A Randomized, Double-Blind, Placebo-Controlled, 24-Week, Phase 2b Outcomes Study of 3 Different Doses of Encenicline or Placebo in Subjects With Mild to Moderate Probable Alzheimer’s Disease (P7.100)

OBJECTIVE: The objective of this Phase 2b study was to evaluate the safety and effects of 3 different encenicline doses (0.27mg, 0.9mg, or 1.8mg) versus placebo on cognition and function in subjects with mild to moderate probable Alzheimer’s disease (AD). BACKGROUND: In AD, progressive deterioration of cognition is associated with reduced function and quality of life. Encenicline is an α7 nicotinic receptor (α7R) partial agonist in clinical development for the treatment of cognitive impairment in AD and schizophrenia. Preclinical research suggests that encenicline potentiates acetylcholine-mediated response at the receptor, releasing neurotransmitters that modulate cognitive neural networks. DESIGN/METHODS: 409 subjects with mild to moderate probable AD who were (add-on) or were not (de novo) administered an acetylcholinesterase inhibitor (donepezil or rivastigmine) were randomized to receive 0.27mg (n=104), 0.9mg (n=101), or 1.8mg (n=100) encenicline, or placebo (n=104), and evaluated every 4 weeks for 6 months. Assessment of treatment outcomes included instruments measuring cognition (ADAS-Cog-13), clinical function (CDR-SB), and quality of life. Safety evaluations included assessment of adverse events, laboratory tests, vital signs, and physical examination findings. RESULTS: Encenicline reported the most significant procognitive effects (ADAS-Cog-13) in the 1.8mg group compared with placebo (P<0.05). Secondary measures of cognition and function supported these primary outcomes. De novo subjects reported somewhat greater cognitive improvement (P<0.05) than add-on subjects; significant dose/exposure-response relationships with increasing effects were observed with higher plasma exposures of encenicline. 46[percnt] of subjects experienced a treatment-emergent adverse event(TEAE) (0.27mg, 42.3[percnt]; 0.9mg, 48.5[percnt]; 1.8mg, 53.0[percnt]; placebo, 40.4[percnt]). Add-on subjects experienced more TEAEs (56.7[percnt]) than de novo subjects (36.3[percnt]). CONCLUSIONS: Across various outcomes scales, encenicline showed significant improvements in cognition and global functioning, and was generally well tolerated. These findings provide support for the continued development of encenicline for the treatment of cognitive impairments in adults with AD. Phase 3 studies in mild to moderate AD patients have been initiated. Disclosure: Dr. Moebius has received personal compensation for activities with FORUM Pharmaceuticals Inc. Dr. Loewen has received personal compensation for activities with FORUM Pharmaceuticals Inc. Dr. Loewen has received personal compensation for activities with FORUM Pharmaceuticals Inc. Dr. Hilt has received personal compensation for activities with FORUM Pharmaceuticals Inc.