After setbacks, CymaBay moves forward with potential treatment for liver disease
CymaBay CEO Sujal Shah / Courtesy of CymaBay Therapeutics
After enrollment failure that led to clinical suspension and delays due to the COVID-19 pandemic, based in Bay Area Therapeutic CymaBay is back in the clinic with lead candidate seladelpar, a potential treatment for primary biliary cholangitis (PBC).
In 2019, CymaBay was conducting studies on seladelpar, a potent and selective agonist of the delta receptor activated by peroxisome proliferators (PPARδ), in PBC, as well as for non-alcoholic steatohepatitis (NASH). The studies were going well, but when the company started evaluating the blinded interim data from the NASH trial, the pathologist on the research team began to see a significant number of atypical histologic findings. About 30% of patients presented with signs of atypical histologies, including histology characterized as a presentation of interface hepatitis, with or without biliary injury, CymaBay CEO Sujal Shah told BioSpace in an exclusive interview. .
By excess of caution, the drug studies in NASH and PBC were discontinued, and the asset has been placed on clinical hold by the United States Food and Drug Administration. There were concerns that these patients had other underlying illnesses or that seladelpar itself was causing harm.
“We had to stop ethically and study what this meant for the drug and for our business,” Shah said.
After about nine months, an independent investigation by liver experts and pathologists determined that all unusual histological features were initially present before patients entered the study, Shah said. It turned out that pathologists did not report these patients when they were first enrolled in the study.
“It was indeed a false alarm. The NASH study and the PBC study should never have been stopped, ”he said. “If we hadn’t had to stop, we could see a potential approval this year. “
The the wedges have been lifted by the FDA in July 2020, but the company’s schedule had been severely delayed by the miscalculation. Still, Shah said there were cash flips to every setback, and they were able to learn even more about the effectiveness of seladelpar, especially in PBC, which was the subject of a small phase III study.
For the discontinued PBC study, CymaBay announced last year that due to the early discontinuation and the small number of patients who had reached the 52 week time point, the primary outcome measure was changed before the Lockdown of the database at a three-month time point that was achieved by 167 of 265 patients. The modified data shows that seladelpar achieved the composite primary outcome with high statistical significance in 78.2% of patients in the 10 mg group and 57.1% in the 5 mg group versus 12.5% in placebo after three months. Shah said the results were promising and confirmed what the company had seen previously. However, a second Phase III study would be required to bring the asset to the finish line in PBC.
“2021 was about going back to the clinic,” he said.
The company anticipates the continued efficacy of seladelpar in PBC during this new phase III study. Last year’s dataset is expected to be reflected in the ongoing Phase III study, said Shah, which may lead to approval of a new treatment option for patients with PBC. PBC is a chronic disease in which the bile ducts in the liver are slowly destroyed, causing toxic bile acids to build up in the liver. The disease mainly affects women and can lead to an increased risk of cancer or death. Two of the most common indicators of the disease are debilitating fatigue, as well as pruritus, an intense itch that goes well below the skin.
Currently, there are only two drugs approved by the FDA for PBC. The first is ursodeoxycholic acid (UDCA), which has been in use for about 30 years. Shah noted that the drug slows the progression of the disease, but a significant number of patients, around 40%, have an inadequate response. The other drug is Intercept Pharma‘s obeticholic acid (Ocaliva), which was approved in 2016. Ocaliva helps some patients, but like UDCA, a significant number of patients are not receiving adequate benefit, Shah said. Worse yet, Ocaliva can cause or worsen the itching associated with PBS.
If seladelpar is ultimately approved by the FDA, Shah believes it will be able to help a significant number of patients without making the itching worse. Recent data presented in November at the annual liver meeting of the American Association for the Study of Liver Disease highlights the potential of the drug CymaBay in these patients. The company is seeing long-term improvements for up to 2 years in patients, which Shah called lasting benefits. He also finds a response rate of around 80% in patients. The data showed that by three months almost 30% had normalized and by two years the numbers had risen to 40%.
“We believe that seladelpar may give a greater proportion of patients a greater degree of disease improvement,” Shah said. “The medical community is now talking about standardization as a goal. “
The new Phase III study is expected to be fully recruited in 2022. From there, the first data is expected around 13 months after that. If the data is right, a new drug application could be filed within six months with potential approval by the end of 2022.
“When we saw the impact seladelpar had on patients, it gave us the energy to tackle the challenges we faced,” Shah said.
For PBC, seladelpar has received an orphan designation from the FDA and the European Medicines Agency. Seladelpar has also received Breakthrough Therapy designation from the FDA and PRIME status from the EMA for PBC.