Effect of REL-1017 (Esmethadone) on Cholesterol, Triglycerides, PCSK9, and hs-CRP in a Phase 2a Double-Blind Randomized Trial in Patients with MDD
Authors: Ferri Nicola , Pappagallo Marco , Patel Sheetal , Folli Franco , De Martin Sara , Lupo Maria Giovanna , Traversa Sergio , Manfredi Paolo L. 
Published: April 2022

AbstractBackgroundAtherosclerotic cardiovascular disease (ASCVD) is the leading cause of morbidity and mortality. Hyperlipidemia and vascular subinflammation play critical roles in the pathogenesis of atherosclerosis. Patients with Major Depressive Disorder (MDD) are at higher risk for ASCVD and current antidepressant therapies may carry ASCVD risks. REL-1017 is a novel NMDAR channel blocker which showed rapid, robust, and sustained antidepressant effects, currently in Phase 3 clinical trials for MDD.MethodsWe analyzed total cholesterol (TC), triglycerides (TG), Proprotein Convertase Subtilisin/Kexin 9 (PCSK9), and high-sensitivity C-reactive protein (hs-CRP) from patients enrolled in a Phase-2, multicenter, randomized, double-blind, placebo-controlled, 7-day, 3-arm trial to assess safety, tolerability, pharmacokinetics, and efficacy of REL-1017. Patients were randomized in a 1:1:1 ratio to either placebo, REL-1017 25 mg QD, or REL-1017 50 mg QD. TC, TG, PCSK9, and hs-CRP levels were measured in patients at baseline, day 7 and day 14, 7 days after treatment discontinuation. 6 out of 21 (28% of patients), 6 out of 16 (37%), and 1 out of 19 (5%), were under statin therapy in the placebo, REL-1017 25 and 50 mg groups, respectively.ResultsAt baseline, day 7, day 14 TC levels (mg/dL) were 117.8 ± 30.8, 124.7 ± 34.1, 114.2 ± 18.1; 123.7 ± 59.3, 119.0 ± 28.1, 115.1 ± 14.8; 113.9 ± 22.9, 118.6 ± 29.5, 115.8 ± 25.5 for placebo (n = 21), REL-1017 25 mg (n = 16) and REL-1017 50 mg (n = 19), respectively. Considering the subgroup not on statins, TC levels were 127.5 ± 28.6, 134.2 ± 35.0, 117.8 ± 14.8; 131.0 ± 71.7, 121.1 ± 32.9, 118.6 ± 15.4; 115.5 ± 22.1, 121.4 ± 27.1, 119.0 ± 21.9 for placebo (n = 15, 72% of patients), REL-1017 25 mg (n = 10, 63%) and REL-1017 50 mg (n = 18, 95%), respectively. TG were 57.0 ± 25.6, 55.7 ± 20.0, 58.0 ± 34.1; 62.7 ± 52.1, 56.0 ± 31.0, 59.5 ± 32.6; 48.5 ± 25.3, 50.2 ± 18.4, 55.1 ± 21.9 for placebo (n = 21), REL-1017 25 mg (n = 16) and REL-1017 50 mg (n = 19), respectively. Considering the group not on statins, TG were 52.9 ± 27.6, 55.7 ± 23.1, 51.3 ± 26.8; 70.6 ± 63.3, 57.6 ± 38.9, 65.2 ± 38.9; 47.4 ± 25.4, 48.9 ± 17.9, 52.6 ± 19.5 for placebo (n = 15), REL-1017 25 mg (n = 10), and REL-1017 50 mg (n = 18), respectively. Levels of PCSK9, a key player of LDL cholesterol levels, significantly (P < .05) increased from baseline to day 7 and did not further change by day 14 for placebo, with similar results for REL-1017 25 or 50 mg groups, suggesting fluctuations unrelated to treatment. A total of 30% of the patients had hs-CRP plasma levels higher than 2 mg/L, thus potentially associated with a higher incidence of CV events. However, 7 days of treatment with REL-1017 did not alter hs-CRP plasma levels, neither at 25 mg/day nor at 50 mg/day. In summary, REL-1017 of 25 or 50 mg for 7 days did not affect TC, TG, PCSK9 and hs-CRP levels.ConclusionA 7-day treatment course with REL-1017 did not significantly alter TC, TG, PCSK9, or hs-CRP, suggesting the absence of detrimental effects on ASCVD risk. These data should be confirmed in longer and larger trials.FundingRelmada Therapeutics, Inc.