Crenezumab safe but clinically ineffective in early Alzheimer's Disease: JAMA

Switzerland: According to an investigation published in JAMA Neurology, despite good tolerability of crenezumab in participants with early Alzheimer's Disease (AD), CREAD and CREAD 2 phase 3 trials were terminated early due to lack of clinically efficient changes in disease-relevant biomarkers.

Amyloid plaques and tau tangles in the brain are the hallmarks of AD. The amyloid burden in AD results from the accumulation of insoluble amyloid-β (Aβ) fibrils, plaques, and soluble Aβ peptide monomers and oligomers. Neurotoxicity is related to soluble Aβ oligomers; therefore, investigational treatment targeting them may alleviate cognitive decline and reduce neurodegeneration.

Crenezumab is an anti-Aβ monoclonal IgG4 antibody having a higher preferential binding affinity for oligomeric Aβ species. The interaction between Aβ oligomers and neurons is blocked by crenezumab in vitro, thereby exerting a neuroprotective effect. Crenezumab minimizes inflammation in brain vasculature and reduces the risk of amyloid-related imaging abnormalities (ARIA) and localized microvascular damage allowing for high doses administration with safety. This is due to the low effector function of the IgG4 backbone and lack of binding to vascular amyloid. There are studies of crenezumab in mild AD, but the primary endpoints are not met. A study used crenezumab at a dose of ≤120 mg/kg IV every four weeks.

Against the above background, Ostrowitzki et al. and team evaluated two phase 3 multicenter randomized placebo-controlled trials for efficacy and safety of crenezumab in participants with early AD. Participants were given a placebo or 60mg/kg crenezumab intravenously every four weeks for up to 100 weeks. Clinical Dementia Rating–Sum of Boxes (CDR-SB) score was the primary outcome.

The key pointers of the study include:

• CREAD and CREAD2, global, multicentre studies, were initiated in 2016 and 2017 to assess crenezumab safety and efficacy in early AD patients.

• The participants enrolled were aged 50 to 85 years

• In CREAD mean age was 70.7years, with 483 females and 330 males. There were 409 participants in the placebo and 404 in the crenezumab group.

• In CREAD2 mean age was 70.9 years, including 456 females and 350 males. The placebo group had 399, and the crenezumab group had 407 participants.

• The mean change from baseline in CDR-SB score was −0.17 with a P value of 0.63 at week 105 in the CREAD study and a relative percentage change of -4.9 %.

• No new safety signals were identified.

• No meaningful changes were observed in AD biomarkers.

• CREAD was unlikely to meet the primary endpoint and was terminated.

• 21.3% completed CREAD before discontinuation.

• CREAD2 was discontinued before study completion by any participants.

• The mean treatment duration was 78.8 weeks, and the mean cumulative dose was 1220.2 mg/kg in CREAD.

• The mean treatment duration was 41.9 weeks, with a mean cumulative dose of 675.6 mg/kg in CREAD2.

• In CREAD2, the mean change difference in CDR-SB score from baseline to week 77 was 1.30, with the relative percentage change being 40.7%.

• In CREAD, a mean change from baseline at week 105 in the crenezumab group was -0.26 for Alzheimer's Disease Assessment Scale 13, 1.88 for Alzheimer's Disease Cooperative Study–Activities of Daily Living Inventory, and 0.33 for the Mini-Mental State Examination.

• The differences in the yearly rate of change between treatment arms in CDR-SB scores in CREAD and CREAD2 were 0.02 and 0.46, respectively, using the random coefficient regression model approach.

• Nineteen participants died during the studies, 13 in CREAD and 6 in CREAD2

• New ARIA-edema findings were reported in 3 participants.

An investigational anti-amyloid drug, crenezumab, did not demonstrate a statistically significant clinical benefit in early AD. CREAD and CREAD2 phase 3 crenezumab trials were terminated early due to lack of efficacy, they mentioned.

"Essential themes in the discussion include uncertainty around the importance of Aβ as a driver of pathophysiology; uncertainty around targeting Aβ species mainly, not all may be equally neurotoxic; uncertainty impacting reduced effector function of the antibody; the question of choosing a sufficiently high dose or long enough duration treatment, etc." researchers highlighted.

References:

• Ostrowitzki S, Bittner T, Sink KM, et al. Evaluating the Safety and Efficacy of Crenezumab vs. Placebo in Adults With Early Alzheimer Disease: Two Phase 3 Randomized Placebo-Controlled Trials. JAMA Neurology.

• Guthrie H, Honig LS, Lin H, Sink KM, Blondeau K, Quartino A, Dolton M, Carrasco-Triguero M, Lian Q, Bittner T, Clayton D, Smith J, Ostrowitzki S. Safety, Tolerability, and Pharmacokinetics of Crenezumab in Patients with Mild-to-Moderate Alzheimer's Disease Treated with Escalating Doses for up to 133 Weeks. J Alzheimers Dis. 2020;76(3):967-