NASH is a chronic liver disorder that results in progressive fibrosis, ultimately culminating in some patients in liver cirrhosis. In cirrhosis, the fibrotic scar tissue distorts the normal liver architecture resulting in impairment of liver cell function as well as an increase in the blood pressure in portal circulation that feeds most of the blood to the liver (portal hypertension). Patients with NASH are typically asymptomatic until they develop cirrhosis when they may develop complications of portal hypertension such as variceal bleeding, ascites, and encephalopathy. Because NASH is a silent disorder, there are many individuals who present to the health care system with NASH cirrhosis. Therefore, a therapy that can halt, and ideally reverse, NASH cirrhosis is a major hope for NASH therapeutics.

However, the drug development landscape for NASH is becoming littered with failures in NASH cirrhosis. As I recently presented at the NASH Summit 2019 (see slides), while there are many drugs in development for pre-cirrhotic NASH, there are only 6 drugs that have been completed or are in clinical trials for NASH cirrhosis, with four of the six having failed to meet the study primary endpoint.


Gilead Bioscience ($GILD)

$GILD has been the leader in studying drugs in NASH cirrhosis, but their drugs have suffered major setbacks. Simtuzumab, a LOXL2 monoclonal antibody delivered either intravenously or subcutaneously, failed to meet primary and secondary endpoints in clinical trials in both cirrhotic and pre-cirrhotic NASH and development on this compound has been abandoned. In February, ($GILD) reported failure of the phase III STELLAR4 trial that evaluated oral selonsertib in patients with NASH cirrhosis (stage 4 fibrosis).

Similarly, in April $GILD reported failure of the phase III STELLAR 3 trial that evaluated selonsertib in NASH patients with stage 3 fibrosis. After the STELLAR4 results, I wrote a blog suggesting STELLAR3 might still have a chance of success, but the results with drug trended to be worse than placebo. Clearly, based on these two large and well-powered studies, selonsertib for fibrosis in NASH is not effective. Therefore, the two major drugs $GILD has studied in NASH cirrhosis are failures.

Galectin Therapeutics ($GALT)

$GALT reported results in December 2017 of their phase 2 NASH-CX clinical trial of intravenous GR-MD-02 (now designated belapectin) for 52 weeks in patients with compensated NASH cirrhosis with HVPG ≥6 mmHg (HVPG=hepatic venous pressure gradient). The trial failed the primary endpoint of a reduction in HVPG in the total population (ITT). The placebo group had an increase in hepatocyte ballooning over the one-year study which was ameliorated by the lower of two doses of belapectin. However, there were no differences discerned between placebo and drug on liver fibrosis using liver biopsy or serum biomarkers.

In a post-hoc analysis of the NASH-CX data, patients without varices at baseline had a significantly reduced HVPG in drug treated patients compared to placebo, but there was no dose response as the effect was only seen in the low dose treatment group. Additionally, in the low dose group there was a lower incidence of varices development over the year of treatment (not a pre-specified endpoint), while ballooning and fibrosis assessment was not reported for this subgroup. These results in the subgroup without esophageal varices require repetition in a study designed specifically to evaluate this patient population with pre-determined endpoints (e.g. varices) to confirm the validity of the results.

While there are no study details to review on clinicaltrials.gov, the company has indicated it plans to initiate a phase 3 study in patients without varices at baseline using belapectin treatment for two years. The company indicated the protocol is being finalized with target start in fall 2019. While accurate estimates of patient recruitment timing cannot be evaluated without study details such as number of patients to be enrolled, results of this study will likely not be available until 4-5 years from now.

Conatus Pharmaceuticals ($CNAT)

$CNAT has reported data on multiple phase 2 studies of its oral pan-caspase inhibitor emricasan in liver disease, including NASH cirrhosis. Generally, in each study emricasan has shown pharmacodynamic effects of caspase inhibition. The ENCORE-PH study evaluated patients with compensated NASH cirrhosis with HVPG ≥12 mmHg, as well as a minority of patients with a single decompensation event, with 24 weeks of therapy of placebo versus 3 doses of emricasan with the primary endpoint of change in HVPG. Results presented at EASL in April 2019 showed no significant difference between treatment and placebo in HVPG in the total patient group. However, in the group of patients with HVPG ≥16 mmHg, there was a significant reduction of HVPG with each of the three doses of emricasan, suggesting efficacy in a more severe group. Of note, the ongoing ENCORE-LF trial which will be reported later this year studies more severe patients with decompensated NASH cirrhosis.

