In the first NIH-backed study to evaluate an experimental prevention therapy in cognitively unimpaired persons at risk for Alzheimer disease, crenezumab showed small numerical, but not statistically significant differences compared with placebo.
According to a recent update to the phase 2 Alzheimer’s Prevention Initiative (API) Autosomal Dominant Alzheimer’s Disease (ADAD) Colombia trial (NCT01998841), Roche’s investigational agent crenezumab did not demonstrate a statistically significant benefit in either of its co-primary end points assessing the rate of change in cognitive abilities or episodic memory function in cognitively unimpaired persons at risk for Alzheimer disease.1
Measured using the API ADAD composite cognitive score and the Free Cued Selective Reminding Test (FCSRT) Cueing Index, small numerical differences favoring crenezumab were observed across the respective co-primary end points; however, none were statistically significant. Roche plans to present initial data from the study at the upcoming Alzheimer’s Association International Conference (AAIC), being held July 31 to August 4, 2022 in San Diego, California.
"We’re disappointed that the treatment did not demonstrate a statistically significant clinical benefit,” study investigator Eric M. Reiman, MD, executive director, Alzheimer’s Institute, Banner Health, said in a statement. “At the same time, we’re proud of the impact that this precedent-setting trial has had in shaping a new era in Alzheimer’s prevention research and we’re extremely grateful to our research participants and their families. This trial, the data, samples and findings that we’ll share with the research community, and the related work that we and others are doing promise to further accelerate the evaluation and approval of future prevention therapies."1
The news is just the latest hit to an already down-trodden clinical community that has watched even FDA-approved therapies for AD like Biogen’s aducanumab (Aduhelm) fizzle out. Just past its 1-year approval anniversary, uptake of the first potentially disease-modifying treatment for AD is poor as support from providers, payors, and even the manufacturer has waned.
The API ADAD trial was a prospective, randomized, double-blind, parallel-group study that enrolled 252 cognitively unimpaired individuals who have no clinical symptoms of AD and carry the PSEN1 E280A autosomal dominant mutation. Patients were randomly assigned 1:1 to either subcutaneous crenezumab 300 mg administered every 2 weeks or placebo for a 260-week treatment period. In total, 94% of participants completed the study.
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Noted as the first trial of an experimental prevention therapy in cognitive unimpaired persons at known risk for AD supported by the National Institutes of Health, two-thirds of the participants also carried the Presenilin 1 E280A mutation, which typically causes cognitive impairment due to AD around age 44. Although crenezumab did not demonstrate statistically significant results on either of the co-primary or secondary end points, there were silver linings to the data, including no new safety signals observed, as well as knowledge gained on the dosing of the study drug.
"While this is a disappointing result, we would like to thank the participants and their families - they have made an enormous contribution to advancing both understanding and the search for new treatments for familial Alzheimer's disease,” Levi Garraway, MD, PhD, chief medical officer, and head, Global Product Development, Roche, said in a statement. “We remain committed to contributing further scientific evidence to advance how Alzheimer’s disease is understood, diagnosed, and treated."1
Originally discovered by AC Immune SA, this was not the first time crenezumab came up short in a clinical trial setting. In January 2019, Roche announced it was discontinuing its phase 3 CREAD 1 and 2 clinical trials assessing the agent in prodromal to mild sporadic AD due to results from a pre-planned interim analysis conducted by an Independent Monitoring Committee. The committee’s analysis suggested that the treatment was unlikely to meet the primary end point of change from baseline in Clinical Dementia Rating-Sum of Boxes (CDR-SB) score.2
No new safety signals were observed in the interim analysis, and the overall safety profile was similar to what had been previously seen in clinical trials. CREAD 1 was a double-blind, placebo-controlled, parallel group study in which participants were randomly assigned 1:1 to receive either an intravenous infusion of crenezumab or placebo every 4 weeks for 100 weeks. The final efficacy and safety assessments were to be performed 52 weeks after the last crenezumab dose. Likewise, CREAD 2 also randomly assigned patients 1:1 to receive either intravenous infusion of crenezumab or placebo every 4 weeks for 100 weeks, though the primary efficacy assessment was to be conducted at 105 weeks, and patients would either enter an open-label extension or long-term follow-up for an additional 52 weeks.