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  • 2 May 2019
    Genkyotex Reports Clinical Evidence of Anti-fibrotic Activity by GKT831 in Liver Fibrosis Patients

    Genkyotex (Euronext Paris & Brussels: FR0013399474 – GKTX) announced today top-line efficacy data for its NOX1/4 inhibitor GKT831 Phase 2 trial in primary biliary cholangitis (PBC). In a pre-defined patient population with an estimated liver fibrosis stage of F3 or higher, GKT831 achieved a 22% reduction in liver stiffness compared to a 4% increase for placebo (p=0.038). The top-line data provide a clinical proof of concept for GKT831 and highlight its potential as an anti-fibrotic therapy in the liver and other organs. Further analyses are ongoing and the full results will be submitted for presentation at an upcoming international liver conference.

    Elias Papatheodorou, Chief Executive Officer of Genkyotex, said: “The trial results provide evidence for a potential breakthrough treatment in complex and difficult to treat fibrotic disorders. We thank participating patients, their families, and the medical teams involved in this landmark clinical trial. We are looking forward to advancing GKT831 into late stage clinical trials in PBC and other fibrotic liver diseases, like NASH and PSC. In addition, we anticipate the launch of the NIH funded Phase 2 trial of GKT831 to treat lung fibrosis in the coming months.”

    The 24-week double-blind, placebo-controlled Phase 2 PBC study enrolled 111 patients in 9 countries, making it one of the largest and longest Phase 2 trials ever conducted in this indication. The primary endpoint was defined as the percent GGT reduction at week 24 and secondary endpoints included ALP changes, Fibroscan® elastography and quality of life (QoL). Statistical significance for all endpoints at week 24 was set at p<0.023, according to the Hochberg adjustment method for multiple analyses.

    At week 24, GGT reductions were -9% for placebo, -5% for 400mg OD, and -19% for 400mg BID. These changes did not achieve statistical significance at week 24, although statistical significance was achieved at the 6-week interim analysis. In patients with higher baseline GGT (≥ 2.5 XULN, n=86), GGT reductions were -6% for placebo, -14% for 400mg OD, and -21% for 400mg BID (p<0.039). A statistically significant reduction in overall treatment effect was observed for alkaline phosphatase (ALP) levels (p=0.002) over the course of the treatment period. At week 24, GKT831 400mg BID achieved meaningful reductions in alkaline phosphatase (ALP). Changes were -3% for placebo, -10% for 400mg OD, and -13% for 400mg BID (p<0.049 vs placebo). No changes were observed for total bilirubin (+11% for placebo, +5% for 400mg OD, and +15% for 400mg BID). On the composite endpoint of serum ALP <1.67xULN, an ALP decrease >15%, and total bilirubin (TB) <ULN, the response rates were 5% for placebo, 18% for 400mg OD, and 25% for 400mg BID. 

    Liver stiffness was measured by Fibroscan® transient elastography. Liver stiffness is an indicator of liver inflammation (edema), cholestasis and fibrosis. In multiple liver diseases, including PBC, NASH and PSC, liver stiffness correlates with liver fibrosis stage (F0 to F4). In PSC, increases in liver stiffness are associated with adverse disease outcomes, including liver transplant, hepatic complication and death.

    In PBC, a value greater than 9.6 kPa measured with Fibroscan® indicates fibrosis stage of F3 or higher. In the GKT831 Phase 2 PBC trial liver stiffness was determined in the intention to treat (ITT) population and in the predefined population of patients with a baseline value of 9.6 kPa or higher. Valid liver stiffness measurements (LSM) were obtained at baseline and at week 24 in 91 patients.

    At baseline median LSM was 10.7 kPa for placebo, 12.5 kPa for 400mg OD, and 8.3 kPa in the 400mg BID group. Median absolute changes at week 24 were +0.4 kPa for placebo, +0.1 for 400mg OD, and -0.4 kPa for 400mg BID. In the 45 patients with baseline LSM > 9.6 kPa (the predefined value for advanced disease), median baseline LSM was 12.3 kPa for placebo, 14.1 kPa for 400mg OD, and 12.1 kPa in the 400mg BID group. Mean percent changes at week 24 were +4% for placebo, -4% for 400mg OD, and - 22% for 400mg BID (p<0.038).

    Quality of life was evaluated with the PBC-40 questionnaire, which evaluates several important quality of life domains, which are presented in the table below. GKT831 improved parameters important for the quality of life of patients, such as fatigue, emotional and social domains.

    Favorable trends on additional secondary endpoints related to liver inflammation and fibrosis were observed but did not reach statistical significance. GKT831 exhibited a favorable safety profile throughout the 24-week treatment period. No drop outs or treatment interruptions due to pruritus or fatigue were reported. Only two serious adverse events were reported, a grade 1 urinary infection and multiple bone fractures related to a traffic accident. Both cases were deemed unrelated to study drug by the investigators.

    Philippe Wiesel, Chief Medical Officer of Genkyotex, said: “These results indicate that GKT831 has the potential to address the major unmet medical need in fibrotic liver diseases, which is to delay disease progression, obviating the need for transplant and death in multiple fibrotic disorders. In addition, in PBC, improvement in quality of life is key for patients and we are excited to see positive trends in multiple QoL domains important to PBC patients. Finally, the excellent safety profile of GKT831 has exhibited over the course of the treatment period clearly indicates that GKT831 may also be developed in combination with other complementary mechanisms of action, like generically available fibrates or UDCA.”