The content of the CTAD oral communication abstract is largely the same as the previously presented AAIC poster.

However, the CTAD poster has some new goodies on SOMAscan proteomic analysis of ASSURE trial samples for changes in serum protein markers of cognitive decline and neurodegenerative disease. They also provide a refresher and a bit more detail on previously announced ASSERT AB40 data:

"Objective: We investigated the effect of apabetalone on serum markers of cognitive decline and neurodegenerative disease progression from archived serum samples from a phase 2 trial in patients with CVD. These findings provide rationale for a cognition sub-study of the ongoing BETonMACE clinical trial. Methods: Serum Aβ40 was assessed in apabetalone phase 1 and 2 clinical trials. Serum Aβ40 was analyzed in phase 2 clinical dose-response trial ASSERT before and after 12 weeks treatment in a stable coronary artery disease population of 299 patients using Invitrogen ELISA assay. In addition, SOMAscan™ proteomic analysis was performed on serum from the Phase 2b ASSURE clinical trial to assess levels of ~1300 proteins in the plasma following 26 weeks of treatment. Proteins of interest were selected based on literature describing their link to pathogenesis of VCI, MCI and/or AD.

Results: In a Phase 1 clinical trial (test study) 8 mg/kg treatment per day for 7 days resulted in an 11.4% (SD 3.0) increase in serum Aβ40 vs. 2.2% (SD 5.8) for placebo. In the ASSERT Phase 2 trial (confirmation study), in patients with the lowest serum Aβ40 level at baseline (below median), treated with a dose of 150 mg, b.i.d., a significant increase of +7.7% in serum Aβ40 was observed in the apabetalone-treatment group (n=30) compared to placebo (n=30). At doses of 50 mg b.i.d. and 100 mg b.i.d, serum Aβ40 increases of +0.8% and +4.5% were observed, respectively. The Invitrogen ELISA method for Aβ42 used was not sufficiently sensitive for detecting serum levels. We have previously reported changes in the plasma proteome of patients treated with apabetalone in the complement and coagulation pathways, the acute phase response and vascular inflammation. Here we report, for the first time, changes in proteins linked to cognitive decline and neurodegenerative disease. In the atherosclerosis regression phase 2 ASSURE trial, proteomic analysis demonstrated significant increases in the apabetalone (n=47) group (100 mg b.i.d.), versus placebo treated (n=47) patients in the following markers; ATP synthase subunit O-mitochondrial (ATP5O) +45%; Amyloid Beta A4 Protein (APP) +33%; BrainDerived Neurotrophic Factor (BDNF) +28%; Annexin A1 +9%; and Gelsolin, +5% (p<0.05 for all markers, except BDNF, which had p<0.1). The following markers were decreased versus placebo: Serum Amyloid P-Component (APCS) -11%; tyrosine (Y), lysine (K) and leucine (L) 40kDa (YKL-40) (CHI3L1), -18.5%; and C-Reactive Protein (CRP), -21% (p<0.05 for APCS and CRP; YKL-40 p<0.1).

Conclusions: In CVD patients, BETi by apabetalone increases serum Aβ40 and modulates cardiometabolic markers. Here we report effects on serum protein markers of cognitive decline and neurodegenerative disease. These BETi effects provide rationale to explore apabetalone as a potential therapeutic for VCI and neurodegenerative disease. Cognition assessment using the MoCA in patients ≥ 70 years of age is currently being performed as a substudy in the BETonMACE Phase 3 CVD outcomes trial. Favorable effects on cognition coupled with mechanistic understanding would open developmental paths for confirmatory trials in VCI and neurodegenerative disorders."