Janssen pulled the plug on a Phase 2b/3 trial and a Phase 2 safety study of its Alzheimer’s disease experimental therapy atabecestat due to toxicity issues as a result of serious elevations in liver enzymes seen in some study participants.
Atabecestat is a BACE inhibitor, intended to slow cognitive impairment. This enzyme mediates the production of beta-amyloid, which is the key component of senile plaques in the brain, and triggers cellular processes that lead to nerve cell death in Alzheimer’s disease.
After reviewing all available liver safety data, the company concluded that the benefit-risk ratio for the development of atabecestat is no longer favorable.
This led Janssen to halt the screening, randomization of participants into experimental groups, and dosing in both the Phase 2b/3 EARLY trial (NCT02569398) in late-onset preclinical (asymptomatic) Alzheimer’s and in a Phase 2 long-term safety and tolerability study (2014-004274-41).
Over 600 subjects received atabecestat or placebo in these studies.
EARLY was a multi-center, double-blind trial of atabecestat (JNJ-54861911) in participants ages 60-85 and at risk for Alzheimer’s dementia. It aimed to evaluate whether the potential therapy slows cognitive decline compared to placebo in people who tested positive for amyloid.
Janssen is now informing the clinical trials’ scientists, participants, health authorities, ethics committees, and institutional review boards of its decision.
All subjects who participated in the trials will be offered safety and efficacy assessments. The company is also updating the study protocol for longer-term follow-up of participants who received atabecestat after treatment was discontinued.
The Global Alzheimer’s Platform Foundation (GAP), a patient-centric organization dedicated to speeding the delivery of innovative medicines in Alzheimer’s, expressed its gratitude to all study participants and clinical trial investigators.
“We at GAP thank those who have courageously joined together in supporting this study. All of these heroes are critical to our collective fight against Alzheimer’s,” John Dwyer, president of GAP, said in a press release. “Janssen spent years of effort and expended substantial resources to find a therapy for the scourge we know as Alzheimer’s. We deeply appreciate that Janssen maintains an unflagging dedication to finding new treatments to end this brutal disease.
“GAP stands with the 5.7 million Americans and many millions more worldwide currently battling Alzheimer’s. We pledge to continue our work to advance clinical trials and someday find a cure,” Dwyer added.
In February 2018, Merck announced it was stopping its Phase 3 clinical trial (NCT01953601) testing verubecestat (MK-8931), also a BACE inhibitor, in patients with early stage Alzheimer’s. Lack of effectiveness was a likely cause for this drawback.
Around the same time, Biogen revealed it will recruit 510 more patients for its two Phase 3 studies — EMERGE (NCT02484547) and ENGAGE (NCT02477800) — of aducanumab (BIIB037), a treatment candidate targeting amyloid plaques in early-onset Alzheimer’s patients.
Biogen’s decision was a result of greater variability found in results than initially estimated. The trials primarily evaluate changes in the Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB) score, an assessment of dementia severity.