Spitfire Pharma's SP-1373 outscored semaglutide and elafibranor in a biopsy-proven translational mouse model of non-alcoholic steatohepatitis (NASH)
- Category: Proteins and Peptides
- Published on Thursday, 04 January 2018 20:44
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SOUTH SAN FRANCISCO, CA, USA I January 4, 2018 I Spitfire Pharma, Inc., ("Spitfire") announced today that SP-1373, its lead glucagon-like peptide-1 (GLP-1) and glucagon receptor dual agonist compound, demonstrated superior outcome measures in liver histopathology and metabolic parameters versus semaglutide (a GLP-1 agonist) and elafibranor (a PPAR alpha/delta agonist) in the biopsy-proven, AMLN-diet Gubra NASH mouse model.
Twelve weeks of treatment with SP-1373 (10nmole/kg SC, QD) significantly reduced body weight of the obese mice to the low normal range while semaglutide (10nmole/kg SC, QD) produced a less significant weight decrease, demonstrating the benefit of the dual agonist SP-1373. Elafibranor (78μmole/kg, PO) also produced significant weight decrease under these conditions yet, historically, this effect has not translated to weight decrease in clinical trials. SP-1373 demonstrated a substantial decrease in whole-body fat mass with minimal effect on lean tissue. Plasma ALT, AST, and total cholesterol levels were also significantly reduced in SP-1373 treated animals versus vehicle controls.
SP-1373-treated mice demonstrated a major decrease in liver weight. Histology revealed a near complete absence of liver steatosis, in contrast to the other treated groups, which showed only modest decreases in steatosis. Liver triglycerides and total cholesterol were significantly reduced by SP-1373 (P<0.0001 vs. vehicle). Total type 1 collagen staining, used as a measure of liver fibrosis, was significantly reversed with SP-1373 treatment (P<0.0001 vs. vehicle) compared to all other treatments. The non-alcoholic fatty liver disease activity score (NAS score), the clinical measure of NASH activity, improved in the majority of treated animals and was reduced to the greatest extent by SP-1373. Of particular note, hepatosteatosis in all SP-1373 treated animals was significantly decreased (P<0.0001 vs vehicle) compared to other treated groups.
Sequencing of mRNA from livers of SP-1373-treated animals suggested significant beneficial effect to many pathways, particularly those involved in fibrosis (col1A1, TGFB1, etc.), inflammation (TLR4, TNFR, ASK1), lipid metabolism (FASN, SCD1), monocyte recruitment (MCP1, CD68), and insulin signaling.
In summary, SP-1373 has demonstrated the ability to reverse fibrosis and substantially improve NAS scores, while also addressing metabolic and glucoregulatory deficits in a well-recognized, biopsy-proven, translational mouse model of NASH by gubra.dk. Based on these results, SP-1373 shows great promise as a potential new treatment for NASH.
"Type 2 diabetes, obesity and non-alcoholic steatohepatitis are major medical problems that are still in need of additional therapeutics. Spitfire Pharma, Inc. and other companies have been interested in harnessing the beneficial effects of the body's natural dual acting hormone oxyntomodulin (GLP-1/glucagon dual receptor agonist). A successful drug of this nature could add to the toolkit of physicians caring for such patients," said Dr. Andrew J. Perlman, Spitfire's Chief Medical Officer.
Non-alcoholic fatty liver disease and NASH are stages in the progression of serious liver disease resulting from nutrient overload and metabolic dysfunction. NASH is associated with excess fat, inflammation and fibrosis in the liver and may progress to cirrhosis and liver cancer. In the United States, studies report a prevalence of NAFLD of 10 to 46 percent, with most biopsy-based studies reporting a prevalence of NASH of 3 to 5 percent. There are no approved drugs for NASH which is projected to be the major cause of liver transplant by 2020.
About Spitfire Pharma, Inc. and Velocity Pharmaceutical Development, LLC . Spitfire Pharma, Inc., is a development stage company managed by Velocity Pharmaceutical Development (VPD) and focused on the development SP-1373, a novel dual GLP-1/glucagon agonist for the treatment of NASH, diabetes and obesity.
Velocity Pharmaceutical Development, LLC (VPD) is dedicated to rapidly advancing promising drug candidates to clinical proof of concept using a highly virtual management model. VPD is staffed by a seasoned team of clinical drug developers with expertise identifying attractive drug candidates, target markets, and designing and managing outsourced clinical trials. This expert team manages multiple single asset companies to remove the costly overhead and misaligned incentives present in traditional biotechnology company structures. Detailed information is available at www.vpd.net.
SOURCE: Spitfire Pharma