Due to the lack of clear endpoints, sponsors have been waiting to advance non-alcoholic steatohepatitis (NASH) candidates into pivotal trials. But with an agreement with FDA on the horizon, the leading candidate should have a Phase III protocol in place in the next few months.

NASH is seen as a coming epidemic of liver disease, presenting a host of serious issues and co-morbidities arising from Western hemisphere lifestyle issues. As warnings about NASH and the risks it poses for fibrosis, cirrhosis and the need for liver transplants increase, the industry is taking notice as clinical development activity and deal-making in the space are inclining sharply.

What Is NASH

Non-alcoholic steatohepatitis has been called the next big crisis in liver disease in part because it has a population, largely undiagnosed, larger than that of hepatitis C. Deutsche Bank analyst Alethia Young estimates that between 12 million and 13 million Americans and citizens of the five largest EU nations may have NASH with advanced liver fibrosis.

The total NASH population in the U.S. is estimated at between 18 million and 30 million people. Projections are very broad at present, but it’s believed that between 15%-40% of obesity cases may lead to NASH and that between 25% and 70% of patients needing bariatric surgery have NASH, Young stated on a March 23 conference call.

The disease remains largely undiagnosed because its natural history is not well understood, and also because there is no approved drug treatment. Exacerbating the issue is that diagnosis typically requires a liver biopsy – one or more biomarkers to assist in identifying patients with the disease would be especially useful.

A relatively simple explanation of NASH is that it represents how the liver expresses metabolic disease, Young said. A common theory holds that NASH may lead to an inflammatory cascade that can go on to affect the extracellular matrix. In a spectrum of liver disease, a patient with a normal liver might progress to steatosis, then NASH, before developing fibrosis, which itself can lead to cirrhosis and the need for a liver transplant.

Several companies pursuing different mechanisms of action are nearing the end of Phase II with their candidates, but a pivotal pathway for this unmet medical need does not yet exist, in part because the growing and widely undiagnosed indication is ill-suited to the kinds of outcomes trials that ordinarily might warrant a drug’s approval.

FDA and the American Association for the Study of Liver Disease convened a working group in late 2013 to consider options for a registrational pathway, and a consensus seems to be emerging that at least the first NASH therapies will be approved on the basis of surrogate endpoints Also see "Searching For Surrogate Endpoints Requires Teamwork" - Pink Sheet, 30 September, 2013..

During an investor briefing March 23, analyst Alethia Young of Deutsche Bank Market Research said a Phase III protocol announcement is on track for the second quarter of 2015, as perhaps the most advanced NASH candidate, Intercept Pharmaceuticals Inc.’s obeticholic acid (OCA), has completed Phase IIb studies and is about ready to move into Phase III ([A#00141117003]).

Coming out of AASLD’s industry forum on NASH and hepatitis B in Durham, N.C., March 21-22, Young said she remained confident “that potential endpoints will focus on reversal of NASH and that OCA can achieve these endpoints in Phase III.”

“To do a trial that would require, for instance, time to cirrhosis or time to transplant [would be] really impractical and hinder drug development.” – Raptor CMO Krishna Polu

Intercept confirmed to “The Pink Sheet” that it expects to finalize the design of its Phase III program in the second quarter. OCA gained FDA “breakthrough” therapy status in January, which has allowed for greater consultation with the agency on the development program.

“We currently believe that we will conduct at least one Phase III clinical outcomes trial of OCA in NASH patients that would incorporate an interim surrogate endpoint and that may serve as the basis for filing for accelerated approval in the U.S. and approval in Europe,” the firm said in a statement. The trial would continue for confirmation of clinical benefit, but that could occur post-market under accelerated approval.

“Potential surrogate endpoints include the use of histological improvement, using the NAS [non-alcoholic fatty liver disease (NAFLD) activity score] or another scoring system, or histological resolution of NASH, or improvements in fibrosis in pre-cirrhotic patients with NASH,” it added, “and examples of potential endpoints to confirm clinical benefit include liver transplant-free survival or progression to cirrhosis.”

Young told the AASLD meeting that she expected potential surrogate endpoints for pivotal trials could be reversal of steatohepatitis without worsening of fibrosis and decrease in NAS with improvement in multiple components, without worsening of fibrosis. A co-primary endpoint could measure decrease in NASH with improvement in fibrosis, she added. Reversal of steatohepatitis and improvement in NAS were among the endpoints discussed at the 2013 FDA/AASLD workshop.

