Roche reports disappointing results for Alzheimer’s candidate
With limited results in Alzheimer’s Disease (AD) for crenezumab from two phase II studies announced this week, Roche must be debating what direction to take in its attempts to treat AD, particularly as its product gantenerumab works in a similar way.
The studies investigated whether crenezumab could delay cognitive and functional decline in people with mild-to-moderate AD.
The larger of two studies, ABBY, did not meet its co-primary endpoints in people with mild-to-moderate AD, but demonstrated initial evidence of a crenezumab treatment effect in people with mild AD, Roche reported. Similar effects were observed in BLAZE, a smaller biomarker study. The findings were presented at the Alzheimer’s Association International Conference (AAIC) 2014 in Copenhagen, Denmark.
In the ABBY study, crenezumab treatment in people with mild-to-moderate AD there was a slowing of the decline of cognitive abilities, measured by the 12-item cognitive subscale of the AD Assessment Scale (ADAS-cog12), but no effect on global functioning, measured by Clinical Dementia Rating-Sum of Boxes (CDR-SOB), the co-primary endpoints. In an exploratory analysis of people with milder disease treated with intravenous (IV) crenezumab, there was an increasing reduction in cognitive decline in progressively milder subsets relative to placebo.
In the BLAZE study, which enrolled people who tested positive for an amyloid imaging biomarker, the primary endpoint was a change in brain amyloid load. In a secondary endpoint analysis, treatment with IV crenezumab was associated with a trend towards slowing cognitive decline in those with mild disease (as measured by ADAS-cog12).
“Data from these phase II studies provide valuable information about crenezumab’s potential clinical activity in people with Alzheimer’s Disease, where there is a great need for treatment options,” said Dr Richard Scheller, executive vice president and head of Genentech Research and Early Development. “These findings support the importance of testing potential disease-modifying agents, such as beta amyloid antibodies, early in the course of the disease.”
Crenezumab is an investigational, fully humanised, monoclonal antibody designed to target all forms of beta amyloid. Discovered by Swiss biotechnology company AC Immune, it is being developed by Genentech, a member of the Roche Group.
The co-primary endpoints of ABBY were to measure a reduction in cognitive decline by change in the ADAS-cog12 and global functional decline by change in the CDR-SOB. A total of 431 patients with a baseline MMSE score of 18-26 received either 300 mg of subcutaneous crenezumab (low dose) every other week (or matching placebo) or 15 mg/kg IV crenezumab (high dose) every four weeks (or matching placebo) for 68 weeks.
In patients with mild-to-moderate AD (MMSE score of 18-26) treated with high-dose IV crenezumab, there was a 16.8 percent reduction in cognitive decline (p=0.19). A 3.1 per cent reduction in global functional decline was observed (p=0.85). There was no significant change in cognition in patients who received low-dose subcutaneous crenezumab.
In the pre-specified subgroup analysis in patients with mild AD (MMSE score of 20-26), treatment with high-dose IV crenezumab led to a 23.8 per cent reduction in cognitive decline (p=0.13), but not in global functional decline (-1.0 percent reduction; p=0.96).
An exploratory analysis in patients with milder symptoms (MMSE 22-26) showed a 35.4 percent reduction in cognitive decline (p=0.036) and a 19.6 percent reduction in global functional decline (p=0.42). Effect sizes and p-values for exploratory analyses were not adjusted for multiplicity.
The primary endpoint of BLAZE was to measure the change in brain amyloid load using florbetapir-PET. A total of 91 patients with a baseline MMSE score of 18-26 and a positive amyloid PET scan received either 300 mg of subcutaneous crenezumab (low dose) every other week (or matching placebo) or 15 mg/kg IV crenezumab (high dose) every 4 weeks (or matching placebo) for 68 weeks.
In patients with mild-to-moderate AD (MMSE 18-26) treated with high-dose IV crenezumab, there was a 10.3 per cent reduction in cognitive decline (p=0.84) and a 7.4 per cent reduction in global functional decline (p=0.84). There was no significant cognitive change in patients who received low-dose subcutaneous crenezumab.
In a post-hoc analysis of a group of patients with mild AD (MMSE 20-26) treated with high-dose IV crenezumab, there was a 52.0 per cent reduction in cognitive decline (p=0.29) and a 41.5 per cent reduction in global functional decline (p=0.44). Effect sizes and p-values were not adjusted for multiplicity.
Roche’s AD research programme focuses on several proteins and pathways believed to play an important role in the disease, including beta amyloid and monoamine oxidase B (MAO-B). Researchers are developing medicines designed to target these proteins in multiple ways and disease stages. The company’s late-stage AD pipeline includes the two anti-amyloid antibodies, crenezumab and gantenerumab, and a MAO-B inhibitor, RG1577.
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