Cirius Therapeutics Announces Results from Phase 2b NASH Study Supporting Advancing to Phase 3 Development of MSDC-0602K; Data Accepted for Late Breaker Presentation at The Liver Meeting

- Treatment with MSDC-0602K resulted in statistically significant improvements in insulin resistance, glucose metabolism, and liver enzyme levels in 12-month EMMINENCE clinical trial

- MSDC-0602K treatment also resulted in dose-dependent trends toward improvement in liver histopathology, which did not reach statistical significance using the primary analysis methodology

- Total adverse event rate was similar across placebo and all MSDC-0602K groups; no signal for peripheral edema was observed

- Strong insulin sensitizing results support potentially pursuing outcomes-based endpoint in addition to liver biopsy surrogate endpoint in Phase 3

SAN DIEGO, CA and KALAMAZOO, MI, USA I November 8, 2019 I Cirius Therapeutics, a clinical-stage pharmaceutical company focused on the development and commercialization of innovative therapies for the treatment of liver and metabolic diseases, today announced data from its recently completed 12-month Phase 2b EMMINENCE clinical trial of MSDC-0602K for the treatment of non-alcoholic steatohepatitis (NASH). The data showed MSDC-0602K to be well-tolerated and demonstrated improvements in liver enzyme levels and markers of glycemic control, as well as dose-dependent trends for improvement in liver histology in NASH patients with or without Type 2 diabetes. Results will be presented in a late-breaking oral presentation at The Liver Meeting® on November 11, 2019 and will be published concurrently in the Journal of Hepatology.

"The results of this study consistently showed that treatment with MSDC-0602K led to significant improvements in glycemic control and laboratory measures of liver injury," said Bob Baltera, Cirius' chief executive officer. "While the histopathologic effects did not reach statistical significance in the primary analysis of this Phase 2 study, we are very encouraged by the consistent evidence of dose response across numerous measures, including biopsy. These results support the potential of an insulin sensitizer to improve liver histopathology in an adequately powered Phase 3 trial and, ultimately to improve cardiovascular outcomes in patients with NASH and diabetes."

MSDC-0602K, a second-generation, oral insulin sensitizer, is designed to selectively modulate the mitochondrial pyruvate carrier (MPC) while minimizing direct PPAR-gamma activation. The MPC mediates at the cellular level the effects of overnutrition, a major cause of non-alcoholic fatty liver disease NAFLD/NASH and Type 2 diabetes. In preclinical studies, modulation of the MPC has been shown to improve insulin sensitivity, lipid metabolism, and inflammation.

EMMINENCE Design
In the trial, 402 patients with biopsy-confirmed NASH (NAFLD activity score, or NAS, of ≥4, fibrosis score F1-F3) were randomized to daily oral doses of MSDC-0602K (62.5, 125 or 250 mg) or placebo. Treatment groups were well balanced in terms of baseline characteristics. Patients in the trial had a mean age of 56.1, a mean ALT of 56.8 U/L, and a mean NAS of 5.3. Overall, 58.2% of patients were female, 52.3% had Type 2 diabetes, and 61.5% had a baseline fibrosis score of F2 or F3.

Results of Biopsy Trend Toward Improvement
In EMMINENCE, baseline liver biopsies were initially read for qualification for the study, and then later mixed randomly among 12-month biopsies and re-read. Biopsy analysis was conducted using the re-read baseline and observed data (primary analysis), as well as using the qualifying baseline read and imputing missing data as a treatment failure (post hoc exploratory analysis), a methodology used in other late stage NASH trials. In the primary analysis, results showed dose-dependent trends toward improvement in NAS reduction by 2 or more points and NASH resolution. In the post hoc analysis, nominal statistical significance was observed at the 250 mg level in >2 point improvement in NAS and NASH resolution with >2 point reduction in NAS (see data below).

