Genkyotex Meets Both Primary and Secondary Interim Efficacy Endpoints in Phase 2 Trial of GKT831 in Primary Biliary Cholangitis

• After only 6 weeks of treatment, gamma glutamyl transpeptidase (GGT) levels were reduced by 23% in the 400mg BID group (p<0.01)
• In patients with higher baseline GGT, reduction in GGT levels was even greater with 29% (p<0.01)
• Alkaline phosphatase (ALP) levels were reduced by 17% in the 400mg BID group (p<0.001)

ARCHAMPS, France I November 05, 2018 I Genkyotex (Paris:GKTX) (Brussels:GKTX) (Euronext Paris & Brussels: FR00011790542 – GKTX) announced today that its lead product candidate GKT831, a NOX1/4 inhibitor, met both the primary and secondary interim efficacy endpoints with high statistical significance after only 6 weeks of treatment. The data establish GKT831 as an attractive therapeutic option in a broad PBC population and support its development in multiple fibrotic diseases including NASH and IPF.

GKT831 achieved even greater GGT reductions (29%, p<0.01 vs placebo) in patients with higher baseline GGT (≥ 2.5 XULN, n=68), suggesting that it may also benefit patients with more advanced disease, the patient population with the highest medical need and limited therapeutic options.

In addition, the progressive reductions from baseline to week 2 and to week 6 suggest that further improvements can be achieved with continued treatment. Specifically, the 400mg twice daily dose (BID) achieved a 15% reduction in GGT at week 2 and a 23% reduction at week 6. ALP reductions were 12% at week 2 and 17% at week 6.

The interim analysis was conducted in 92 patients after 6 weeks of treatment. Final study results after 24 weeks of treatment in 111 PBC patients are expected in Spring 2019. The final results will also include additional endpoints assessing quality of life (fatigue and pruritus), fibrosis and cholestasis.

Elias Papatheodorou, Chief Executive Officer of Genkyotex, commented: “The clinical data further establish GKT831 as a novel anti-fibrotic candidate and confirm the therapeutic value of NOX inhibition for patients. NOX inhibitors are an emerging therapeutic class able to address many human diseases with unmet medical need. Following these interim results we are investigating options in non-alcoholic steatohepatitis (NASH) and primary sclerosing cholangitis (PSC).”

Philippe Wiesel, Chief Medical Officer of Genkyotex, commented: “The significant effect on the primary endpoint GGT, a marker of inflammatory and cholestatic liver injury, provides clinical confirmation of GKT831’s mechanism of action. We are very impressed by the highly significant effect on ALP, which indicates cholangiocyte protection. Importantly, ALP is a key endpoint used globally for regulatory approval. We are looking forward to the launch of the NIH funded IPF Phase 2 trial scheduled in H1 2019, the continuation of the JDRF funded DKD Phase 2 trial, and of course, seeing the final data of the PBC Phase 2 trial at week 24 in Spring 2019.”

About the PBC phase 2 trial of GKT831

The 24-week placebo-controlled study is being conducted in 62 centers (US, Canada, Belgium, Germany, Greece, Italy, Spain, UK and Israel). The trial enrolled PBC patients with inadequate response to ursodeoxycholic acid (UDCA). This is a difficult to treat patient population likely to progress to cirrhosis and eventually liver transplant or death. To be eligible for the trial, patients were required to have elevated alkaline phosphatase (ALP; >1.5XULN) and elevated gamma glutamyl transpeptidase (GGT; >1.5 XULN).

The primary efficacy endpoint is change in GGT at week 24. Key secondary endpoints include additional markers of liver and bile duct injury, markers of inflammation, non-invasive markers of liver fibrosis including liver stiffness assessed by transient elastography, the Enhanced Liver Fibrosis (ELF) score, and circulating collagen fragments including proC3. In addition, indicators of quality of life including pruritus and fatigue will be assessed. Markers of bile acid metabolism and immune activation will be also investigated.

A total of 111 patients have been allocated according to a 1:1:1 randomization ratio to three groups: UDCA plus placebo, UDCA plus GKT831 400mg once a day (OD) and UDCA plus 400mg twice a day (BID). This trial is one of the largest phase 2 PBC trials conducted to date.

For additional information about the trial design and eligibility criteria, please refer to the ClinicalTrial.gov website: NCT03226067.

About the interim analysis and baseline patient characteristics

The interim efficacy analysis was conducted when 92 patients completed 6 weeks of treatment. At baseline, mean ALP levels were respectively 304, 282, and 350 IU/L in the placebo, 400mg GKT831 OD, and 400mg GKT831 BID groups. Mean baseline GGT levels were respectively 224, 215, and 237 IU/L in the placebo, 400mg GKT831 OD, and 400mg GKT831 BID groups.

Changes in the primary efficacy endpoint GGT, a marker of liver and bile duct injury, were: -7% in the placebo, -12% in the 400mg OD, and -23%, in the 400mg BID groups (p<0.01 for the 400mg BID group vs placebo).

Changes in the key secondary efficacy endpoint ALP, a marker of bile duct injury, were: -2%, in the placebo, -8%, 400mg OD and -17% 400mg BID groups (p<0.001 for the 400mg BID group vs placebo). In PBC, a reduction in ALP of at least 15% is considered a meaningful biochemical response. Reduction of 15% in ALP was achieved in 53% of patients in the 400mg BID group compared to 16% in the placebo and 26% GKT831 400mg OD groups.

Markers of liver injury and inflammation were assessed. Although enrolled patients had relatively low levels of liver transaminases and high sensitivity C-reactive protein, dose dependent reductions were observed.

About clinical safety and pharmacokinetic (PK) analysis

To date, GKT831 has been well tolerated in PBC patients. On October 25 2018, the 3rd Safety Monitoring Board assessed safety data collected in 110 patients allocated to GKT831 400mg OD, GKT831mg BID, or placebo. From the patients reviewed, 87 patients had completed 6 weeks of treatment, 69 subjects had reached week 12 and of these 41 had completed the full 24-week treatment. The SMB provided a positive recommendation. A single serious adverse event (SAE), a case of grade 1 urinary tract infection, has been reported to date. Study drug was not interrupted and the SAE was deemed unrelated to study drug. Importantly, to date there has been no patient drop out due to pruritus.

An initial PK analysis was conducted. Plasma levels of GKT831 and its main active metabolite GKT138184 were measured after 2, 12, and 18 weeks of dosing. Available drug levels at the time of the interim analysis were analyzed. As anticipated, patients receiving 400mg BID had higher through (pre-dose) levels compared to patients receiving 400mg OD. Overall, these results indicate that drug exposure levels were consistent with expectations and with the two dosing levels included in the trial. These results will inform dose selection for future clinical trials of GKT831 in multiple fibrotic disorders.

About Primary Biliary Cholangitis

PBC is an orphan chronic autoimmune disease resulting in the progressive destruction of bile ducts. Decreased bile flow and build up of toxic bile acids results in further bile duct damage and liver injury. Over time, patients develop progressive liver fibrosis, cirrhosis, liver failure and are at higher risk of developing liver cancer. PBC affects primarily women and has a major impact of quality of life by causing fatigue and itching.

About Genkyotex

Genkyotex is the leading biopharmaceutical company in NOX therapies, listed on the Euronext Paris and Euronext Brussels markets. A leader in NOX therapies, its unique therapeutic approach is based on a selective inhibition of NOX enzymes that amplify multiple disease processes such as fibrosis, inflammation, pain processing, cancer development, and neurodegeneration.

SOURCE: Genkyotex