Genentech, a member of the Roche Group, said today it will terminate two Phase III trials assessing its Alzheimer’s disease candidate crenezumab, adding to the list of candidates that have failed clinical studies in the memory-robbing ailment.

Genentech said it was ending the CREAD 1 (BN29552; NCT02670083) and CREAD 2 (BN29553; NCT03114657) trials, designed to evaluate crenezumab in early (prodromal to mild) sporadic Alzheimer’s.

The company said it was acting upon the recommendation of the Independent Data Monitoring Committee, which advised that crenezumab was unlikely to meet the primary endpoint of change from baseline in Clinical Dementia Rating-Sum of Boxes (CDR-SB) Score following a pre-planned interim analysis assessing the safety and efficacy of the anti-beta-amyloid molecule.

Data from CREAD 1 and CREAD 2 studies will be shared with the scientific community at an unspecified upcoming medical congress, Genentech added.

“While the results with crenezumab are disappointing, they meaningfully contribute to our understanding of Alzheimer’s disease,” said Sandra J. Horning, MD, Genentech CMO and head of global product development.

Crenezumab is a monoclonal antibody designed to preferentially bind to and promote removal of neurotoxic oligomers, a form of beta-amyloid. Crenezumab has an antibody backbone (IgG4) designed to minimize the inflammatory response in the brain, which according to Genentech may result in a lower risk of certain MRI abnormalities known as amyloid-related imaging abnormalities or ARIA.

Crenezumab was discovered by Immune SA, which outlicensed the candidate to Genentech in 2006 for a clinical program targeting amyloid-beta, with the Swiss biopharma set to receive up to $340 million tied to achieving milestones. Three years later, Roche acquired Genentech for $47 billion.

In 2012, Immune and Genentech inked a second collaboration agreement focused on targeting tau protein, in return for an undisclosed upfront payment and up to $418 million in research, development, and commercialization milestone payments.

1,500 participants

CREAD 1 and 2 are two-year global, randomized, double-blind, placebo-controlled, parallel-group Phase III trials designed to assess the efficacy and safety of crenezumab in 1,500 people worldwide with early Alzheimer’s with confirmed evidence of cerebral beta-amyloid pathology (CSF or amyloid PET). CREAD 1 was initiated in early 2016 and CREAD 2 in mid-2017. Both studies used doses that were four times higher than that studied in the Phase II trials, Genentech pointed out

According to Genentech, no safety signals for crenezumab were observed in the analysis of data from CREAD 1 and 2, and the overall safety profile was similar to that seen in previous trials.

Crenezumab continues to be studied in the Alzheimer’s Prevention Initiative (API) trial investigating the drug in a different population from the CRAD studies, cognitively healthy individuals in Colombia with an autosomal dominant mutation who are at risk of developing familial Alzheimer’s. The five-year study is in collaboration with the Banner Institute and is also funded by the National Institute on Aging.

Horning added that Genentech remained dedicated to the Alzheimer’s community, citing the company’s plans to continue clinical studies for two other Alzheimer’s candidates.

The company is continuing its Phase III GRADUATE 1 and GRADUATE 2 trials assessing gantenerumab, an investigational, IgG1 monoclonal antibody designed to bind to aggregated forms of beta-amyloid, and which has previously shown amyloid plaque lowering in Alzheimer’s patients. The GRADUATE studies are enrolling more than 1,500 patients in up to 350 study centers in more than 30 countries worldwide. Data readout is expected in 2022.

Gantenerumab is also being studied in the Dominantly Inherited Alzheimer Network Trials Unit trial (DIAN-TU; NCT01760005), a global clinical study evaluating multiple compounds in individuals at risk for or with familial Alzheimer’s.

Genentech said it is also continuing its Phase II TAURIEL trial (NCT03289143) evaluating the anti-tau molecule RG6100, a monoclonal IgG4 antibody that binds to multiple tau species and is also part of a collaboration with AC Immune; as well as imaging and fluid-based diagnostic solutions.

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