Galectin Offers Subgroup Approach For Struggling NASH Candidate

Having failed to meet its primary endpoint in consecutive Phase II studies, Galectin hopes to move GR-MD-02 forward in NASH in patients with cirrhosis who have not developed esophageal varices.

Galectin Therapeutics Inc. thinks subgroup analysis of its failed Phase IIb study in non-alcoholic steatohepatitis (NASH) highlights a way forward for its complex carbohydrate drug GR-MD-02, but investors don't seem to agree.

The Norcross, Ga., biotech reported Dec. 5 that GR-MD-02, targeting the galectin-3 protein which plays a role in fatty liver and fibrotic pathogenesis, failed to meet the primary endpoint of measurement of hepatic venous pressure gradient (HVPG) from baseline compared to placebo in a 52-week, 162-patient study. (Also see "Galectin Hopes To Set Surrogate Endpoints For NASH Cirrhosis, Despite Trial Failure" - Pink Sheet, 28 Sep, 2016.) But the company said a subgroup representing 50% of the trial enrollment and approximately half of NASH patients with cirrhosis – patients without esophageal varices – did show statistically significant and clinically meaningful results on the primary endpoint.

The drug, however, did not show similar benefit for patients with esophageal varices, which is a sign of increased portal hypertension in the liver and diverts blood flow through the esophagus rather than the liver, the company said. Bleeding from esophageal varices – essentially dilated veins in the esophagus – can be a major cause of morbidity and mortality in NASH patients with cirrhosis.

"We believe that this was because there was more variability in HPVG measurements for patients with esophageal varices," Galectin CEO Peter Traber told a same-day investor call. However, in patients without esophageal varices, benefit from treatment with GR-MD-02 was seen regardless of the patient's level of portal hypertension, he added.

Confounding the Phase IIb findings is the fact that more positive data trends, sometimes the difference between reaching statistical significance or not, were seen with the lower dose tested in the study than with the higher dose.

Looking at the entire patient population for absolute change in HVPG, a 0.4 mmHg increase was seen in the placebo group, while HVPG decreased 0.2 mmHg in a treatment arm receiving 2 mg/kg of GR-MD-02 and 0.4 mmHg in a group receiving 8 mg/kg of the drug. In each case, this showed a positive trend for therapy, but fell short of statistical significance. When looking at the findings in terms of percent change in HVPG from baseline, placebo arm patients were up a mean 8%, while the lower-dose treatment arm was down 1% and the higher-dose arm was down 2%.

However, for patients who had no esophageal varices at baseline, absolute change in HVPG from baseline was a 0.8 mmHg increase in placebo patients, a 1.2 mmHg decrease in patients receiving 2 mg/kg of GR-MD-02 and a 0.2 mmHg increase in patients getting the 8 mg/kg dose. Looking at percentage change in HVPG from baseline, this subgroup saw a 12% increase for the placebo arm, a 9% decrease for the lower-dose arm and a 0.5% increase for the higher-dose arm.

Traber had no answer for why there was a consistently greater and statistically significant effect with the 2 mg/kg dose, and said this was an important question for further study. Because the data suggest that higher doses of GR-MD-02 would not likely prove more efficacious, he suggested a logical approach in future studies would be to increase the duration of therapy rather than increasing the dose.

Improvement In Hepatocyte Ballooning Seen

Galectin also stressed data on a pair of secondary endpoints suggests a positive role for GR-MD-02 in NASH therapy. In the overall study population, a statistically significant effect was seen in improving hepatocyte ballooning (which essentially is liver cell death, Traber noted). Biomedtracker analysts concluded these data were modest and did not result in an overall improvement in non-alcoholic fatty liver activity disease score (NAS), even though hepatocyte ballooning is a component of NAS.

An analysis of a secondary endpoint of cirrhosis complications also showed that there was a statistically significant reduction in development of new esophageal varices in patients without varices at baseline. This might suggest a preventative role for the drug, the company claimed. Biomedtracker also questioned the value of these data, because there were only three new cases of varices seen in patients with varices at baseline, suggesting the drug itself may not have played a major preventative role.

