It’s fair to assume that drug developers and clinicians, not to mention trial participants, are biting their nails about the remaining BACE inhibitors. Yesterday, Eisai and Biogen offered a small measure of good news with topline results from their Phase 2 trial of the BACE inhibitor elenbecestat. During the 18-month trial, participants tolerated the drug well, and no serious safety issues or signs of liver toxicity cropped up. In addition, the brain amyloid load reportedly eased off in people taking the drug, and their clinical decline may possibly have slowed (see press release). “This is the first time a BACE inhibitor has shown a statistically significant difference in brain amyloid in a clinical study,” Eisai’s Lynn Kramer told Alzforum.
- The BACE inhibitor elenbecestat cleared safety and tolerability in Phase 2.
- Brain amyloid load dropped significantly in treatment groups.
- Cognitive decline appeared to slow a bit, as well.
Coming just two weeks after Janssen threw in the towel on its BACE inhibitor atabecestat, and four months after Merck terminated verubecestat, Eisai’s new data may calm jitters about the future of this class of drugs (May 2018 news).
Atabecestat’s liver toxicity brought to a halt the Phase 2/3 EARLY trial, which enrolled people at preclinical disease stages. “After the major disappointment in the EARLY trial, the news on the Phase 2 elenbecestat study offers at least a bit of encouragement,” Paul Aisen at the University of Southern California, San Diego, wrote to Alzforum. “This was a very small study, but apparently there were no major safety concerns.”
The elenbecestat trial enrolled 70 patients with either mild cognitive impairment due to AD or mild to moderate AD. Each had a positive amyloid PET scan. Participants received an oral dose of 5, 15, or 50 mg of elenbecestat daily, or a placebo. After about six months of safety monitoring, all patients were put on the 50 mg dose, which the company plans to take into Phase 3. Overall, the main side effects reported were rash, headache, diarrhea, falls, and upper respiratory infection. All were mild and occurred at roughly similar frequencies in the placebo and treatment groups, Kramer noted.
The Phase 2 trial was primarily a safety study; amyloid and cognitive endpoints were exploratory. The reduction in amyloid load has not yet been fully quantified because some study sites used the PET tracer florbetapir, others florbetaben, and the two have different thresholds for positivity. Investigators are converting their SUVR data to the centiloid scale to make results comparable, Kramer said (Feb 2013 conference news; Nov 2014 news). Companies are starting to report their amyloid PET trial results in centiloids (May 2018 conference news). Even so, Kramer said that the results for each tracer were statistically significant, and amyloid reductions were larger than those in Merck’s verubecestat study, which reported declines of 0.02 to 0.04 in standard uptake value ratios. Verubecestat failed over lack of efficacy (May 2018 news).
On two clinical measures, the CDR-SB and ADCOMS, the treatment groups declined more slowly than did the placebo group; however, the trial was not powered to detect statistical significance on these measures. ADCOMS is a cognitive composite Eisai developed to detect subtle changes in preclinical and prodromal AD (Wang et al., 2016). Eisai and Biogen will present full results at a scientific meeting later this year.
Meanwhile, the companies are testing the 50 mg dose of elenbecestat in two Phase 3 studies of prodromal AD that will run for 24 months. Both trials are currently enrolling. Kramer expects MISSION AD 1 and MISSION AD 2 to be fully enrolled by the end of this year.—Madolyn Bowman Rogers
- Merck Axes Verubecestat for Prodromal AD, Researchers Say ‘Go Earlier’
- Liver Tox Ends Janssen BACE Program
- HAI—Standardizing Amyloid PET: The Centiloid Project
- Paper Alert: Centiloid Scale Aims to Unify Amyloid PET
- New Alzheimer’s and Parkinson’s Immunotherapy Data at AAN
- Paper Alert: Verubecestat EPOCH Findings Published
- Wang J, Logovinsky V, Hendrix SB, Stanworth SH, Perdomo C, Xu L, Dhadda S, Do I, Rabe M, Luthman J, Cummings J, Satlin A. ADCOMS: a composite clinical outcome for prodromal Alzheimer's disease trials. J Neurol Neurosurg Psychiatry. 2016 Sep;87(9):993-9. Epub 2016 Mar 23 PubMed.