Earlier this month, Raptor Pharmaceutical Corp.'s RP103 (cysteamine bitartrate delayed-release) failed a phase IIb trial in pediatric nonalcoholic steatohepatitis (NASH), but the letdown hasn't dampened other companies' enthusiasm for the lucrative NASH market. Good thing, considering there are nearly 90 trials in NASH patients planned or being run by 17 biopharmas and dozens of research institutions, according to Cortellis Clinical Trials Intelligence.

Raptor's trial, dubbed Cysteamine Bitartrate Delayed-Release for the Treatment of Nonalcoholic Fatty Liver Disease [NAFLD] in Children (CyNCh), did not achieve its primary endpoint, defined as a two-point decrease in NAFLD activity score (NAS) and no worsening of fibrosis ("p" value = 0.34). (See BioWorld Today, Sept. 15, 2015.)

Much of the high spirits from the rest of the industry come from the low level of confidence everyone had that RP103 would show a clinical effect in the phase IIb trial based on the initial data phase IIa data.

"We viewed previous phase IIa NAFLD data as intriguing, but the small, open-label, single-arm nature of the study limited its utility. The primary endpoint of reduction in alanine aminotransferase (ALT) at 24 weeks along with other serologic metrics (CK18 and adiponectin) was improved in a statistically significant manner. Without histological data, this was necessary but not sufficient to de-risk phase IIb in our view," Leerink Partners LLC analyst Joseph Schwartz wrote in a note to clients.

The serological improvements seen in the phase IIa trial were repeated in the phase IIb trial, supporting Schwartz's assertion that surrogate endpoints don't necessarily translate to a clinical improvement in the NAS score.

Novato, Calif.-based Raptor isn't done with RP103 yet though, vowing to continue testing the drug in Huntington's and Leigh Syndrome.

"We see no reason to change our probabilities of success for other RP103 pipeline programs given the fundamental differences in disease pathologies. NASH is a multifactorial liver disease likely related to lipotoxicity, whereas Huntington's and Leigh Syndrome (RP103 is in phase I/II or phase II development for both) are more fundamental mitochondrial toxicities that manifest as neurological degeneration," Cowen and Co. LLC analyst Ritu Baral wrote in a research note.

PRESSING ON

Just two days after Raptor's announcement, Galectin Therapeutics Inc. said it was starting a second phase II trial testing GR-MD-02 in patients with NASH who have advanced fibrosis.

In June, Galectin started its first phase II trial, called NASH-CX, in NASH patients with advanced fibrosis and cirrhosis. The trial is expected to enroll 156 patients split between two doses – 8 mg/kg or 2 mg/kg – or placebo. The primary endpoint is the change in hepatic venous pressure gradient, which correlates with the amount of cirrhosis. The trial will also take biopsies to measure fibrosis stage and the percent of collagen after one year of treatment, which will act as secondary endpoints. Galectin, of Norcross, Ga., expects to complete enrollment by August 2016 and have data a little over a year later.

The new trial is smaller with just 15 patients receiving 8 mg/kg of GR-MD-02 and 15 in a placebo group. The NASH patients will be earlier in the disease development, having advanced fibrosis but not cirrhosis. With a shorter four-month treatment, biopsies aren't possible, so the primary endpoint will be a non-invasive LiverMultiScan using multi-parametric magnetic resonance imaging. Secondary endpoints will evaluate liver stiffness, which correlates to the degree of liver fibrosis. Galectin expect data for this shorter trial will be available in the third quarter of 2016.

GR-MD-02 is a complex carbohydrate drug that targets galectin-3, which is expressed on macrophages and is involved in the pathways leading to inflammation and fibrosis of the liver. A phase I trial in NASH patients with advanced fibrosis showed that three out of five patients lowered their liver stiffness to below 80 percent of baseline, compared to zero out of three for the placebo group.

LEADING THE PACK

New York-based Intercept Pharmaceuticals Inc. is ahead of Galectin both literally because the company has already worked out details for a phase III trial testing obeticholic acid scheduled to begin this quarter and figuratively because the trial is testing patients early in their NASH development before cirrhosis has set in. (See BioWorld Today, May 20, 2015.)

Most of the rest of the NASH drugs are also testing NASH patients without cirrhosis. For example, Genfit SA's positive phase IIb trial testing elafibranor (GFT505) specifically excluded patients with stage 4 NASH, when advanced fibrosis and cirrhosis sets in. Genfit SA, of Lille, France, is planning a phase III trial for elafibranor, but hasn't released the details of the trial yet.

Gilead Sciences Inc., of Foster City, Calif., is one of the only exceptions besides Galectin of a company treating late-stage NASH patients. Simtuzumab, which targets LOXL2 that lays down the collagen, creating scar tissue that destroys the liver's architecture and function, is in a phase IIb trial in NASH patients with cirrhosis.

Treating NASH before cirrhosis develops is theoretically easier because the drug doesn't need a mechanism that removes the cirrhosis. But measuring the treatment effect is complicated by NASH's long disease progression. A study published this year in Hepatology by Ekstedt, et al. found that early stage 1 and 2 NASH patients had no increase in mortality. But by the time they reached stage 3 and 4, patients had increased mortality compared to matched counterparts.

"It's the cirrhotics that have complications eventually," Galectin's CEO, CMO and president Peter Traber told BioWorld Insight.

Will it be easier to gain approval for later-stage NASH patients? "It'll be more straightforward to get approval; I won't say easier," said Traber, highlighting the clearer clinical endpoints for late-stage disease.

Once approved though, Traber believes it'll be easier for GR-MD-02 to gain reimbursement compared to drugs for early stage NASH. "Getting payers to pay for it will be easier because you're closer to clinical outcomes," he said.