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


  1. It is encouraging to learn of this BACE inhibitor’s promising preliminary findings, including the possibility of treatment-related difference in PET measurements of amyloid plaque deposition, initial evidence of the drug’s safety and tolerability, and the very preliminary suggestion that the treatment might have beneficial clinical effects. It will be helpful to review the detailed study results when they become available, and it will be necessary to clarify the treatment’s efficacy, safety, and tolerability in more definitive Phase 3 trials.

    It will also be important to clarify BACE inhibitor effects in the earlier, preclinical stages of AD, when these treatments might have their most profound benefit. For instance, my Banner Alzheimer’s Institute colleagues and I are excited about our ongoing collaboration with Novartis and Amgen to evaluate the BACE inhibitor CNP520 in Alzheimer’s Prevention Initiative (API) Generation Studies 1 and 2.

  2. Elenbecestat trial starts with hope and elan

    We were pleased to hear that elenbecestat (Eisai/Biogen) has passed Phase 2 trials with no apparent toxicity and successful changes in “pathology”—although not in actual cognitive symptoms. Several candidate BACE1 inhibitors did not make it that far. However, it’s better if a candidate drug fails in earlier stages than later. When a drug is withdrawn during Phase 3, such as verubecestat was, a great deal of resources have been expended to even start that study.

    A target such as BACE1, in particular, may provide shaky footing due to several issues. One of these would be titration between toxicity and efficacy, particularly if “toxicity” methods may not actually measure important liver effects. The conventional “liver panel” does not assay BACE1’s primary substrate in liver and may not detect an “OnTOS” (on target-off site) effect, as we discussed earlier on Alzforum and elsewhere (Lahiri, Maloney, et al., comment on Liver Tox Ends Janssen BACE Program, 2014; Lahiri et al., 2014). 

    Efficacy for treatment of AD is a not a trivial measure. Multiple drug candidates have shown reduction in “pathology” markers, but cognitive recovery has been more modest. Even elenbecestat, while it reduced brain Aβ levels measured by PET, did not also produce a significant improvement in cognitive function by either of two measures. The study was “not powered” to detect such a difference, but any study that fails to achieve statistical significance is, by definition, “underpowered” to do so, whether or not by design. AD is inherently more complex than many other chronic conditions. In diabetes, for example, reducing the chemical marker (blood sugar) is the meaningful outcome. In AD, cognitive function is the most meaningful outcome, and its relationship to brain pathology is not simple.

    This complex relationship has contributed to a paradigm that effective treatment of AD requires starting ever earlier, proposing treatments before clinical disease thresholds are crossed, and it would not be too far-fetched to posit that some would be amenable to testing treatments even before signs of MCI. This raises another question. When we treat so early, can that treatment ever be stopped? If a treatment is to be administered for 20 or 30 years, daily, how safe is actually safe? Effects that would be invisible in an 18-month Phase 2 study or even a five-year study could be significant after 20 years of medication. This is a valid question for any chronic treatment, of course.

    Nevertheless, we have nothing but best wishes for elenbecestat and hope it shows meaningful improvement in cognitive symptoms. Even barring that, given its apparent low toxicity and PET Aβ results, it may prove efficacious in a combined therapy that would attack BACE1 on two fronts, perhaps combining nullification of its enzymatic activity with reduction of BACE1 levels (Lahiri, Maloney, et al., comment on Liver Tox Ends Janssen BACE Program, 2014). 


    . Lessons from a BACE1 inhibitor trial: off-site but not off base. Alzheimers Dement. 2014 Oct;10(5 Suppl):S411-9. Epub 2014 Feb 12 PubMed.

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Therapeutics Citations

  1. Elenbecestat
  2. Atabecestat

News Citations

  1. Merck Axes Verubecestat for Prodromal AD, Researchers Say ‘Go Earlier’
  2. Liver Tox Ends Janssen BACE Program
  3. HAI—Standardizing Amyloid PET: The Centiloid Project
  4. Paper Alert: Centiloid Scale Aims to Unify Amyloid PET
  5. New Alzheimer’s and Parkinson’s Immunotherapy Data at AAN
  6. Paper Alert: Verubecestat EPOCH Findings Published

Paper Citations

  1. . 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.

External Citations

  1. Phase 2
  2. press release
  3. Phase 2/3 EARLY

Further Reading