Genfit SA is venturing into nearly untapped territory by launching a program in children with nonalcoholic steatohepatitis (NASH) with elafibranor, its dual PPAR alpha/delta agonist. The Lille, France-based company said the FDA signed off on its initial pediatric study plan, or PSP, for a NASH pediatric trial in the U.S. that is consistent with a previous concord with the EMA on its pediatric investigation plan, or PIP. In the coming weeks, Genfit plans to open enrollment in a dose-ranging study in the U.S. on children with NASH who are 8 to 17 years of age that, if successful, will lead to a single pivotal trial designed for filings on both sides of the Atlantic.

Genfit is one of the few companies making tangible progress in the growing pediatric NASH indication, which has bedeviled other comers. Gilead Sciences Inc. made a move in that direction with now-abandoned simtuzumab (GS-6624), a monoclonal antibody targeting the human lysyl oxidase-like 2 protein that it picked up in its $225 million buyout of privately held Arresto Biosciences Inc. (See BioWorld Today, Dec. 21, 2010.)

Raptor Pharmaceutical Corp. crashed and burned in its phase IIb effort, dropping its shares more than 40 percent after top-line data showed the Cysteamine Bitartrate Delayed-Release for the Treatment of Nonalcoholic Fatty Liver Disease (NAFLD) in Children, or CyNCh, study missed its primary endpoint, defined as a two-point decrease in NAFLD activity score (NAS) and no worsening of fibrosis ("p" value = 0.34).

A year later, Horizon plc picked up Novato, Calif.-based Raptor and its core rare disease pipeline in an all-cash deal valued at approximately $800 million. (See BioWorld Today, Sept. 15, 2015, and Sept. 13, 2016.)

Genfit is more emboldened by the opportunity in pediatric NASH, which has no approved therapies, than deterred by the earlier failures. Securing approval of the full development plan in both the EU and U.S. was key to taking the next step, according to Sophie Mégnien, the company's chief medical officer and a member of the steering committee of the Liver Forum.

Concurrence with the FDA and EMA was based, in part, on data from the phase IIb GOLDEN-505 study, which supported elafibranor's potential benefit in pediatric NASH based on the drug's safety, histology and cardiometabolic efficacy, Mégnien said. Although the phase IIb investigation missed its primary endpoint, findings, published in Gastroenterology, showed that elafibranor had an effect on histology, or resolution of NASH without worsening of fibrosis, as defined in subsequent protocols for the randomized, double-blind, placebo-controlled phase III RESOLVE-IT study in adult NASH, now underway and expected to enroll some 2,000 participants.

Cardiometabolic benefits of elafibranor – reduction in risk factors such as lipids, insulin resistance, glucose homeostasis and inflammation – also turned up during GOLDEN-505, and the drug was shown to be safe and well tolerated. (See BioWorld Today, March 27, 2015, and Nov. 17, 2015.)

"We're not giving a lot of details on the studies, but in the pediatric population, just like any specific population, you start with dose-ranging and [pharmacokinetics], and this will be immediately followed by a large phase III pivotal trial," Mégnien told BioWorld.

Children progress into NASH 'just like adults but even quicker'

What's still under discussion with regulators is whether endpoints for the pivotal trial in children will be the same as those for the phase III in adults. According to Cortellis Clinical Trials Intelligence, RESOLVE-IT is measuring co-primary endpoints: the proportion of elafibranor-treated patients who achieve NASH resolution without worsening of fibrosis compared to those on placebo and a composite long-term outcome composed of all-cause mortality, cirrhosis and liver-related clinical outcomes. Among the secondary outcome measures are improvement in histological scores in NASH, in fibrosis, and in cardiometabolic and liver markers in patients on the study drug vs. placebo, along with safety measures.

"We're actively discussing this with regulators," Mégnien said. "We also have a specific working group in the Liver Forum to come to a consensus among the experts in the industry and the FDA on the endpoints to be used in those pediatric trials."

Genfit also expects those discussions to yield guidance on a suitable enrollment target for regulatory filings.

