Marking the fall of the only remaining BACE inhibitor currently being tested for AD, Biogen and Eisai announced today the discontinuation of two Phase 3 studies of elenbecestat in people with mild cognitive impairment and mild AD. The companies have yet to release details about the decision, but noted it was based on a safety review. The announcement struck an all-too-familiar chord after a spate of other BACE Phase 3 failures caused by side effects (Dec 2017 newsFeb 2018 news; Nov 2018 news; and Jul 2019 news). An open-label, long-term extension program of a Phase 2 study on elenbecestat will also halt.

  • Two Phase 3 trials testing elenbecestat in early AD are stopping.
  • The trials were halted due to safety concerns.
  • Elenbecestat was the last active BACE inhibitor trial for AD.

The Phase 3 elenbecestat clinical program, called MISSION AD, comprised two global, multicenter trials with identical protocols. MISSION AD1 and AD2 aimed to enroll a total of 2,100 participants diagnosed with mild cognitive impairment or mild AD and confirmed Aβ pathology. Participants were randomized to receive placebo or 50 mg elenbecestat daily for two years. The Clinical Dementia Rating Sum of Boxes served as the primary endpoint.

Paul Aisen, University of Southern California, San Diego, called the trial discontinuation another terribly disappointing result for the field. Unlike some others in the field, he does not view elenbecestat’s demise as a nail in the coffin for the amyloid hypothesis, nor for β- or γ-secretase inhibition, both of which he said still warranted further study. “We must vigorously pursue non-amyloid targets such as tau pathology and microglial modulation,” Aisen added. “But the numerous setbacks should not deter our efforts to control the amyloid dysregulation that is the key driver of this illness.”

What about the Alzheimer’s Clinical Trials Consortium’s planned A3 and A45 trials? “They will move forward. ACTC and Eisai are evaluating the emerging data, and will adapt the trial designs accordingly,” Aisen wrote to Alzforum.—Jessica Shugart.

Comments

  1. This is one more terribly disappointing result in our field. BACE inhibition would seem to be a powerful tool against the accumulation of toxic amyloid species that drives AD neurobiology in the early stages of the diseases. Secretase inhibition has been a leading candidate for primary prevention. But both γ-secretase and β-secretase inhibition are associated with a risk of cognitive worsening and other adverse effects that have halted all major development programs of these drugs to date. Off-target and on-target mechanisms behind these effects remain uncertain. It is possible that substantial inhibition of amyloid peptide generation interferes with synaptic function.

    The scientific community must continue to share data, analyze findings collaboratively, and consider the best path forward. The amyloid hypothesis remains highly compelling. Is the cognitive toxicity observed with secretase inhibition reversible? Can we succeed in targeting amyloid safely by treating early and limiting the degree of secretase inhibition? Do we need to test other, less-direct approaches to limit amyloid generation? Should we focus on anti-aggregation or amyloid removal strategies? Do we need combination therapies? Obviously we must vigorously pursue non-amyloid targets such as tau pathology and microglial modulation. But the numerous setbacks should not deter our efforts to control the amyloid dysregulation that is the key driver of this illness.

  2. I agree with Paul Aisen’s remarks. The evidence that Aβ is a key initiator of AD is overwhelming, and BACE inhibition early in the disease process should therefore prevent AD. However, BACE has many substrates that perform important functions in the brain, and achieving the right dose to provide efficacious Aβ lowering while avoiding toxicity associated with other substrates is challenging, but I believe not impossible.

    Aside from the EARLY and GENERATION trials, all the BACE inhibitor trials that were terminated were conducted in subjects with early to mid-AD. Testing BACE inhibitors in cognitively normal presymptomatic subjects using prevention trial paradigms like EARLY and GENERATION should continue. Most important, the doses of all the BACE inhibitors in clinical trials reduced CNS Aβ by greater than 50 percent. Lower doses were never tested. The available evidence suggests that long-term BACE inhibition resulting in over 50 percent Aβ lowering is too high and causes cognitive worsening. The good news is that Aβ lowering need not be that dramatic to have a protective effect. For example, the protective Icelandic mutation in APP (A673T) lowers Aβ by only ~28 percent. In addition to vigorous pursuit of other therapeutic approaches and continued efforts to control amyloid dysregulation as Paul suggests, my entreaty to the AD research community is to explore lower doses of BACE inhibitors, well below 50 percent Aβ lowering, in prevention clinical trials for AD.    

  3. This is very disappointing news—both for the patients and for drug development using BACE1 as a drug target. A major question that arises from the stopped elenbecestat trials is: What is the nature of the side effects observed? Is it an off-target effect, such as hepatotoxicity, which would invalidate the compound but not BACE1 as a drug target? Or is it cognitive decline, similar to other BACE inhibitors? In the latter case, we urgently need to understand the mechanistic basis of the cognitive decline. Is it caused by inhibition of the BACE1 homolog BACE2? Some would argue that this may not be the case, as elenbecestat and the recently stopped umibecestat were apparently more selective to BACE1 than BACE2. Let’s keep in mind, however, that even a 30-fold difference in selectivity—as observed for these compounds in in vitro assays—is not a huge factor, so that we may require more specific drugs than the ones tested so far. We also need an easily measurable biomarker for in vivo BACE2 target engagement (outside the skin), which is still lacking.

    If, however, the cognitive decline results from mechanism-based BACE1 inhibition, we need to wonder whether BACE1 is indeed still a reasonable drug target. While this concern is understandable, it is too early to give up BACE1—in particular because there is no other drug currently available and because it may take years before other drug targets yield effective drugs. What can we do with regard to BACE1? Lower the dose of the drug below 50 percent inhibition and use it for prevention rather than for treatment of AD.

  4. In agreement with several of the statements above, the clinical trial failure of BACE does not take away the importance of Aβ and senile plaques as key initiators of AD-associated dementia. I will emphasize that these disappointments are due to toxicity associated with blocking critical activities such as BACE and γ-secretase that are subclinical over the short term and therefore pass initial hurdles for clinical trials, but ultimately the substrates that accumulate and signals that get altered by the inhibitors lead to a system-wide failure that becomes toxic to even induces degeneration. It is particularly important to note that the association between dementia and both senile plaques, neurofibrillary tangles are supported at many levels from pathology to genetics. However, these associations have failed to produce a coherent and testable mechanism for neurodegeneration that appears to be relevant to the known clinical profile of AD. It is therefore particularly important to develop a detailed understanding of the mechanisms by which plaques and tangles induce dementia that goes beyond individual molecular determinants that fail to show any relevant manipulatable acute effects.

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References

Therapeutics Citations

  1. Elenbecestat

News Citations

  1. Verubecestat Negative Trial Data: What Does it Mean for BACE Inhibition?
  2. Merck Axes Verubecestat for Prodromal AD, Researchers Say ‘Go Earlier’
  3. Bump in the Road or Disaster? BACE Inhibitors Worsen Cognition
  4. Cognitive Decline Trips Up API Trials of BACE Inhibitor

Further Reading