Results from Verubecestat APECS Trial Published
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Results were published today from the APECS trial, a Phase 3 study of the BACE1 inhibitor verubecestat. In the April 11 New England Journal of Medicine, researchers led by Michael Egan, Merck, Kenilworth, New Jersey, reported that dementia progressed faster in patients treated once daily for 104 weeks with the higher, 40 mg dose of the drug than it did in those on placebo or the lower, 12 mg dose. This despite the drug appearing to slightly decrease plaque load in the brain. Alzforum reported on these findings when they were presented at last year’s CTAD meeting in Barcelona, Spain (Nov 2018 news). Merck had earlier terminated the EPOCH trial for verubecestat in mild to moderate AD (Feb 2017 news).
- The Phase 3 APECS trial of verubecestat stopped early.
- Patients on the drug declined faster than those on placebo.
- The drug appeared to slightly lower plaque load in the brain.
Merck decided to halt APECS a year early when an interim analysis predicted the drug would not provide benefit. Their subsequent presentation at CTAD told a deeper story. On the primary outcome measure, the high-dose group worsened by 2.02 points compared with 1.65 for the low-dose and 1.58 for the placebo group. More patients on the drug progressed to dementia, with 25.5 and 24.5 patients converting per 100 patient-years in the high- and low-dose groups, respectively, compared with 19.3 in the placebo group. Scores on the Alzheimer’s Disease Cooperative Study–Activities of Daily Living for Mild Cognitive Impairment scale also worsened more in the treatment groups. The ADL-MCI comprises tests of episodic memory, executive function, and attention.
Getting Worse Faster. On average, prodromal AD patients on 40 mg of verubecestat scored worse on the CDR-SB than those on 12 mg or placebo. [Courtesy of Egan et al., The New England Journal of Medicine ©2019.]
This worsening occurred despite a PET substudy suggesting that the drug slightly lowered levels of Aβ plaque in the brain. Standard uptake value ratios of 18F-flutemetamol fell by about 0.035 in the treatment arms, while it increased by about 0.02 in the placebo group.
Scientists are unsure why multiple BACE1 inhibitors have now been shown to worsen cognition, but suspect they either inhibit BACE1 too strongly or also block BACE2.
In an accompanying editorial, David Knopman, Mayo Clinic, Rochester, Minnesota, wrote that the outcome was unsurprising given the earlier termination of a verubecestat trial in patients with mild to moderate AD. “The dissociation between Aβ lowering and cognitive benefits with both BACE1 inhibition and anti-amyloid antibody therapy is troubling,” he wrote. “To be blunt, Aβ lowering seems to be an ineffective approach, and it is time to focus on other targets to move therapeutics for Alzheimer’s disease forward.”
Other scientists believe a lower or intermittent dose of a BACE1 inhibitor may yet be found to be safe and effective (Feb 2018 news and comments).—Gwyneth Dickey Zakaib
References
Therapeutics Citations
News Citations
- Bump in the Road or Disaster? BACE Inhibitors Worsen Cognition
- Merck Pulls Plug on Phase 2/3 BACE Inhibitor Trial
- Merck Axes Verubecestat for Prodromal AD, Researchers Say ‘Go Earlier’
External Citations
Further Reading
Primary Papers
- Egan MF, Kost J, Voss T, Mukai Y, Aisen PS, Cummings JL, Tariot PN, Vellas B, van Dyck CH, Boada M, Zhang Y, Li W, Furtek C, Mahoney E, Harper Mozley L, Mo Y, Sur C, Michelson D. Randomized Trial of Verubecestat for Prodromal Alzheimer's Disease. N Engl J Med. 2019 Apr 11;380(15):1408-1420. PubMed.
- Knopman DS. Lowering of Amyloid-Beta by β-Secretase Inhibitors - Some Informative Failures. N Engl J Med. 2019 Apr 11;380(15):1476-1478. PubMed.
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Comments
University of Pittsburgh School of Medicine
There really is no way to spin this that avoids the conclusion that these findings weaken, if not falsify, the hypothesis that Aβ production produces Alzheimer’s disease. If there were no effect, there might be some wiggle room left. The fact is that, just like the γ-secretase trials, people get worse; and it looks to be dose-dependent. Can we please redirect our priorities? Sooner rather than later?
CAST, Center for Advanced Studies and Technologynal Medicine University “G. d’Annunzio” Chieti-Pescara
I side with the closing comments of David Knopman: "To be blunt, Aβ lowering seems to be an ineffective approach, and it is time to focus on other targets to move therapeutics for Alzheimer’s disease forward." We do need a fresh start and also to consider combination therapies and cost-effective multi-arm clinical trials.
References:
Knopman DS. Lowering of Amyloid-Beta by β-Secretase Inhibitors - Some Informative Failures. N Engl J Med. 2019 Apr 11;380(15):1476-1478. PubMed.
Not discoursing on the amyloid hypothesis ... However, I do believe one shouldn't forget the alternative BACE1-amyloidolytic activity when attempting to use BACE1-inhibitors in the clinic (Liu et al., 2002; Shi et al., 2003; Kimura et al., 2016).
References:
Liu K, Doms RW, Lee VM. Glu11 site cleavage and N-terminally truncated A beta production upon BACE overexpression. Biochemistry. 2002 Mar 5;41(9):3128-36. PubMed.
Shi XP, Tugusheva K, Bruce JE, Lucka A, Wu GX, Chen-Dodson E, Price E, Li Y, Xu M, Huang Q, Sardana MK, Hazuda DJ. Beta-secretase cleavage at amino acid residue 34 in the amyloid beta peptide is dependent upon gamma-secretase activity. J Biol Chem. 2003 Jun 6;278(23):21286-94. PubMed.
Kimura A, Hata S, Suzuki T. Alternative Selection of β-Site APP-Cleaving Enzyme 1 (BACE1) Cleavage Sites in Amyloid β-Protein Precursor (APP) Harboring Protective and Pathogenic Mutations within the Aβ Sequence. J Biol Chem. 2016 Nov 11;291(46):24041-24053. Epub 2016 Sep 29 PubMed.
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