Intercept had previously, in a March 2014 SEC filing, indicated it was planning two Phase III trials, both powered for clinical outcomes with interim endpoints, one in pre-cirrhotic NASH patients with advanced fibrosis and one in cirrhotic patients with NASH and other chronic liver diseases – and it was hoping to have discussions with regulators about biomarkers that could avoid the need for liver biopsy ([A#00140324003]).

Agreement on validated biomarkers that could obviate the need for liver biopsy would drastically ease drug development, and surrogate endpoints are essential because waiting for outcomes data would take so long – though FDA might be content, under accelerated approval, with outcomes assessment after approval.

In an interview, executives at Raptor Pharmaceutical Corp., which is developing cysteamine bitartrate for pediatric NASH, explained that waiting for outcomes data could be especially difficult because many trials are using early-stage patients ([A#14130730003]).

The Impact Of Earlier-Stage Patients

“If you look at many of the studies that have been conducted to date in NASH, they are in earlier stages of NASH and so to do a trial that would require, for instance, time to cirrhosis or time to transplant [would be] really impractical and hinder drug development,” Raptor Chief Medical Officer Krishna Polu said in an interview.

Raptor is nearing the completion of a Phase IIb trial of its cysteamine bitartrate (RP103) and is starting to plan the clinical and regulatory strategy to progress to Phase III and approval. In this regard, unofficial guidance from the FDA/AASLD meetings on NASH in 2013 has been very helpful, Polu added.

“In general, NASH is a disease that is slowly progressive, and in many cases patients are asymptomatic,” he continued. “There is a lot of focus on trying to enable therapies to move forward in this space without requiring initially typical hard clinical endpoints required by the FDA for drug approval.”

“The usual hard endpoints would [measure] how a patient feels, functions or survives,” he said. “So the document published by the FDA and AASLD provided a lot of guidance, although it is not an FDA guidance document, to sponsors on potential approvable endpoints, either to support full approval and opportunities for … accelerated approval. I think we and others are looking to that document to guide us.”

“What appears to be the case is that [FDA] is willing to consider histological improvements in the liver with treatment as an approval pathway,” Polu said.

“In general, what appears to be the case is that the agency is willing to consider histological improvements in the liver with treatment as an approval pathway for drugs in NASH. Largely, that is a reversal in steatohepatitis without progression of fibrosis,” the exec said.

That would be a positive development for Raptor, he clarified, because its Phase IIb program is using a primary endpoint of histological evaluation of changes in NAS from baseline to 52 weeks, as well as documentation that there is no progression of fibrosis.

Raptor is focusing on pediatric NASH with its candidate because cysteamine bitartrate (RP103) already is approved as Probysci for adults and children six years and older for nephropathic cystinosis in the U.S. and Europe ([A#14130501008]). Raptor believes the safety data it has for Probysci in the pediatric population could hasten its approval in NASH.

The lysosomal cysteine transporter is being tested in 160 pediatric patients in a randomized, double-blind, placebo-controlled Phase IIb trial being conducted by the National Institute of Diabetes and Kidney and Digestive Diseases and its NASH Clinical Research Network, though Raptor retains development and commercialization rights in NASH, CEO Julie Anne Smith explained.

Raptor expects data from the trial in the second half of this year now that all patients have completed 52 weeks of treatment. What remains is for each patient to be biopsied, which could occur one to two months after each completes treatment, and for those scans to be evaluated, Polu said.

The Phase IIb data are “going to tell us a lot about probability of success in subsequent studies that may be required to advance the program,” Polu said. Raptor hopes to be able to participate in end of Phase II discussions with FDA later this year, and to discuss an accelerated approval pathway for the pediatric indication.

But Smith said Raptor would be unlikely to seek approval based on Phase II data. “I think others [who are] being a bit more aggressive in their assumptions have said there’s a case to be made with regulators that if the data are overwhelmingly positive, you could make a case for some sort of approval with a post-approval confirmatory trial,” the CEO explained. “Right now, our base assumption is that additional clinical development is warranted.”

Deal-Making Heating Up, Market Projections Are High

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AASLD’s recent industry forum on NASH drew between 100 and 200 attendees, Deutsche Bank’s Young noted, and organizers said interest level was so great that registration had to be closed early. Among the companies presenting on their NASH programs at the meeting were Intercept, Gilead Sciences Inc., Tobira Therapeutics Inc., NGM Biopharmaceuticals Inc. and Galectin Therapeutics Inc.

