Lilly's early data on next-gen Alzheimer's drug show 'robust' amyloid reduction but a familiar adverse event

Eli Lilly’s up-and-coming Alzheimer’s disease treatment remternetug seems to have resulted in an early, dose-dependent reduction in amyloid plaques during a small phase 1 study. But the therapy also ran into a common side effect for the anti-amyloid monoclonal antibody class—although it is early days for the data.

In a short abstract presented Friday at the Alzheimer’s & Parkinson’s Disease (AD/PD) Conference in Sweden, Lilly showcased the first look at remternetug. The interim analysis featured 41 participants with mild cognitive impairment or mild-to-moderate dementia from Alzheimer’s disease. The patients were randomized to receive infusions of placebo or the study drug in various doses every four weeks, then screened via PET imaging at days 85 and 169.

Lilly found that the therapy produced “rapid and robust” plaque clearance, according to the abstract. A dose-dependent reduction in amyloid was seen across all dosing groups in the trial, although the smaller 250 mg dose had a less robust response at day 85 than the higher doses. By day 169, amyloid clearance was achieved in 18 out of the 24 patients who received the therapy.

On safety, Lilly reported a common side effect for the class called amyloid-related imaging abnormality (ARIA). This side effect has dogged Eisai and Biogen’s now-approved therapy Leqembi. In the Lilly study, there were 10 cases of ARIA out of the 41 participants, with 24 patients receiving the drug. Only one of these events was listed as symptomatic.

ARIAs show up on MRI imaging and can signal swelling or bleeding in the brain. It has been a problematic side effect for Alzheimer’s drugmakers as therapies have finally broken through the clinic to patients.

In the more detailed presentation (PDF) of the results, the one instance of symptomatic brain swelling, which was noted as ARIA-E, ARIA-H (small brain hemorrhage) and “suicidal attempt” was reported as a serious adverse event in a patient in the 700-1,400 mg dose cohort. The patient experienced imbalance, visual field defect and aphasia, or the loss of the ability to understand or express speech.

The symptomatic event was listed on a slide detailing participants who had safety events or discontinued early. There were nine total discontinuations across all the study groups.

"In the data we presented at AD/PD, one participant experienced a serious adverse event due to ARIA, with symptoms resolving after discontinuation of the study drug and the administration of oral steroids,” a spokesperson for Lilly told Fierce Biotech in an email. The spokesperson confirmed that all other instances of ARIA were asymptomatic, and ARIA-E was the most common treatment-emergent adverse event seen in the 10 participants.

In terms of asymptomatic ARIA cases, three patients in each of the 1,400 mg, 2,800 mg and 700-1,400 mg group experienced ARIA-E, while three, one and two had ARIA-H, respectively. The 700 mg cohort saw one case each of ARIA-E and ARIA-H. There were no treatment-emergent adverse events in the low dose 250 mg cohort. There were also no macrohemorrhages observed in any study group.

While it’s tempting to try and make an apples-to-apples comparison of the data with Eisai and Biogen’s new therapy Leqembi, Lilly’s results are early and in far fewer patients than the now-approved drug. With so many doses being tested, Lilly will whittle down to the safest dose in further clinical testing.

The company spokesperson confirmed, however, that today’s results support the initiation of a planned phase 3 trial, which should produce more robust safety and efficacy data.

Eisai has repeatedly pushed back against concerns about the safety of Leqembi, which was the first monoclonal antibody and disease-modifying therapy approved for Alzheimer’s in decades. It earned an FDA nod earlier this year.

The Japanese pharma has reported a few different stats on the ARIA rate over the past few months, but the drug’s label lists ARIA as a risk, with a symptomatic rate of 3% in a trial called study 1, which featured 161 patients. Including symptomatic cases, ARIA was seen in 12% of patients who took Leqembi and 5% of those on placebo.

A trio of deaths dimmed the glow of a positive phase 3 readout for Leqembi, which dropped in September 2022. Two of those deaths were attributed to ARIA.

Lilly is positioning remternetug as the next-generation anti-amyloid therapy behind donanemab. That therapy is due for a critical phase 3 readout this year.