乌鸦传媒

Verubecestat, a once-promising Alzheimer's disease drug, was linked to worse cognition and daily function in prodromal Alzheimer's patients in a that had been terminated for futility.

Cognition and structural brain imaging results were worse among prodromal Alzheimer's patients with verubecestat than with placebo, reported Michael Egan, MD, of Merck in Kenilworth, New Jersey, and colleagues, in the .

Verubecestat, a small molecule inhibitor of the beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), also had failed in a previous trial of patients with in Alzheimer's disease.

"In this trial of two dose levels of a BACE inhibitor in patients with prodromal Alzheimer's disease in whom deposition of brain amyloid had been detected on PET, verubecestat showed no benefit with respect to the primary clinical outcome (a change in the [Clinical Dementia Rating Scale-Sum of Boxes] score from baseline to week 104), as compared with placebo," Egan and colleagues wrote. "The 40-mg group, but not the 12-mg group, had a worse outcome on this measure."

In a of the phase IIb/III also published in NEJM, atabecestat, another BACE-1 inhibitor, was linked to worse cognitive decline in patients with preclinical Alzheimer's disease, reported David Henley, MD, of Janssen Research and Development in Pennington, New Jersey, and colleagues.

"A third BACE-1 inhibitor, lanabecestat, was associated with in cognition," noted David Knopman, MD, of the Mayo Clinic in Rochester, Minnesota, in an . "Together, these results suggest that preserved BACE-1 activity may be critical to normal synaptic functions. These observations place a limitation on how Aβ lowering can be accomplished."

"The disheartening results with BACE-1 inhibitors follow on the heels of a press announcement on March 21, 2019, that aducanumab, an anti-amyloid antibody that has been shown to lower levels of Aβ, was deemed a failure after a planned interim futility analysis," Knopman added.

"The dissociation between Aβ lowering and cognitive benefits with both BACE-1 inhibition and anti-amyloid antibody therapy is troubling," he continued. "To be blunt, Aβ lowering seems to be an ineffective approach and it is time to focus on other targets to move therapeutics for Alzheimer's disease forward."

Verubecestat showed slight but significant reduction in levels of brain amyloid on PET imaging and reductions in levels of Aβ in cerebrospinal fluid of >60% in prodromal patients, indicating target engagement of the drug, but worse cognition and structural brain imaging results.

The verubecestat trial was stopped after 1,454 patients with prodromal Alzheimer's disease had been enrolled: 485 patients had been assigned to receive verubecestat 12 mg/day, 484 to receive verubecestat 40 mg/day, and 485 to receive placebo. A total of 234 patients, 231 patients, and 239 patients in each group, respectively, completed 104 weeks of the trial regimen.

The estimated mean change from baseline to week 104 in the Clinical Dementia Rating Scale–Sum of Boxes (CDR-SB) score was 1.65 in the 12-mg group, 2.02 in the 40-mg group, and 1.58 in the placebo group (P=0.67 between 12-mg group and placebo; P=0.01 between 40-mg group and placebo), suggesting a worse outcome in the higher-dose group than in the placebo group (Scores on CDR-SB range from 0 to 18, with higher scores indicating worse cognition and daily function).

The estimated rate of progression to dementia due to Alzheimer's disease was 24.5, 25.5, and 19.3 events per 100 patient-years in the 12-mg group, 40-mg group, and placebo group, respectively, favoring placebo (HR 40-mg vs placebo 1.38; 97.51% CI 1.07-1.79).

Hippocampal volume on MRI was lower at week 104 than at baseline by 6.1% in the placebo group and by 6.5% to 6.7% in the verubecestat groups.

Adverse events were more common in the verubecestat groups than in the placebo group, and included rash, dermatitis, or hives, sleep disturbance, weight loss, and cough. Hair color changed in both the 12-mg group (2.5%) and the 40-mg group (5.0%), but not in placebo.

Observational studies of patients with sporadic late-onset dementia due to Alzheimer's disease show that the accumulation of Aβ precedes overt clinical symptoms by decades, noted Knopman. "It therefore seems likely that Aβ accumulation is distant mechanistically -- by an unknown number of intervening steps and modifying factors -- from the onset of overt cognitive decline."

"These observations do not negate the genetic and neuropathological evidence supporting a key role of Aβ early in the pathogenesis of Alzheimer's disease, but administering agents early enough to be effective in Alzheimer's disease may not be practical," he added. "The atabecestat trial enrolled patients earlier in the Alzheimer's disease process than did the verubecestat trial, but the issue of timing remains a challenge."