With top-line data from a potential registrational trial in nonalcoholic steatohepatitis (NASH) patients with cirrhosis not coming until the end of 2017, investors were seeking some positive signs from an exploratory phase II study of Galectin Therapeutics Inc.'s galectin-3-targeted candidate, GR-MD-02, in NASH fibrosis. Instead, the Norcross, Ga.-based company reported late Tuesday that the trial, dubbed NASH-FX, missed both primary and secondary endpoints, raising doubts on Wall Street for the drug's overall prospects in the blockbuster indication.

Galectin's stock (NASDAQ:GALT) tumbled Wednesday, falling as low as $1.13 and ending the day at $1.40, down $1.07, or 43.3 percent. Shares traded hands at more than 18 times the average volume.

For now, investors will have to wait until December of next year for readout in the ongoing NASH-CX trial. No interim analysis currently is included in the study protocol, Peter Traber, Galectin's president, CEO and chief medical officer, confirmed during a late Tuesday conference call. "But it is something we can consider and we'll be looking into," though he stressed that no decision has been made at this point.

Despite the miss, both Traber and Stephen Harrison, who served as the lead investigator for NASH-FX and is the co-lead investigator for NASH-CX, said they believe GR-MD-02 remains a promising treatment for NASH, while co-lead NASH-CX investigator Naga Chalasani, chief of the Division of Gastroenterology and Hepatology at Indiana University, said the NASH-FX results "do not diminish the significance" of the ongoing phase IIb trial in NASH cirrhosis.

The pilot NASH-FX study was designed based on positive – though limited – data from an earlier phase I study suggesting that Fibroscan measurements improved in patients after just four doses of study drug, said Harrison, medical director of Pinnacle Clinical Research in San Antonio and a visiting professor of medicine at the University of Oxford, U.K.

Fibroscan is a noninvasive technique for measuring liver stiffness, which correlates to fibrosis.

"While most experts, including myself, feel that liver fibrosis trials should have treatment phases for at least a year in duration, the results from the phase I study provided a rationale for studying a larger group of patients with a shorter therapy and exploring noninvasive techniques for assessing liver disease, liver stiffness and fibrosis," Harrison explained.

In addition to looking for efficacy, the NASH-FX trial also was designed specifically to test three of those noninvasive techniques – Fibroscan, magnetic resonance elastography (MRE) and Livermultiscan (LMS) – for potential use in later trials. Liver biopsy currently is the gold standard for diagnosis and monitoring the progression of NASH, though it is invasive and prone to sampling error.

NASH-FX enrolled 30 patients with advanced fibrosis to test four months of GR-MD-02 treatment. The primary endpoint was LMS, a magnetic resonance imaging test designed to evaluate inflammation and fibrosis. Fibroscan and MRE assessments were secondary endpoints. All patients had a liver biopsy prior to treatment in the study; however, biopsies were not performed at the conclusion of the trial, due to safety considerations.

Harrison noted that it was "encouraging" that GR-MD-02 indicated improved clinical effect in moderate to severe psoriasis, "suggesting the compound has activity in a human disease that can occur in association" with NASH.

Studies have shown that nonalcoholic fatty liver disease is prevalent in patients with psoriasis. Galectin has studied GR-MD-02 in that indication, reporting in May results from a 12-week study showing significant improvements in Psoriasis Area and Severity Index. Given the further testing required to differentiate the compound in the heavily competitive psoriasis space, Galectin opted not to pursue psoriasis on its own.

"The company's attention has always been focused on completing the NASH-CX trial and reporting results in a timely fashion," Traber told investors and analysts on Tuesday's call. The launch of any additional studies, such as a longer trial in NASH fibrosis using liver biopsy as the endpoint, will have to wait.

ACCEPTABLE ENDPOINTS?

Galectin recently reported that it completed recruitment for NASH-CX a month ahead of schedule, with a total of 162 patients, exceeding the 156-patient goal for the one-year study.

"In determining the number of patients to meet the statistical requirements," Traber said, Galectin plans for the possibility that as many as 25 percent of enrolled patients would drop out during the trial. Only three so far have done so, however, "a trend that suggests that we will have a robust number of patients." NASH-CX was designed to be powered at 80 percent with 117 patients. "Anything above 117 simply increases the power" and the trial could be powered "well over 95 percent" if the full 162 complete the trial.

The study's primary endpoint is hepatic venous pressure gradient (HVPG), which measures the blood pressure in the liver and is "well-correlated with the clinical outcomes of patients," Traber explained. Liver biopsy will be a secondary endpoint, as will evaluations by noninvasive tests, including Fibroscan.

While noting the firm has received no official determination from the FDA, Traber said the possibility exists that the agency might accept the endpoints from the phase IIb NASH-CX trial as acceptable surrogates for outcomes in that patient population. Should the HVPG data prove sufficiently robust, the FDA could decide to consider NASH-CX a pivotal trial.

To date, the agency has not set out specific parameters for proving efficacy with surrogate endpoints.

"At this point, a HVPG of 10 mmHg has been kind of defined as clinically relevant portal hypertension," Traber said. "Portal hypertension occurs at a pressure of 6 [mmHg] or greater. A clinically relevant, quote-unquote, portal hypertension is 10 mmHg [so] we targeted our patient population of well-compensated cirrhosis to have an HVPG of between 12 [mmHg] and 15 [mmHg]."

Though "I don't want to speak for the FDA," Traber said reducing HVPG from above 10 mmHg to below 10 mmHg is "likely to be an endpoint they would accept as clinically significant."

Other research has indicated that a 10 percent to 20 percent reduction in HVPG is also clinically significant. Traber pointed to a study conducted by researcher Guadalupe Garcia-Tsao, testing beta-blocker timolol in gastroesophageal varices, which showed reductions of HVPG mmHg greater than 10 percent reduced the complications of variceal hemorrhage, ascites and the progression of cirrhosis. Whether the FDA would accept that as a registration endpoint "has not been completely sorted out," Traber acknowledged, though he added that Galectin's study was designed with both of those measurements in mind.

"There hasn't been a drug approved based on HVPG as yet, but those are the types of endpoints the FDA is talking about finding acceptable," he said. "We just have to wait until the end of the trial to see how the FDA is going to respond."

As of Tuesday's call, four patients in NASH-CX have completed the entire protocol. Sixty-seven have completed six months, and a total of 1,883 drug transfusions have been given, "representing nearly 45 percent of the total infusions for the study," Traber noted. "So we're quite pleased that this study is well along in its development."

Galectin also reported a vote of confidence from another quarter. Existing stakeholder Richard Uihlein agreed to a $1.5 million private placement financing, investing the funds through limited partnership investment fund 10X. And Traber said on Tuesday's call that Uihlein has committed to helping the firm progress through the completion of the NASH-CX trial, though he declined to provide specifics. "Our intention is to pursue additional funding," he said.

As of June 30, Galectin had about $18 million on its balance sheet.

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