAILBLAZER-ALZ 2 study of donanemab at the 2023 Alzheimer’s Association International Conference, affirming positive results initially published in May.

The full data set was presented and simultaneously published along with additional subpopulation analyses in the Journal of the American Medical Association.

As reported in May, study participants with low-medium levels of tau—a protein responsible for the neurofibrillary tangles widely associated with Alzheimer’s disease (AD)—saw their cognitive decline decrease by 35% on the Integrated Alzheimer’s Disease Rating Scale (iADRS) and 36% on the Clinical Dementia Rating-Sum of Boxes (CDR-SB) compared to placebo. Across all amyloid-positive early symptomatic participants, these numbers were 22% and 29%, respectively.

Study participants at the earliest stage of AD saw an even greater benefit, with a 60% slowing of decline compared to placebo after one year of treatment, according to a prespecified subpopulation analyses. Younger participants also fared better, with those under 75 years seeing a 48% slowing of decline on the iADRS and a 45% improvement on CDR-SB, respectively. This was compared to 25% on the iADRS and 29% on the CDR-SB in participants over 75.

On the safety side, amyloid-related imaging abnormalities (ARIA) continue to be a challenge for anti-amyloid antibodies—which includes donanemab and Eisai and Biogen’s Leqembi—as 37% of donanemab-treated patients had ARIA-related side effects. Three patients died.

In a statement sent to BioSpace, Howard Fillit, co-founder and chief science officer of the Alzheimer’s Drug Discovery Foundation, said these results make it “all the more apparent that anti-amyloid therapies will serve as the first line of defense in the arsenal of drugs needed to treat [Alzheimer’s] disease.”

Lilly said it submitted donanemab to the FDA for traditional approval in the second quarter of this year and expects a decision by the end of 2023.

Original article published 7.17

Alzheimer’s Leaders Converge at AAIC in Transitional Moment for the Space

When Alzheimer’s drug developers arrive in Amsterdam this week for the 2023 Alzheimer’s Association International Conference, they can expect to hear further analysis from Eisai on the now traditionally approved Leqembi and a highly anticipated update on Eli Lilly ‘s donanemab.

Eisai will give five oral presentations focused on Leqembi (lecanemab), including data showing that a subcutaneous form of the drug is predicted to offer comparable efficacy and improved safety compared to the currently approved intravenous version in early Alzheimer’s disease. A single dose of subcutaneous lecanemab is being assessed in a Phase I trial of healthy volunteers.

On Sunday, Eisai presented results of a Phase I study of E2814, an anti-microtubule binding region (MTBR) tau antibody. The company provided insights on target engagement and some of the downstream effects of E2814, Michael Irizarry, Eisai’s deputy chief clinical officer and senior vice president of clinical research, Alzheimer’s disease and brain health, told BioSpace prior to the oral presentation. In particular, it will focus on different tau species measurable in spinal fluid, he said. “With increasing doses of the antibody, we see increased levels of those species bound to the antibody and the [cerebrospinal fluid].”

Irizarry shared that there will be an announcement at the conference about new biological staging for Alzheimer’s disease. He said that while the prior staging was broadly focused on amyloid, tau and neurodegeneration, with the availability of new cerebrospinal fluid and plasma biomarkers as well as tau positron emission tomography (PET) imaging, “the tau portion is now being stretched out, and there’s now early tau stages and later tau stages.

“That’s been helping us in terms of understanding the pharmacodynamic effects of our tau antibody,” Irizarry said.

Meanwhile, AAIC attendees won’t have to wait long for Lilly to provide an update on the Phase III TRAILBLAZER-ALZ 2 study of donanemab as the company will hold a webcast on Monday at 1:30 pm EST.

Lilly reported data from the trial in May showing that treatment with donanemab significantly slowed cognitive and functional deterioration by 35% compared to placebo in the trial’s target population—patients with intermediate levels of the tau protein and clinical symptoms of Alzheimer’s as measured by the integrated Alzheimer’s Disease Rating Scale (iADRS). But researchers are eager to hear further analysis.

“All we’ve seen from donanemab is a high-level press release,” said Constantine (Kostas) Lyketsos, a professor and Alzheimer’s researcher at the Johns Hopkins University School of Medicine. Lyketsos told BioSpace he expected to hear more details about the data at AAIC.

The FDA rejected Lilly’s bid for accelerated approval of donanemab in January, citing trial design in its Complete Response Letter. Lilly expressed its intentions to re-submit the drug for FDA approval in the second quarter of this year, but an announcement is yet to be made.

And on Wednesday, another contender in the space, Athira Pharma, will present biomarker analysis of the ACT-AD and open-label extension clinical trials of fosgonimeton, a small molecule designed to enhance the activity of hepatocyte growth factor (HGF) and its receptor, MET, a naturally occurring repair mechanism in the nervous system. This follows data reported from ACT-AD at the 15th Clinical Trials on Alzheimer’s Disease (CTAD) conference in November 2022 showing that the candidate elicited reductions in biomarkers of neurodegeneration and neuroinflammation.

BioSpace will have continuing coverage of AAIC throughout the week.

Heather McKenzie is a senior editor at BioSpace, focusing on neuroscience, oncology and gene therapy. You can reach her at heather.mckenzie@biospace.com. Follow her on LinkedIn and Twitter @chicat08.