"We have the NASH pediatric experts on board," Mégnien said, citing Joel Lavine, co-chair of the NASH clinical research network at the National Institute of Diabetes and Digestive and Kidney Diseases and chief of the division of pediatric gastroenterology (GI)/hepatology/nutrition at New York Presbyterian Children's Hospital and Columbia University.

Increasingly, pediatric GI and liver specialists are seeing children and adolescents "who already have NASH when they're 4-year-olds and have cirrhosis when they're 12-year-olds," Mégnien pointed out. "They're all pre-diabetic. They have very high triglycerides. It's really a metabolic dysfunction, and the children progress into NASH, into fibrosis and into cardiovascular disease just like adults but even quicker. For us, it's a matter of targeting both patient populations in parallel."

The safety profile and metabolic effects of elafibranor make the drug well suited for chronic treatment as early as childhood, where the main goal is to halt and reverse liver injury, she said. The ultimate aim of pediatric NASH treatment is to improve quality of life by reducing long-term morbidity and mortality related to the metabolic consequences of fatty liver disease and the impeding progression to cirrhosis and its complications.

The trends aren't pretty. Fatty liver is the most common liver abnormality in children ages 2 to 19 years, according to data on pediatric NASH and NAFLD from the Clarivate Analytics Incidence and Prevalence Database (IPD). However, the true prevalence of NAFLD and NASH in children isn't known, given that the definition and modalities used for diagnosis are not standardized.

Most studies of the prevalence of fatty liver in children have been restricted to the use of indirect measures, such as blood tests or ultrasound, to predict a histological outcome. Population-based approaches suggest an overall prevalence of at least 3 percent for suspected fatty liver disease among children and adolescents in the U.S. and Asia. The histology of the liver, the most important criterion for diagnosis, is usually not used for screening but, according to retrospective studies in autopsy findings, fatty liver was present in about 13 percent of children and adolescents, and histological evidence of steatohepatitis was shown in 23 percent of that group.

About two-thirds of obese adults and half of obese children may have fatty liver, according to the IPD data. The consequences are dire: When compared with their normal counterparts, overweight and obese adolescents had 4.14 and 5.98 times, respectively, greater risk of having NAFLD. In reported clinical series of pediatric NAFLD, the mean age was between 11 and 13 years. After controlling for gender, race and ethnicity, the prevalence of fatty liver increased with age ranging from 0.7 percent for ages 2 to 4 years to 17.3 percent for ages of 15 to 19.

In the course of its development program for elafibranor, Genfit aims to tease out more data on the natural history of the disease in adults and children.

"The first clinical trials in children will be very important to get longitudinal data with a pharmacologic intervention," Mégnien pointed out. "That will add a lot of information for everybody. Regulators are really looking forward to these data, as well."

For all the action in adult NASH, Genfit has little competition in pediatric NASH, at least for the present. Some companies have hinted at exploring NASH candidates in children, including Gemphire Therapeutics Inc. with its small molecule, gemcabene, but none has yet moved an asset into the clinic.

Pediatric NASH also is in the sights of Axcella Health Inc. (formerly Pronutria), a well-funded Flagship Ventures launch that is investigating its Designed Amino Acid Compositions, or DAAC, candidates across the spectrum of liver conditions, from early stage NAFLD to NASH and cirrhosis. Axcella, however, is conducting its studies under FDA food and dietary supplement guidelines so any product approvals would not compete directly with elafibranor.

All of which position elafibranor as "the first compelling molecule to launch an established pediatric program, built on solid phase II ground," observed Roth Capital Partners analyst Yasmeen Rahimi in a flash note on FDA approval of Genfit's PSP. She characterized pediatric NASH as a "continually growing space with high unmet medical need," suggesting that, "given the obesity epidemic in the U.S., we suspect prevalence will only rise."

On Tuesday, shares of Genfit, traded as GNFT on the Euronext Paris, closed at €27.50 (US$33.81) for a gain of €0.62 (US$0.76).