Oblak AL, Cope ZA, Quinney SK, Pandey RS, Biesdorf C, Masters AR, Onos KD, Haynes L, Keezer KJ, Meyer JA, Peters JS, Persohn SA, Bedwell AA, Eldridge K, Speedy R, Little G, Williams SP, Noarbe B, Obenaus A, Sasner M, Howell GR, Carter GW, Williams H, Lamb BT, Territo PR, Sukoff Rizzo SJ. Prophylactic evaluation of verubecestat on disease- and symptom-modifying effects in 5XFAD mice. Alzheimers Dement (N Y). 2022;8(1):e12317. Epub 2022 Jul 14 PubMed.
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University of Melbourne
The authors are on the right track, with some success in lowering the Aβ amyloid load after three months treatment, starting at three months of age.
The pharmacokinetics of verubecestat ad libitum in mouse chow proved difficult, with sex differences complicating things even further. The authors settled on doses of 10/30/100 mg/kg/day, which seem extraordinarily high, given that the human dosages were 12 or 40 mg/day (Egan et al., 2018).
Even these human dosages were very high, achieving 70-80 percent lowering of CSF Aβ. Most of the neurological side effects/adverse events in the BACE inhibitor field can be attributed to “on-target” inhibition of the normal function of APP, which involves synaptic plasticity and long-term potentiation.
Finding the correct “therapeutic window” in both animal models and humans has proven difficult. We have argued elsewhere (McDade et al., 2021) that the field needs to find the correct dose which is both safe and efficacious.
I think, based on the rates of accumulation of Aβ, that 10-30 percent lowering of resting state levels or production of Aβ should be sufficient, if given early enough in the natural history of AD, or even if used in combination with a monoclonal antibody-mediated clearance followed by low-dose maintenance with a BACE inhibitor.
The mouse data in this paper are difficult to interpret in terms of percentage inhibition of Aβ production rates. Much more work is needed to find this therapeutic window.
References:
Egan MF, Kost J, Tariot PN, Aisen PS, Cummings JL, Vellas B, Sur C, Mukai Y, Voss T, Furtek C, Mahoney E, Harper Mozley L, Vandenberghe R, Mo Y, Michelson D. Randomized Trial of Verubecestat for Mild-to-Moderate Alzheimer's Disease. N Engl J Med. 2018 May 3;378(18):1691-1703. PubMed.
McDade E, Voytyuk I, Aisen P, Bateman RJ, Carrillo MC, De Strooper B, Haass C, Reiman EM, Sperling R, Tariot PN, Yan R, Masters CL, Vassar R, Lichtenthaler SF. The case for low-level BACE1 inhibition for the prevention of Alzheimer disease. Nat Rev Neurol. 2021 Nov;17(11):703-714. Epub 2021 Sep 21 PubMed.
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