Hot topic: a double-whammy for BACE1 inhibitors

BACE1  (beta secretase 1, BACE-1 or BACE) has been a key target for Alzheimer’s disease (AD) for nearly two decades (1).  However, there was a major disappointment when the Phase III trials with the Merck inhibitor verubecestat failed unequivocally despite lowering A-beta levels.  The termination is reported both in NCT01739348  and the  May 2018  full paper on the trial results (2).  The gravity of this setback is underlined by the “In The Pipeline” commentary title “Merck’s BACE-Inhibitor Alzheimer’s Wipeout” wherein it is suggested that this brings the validation status of this target and, by definition, other inhibitors in late-stage development into doubt.  Thus, even glimmers of success for any mechanistic class of AD  therapy would seem to be currently extinguished.   There remains perhaps the slimmest of hopes from the recent report that the initial process of plaque formation might yet prove sensitive to therapeutic BACE1 inhibition (3).  However, there may be no diagnostic and/or biomarker specific enough to identify prospective asymptomatic patients this early in disease development.

The bad news for BACE1 inhibitors was compounded by a press release from Janssen in the same month. They reported serious liver enzyme elevations for some participants in Janssen’s atabecestat  (JNJ-54861911) Phase 2b/3 trial.  While this may be a chemotype liability for this series rather than a target-related issue, it does mean that yet another AD drug candidate has bitten the dust.  We would hope that a full clinical data report on this trial cessation could be pending,  However,  despite a number of early clinical reports, Janssen has not so far published any primary in vitro medicinal chemistry papers on this compound.  Comments about both these failures have also just  appeared in Nature Reviews in Drug Discovery

N.b. Our BACE1  target entry is in the process of being updated so a number of new inhibitors and curatorial comments will appear in database release 2018.3.  The technicalities of gathering these new structures, including unblinding JNJ-54861911, as well as what might still be progressing,  are described in this blog post.

Comments by Chris Southan (@cdsouthan)

1) Southan and Hancock  (2013) A tale of two drug targets: the evolutionary history of BACE1 and BACE2. Front Genet. Dec 17;4:293. doi: 10.3389/fgene.2013.00293.[PMID 24381583]

2) Egan et. al.  (2018)  Randomized Trial of Verubecestat for Mild-to-Moderate Alzheimer’s Disease. N. Engl. J. Med., 378 (18): 1691-1703, [PMID 29719179]

3) Peters et. al. (2018) BACE1 inhibition more effectively suppresses initiation than progression of β-amyloid pathology, Acta Neuropathol. May;135(5):695-710. doi: 10.1007/s00401-017-1804-9. [PMID 29327084]

 

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