Roche Phase III failure is out? Biogen/Eisai and Eli Lilly seize the AD opportunity

ON NOVEMBER 14, ROCHE ANNOUNCED THAT GANTENERUMAB DID NOT MEET THE PRIMARY ENDPOINT IN TWO PHASE III TRIALS (GRADUATE I AND II) IN PATIENTS WITH EARLY-STAGE ALZHEIMER'S DISEASE (AD).

Gantenerumab is a fully human monoclonal IgG1 antibody that binds to β-amyloid aggregates such as plaques, fibers, and oligomers. At the same time, the drug activates immune cells in the brain, which helps remove aggregates and prevent their further formation. In addition, gantenerumab is designed for subcutaneous injection and is the first and currently the only Aβ antibody to be administered in this type of administration.

The published GRADUATEI and II studies are two global, double-blind, randomized, placebo-controlled clinical trials designed to evaluate the safety and efficacy of gantenerumab in patients with mild cognitive impairment (MCI) caused by AD and AD dementia. Nearly 2000 patients were randomized to either gantenerumab or placebo in a 1:1 ratio.

The results showed that gantenerumab slowed clinical progression by 8% and 6%, respectively, in two trials compared with placebo. However, in terms of the primary clinical endpoint, the CDR-SB scores of patients treated with gantenerumab decreased by 0.31 and 0.19 points from baseline, respectively, which were not statistically significant. CDR-SB assesses multiple aspects of patient memory, orientation, and problem solving. In addition, gantenerumab clears lower than expected levels of β-amyloid.

In terms of safety, gantenerumab is well tolerated. Imaging abnormalities associated with amyloid, including edema or exudation, were present in approximately 25% of the pooled treatment group of the two studies. Most cases are asymptomatic and rarely result in discontinuation of treatment. More data from Roche will be presented at the upcoming AD Clinical Trials Meeting.

But Roche has already taken a stand for the results — given the results of the GRADUATE project, all gantenerumab studies for early-stage AD will be stopped. Not only that, Roche also stopped the study of gantenerumab's role in secondary prevention of AD, that is, the SKYLINE study.

And this is not Roche's first failure in AD this year. In June, crenezumab, also a monoclonal antibody, failed in a study to slow or prevent a rare form of autosomal dominant Alzheimer's disease (ADAD). ADAD is a rare genetic disorder caused by a single mutation in the APP, PSEN1 or PSEN2 genes, and affects less than 1% of patients worldwide.

In 2019, two phase III trials, known as CREAD 1 and 2, failed. The studies were designed to assess the effects of crenezumab on early AD, but the trials were eventually terminated due to poor results.

Does this mean Roche is completely out of the AD space? It is not yet possible to draw firm conclusions.

According to a Roche spokesperson, the company still has several product candidates for AD drugs, such as bepranemab for early-stage AD in phase II clinical trials and semorinemab for mild to moderate AD drugs undergoing phase II analysis. The above two drugs are monoclonal antibodies against tau protein.

But what is clear is that Roche has fallen behind rivals Biogen/Eisai and Eli Lilly in the AD race.

Previously, in September, Biogen/Eisai jointly announced that Clarity AD, a phase III confirmatory clinical trial of lecanemab for the treatment of AD, met the primary endpoint and all key secondary endpoints, with highly statistically significant results that slowed memory and cognitive decline in patients with mild to moderate AD.

In May, Eisai announced that it had completed lecanemab's BLA application in an attempt to obtain accelerated FDA approval. FDA granted it a priority review, and the PDUFA date is set for January 6, 2023. At the same time, Eisai revealed that the FDA has agreed that Clarity AD can be used as a validation study, that is, if the results are positive, Eisai will submit a traditional approval application to the FDA by the end of fiscal year 2022.

But in terms of specific results, the industry believes that Lilly's Donanemab has a better chance of winning. Phase II data showed that donanemab slowed the decline by 32% compared with placebo, which was statistically significant. In terms of biomarkers, at 76 weeks, Donemaba caused the largest drop in amyloid plaque levels in the brain, faster than the competition.

In addition, the differentiating advantage of donanemab lies in the direct targeting of deposited plaques. Most drugs, including lecanemab and gantenerumab, bind to β-amyloid in oligomers and fibril forms and have a low affinity for deposited amyloid plaques.

Aduhelm precedent is ahead, and the industry remains cautiously optimistic about subsequent AD products. Even if a product is successfully launched, there is still a long way to go before the desired commercialization goal can be reached.