Evaluation of HP 029 (Velnacrine Maleate) in Alzheimer's Diseasea

Abstract

HP 029 (1,2,3,4-tetrahydro-9-aminoacridin-1-ol-maleate) is a cholinesterase inhibitor and one of a series of compounds synthesized at Hoechst-Roussel Pharmaceuticals Inc. (HRPI) as a potential therapeutic agent for senile dementia of the Alzheimer type (SDAT). An ongoing clinical development program for HP 029 (velnacrine maleate) reflects a rational, traditional progression from therapeutic concept through clinical evaluation. Prior to the initiation of outpatient studies, sufficient data had been obtained from normal volunteers and hospitalized patients to support the following conclusions: the pharmacokinetic profile of HP 029 in young and elderly normal men is predictable; tolerance and safety data for HP 029 using normal volunteers poorly correlates with experience in patients with SDAT; patients with SDAT exhibit marked intersubject variability in tolerance within a suspected therapeutic dose range; mandatory endpoints for drug discontinuation for outpatients can be reliably established in an inpatient environment. Subsequently, Protocol 201 was initiated as a multicenter, multistage investigation of HP 029 in patients with probable SDAT (NINCDS-ADRDA criteria). A dose-ranging component determined patient eligibility for a subsequent dose-replication phase based upon explicit safety and efficacy criteria defined within protocol. One a priori specified interim analysis was conducted by the sponsor (HRPI) for administrative purposes after completing approximately 50% of the planned sample (September 1989). Results suggested that (1) beneficial effects of HP 029 existed on key and secondary measures for the approximately 30% of enrolled patients; (2) interim results would provide an accurate reflection of the results at the conclusion of the study (1991); (3) HP 029-induced hepatocellular injury appeared to be a reversible, predominantly dose-related event; and (4) cholinergically mediated adverse events are infrequent and clinically inconsequential at dosages less than or equal to 225 mg/day. Post hoc hypotheses based on the interim dataset suggest that: (1) carry-over effects of HP 029 exist within a dose-ranging/dose-replication paradigm that militate against the utility of an "enriched population" design; (2) beneficial effects are more robust on initial exposure to HP 029 with effects discerned on both memory and arousal; (3) patient characteristics associated with toxicity or response are not identified; (4) dosage reduction in subsequent efficacy trials may reduce hepatocellular injury and yield clinically unimportant differences in overall efficacy results.

Liver Reactions to Tacrine

“…(1993) suggests that a correlation may exist with ALT elevations and tacrine or tacrine to metabolite (l-hydroxytacrine) plasma ratios. These findings are not definitive as 1-hydroxytacrine (velnacrine) administration is also known to produce ALT elevations (SCHNEIDER 1993;MURPHY et al 1991;CUTLER et a1. 1990a).…”

Effect of tacrine hydrochloride on hepatic drug metabolism

“…Velnacrine is, like THA, a centrally acting cholinesterase. It has been shown to have some effect in the treatment of Alzheimer's disease (24). In 1997, Eccles et al (25) showed that velnacrine inhibits the hepatic oxidative enzymes responsible for the metabolism of AP to OHA and NORA but not to HMA.…”

Cholinesterase inhibitors for behavioral disturbance in dementia

“…A major limitation of AChE inhibitors, in general, is that cognitive response rates range from 30% to 60% among patients who can tolerate effective doses [30,[34][35][36].…”