On February 19, Intercept announced that olbecholic acid (OCA) has achieved positive results in the mid-phase analysis of the key phase III REGENERATE study of patients with nonalcoholic steatohepatitis (NASH) with grade 2 to 3 liver fibrosis.
Efficacy data from the primary endpoint showed: 1) At the 18th month of OCA 25mg once-daily treatment, the proportion of patients with at least grade 1 liver fibrosis and no worsening NASH was significantly higher than the placebo group (23.1% vs 11.9%) , p=0.0002). 2) At the 18th month of the OCA 10mg and 25mg treatment groups, the proportion of patients with improved histopathology (reduced fat accumulation) and no worsening of fibrosis was higher than that of the placebo group, but there was no statistically significant difference.
In terms of safety, adverse events in the REGENERATE study are usually mild to moderate. The most common adverse events were consistent with the results of previous clinical trials of oleic acid, mainly dose-related pruritus, with a prevalence of 19%, 28% in the placebo group and in the 10 mg and 25 mg groups. 51%. Most of the pruritus events were mild to moderate, and the incidence of severe pruritus in the 3 groups was <1%, <1% and 5%, respectively. The proportion of patients who discontinued treatment in 3 groups due to severe itching was <1%, <1% and 9% respectively.
The incidence of serious adverse events was similar in the 3 treatment groups (11%, 11%, 14%), and no serious adverse events occurred in each group with a prevalence of more than 1%. Three patients died but were not associated with medication. Two patients in the placebo group died of bone cancer and cardiac arrest, and one patient in the OCA 25mg group died of glioma.
In addition, elevated levels of LDL-C associated with oleic acid treatment were also seen in the REGENERATE study, which reached a peak of 22.6 mg/dL at week 4 and then gradually returned to the baseline level of 18 mg/dL. Severe cardiovascular events were rare in the three groups and clinical manifestations were significantly different, with incidences of 2%, 1%, and 2%, respectively.
Abecholic acid is a farnesoid X-receptor agonist. In January 2015, the FDA was awarded a breakthrough drug qualification for treating patients with liver fibrosis with NASH. It is the first NASH to enter phase III clinical practice in the world. drug. The REGENERATE study was officially launched in September 2015. It is a very ambitious clinical trial. It was originally planned to recruit 2,500 people worldwide for 72 weeks (18 months). After completing 1400 patients, an interim analysis was performed. Because the test of the enrollment and composite endpoints of this trial requires liver biopsy of the patient, it is difficult to implement, resulting in slow recruitment of patients, and the progress of the trial is not satisfactory.
In February 2017, Intercept announced that it had communicated with the FDA and obtained FDA approval to change the number of patients meeting the mid-term analysis from 1400 to 750, while changing the criteria for successful trials from reaching the composite endpoint to reaching only one of them. One end point
After the difficulty of the trial was reduced, Intercept originally expected to be able to conduct interim analysis in mid-2017, but the interim analysis results were not released until early 2019, which also confirmed the difficulty of NASH new drug clinical trials, including patients’ awareness of the disease. Adequate, NASH drug clinical trials set the end point standards are not uniform.
Intercept’s competitor Genfit also encountered difficulties in recruiting patients. A week ago, Gilead’s ASK1 inhibitor selonsertib (GS4997) missed the first-level endpoint in its first phase III clinical trial of NASH (STELLAR-4 study) and even collapsed Intercept’s share price.
Regardless of the external environment, abecholic acid was the first NASH drug to be successful in a key phase III study. Intercept plans to submit a new drug for the treatment of NASH on the 2019H2 to the FDA and EMA for the treatment of NASH. Abecholic acid is also the only drug currently approved by the FDA for the treatment of breakthrough therapy for patients with liver fibrosis with NASH.
Dr. Mark Pruzanski, President and CEO of Intercept, said: “We are the first company to report a successful Phase III clinical trial of NASH New Drugs. The first-line data from the REGENERATE study confirms our confidence in launching the first therapeutic drug for NASH patients with liver fibrosis. Thanks to the test subjects, the investigators, and all the staff involved in the trial, and thanked them for helping NASH patients take a major step toward new treatment options.”
Intercept’s share price surged more than 20% during the pre-market trading session on February 19.
NASH is a serious progressive liver disease caused by excessive accumulation of fat in the liver and is the main cause of liver fibrosis, cirrhosis, liver failure, liver cancer and death. NASH patients with a higher degree of liver fibrosis have a higher risk of death from liver-related diseases.
Diet and exercise can effectively reverse early fatty liver disease, but the obesity rate in the United States is rising, leading to a high prevalence of NASH in the United States. According to the US Liver Foundation, according to the definition of disease, the number of NASH patients in the United States is between 15 million and 30 million. By 2020, NASH will be the leading cause of liver transplantation in the United States.
There are currently no drugs for the treatment of NASH approved. In 2014, Deutsche Bank issued a report stating that the size of the global NASH therapeutics market is expected to exceed $30 billion by 2024. EvaluatePharma predicts that the market size of NASH drugs worldwide will reach $40 billion by 2025.
Ocaliva was approved by the FDA in May 2016 for the treatment of primary biliary cirrhosis (PBC), which was also conditionally approved by the European Union in December 2016. Ocaliva’s sales revenue for the first nine months of 2018 was $125 million.
Intercept’s strategy for the development of olbecholic acid is first approved by small indications for primary biliary cirrhosis, and it provides strong support for the development of NASH indications through widespread use in the real world. As it turns out, the current income of oleic acid is nearly 200 million US dollars, which not only provides support for the company’s new drug development, but after nearly three years of market tempering, Intercept’s liver disease business has taken shape, and the accumulated expert resources are more Conducive to the promotion of NASH indications.