Verubecestat

Verubecestat (MK-8931) was an experimental drug for the treatment of Alzheimer's disease.^[1] It is an inhibitor of beta-secretase 1 (BACE1),^[2][3][4] which, after initial promise proved disappointing.

Verubecestat

Clinical data
Other names	MK-8931
ATC code	None
Legal status
Legal status	Investigational
Identifiers
IUPAC name N-{3-[(5R)-3-amino-2,5-dimethyl-1,1-dioxo-1,2,5,6-tetrahydro-1λ6,2,4-thiadiazin-5-yl]-4-fluorophenyl}-5-fluoropyridine-2-carboxamide
CAS Number	1286770-55-5
PubChem CID	51352361
ChemSpider	31399364
UNII	J1I0P6WT7T
KEGG	D10739
CompTox Dashboard (EPA)	DTXSID301020622
Chemical and physical data
Formula	C17H17F2N5O3S
Molar mass	409.41 g·mol−1
3D model (JSmol)	Interactive image
SMILES C[C@]1(CS(=O)(=O)N(C(=N1)N)C)c2cc(ccc2F)NC(=O)c3ccc(cn3)F
InChI InChI=1S/C17H17F2N5O3S/c1-17(9-28(26,27)24(2)16(20)23-17)12-7-11(4-5-13(12)19)22-15(25)14-6-3-10(18)8-21-14/h3-8H,9H2,1-2H3,(H2,20,23)(H,22,25)/t17-/m0/s1 Key:YHYKUSGACIYRML-KRWDZBQOSA-N

In April 2012 phase I clinical results were announced.^[5] Phase 1b results have also been reported.^[3][2]

As of December 2016^[update] it was in two phase 2/3 clinical trials that have progressed to phase 3.^[1][6][7] EPOCH, was to complete data collection for the primary outcome measure by June 2017.^[7] However, in February 2017 Merck halted its late-stage trial of verubecestat for mild to moderate Alzheimer's disease after it was reported as having "virtually no chance of finding a positive clinical effect" according to an independent panel of experts.^[8] The results of Merck's trial of verubecestat on patients with prodromal (early stage) Alzheimer's were expected in February 2019. However, the trial was terminated in February 2018, after a data monitoring committee concluded it was unlikely that the drug would show a positive benefit/risk ratio.^[9][10] The final conclusion was that "verubecestat did not reduce cognitive or functional decline in patients with mild-to-moderate Alzheimer’s disease and was associated with treatment-related adverse events". Verubecestat was projected to be a breakthrough medicine for dementia related illness, however it is still unknown why the medicine was not effective in humans. ^[11]

References

1. Makin S (2 November 2016). "New Alzheimer's drug clears milestone in human clinical trial". Scientific American.
2. Forman M, Kleijn H, Dockendorf M, Palcza J, Tseng J, Canales C, et al. (2013). "The novel BACE inhibitor MK-8931 dramatically lowers CSF beta-amyloid in patients with mild-to-moderate Alzheimer's disease". Alzheimer's & Dementia. 9 (4): P139. doi:10.1016/j.jalz.2013.04.083. S2CID 54387517.
3. Yan R, Vassar R (March 2014). "Targeting the β secretase BACE1 for Alzheimer's disease therapy". The Lancet. Neurology. 13 (3): 319–329. doi:10.1016/S1474-4422(13)70276-X. PMC 4086426. PMID 24556009.
4. Kennedy ME, Stamford AW, Chen X, Cox K, Cumming JN, Dockendorf MF, et al. (November 2016). "The BACE1 inhibitor verubecestat (MK-8931) reduces CNS β-amyloid in animal models and in Alzheimer's disease patients". Science Translational Medicine. 8 (363): 363ra150. doi:10.1126/scitranslmed.aad9704. PMID 27807285. S2CID 4579605.
5. "Merck presents results of a phase I clinical trial evaluating investigational BACE inhibitor MK-8931 at American Academy of Neurology". Merck Sharp & Dohme Corp. April 2012. Archived from the original on 2012-07-28. Retrieved 2012-07-16.
6. Clinical trial number NCT01953601 for "Efficacy and safety trial of verubecestat (MK-8931) in participants with prodromal Alzheimer's disease (MK-8931-019) (APECS)" at ClinicalTrials.gov
7. Clinical trial number NCT01739348 for "An efficacy and safety trial of verubecestat (MK-8931) in mild to moderate Alzheimer's disease (P07738) (EPOCH)" at ClinicalTrials.gov
8. "Merck announces EPOCH study of verubecestat for the treatment of people with mild to moderate Alzheimer's disease to stop for lack of efficacy" (Press release). Merck Sharp & Dohme Corp. 14 February 2017.
9. Barber J (13 February 2018). "Merck & Co. terminates Phase III study of verubecestat in prodromal Alzheimer's disease". FirstWord Pharma.
10. Clinical trial number NCT01953601 for "Efficacy and Safety Trial of Verubecestat (MK-8931) in Participants With Prodromal Alzheimer's Disease (MK-8931-019)" at ClinicalTrials.gov
11. Egan MF, Kost J, Tariot PN, Aisen PS, Cummings JL, Vellas B, et al. (May 2018). "Randomized Trial of Verubecestat for Mild-to-Moderate Alzheimer's Disease". The New England Journal of Medicine. 378 (18): 1691–1703. doi:10.1056/NEJMoa1706441. PMC 6776074. PMID 29719179.