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Another amyloid bust as Roche pulls crenezumab trials

Undermines amyloid hypothesis hopes. including Biogen candidate

brain

Roche has halted a pair of phase 3 trials for its amyloid-targeting antibody crenezumab in Alzheimer’s disease (AD) after an interim look at the data showed little chance of a positive outcome.

The setback for the AC Immune-partnered drug is yet another blow to proponents of the amyloid hypothesis for AD – which holds that interrupting the formation of amyloid plaques in the brain may delay cognitive decline – and removes any chance of crenezumab making it to market any time soon.

The trials (CREAD 1 and 2) were testing crenezumab in people with ‘prodromal’ AD - who have mild cognitive symptoms but are not yet considered to have dementia – as well as those with mild, sporadic AD, following the current trend to use amyloid-targeting drugs as early as possible in the course of the disease.

Roche and AC Immune’s drug failed to move the needle on Clinical Dementia Rating-Sum of Boxes (CDR-SB) scores, the primary outcome measure in both trials, prompting the decision to stop the trials. The two companies gambled on the phase 3 programme after crenezumab missed the mark in a phase 2 study reported in 2014 but seemed to show some signs of activity in patients with mild AD.

It’s not the end of the story for the drug however, as another study of crenezumab in familial Alzheimer’s disease, the Alzheimer’s Prevention Initiative (API), is still ongoing.

That is taking the early intervention hypothesis even further, testing the drug in cognitively healthy individuals in Colombia who have an autosomal dominant mutation that puts them at risk of developing AD. It’s due to read out in 2022, according to clinicaltrials.gov.

AC Immune shares took a hammering in the wake of the announcement, losing a third of their value on the Nasdaq, and also weighed on Biogen which has two amyloid-targeted drugs for AD in development.

Analysts at William Blair say the outcome of CREAD 1 and 2 will “undoubtedly be viewed negatively” for Biogen’s lead drug aducanumab, but they believe “there are fundamental differences between crenezumab and aducanumab that make any read-through very limited, if at all.”

They point to differences in the structure and binding profile of the two drugs which mean that aducanumab is more likely to bind to amyloid effectively and prevent it forming beta sheets – the precursor to plaques – and activate the immune system to remove the protein. They also suggest there are much stronger signs of efficacy in aducanumab’s mid-stage study than the equivalent crenezumab trial.

Roche and AC Immune have another iron in the AD fire, as they are collaborating on another antibody – called RG-6100 (and also RO7105705) – that instead of amyloid targets tau protein, which has also been linked to the pathology of the disease. Tau forms neurofibrillary tangles in the brain that are also observed in AD patients.

RG-6100 is in a phase 2 trial called TAURIEL due to report its first data next year, although it is worth pointing out that other attempt to target tau in AD have also yielded disappointing results for companies including TauRx, Zeltia, Bristol-Myers Squibb and Allon/Paladin Labs.

Meanwhile, Roche is independently developing another amyloid-target drug called gantenerumab in phase 3, despite disappointing data in a mid-stage study.

Article by
Phil Taylor

30th January 2019

From: Research

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