Roche’s Crenezumab Creeps Forward But Has All To Play For In Phase III Trials
Executive Summary
Phase II data for Roche’s Alzheimer’s disease MAb, crenezumab, has upheld its proposed mechanism of action but competitor aducanumab still has the upper hand with evidence of disease-modifying potential.
Crenezumab, Roche’s Alzheimer’s disease (AD) candidate, has been shown to significantly reduce amyloid beta (A-beta) oligomers in cerebrospinal fluid (CSF) in patients in Phase II trials, supporting the proposed mechanism of action for the drug and moving it along the road to commercialization in a therapy area that has seen a lot fall by the wayside. However, the candidate has some significant ground to make up when compared with Biogen Inc.’s aducanumab.
Crenezumab is a fully humanized IgG4 monoclonal antibody that binds all forms of misfolded A-beta proteins, but especially to A-beta oligomers, to prevent and break up A-beta aggregation and promote A-beta disaggregation. The IgG4 subclass has reduced effector function, allowing microglia to clear A-beta from the brain while minimizing an inflammatory response.
The data showed that treatment with crenezumab was associated with a consistent decrease in A-beta oligomer levels in the CSF. It also presented findings that 86% of IV patients and 89% of SC patients had lower levels of A-beta oligomers at week 69 than at baseline (p<0.01 for IV and p<0.001 for SC vs. placebo. The median change was -43% (p=0.01) in those treated intravenously (I.V.) and -48% (p=0.001) in those treated subcutaneously (SC), with 20% (I.V.) and 14% (SC) of patients falling below the LLoQ after treatment, respectively.
A spokesperson for AC Immune, from which Roche licensed the candidate, said: "AC Immune is very encouraged as these [data] show treatment with crenezumab significantly lowered beta-amyloid oligomer levels in CSF in the majority of patients assessed in an exploratory analysis. Oligomers are thought to be neurotoxic and reducing their level may lead to clinical benefit. Additionally, these data support crenezumab’s proposed mechanism of action and support exploring its potential clinical benefit in the ongoing phase III CREAD trials.
"Furthermore this data is the first time a potential disease modifying therapy has been able to show oligomer engagement in patients."
However, analysts were cautious.
“While it is positive that crenezumab has demonstrated efficacy in targeting A-beta oligomers and promoting their clearance, previous results from crenezumab's Phase II trials showed questionable cognitive efficacy,” said Datamonitor Healthcare analyst Stephanie Yip. “In this way, crenezumab is yet to produce evidence on par with aducanumab as the latter has elicited cognitive and functional improvements, as well as disease-modifying potential,” she continued.
The data presented were from 98 subjects treated in the ABBY and BLAZE Phase II trials for mild-to-moderate Alzheimer's disease (AD), at the Alzheimer's Association International Conference (AAIC) on July 25. Roche also presented long-term safety data on its other AD candidate, gantenerumab, and updates from open-label extension studies, including data on the effects of higher doses of gantenerumab in reducing amyloid PET load at 24 months.
Based on results from the two completed Phase II trials, ABBY and BLAZE, the Phase III CREAD studies are using higher doses. Roche is positioning the candidate to be distinguished by its tolerability, and potential to allow for higher doses versus other amyloid antibodies, as it promotes microglia-induced phagocytosis resulting in amyloid-beta clearance, while avoiding the activation of microglia-mediated inflammatory responses. However, this will be “redundant”, according to Yip, if crenezumab is unable to establish competitive cognitive efficacy through its Phase III program. The CREAD studies completed global recruitment at the beginning of July 2018 and final data are expected in 2020.
The MAb was discovered by AC Immune SA using its SupraAntigen technology platform and out-licensed to Roche's Genentech Inc. for development in 2006. Andrea Pfeifer, CEO of AC Immune, said she was excited about the potential of crenezumab, because of the “distinct differentiation from other beta-amyloid antibodies in terms of target specificity and safety.”
The MAb is also being studied in a landmark Alzheimer’s Prevention Initiative (API) trial of cognitively healthy individuals in Colombia with an autosomal dominant mutation who are at risk to develop early-onset AD.
If it bucks the trend for Alzheimer's therapies and continues its clinical journey successfully, the drug is expected to be launched in or around 2022.