New data from trials testing the efficacy and safety of Roche’s crenezumab, a humanised anti-amyloid β (Aβ) IgG4 monoclonal antibodies (mAb) in prodromal to mild Alzheimer’s disease (AD), were presented at the 2019 International Congress on AD and Parkinson’s disease (PD) in Lisbon, Portugal.

Roche’s crenezumab 2019

Crenezumab is designed to neutralize Aβ oligomers by blocking the interaction of oligomers with neurons and promoting the phagocytic removal of oligomers by microglia.

It also localises to a periphery of amyloid plaques that are proposed to be rich in Aβ oligomers and crenezumab’s ability to bind to all forms of the peptide is thought to contribute to crenezumab’s relatively low risk of Amyloid-Related Imaging Abnormalities (ARIA).

Crenezumab was being studied in one Phase III trial, CREAD1 trial of 750 participants with prodromal or mild AD. CREAD1 began despite crenezumab’s failure in its Phase II trial, named ABBY, because the dosing was limited to 15mg/kg in Phase II but was increased to 60mg/kg in Phase III.

Phase III trial

In March 2017, Roche initiated a second Phase III trial with an identical study design to CREAD1, called CREAD2, which recruited further 750 participants with prodromal and mild AD.

Phase III CREAD were two-year global, randomized, double-blind, placebo-controlled, parallel-group Phase III studies and designed to investigate the safety and efficacy of crenezumab at a dose of 60mg/kg IV q4w in patients with early prodromal or mild AD with confirmed evidence of cerebral beta-amyloid pathology (CSF or amyloid PET).

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Initial conclusion, presented at the conference, says that the CREAD1 and 2 Phase III studies are being discontinued based on a pre-planned CREAD interim analysis that indicated that crenezumab was unlikely to meet the primary endpoint of change from the baseline in Clinical Dementia Rating scale Sum of Boxes (CDR-SB score).

Results from the post-hoc analysis in secondary endpoints (ADAS-Cog 13, MMSE, ADL) and in subgroups (earlier vs later stage AD, ApoE-e4 carrier status) were consistent with the primary outcome.

Target exposures were achieved and no safety signals for crenezumab were observed in the analysis and the overall safety profile was similar to that seen in previous trials.

Adverse events

Furthermore, the safety data of the trials showed that the majority of adverse events (AEs) were of mild to moderate intensity and small imbalances between the treatment arms have been observed in infections, neurologic, psychiatric and gastrointestinal AEs and AEs related to injuries and to investigations.

No meaningful differences with regards to treatment-emergent AEs overall, AEs of interest (pneumonia an ARIA), SAEs, AEs leading to treatment discontinuation or deaths.

Moreover, the incidence of treatment-emergent anti-drug antibodies was low, n=2 in crenezumab arm and n=1 in placebo arm. However, data presented were preliminary as patients are still completing their post-treatment visits and data review and analysis are ongoing.

Roche discontinued crenezumab in January 2019 and another AD drug targeting the amyloid pathways Biogen/Eisai aducanumab, the most promising drug in the AD pipeline, failed last week.

Several clinical trials have been discontinued due to failure to reverse or even slow the cognitive decline associated with the disease, leading some researchers to question if they are pursuing the right target.

However, scientists and researchers have still hope in target amyloid as a potential treatment of AD even though they all agreed that the approval of a new drug for this indication is still far away.