Post by icemandios on May 3, 2023 13:14:15 GMT
May 3, 2023 06:00 AM EDTUpdated 07:45 AM
Lilly’s Alzheimer’s drug donanemab slows cognitive decline by 35% in PhIII, setting up showdown with Eisai’s Leqembi
Ryan Cross
Senior Science Correspondent
At long last, Eli Lilly has found success in its decades-long effort to develop a treatment for Alzheimer’s disease.
The company announced Wednesday morning that its experimental drug, donanemab, slowed a key measure of cognitive and functional decline by 35% over 18 months in a subset of patients with early Alzheimer’s disease.
The highly anticipated Phase III study, known as TRAILBLAZER-ALZ 2, also succeeded on all its primary and secondary endpoints, bucking a long series of failed Alzheimer’s studies from Lilly and others. The company said it plans to submit the drug to the FDA “as quickly as possible” this quarter.
An approval would set up a showdown between Lilly and its competitors Eisai and Biogen, which got a similar Alzheimer’s therapy cleared by the agency in January. The study results seem certain to reinvigorate a push to have the US government pay for the drugs through Medicare. And they will restart a debate about safety concerns — including at least two deaths in the trial — from a condition in the brain known as ARIA that can be associated with hemorrhages and swelling.
Eisai and Biogen’s drug, Leqembi, slowed the disease by 27% on one common scale used to measure cognitive decline. On the same scale, known as the Clinical Dementia Rating-Sum of Boxes or CDR-SB, donanemab slowed the disease by 29% overall and by 36% in the trial’s main subset of patients.
“We are very excited about the results,” Dawn Brooks, Lilly’s head of global brand development, neuroscience, told Endpoints News. The trial’s solid statistical significance, with p<0.0001 for the primary endpoint and key secondary endpoint, “should give confidence in the results,” she added.
The company said it will closely watch the safety issues. ARIA was confirmed as a cause of two deaths in the trial and was associated — but not explicitly linked — with a third. Those deaths add up to about 1 in 300 people who got the drug.
“This is an area that probably needs more investigation,” said John Sims, Lilly’s head of medical, Alzheimer’s disease development. “Lilly is committed to this area” and to understanding “what we can do to increase the benefit and decrease the risk” of the drug, he said in an interview.
Shares $LLY of the drugmaker surged after the news was released. In early trading Wednesday, the stock was up about 7%, adding to a five-year run in which the company’s value has more than quadrupled. Biogen’s stock $BIIB fell by more than 5%.
Success at last
The Indianapolis-based pharma company has persisted in its fight against the memory-robbing disease for more than 30 years, holding steadfast to its belief that removing sticky clumps of brain proteins called amyloid could treat the condition, even as drug after drug based on that hypothesis has failed.
Lilly is now testing donanemab in other clinical trials, including a large prevention study of people who are not yet experiencing symptoms of Alzheimer’s disease despite evidence of amyloid in their brains. Clearing amyloid quickly and early in the disease “is key” to better outcomes, Sims said.
Direct comparisons between donanemab and Leqembi are complicated by discrepancies in which patients were allowed to join the clinical trials, how the drugs were dosed, and how efficacy was measured.
Eisai and Lilly focused on people in the early stages of Alzheimer’s disease. Both companies only enrolled participants with amyloid accumulation in their brains, but Lilly also tested for levels of a second protein called tau, which some scientists hypothesize builds up and damages neurons in the wake of amyloid pathology.
About two-thirds of Lilly’s trial participants had intermediate levels of tau, similar to people enrolled in its earlier Phase II study. Donanemab slowed the disease by 35% over 18 months in these people. The overall effectiveness across all participants, including the other one-third with high levels of tau, dropped to 22%.
Those primary endpoints were based on the so-called integrated Alzheimer’s Disease Rating Scale (iADRS), a measurement that Lilly created by combining two other standard scales that assess cognition and activities of daily living.
The decision to use the unique scale could make the results harder to parse for doctors and regulators unfamiliar with the iADRS. But Lilly also measured the drug’s performance on multiple common scales, including the scale that Eisai used to assess Leqembi: the CDR-SB.
Donanemab slowed decline by 36% on that scale in the intermediate tau group and 29% overall. Eisai’s study of Leqembi slowed decline by 27% on the same scale. Lilly also said that 47% of donanemab recipients “had no clinical progression” after one year on the CDR-SB, compared to 29% of those who got a placebo.
Dosing is another differentiator. Leqembi requires infusions every two weeks indefinitely. Donanemab, in contrast, is infused every four weeks and is stopped once a patient’s amyloid drops below a certain level in brain scans. Lilly said that 52% of participants had cleared their amyloid and no longer needed the drug within a year, and 72% within 18 months.
“We think it buys patients more time in a stable condition,” perhaps stalling their progression for six or seven months, Sims said.
Safety concerns
All amyloid antibodies tested to date have some risk of the ARIA side effect. While the majority of cases go unnoticed by patients and are only observed on brain scans, when symptoms do arise, they can be dangerous.
Lilly said that ARIA-E, meaning there were signs of brain swelling, was detected in 24% of treated patients and was symptomatic in 6.1%. ARIA-H, associated with microhemorrhages, was observed in 31.4% of treated patients and 13.6% of those who got placebo.
ARIA was roughly half as common in Eisai’s Phase III study of Leqembi, with ARIA-E observed in 12.6% of people who got the drug and ARIA-H in 17.3% of people.
Lilly insists that ARIA is often a manageable side effect, but 1.6% of patients developed serious cases leading to two deaths from the complication. A third person died following a serious case of ARIA, although the complication was not explicitly linked.
The company has recently begun recruiting patients for another study that aims to find ways to lower the frequency and severity of ARIA by assessing different dosing regimens of donanemab and searching for risk factors tied to the complication.
Lilly said that it will present the full results of the study at the Alzheimer’s Association International Conference in July and submit the data to a peer-reviewed publication.