In another setback this year, the ENCORE-NF trial in patients with pre-cirrhotic NASH (F1-3) failed to show an effect on liver fibrosis. Patients (n=318) were randomized to receive two doses of emricasan or placebo twice daily for 72 weeks with the primary endpoint of at least a one stage reduction in liver fibrosis. Taken together, these trial results suggest that emricasan does not have an important effect on liver fibrosis but may impact portal hemodynamics in later stages of cirrhosis. Once all the data analyzed by $CNAT and its partner Novartis, we will learn whether they wish to progress emricasan in targeted patient populations of advanced cirrhosis, or in combination therapy. In any event, approval of emricasan in NASH cirrhosis does not appear to be on the horizon for at least 5 years.

Intercept Pharmaceuticals ($ICPT)

The REGENERATE trial results in April 2019 with obeticholic acid in pre-cirrhotic NASH represents a watershed moment in NASH drug development. This is the first positive phase 3 clinical trial in patients with NASH (fibrosis stage 2-3). While the effect was only positive in 23% of all patients and there was no effect on NASH resolution, the magnitude of the effect was generally in line with expectations from phase 2, all secondary analyses were consistent, and AEs were consistent with the known profile for obeticholic acid. I view these results as the “glass half full” with likely approval in NASH but a lot of room for improved efficacy with other drugs or combinations.

$ICPT is conducting the REVERSE trial in compensated NASH cirrhosis with the primary endpoint of a one-stage reduction in fibrosis with data expected in July 2020. Given the results in REGENERATE, it is possible that REVERSE will have positive results, but since fibrosis in cirrhosis is greater and appears recalcitrant to therapy, I would not be surprised if this trial fails to meet its endpoint. Even if positive, obeticholic acid would not likely have a label for NASH cirrhosis for 2-3 years.

Bristol-Myers Squibb ($BMY)

Pegbelfermin, a subcutaneously administered pegylated version of FGF21, is being studied by $BMY in both pre-cirrhotic NASH and compensated NASH cirrhosis. Two multiple-dose phase 2b trials are expected to report results in January 2020. There is a strong scientific rationale for FGF21 treatment in NASH given its pleotropic hormonal effects on metabolism and extensive pre-clinical and clinical data. However, since its anti-fibrotic effects are not well documented, the efficacy in NASH cirrhosis is more speculative. Even if the phase 2 in NASH cirrhosis is positive, eventual approval for this indication is likely to be 4-5 years in the future.

Summary

This review of the advanced stage clinical trials in NASH cirrhosis does not paint a pretty picture for patients with this disease or their treating physicians. There is a hope that the REVERSE trial is positive and will lead to approval of obeticholic acid in NASH cirrhosis in 2-3 years, although the efficacy is not likely to be robust. The $GILD assets, simtuzumab and selonsertib, failed large well-controlled trials. The $GALT and $CNAT phase 2 trials failed their primary endpoints, with subgroup analysis suggesting the drugs may be useful in certain patient populations. The subgroup results with both drugs require validation in clinical trials designed to enroll the targeted subgroups.

My overall assessment is that marketing approval for a drug in NASH cirrhosis, beyond the possible exception of obeticholic acid, is at least 5 years away. Many of the companies with drugs in development for pre-cirrhotic NASH and mechanisms that may work in NASH cirrhosis, are likely to avoid the NASH cirrhosis indication because the regulatory pathway for pre-cirrhotic NASH is better defined and likely easier to achieve. In the end, the field requires additional drugs with mechanisms that focus on both reduction in fibrotic tissue synthesis (fibrogenesis) and breakdown of fibrotic tissue (fibrolysis) to progress therapeutic options in this challenging disorder.

Date of Publish: May 1, 2019

Disclosure: The author previously was an employee of Galectin Therapeutics (ended June 2018).

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