Biopsy results- primary analysis

  Placebo 62.5 mg 125 mg 250 mg
>2 point improvement in NAS 29.7% 29.8% 32.9% 39.5%
    p=0.747 p=0.575 p=0.158

Biopsy results- post hoc exploratory analysis

  Placebo 62.5 mg 125 mg 250 mg
>2 point improvement in NAS 27.7% 33.3% 39.8% 42.6%
    p=0.446 p=0.057 p=0.029
NASH Resolution with >2 point reduction in NAS 13.8% 18.2% 22.4% 26.7%
    p=0.348 p=0.146 p=0.026
Improvement of fibrosis with no worsening of NASH 20.2% 25.3% 27.6% 30.7%
    p=0.333 p=0.209 p=0.068

Statistically Significant Improvement in Liver Enzymes
Consistent with previously reported six-month data from EMMINENCE, Cirius reported a statistically significant improvement in levels of the liver enzymes alanine aminotransferase (ALT) and alkaline phosphatase at the 125 mg and 250 mg dose, aspartate aminotransferase (AST) at the 125 mg level, and gamma-glutamyl transferase at the 62.5 mg and 250 mg levels.  Notably, statistically significant higher rates of ALT normalization, as measured by the percentage of patients with high baseline values who returned to normal range at 12 months, were observed in the 125 mg and 250 mg doses of MSDC-0602K compared to placebo (see data below).

ALT Normalization Rates*
  Placebo 62.5 mg 125 mg 250 mg
ALT Normalization 6.8% 10.6% 20.8% 33.3%
    p=0.413 p=0.019 p<0.001

*ALT upper limit of normal defined as 19 U/L and 30 U/L for women and men, respectively

Glycemic Control Data Shows Robust Improvements
Across all patients, including diabetics and non-diabetics, MSDC-0602K demonstrated improvements in multiple parameters of glycemic control, with statistically significant reductions in HbA1c for all MSDC-0602K dose groups and in HOMA-IR,fasting insulin levels and fasting glucose for the 125 mg and 250 mg dose groups.

Dr. Stephen Harrison, EMMINENCE trial principal investigator, commented, "Insulin resistance is a common feature of the NASH population, and the results on objective measures showing MSDC-0602K's comprehensive improvements on insulin handling are very encouraging. There is an opportunity with this agent to directly evaluate the impact on cardiovascular outcomes without relying solely on the surrogate liver biopsy endpoints, which historically have been hampered by sampling error and variability in reading."

Treatment with MSDC-0602K Appears Well-Tolerated
In this study, MSDC-0602K was well-tolerated with similar proportion of patients across treatment groups experiencing one or more adverse or serious adverse events, including edema, bone fractures and hypoglycemia – side effects of some first-generation insulin sensitizers known to be related to direct PPARγ activity. Non-cardiac chest pain, which occurred in 4 patients (2 in the placebo group and 1 in each of the 62.5 mg and 125 mg groups), was the only serious adverse event that occurred in >2% of patients in any treatment group.  Discontinuation rates were numerically higher in placebo than in the active groups. Consistent with insulin sensitizing pharmacology, modest, dose-dependent weight gain was observed, with median increases of 0.8%, 1.1%, and 2.3% in the 62.5 mg, 125 mg, and 250 mg dose groups, respectively, compared to a median decrease of 0.5% in the placebo group.

Based on the results from EMMINENCE, Cirius plans to meet with regulatory authorities to discuss design for the planned Phase 3 study for MSDC-0602K.

"Insulin resistance is a cause of both diabetes and NAFLD, which lead to increased cardiovascular risk; therefore, a safe compound that increases a body's sensitivity to insulin has the potential to address the underlying pathophysiology of both diseases," said Howard Dittrich, M.D., chief medical officer of Cirius."These results indicate that MSDC-0602K can be dosed to full insulin-sensitizing pharmacology without dose-limiting side effects, with the greatest effects in patients with more severe liver injury and poorer glycemic control, a group who have an elevated risk for adverse cardiovascular outcomes."

About Cirius Therapeutics
Cirius is a clinical-stage pharmaceutical company focused on the development and commercialization of innovative therapies for the treatment of liver and metabolic diseases. Its lead product candidate, MSDC-0602K, is a novel small molecule being developed as a once-daily oral therapy to treat NASH. MSDC-0602K is designed to selectively modulate the mitochondrial pyruvate carrier (MPC), which mediates at the cellular level the effects of overnutrition, a major cause of NASH and other metabolic disorders.

For more information about Cirius Therapeutics, visit www.ciriustx.com.

SOURCE: Cirius Therapeutics

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