Deal-making has been heating up in NASH in recent months (see sidebar). One recent highlight was Merck & Co. Inc.’s Feb. 23 wide-ranging collaboration with NGM, in which the pharma obtained, among other things, worldwide rights to preclinical “diabesity” candidate NP201, which will be studied in diabetes, obesity and NASH ([A#14150223002]).

While Intercept’s mechanism, a synthetic farnesoid X receptor (FXR) agonist, is seen as the leading candidate in NASH, Young pointed out that numerous different pathways and targets are being investigated in the indication. The natural history of NASH is not well understood, the analyst said, and the patient population is highly heterogeneous as well as greatly undiagnosed at present. Diagnosis, development and update will improve with the identification of reliable biomarkers, she predicted.

Young reported that 106 NASH clinical trials are underway in the U.S. at present. A review on BioMedTracker found 12 clinical candidates currently in Phase II worldwide, as well as 10 in Phase I (see sidebar).

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She projects the market will grow steadily and sharply as the first therapies come online later in this decade. Deutsche Bank projects that a sub-billion-dollar market in 2019 will grow to $9.2 billion worldwide in 2021 and continue that trajectory, passing the $30 billion barrier in 2025. Young anticipates peak annual sales of NASH agents at between $35 billion and $40 billion toward the end of the next decade.

As in hepatitis C and HIV, the NASH market may evolve to a point where combination therapy becomes the ideal, perhaps the standard of care, Young added. If so, it is Gilead, which has commanded a significant market share in HCV and HIV, that might be best positioned as it is investigating three different mechanisms in NASH.

Gilead’s lead candidate for the indication is Phase II monoclonal antibody simtuzumab, which would prevent the fibrosis matrix from forming, but the California specialty pharma also has an apoptosis signal-regulating kinase 1 (ASK1) inhibitor (GS4997) in Phase I as well as a Phase IIb FXR agonist, Fx-104 [See Deal]. The last was in-licensed from Phenex Pharmaceuticals AG in January, part of a recent wave of business activity related to NASH drug development Also see "Deal Watch: Gilead’s Move Into NASH Highlights Post-Holiday Deal-Making" - Pink Sheet, 12 January, 2015..

Still in the preclinical stage, Nimbus Therapeutics is exploring yet another mechanism with its acetyl-CoA carboxylase (ACC) inhibitor ([A#14150318003]).

Along with Intercept, Young has cited French biotech Genfit SA as a co-leader in the NASH first-mover competition, but the company announced disappointing top-line data March 26 from a Phase II study of its candidate, GFT505, a dual regulator of peroxisome proliferator-activator receptor (PPAR) alpha and delta. The company reported that a 120 mg dose of ‘505 failed to meet the primary endpoint of reversal of NASH without worsening of fibrosis, attributing the failure in part to a greater-than-expected placebo response.

Meanwhile, San Diego-based Conatus Pharmaceuticals Inc. announced March 26 that emricasan, a first-in-class orally active pan-caspase protease inhibitor, met its primary endpoint in a Phase II study of 38 patients with nonalcoholic fatty liver disease, including a subset of patients with NASH. In top-line data, emricasan demonstrated a statistically significant reduction in alanine amino transferase in patients treated for 28 days compared to placebo.

Conatus CEO Steve Mento told “The Pink Sheet” that he thinks the growing focus on NASH is misguided, however, as that disease should be seen as part of a larger cascade toward late-stage liver disease. Conatus believes emricasan will demonstrate a profile to provide therapeutic benefit at several points along the liver disease spectrum, he said, including in patients with NASH.

The primary issue in liver disease is cirrhosis, the exec asserted. “It’s really the consequences of insults like fat in the liver, viruses such as HCV or HBV, or alcohol or autoimmune diseases that should be the focus of what people are talking about with respect to liver disease,” he said. “The consequences of these damaging events really are what I think the drugs are being developed to treat, not so much the fat in your liver per se.”

“The reason why we’re so interested in later-stage disease, chronic liver disease and cirrhosis particularly, [is that] the MOA of our lead drug emricasan is powerful enough we believe to treat liver disease across the full spectrum, early to late,” Mento added. “Currently, the NIH estimates that there are over 5 million Americans who have cirrhosis, but only about 1 million are diagnosed, and there are about 32,000 deaths a year due to cirrhosis.”

NASH Drugs Soon May Have A Registrational Pathway, Finally

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