"We believe there may be a link between this improvement in [hepatocyte ballooning] and the improvement seen in HVPG," Traber said. "Importantly, we found that a statistically significant clinical outcome effect of GR-MD-02 treatment was observed on reducing the development of varices in patients without esophageal varices at baseline. Esophageal varices are major contributors to patient morbidity and mortality in NASH cirrhosis and a critical link between portal hypertension and clinical symptoms of NASH cirrhosis."

Lead investigator Stephen Harrison of San Antonio-based Pinnacle Clinical Research said GR-MD-02's potential benefits, including prevention of esophageal varices, could be clinically valuable. He posited that a NASH sub-indication of NASH cirrhosis without varices would be meaningful to clinicians because standard of care for cirrhosis is an upper endoscopy to check for such varices. Galectin has been focused on surrogate endpoint findings with the drug because in previous trials it did not show a clear signal of efficacy on liver fibrosis, an endpoint used in most NASH trials so far. (Also see "Seven Clinical Trial Read-Outs Due In Q4" - Scrip, 11 Oct, 2017.)

Traber added that Galectin's subgroup data offer a large, easy-to-identify group of NASH patients and that the company's subgroup analyses might point to potential registrational endpoints in NASH, such as considering development of esophageal varices as a clinical outcome. Change in HVPG has been suggested by US FDA as an acceptable surrogate measure for outcomes in clinical trials, he pointed out, and the Phase IIb data indicate that either absolute or percentage change in this marker could prove useful.

Galectin intends to discuss design of a Phase III program for NASH cirrhosis without varices with regulators, as well as key opinion leaders and pharmaceutical companies, Traber said.

Outside Optimism Waning

Neither investors nor Biomedtracker shared Galectin's optimism, however. Galectin's stock closed down nearly 31% at $1.72 per share on Dec. 5 and continued declining during the trading day on Dec. 6.

Biomedtracker reduced GR-MD-02's likelihood of approval by two percentage points to 13% after the Phase IIb data were reported, placing the drug's chances 11 percentage points below the average 24% likelihood of approval anticipated for Phase II NASH candidates.

This makes GR-MD-02 the lowest rated candidate for the disease in Biomedtracker's assessment of 26 current Phase II candidates. Four of the candidates – Novartis AG's emricasan (25%), Bristol-Myers Squibb Co.'s ARX618 (26%), Gilead Sciences Inc.'s GS-0976 (25%) and NGM Biopharmaceuticals Inc.'s NGM282 (27%) – are given above-average likelihood for approval, while the other 21 candidates all are given a 24% chance. (Also see "Behind The NASH Leaders, Pursuers Already Anticipating Second-Wave Improvements" - Scrip, 3 Nov, 2017.)

(Meanwhile, Madrigal Pharmaceuticals Inc. unveiled impressive interim Phase II efficacy data Dec. 6 for its NASH candidate, MGL-3196, leading to both investor and market analyst enthusiasm.) (Also see "Madrigal's Early Phase IIb NASH Data Show Clinically Meaningful Fat Reduction" - Scrip, 6 Dec, 2017.)

"Though investigators did highlight that analysis of the 2mg/kg dose in patients without esophageal varices met the primary endpoint, the reproducibility of this result in unclear," Biomedtracker stated in its overview of the data. "Only 25 of the 162 patients randomized into the trial were included in this arm of the trial, significantly limiting the sample available for analysis. Additionally, data presented by Galectin in that subgroup analysis did not exhibit a dose dependent response to the medication further increasing level of doubt. There was a numerical dose response in the overall population, but the effects were quite modest (10% improvement or less) and there was substantial variability."

Biomedtracker had said Galectin's previous Phase IIa study with GR-MD-02 showed no signal of efficacy for liver fibrosis, and reduced the drug's likelihood of approval by 10 percentage points to 15% after the top-line data were reported in September 2016.