Lilly debuts next Alzheimer’s drug, will test subcutaneous potential
Published: Apr 04, 2023
By Heather McKenzie
While the Alzheimer’s space awaits data from the Phase III trial of Eli Lilly’s donanemab, the company unveiled the first clinical data from another anti-amyloid antibody at the International Conference on Alzheimer’s and Parkinson’s Diseases (AD/PD 2023).
An interim analysis presented Friday showed remternetug lowered beta-amyloid plaques after 85 days in all but the lowest dosing regimens, compared with placebo, in patients with mild to moderate dementia due to Alzheimer’s. Amyloid was cleared—with clearance defined as less than 24.1 centiloids, down from baselines of between 82 and 96—in 18 of 24 participants receiving the three highest doses of remternetug after 169 days.
In an interview with BioSpace, Dawn Brooks, Lilly’s global development leader for remternetug and donanemab, called the data “remternetug’s coming out party.”
Brooks highlighted the “speed and depth of plaque removal” seen in the small study. “Even in Phase I,” she said, “we’re seeing very robust results across a range of doses.”
Matan Dabora, associate vice president of Alzheimer’s disease clinical development and medical director for remternetug, added that no anti-drug antibodies (ADAs) were detected in the interim analysis. “I think that’s also something that is exciting for the community given we know that some other drugs do have ADAs.”
Potential for Subcutaneous Dosing
Remternetug also has properties that Lilly executives suggest will enable subcutaneous dosing. Brooks said that while the field is beginning to see good efficacy results with intravenous dosing, some patients and their caregivers may view this alternate mode of delivery as another step forward.
Eisai and Biogen are developing a subcutaneous formulation of their anti-amyloid antibody Leqembi (lecanemab), which received accelerated approval from the FDA in January. The companies will test whether subcutaneous administration reduces the incidence of amyloid-related imaging abnormalities (ARIA-E), a common side effect of anti-amyloid antibodies associated with headache, confusion, nausea and gait disturbances.
ARIA-E was observed in 10 remternetug recipients in Lilly’s Phase I study. It was the most common treatment-related adverse effect, with one patient discontinuing treatment due to a serious adverse event.
Howard Fillit, co-founder and chief science officer at the Alzheimer’s Drug Discovery Foundation who was not involved in either the donanemab or remternetug trials, told BioSpace that subcutaneous administration is critical to the ultimate utilization of anti-amyloid antibodies for elderly Alzheimer’s patients. This is because it would enable them to do self-injections at home as opposed to going to an infusion center every four weeks, he said.
Lilly has initiated a Phase III trial to determine the safety and efficacy of remternetug, during which Brooks said the company would have latitude to explore the best dosing regimen. This trial is expected to read out in 2025.
Lilly’s Treat-to-Clear Approach
With donanemab, Lilly has taken a treat-to-clear approach, meaning that when a patient’s plaques are cleared, they’re done with treatment—until plaques return. In donanemab’s trials, Lilly is assessing this by positron emission tomography (PET) scan at baseline, 6, 12 and 18 months.
In donanemab’s Phase I and II trials, participants started at a mean of 100 centiloids of plaque and, like the remternetug trial, were considered cleared at 24 centiloids, Brooks said. Lilly’s modeling showed that plaques reaccumulated at three or four centiloids per year.
“That would suggest that it’s three or four years after you’ve been cleared before you become . . . positive again, and then it would take 10 years until you would be back to 100 centiloids,” she said. Brooks noted that some people may deviate from this model.
While there is debate as to the proper threshold between amyloid negativity and positivity, Lilly’s PET tracer has found 24 centiloids to be a good negative threshold.
Lilly will continue to add to the model as patients who were cleared at 6 months move from the Phase III donanemab study into open label extension trials where they will begin their time off the drug.
Fillit said that if patients only need to be treated for six months, followed by monitoring, there would be “tremendous cost savings” and the burden of the drug would be greatly reduced.
“I imagine a world in the future where [patients] will be put on maintenance therapy with other small molecules that are directed toward other mechanisms of action like metabolic disturbances [or] mitochondrial disorders,” he said. “I think we’re seeing a future of precision medicine here that’s really exciting.”
He added that he believes Lilly’s results with donanemab are replicable by other anti-amyloid antibodies, and that this could become the standard of care.
With remternetug, Brooks said Lilly might take the same treat-to-clear approach or consider fixed-duration treatment. This would involve a data-informed model that predicts the number of months to amyloid clearance and allows physicians to set a fixed number of IV infusions or subcutaneous injections to get there.
Brooks confirmed earlier guidance, saying the results from donanemab’s Phase III trial are expected in Q2 2023. “It’s just around the corner now, so lots of anticipation, both inside and outside of the company.”