Reference
Crater, G. D., Lalonde, K., Ravenelle, F., Harvey, M., & Després, J.-P. (2024). Effects of CB1R inverse agonist, INV-202, in patients with features of metabolic syndrome. A randomized, placebo-controlled, double-blind phase 1b study. Diabetes, Obesity and Metabolism, 26(2), 642–649. https://doi.org/10.1111/dom.15353
Info
FirstAuthor:: Crater, Glenn D.
Author:: Lalonde, Karine
Author:: Ravenelle, François
Author:: Harvey, Michael
Author:: Després, Jean-Pierre
~
Title:: Effects of CB1R inverse agonist, INV-202, in patients with features of metabolic syndrome. A randomized, placebo-controlled, double-blind phase 1b study
Year:: 2024
Citekey:: CraterEtAl_2024_EffectsCB1RInverse
itemType:: journalArticle
Journal:: Diabetes, Obesity and Metabolism
Volume:: 26
Issue:: 2
Pages:: 642-649
DOI:: 10.1111/dom.15353
Link
Abstract
Abstract Aims To evaluate the clinical safety, tolerability, and pharmacokinetic and pharmacodynamic profile of the novel cannabinoid receptor-1 (CB1R) inverse agonist, INV-202, in adults with features of metabolic syndrome. Materials and Methods This was a multicentre, randomized, double-blind, placebo-controlled, 28-day repeat-dose (INV-202 [25?mg] or placebo, once-daily oral tablet), parallel-group study in 37 participants aged 18 to 65?years (46% female, mean age 55?years, glycated haemoglobin 5.7% [39 mmol/mol], body mass index [BMI] 38.1?kg/m2) with features of metabolic syndrome and glucose intolerance. An oral glucose tolerance test (OGTT) was performed at baseline and at the end of the study. Lipid profiles, weight, waist circumference and biomarkers were assessed weekly. Statistical comparisons were performed post hoc. Results INV-202 was well tolerated with no serious or severe treatment-emergent adverse events; the most common events related to known effects of CB1R blockade in the gastrointestinal tract. INV-202 produced a significant mean weight loss of 3.5?kg (3.3% compared with placebo participants who gained a mean 0.6?kg [0.5%]). INV-202 also exhibited significant reductions in waist circumference and BMI (P?≤?0.03). There was no significant difference in OGTT 0- to 3-hour area under the curve for INV-202 versus placebo: least squares mean 29.38 versus 30.25?h*mmol/L, with an INV-202: placebo ratio of 97.1% (95% confidence interval 90.2, 105.6; P?=?0.43). Conclusions INV-202 was well tolerated, producing a signal for rapid weight loss with improvements in other metabolic syndrome markers in this population. These findings support further exploration and long-term assessment of cardiometabolic effects.
Blue: Important conclusions
Highlight ( Page 7)
Over 28 days, INV-202 (25 mg daily) was well tolerated, with no reported serious adverse events (SAEs) or severe TEAEs. A signal for rapid weight loss was observed with improvements in several markers of cardiometabolic risk. INV-202 systemic PK exposure was as expected.
Yellow: Interesting
Highlight ( Page )
28-day repeat-dose (INV-202 [25 mg] or placebo, once-daily oral tablet), parallel-group study in 37 participants aged 18 to 65 years (46% female, mean age 55 years, glycated haemoglobin 5.7% [39 mmol/mol], body mass index [BMI] 38.1 kg/m2) with features of metabolic syndrome and glucose intolerance.
Highlight ( Page 2)
Participants were randomly assigned (1:1) to INV-202 (1 25 mg tablet) or placebo (1 tablet) taken orally, once daily with food
Highlight ( Page 2)
Administration INV-202 with food (standard meal) is recommended to reduce the incidence of gastrointestinal adverse effects and to improve tolerance
Highlight ( Page 3)
INV-202 was well tolerated over 28 days of treatment,
Highlight ( Page 4)
The most common TEAEs were related to the known effects of CB1R blockade in the gastrointestinal (GI) tract, namely, increased GI motility (nausea, diarrhoea), abdominal discomfort, and decreased appetite
Highlight ( Page 4)
Participants treated with INV-202 showed decreasing trends in mean weight and mean waist circumference
Highlight ( Page 6)
There were favourable trends for HbA1c
Highlight ( Page 6)
Mild accumulation of both analytes (INV-202 and DA-INV-202) was observed following daily INV-202 doses over 28 days, with increased mean Ctrough from D8 to D29 (24 hours post-dose; Figure 2).
Image ( Page 6)
Red: Disagree with the paper
Highlight ( Page 4)
EAEs of special interest (depression, anxiety, irritability, and insomnia) were experienced by four participants (20%; INV-202), of which one experienced three events (insomnia, depressed mood, irritability). However, three of these participants had pre-existing related conditions including mood disorder, depression and insomnia, and two were menopausal with a history of related insomnia. One participant on placebo reported anxiety
Purple: To learn more
Highlight ( Page 6)
Individual and mean change in trough plasma concentrations for INV-202 and its metabolite, DA-INV-202 by study day.