Roche Failure Leaves Industry Reassessing Alzheimer's Space

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The beta-amyloid theory in Alzheimer’s disease took another hit Monday when Roche announced that gantenerumab failed to meet the primary endpoint in two Phase III studies.

The biopharma industry has spent the past two days responding in various ways. Several of Roche’s competitors, including Biogen, Cassava Sciences and Eli Lilly saw their stocks rise as a result.

While it may seem that a negative result for one anti-amyloid drug would be negative for the entire class, Dr. Howard Fillit, co-founder and chief science officer at the Alzheimer’s Drug Discovery Foundation (ADDF), had a different take.

“If you’ve seen one anti-amyloid therapy, then you’ve seen one anti-amyloid therapy,” he said in a statement Monday.

Gantenerumab, a fully human monoclonal IgG1 antibody that targets and binds beta-amyloid aggregates such as plaques, fibrils and oligomers, slowed clinical decline by 8% compared to placebo in the GRADUATE I study and 6% in GRADUATE II.

Roche plans to present further data on gantenerumab at the Clinical Trials on Alzheimer's Disease conference taking place from Nov. 29 to Dec. 2. 

Lecanemab in a "Unique Position"

In the opposite corner and benefiting from Roche’s woes is lecanemab, being developed by Biogen and Eisai.

In the Phase III CLARITY AD trial, lecanemab reduced clinical decline by 27% compared to placebo after 18 months, based on the Clinical Dementia Rating-Sum of Boxes (CDR-SB) assessment.

Fillit highlighted these results, saying, “This is further proof not all drugs that attack the same target are identical. The complexity of the aging brain means there are likely nuances in how drugs work to do things like clear amyloid and tau proteins, reduce inflammation and improve the brain’s metabolism."

He emphasized, "Each drug needs to be evaluated individually.”

In a note issued Monday, Baird senior biotechnology analyst Brian Skorney said Roche’s trial failure “takes out the biggest competitive risk to lecanemab.”

Skorney told BioSpace that Biogen is in a “unique position”, having for all intents and purposes, “passed the threshold of demonstrating efficacy on a large phase three study.”

After the CLARITY-AD data, Skorney said there has been a re-analysis of the beta-amyloid space and the validity of targeting amyloid as a valid target. He called these “the first compelling data set” and an “outlier” in this space, while cautioning it has yet to be peer-reviewed.

Skorney said that to him, gantenerumab had the most potential in terms of a major competitive threat to lecanemab. Its subcutaneous administration – compared with the other drugs tested thus far in Phase III studies that were administrated intravenously – could have been a “major competitive advantage,” he said.

While Eli Lilly’s donanemab has yet to yield Phase III data, treatment with the antibody reportedly slowed decline by 32% compared to placebo, according to the Integrated Alzheimer's Disease Rating Scale in the Phase II TRAILBLAZER-ALZ study.

Data from the Phase III study is expected in mid-2023. Depending on the results, donanemab could be a dark horse, or rather, an unknown-as-yet horse.

Skorney additionally pointed to what he called lecanemab’s “definitely better ARIA data,” over donanemab and Biogen’s approved Alzheimer’s treatment aducanumab (Aduhelm).

Amyloid-related imaging abnormalities (ARIA) has been a primary safety concern linked to Aduhelm. In the CLARITY-AD trial, the rate of ARIA-H (ARIA cerebral microhemorrhages, cerebral macrohemorrhages and superficial siderosis) was 17% in the lecanemab group compared to 8.7% in the placebo group. The ARIA-E rate was 12.5% in the lecanemab group and 1.7% in the placebo group, Biogen and Eisai reported.

In two Phase III trials (EMERGE and ENGAGE), ARIA was seen in 41.3% of participants on a10 mg/kg doses of aducanumab compared with 10% receiving a placebo.

ARIA is a known adverse event associated with anti-amyloid antibodies. Aduhelm’s label contains a warning to physicians to monitor for ARIA-E.

In October, an investigator in the CLARITY-AD study alleged that treatment with lecanemab led to a patient’s death from ARIA.

Biogen and Eisai also intend to present lecanemab data at CTAD. 

A New Approach?

When all the data comes in and is analyzed, “it's still debatable that this mechanism even really clearly works,” Skorney said. Aduhelm, after all, was approved on the “reasonably likely” correlation between the removal of plaque and a reduction in clinical decline.

“The results we’ve seen from drugs in this class points to the urgent need to bring a range of amyloid and non-amyloid therapies to market to slow the course of Alzheimer’s Disease,” Fillit said in the same statement.

According to a recent analysis of Alzheimer’s clinical trials by ADDF, more than three in four drugs in the clinic today are focused on non-amyloid targets.

“I would argue we are at the infancy of understanding the pathophysiology of Alzheimer's,” Skorney said.