ConSynance Therapeutics

CSTI-100/ALB-127158

Mechnism of Action

Melanin-concentrating hormone Receptor Type 1 (MCHR1) Antagonist  https://www.ncbi.nlm.nih.gov/gene/?term=MCHR1

Overview

CSTI-100 (also known as ALB-127158) is a novel melanin-concentrating hormone receptor-1 (MCHR1) receptor antagonist. CSTI-100 has high affinity (IC50 Human recombinant MCHR1, 7 nM) for MCHR1 with good selectivity over a range of other G-protein coupled receptors (GPCRs), ion channels and transporters, including the MCHR2. In functional assays, CSTI-100 was shown to be a potent and selective MCHR1  antagonist (IC50 = 47 nM). In a mouse diet induced obesity (DIO) model, treatment with CSTI-100  in the range of 5 – 15 mg/kg bid produced a significant, sustained decrease in body weight and food intake. The weight reduction was predominantly due to a decrease in fat content. The weight loss was accompanied by an improvement in glycemic control and increased insulin sensitivity in an oral glucose tolerance test (OGTT).  In rats, CSTI-100 administered orally produced significant and dose-related occupancy of MCHR1 in an ex vivo binding assay and doses >1.25 mg/kg po produced significant occupancy in excess of 60% for up to 24 hours. There was a strong correlation between MCHR1 occupancy, reduction in food intake and weight loss, consistent with the weight loss being mediated by MCHR1. The oral bioavailability in rat and monkey was approximately 66% and 55% respectively with t1/2 of approximately 5 h in both species. For additional preclinical pharmacology and safety data see: http://www.amriglobal.com/img/document_files/Pharmacology%20of%20ALB-127158(a),%20an%20antagonist%20of%20the%20MCH1%20receptor%20for%20the%20treatment%20of%20obesity.pdf    

Safety/Tolerability

In clinical studies, ALB-127158(a) was safe, well tolerated, with minimal adverse events reported in both a Single Ascending Dose (SAD) (up to 475 mg QD) and Multiple Ascending Dose (MAD) (up to 300 mg QD for 14 days). There were no dose limiting cardiovascular, ECG or behavioural adverse events observed. Sufficient brain exposure (as measured by CSF sampling) of CSTI-100 was achieved although the peripheral exposure level was much higher. To date, a total of 62 patients have received CSTI-100.  Preclinical studies of up to 28-day duration have been performed.

Additional Information

Reductions in ‘Hunger’ and ‘Desire to Eat’ using the Visual Analog Scale were observed at 300 mg in the 14-Day MAD studies.

Suitable for and Exclusions

There are no known contraindications for CSTI-100. No study has been performed in pediatric subjects ( 6 – 15 years of age).   There are no preclinical reproductive toxicology available.

Clinical Trials

The studies were conducted in the UK: http://www.hra.nhs.uk/news/research-summaries/a-study-to-investigate-concentrations-of-alb-127158-in-plasma-and-csf/ .  See publication: https://www.ncbi.nlm.nih.gov/pubmed/?term=alb-127158

Additional Characteristics: CNS Penetrance/Pediatric Diseases

Based upon concentrations of CSTI-300 in CSF of volunteers, the compound is expected to have significant CNS receptor occupancy at tolerated doses. Studies in pediatric populations for which there is no adult population will be considered. Due to the significant peripheral exposure, it might be suitable for non-CNS indications as well.  Studies for diseases/conditions that have a pediatric and adult population will also be considered if studies in a pediatric population are scientifically justified. However, due to the lack of juvenile toxicology data or prior experience in pediatric subjects, use will depend on risk/benefit, dosing duration and regimen, and age of the pediatric population.

Publications

https://www.ncbi.nlm.nih.gov/pubmed/?term=alb-127158