Pharmacokinetics, Safety, Tolerability, and Pharmacodynamics of Alicapistat, a Selective Inhibitor of Human Calpains 1 and 2 for the Treatment of Alzheimer Disease: An Overview of Phase 1 Studies

Abstract

Alicapistat is an orally active selective inhibitor of calpain 1 and 2 whose overactivation has been linked to Alzheimer disease (AD). Three studies were conducted in healthy subjects (18-55 years), 1 in healthy elderly subjects (≥65 years), and 1 in patients with mild to moderate AD. Four studies assessed pharmacokinetics, 1 study in healthy subjects assessed pharmacodynamics (sleep parameters, particularly rapid eye movement [REM], as a measure of central nervous system [CNS] penetration and activity), and all studies assessed safety. Participants received single doses or multiple twice-daily doses of alicapistat for up to 14 days. Maximum alicapistat plasma concentrations were reached in 2 to 5 hours; half-life was 7 to 12 hours postdose. Alicapistat exposure was dose proportional in the alicapistat 50- to 1000-mg dose range. Exposure of the alicapistat R,S diastereomer was approximately 2-fold greater than exposure of the R,R diastereomer in healthy young and elderly subjects and patients with AD. Alicapistat at 400- or 800-mg twice-daily doses had no effect on REM sleep parameters, whereas the active control, donepezil at 10 mg twice daily, affected sleep parameters. Across all trials, the incidence of treatment-emergent adverse events was similar in the placebo and alicapistat groups. There were no clinically significant changes in vital signs and laboratory measurements. The lack of an effect of alicapistat on sleep suggests that concentrations in the CNS were inadequate or that preclinical studies do not predict alicapistat effects in humans.

The Alpha Keto Amide Moiety as a Privileged Motif in Medicinal Chemistry: Current Insights and Emerging Opportunities

“… 197 However, the study was unable to demonstrate a pharmacodynamic effect in the CNS, posing a major risk in further clinical development of the molecule for AD treatment. 205 …”

Synthesis of α‐Ketoamide‐Based Stereoselective Calpain‐1 Inhibitors as Neuroprotective Agents

“…Among factors that have held back the field have been: achieving selectivity for calpain‐1; achieving brain bioavailability at concentrations above the IC 50 ; and the question of whether selective calpain‐1 inhibition or inhibition of calpain‐1, calpain‐2, and cathepsin‐B is necessary or desirable [7b] . Very recently, the rationale for the termination of AD clinical trials for the selective calpain‐1 inhibitor, ABT‐957 (alicapistat), was reported as the failure to achieve the pharmacodynamic endpoint [11] . The structure of ABT‐957 was only published very recently, [9e] and after we had completed the synthesis of calpain‐1 inhibitors that contained the ABT‐957 pharmacophore for comparative preclinical studies.…”

“…The selection of interruption of REM‐sleep as a clinical pharmacodynamic endpoint for ABT‐957 was based upon preclinical animal studies in which sleep perturbations were observed for ABT‐957 and were proposed to be a functional consequence of increased extracellular acetylcholine (ACh) [20] . In 17 healthy men aged 25–45 years with regular sleep habits, ABT‐957 failed to achieve this primary endpoint [11] . However, this pharmacodynamic readout does not directly test the calpain‐cathepsin hypothesis, or calpain‐1 engagement.…”

“…[7b] Very recently, the rationale for the termination of AD clinical trials for the selective calpain-1 inhibitor, ABT-957 (alicapistat), was reported as the failure to achieve the pharmacodynamic endpoint. [11] The structure of ABT-957 was only published very recently, [9e] and after we had completed the synthesis of calpain-1 inhibitors that contained the ABT-957 pharmacophore for comparative preclinical studies. Importantly, we optimized a key oxidation step to obtain novel, potent, diastereomeric inhibitors with good selectivity for calpain-1.…”

“…[20] In 17 healthy men aged 25-45 years with regular sleep habits, ABT-957 failed to achieve this primary endpoint. [11] However, this pharmacodynamic readout does not directly test the calpain-cathepsin hypothesis, or calpain-1 engagement. Measured CSF concentrations of ABT-957 (9-21 nM) did not reach the IC 50 for calpain inhibition in biochemical assays, even at the highest doses.…”