Some substance was added to all the hype around non-alcoholic steatohepatitis (NASH) and non-alcoholic fatty liver disease (NAFLD) in 2017. New drug candidates emerged, some made important advances, others had setbacks, and a multitude of companies are now looking to bring new technologies to market that will help treat this vital public health issue. Perhaps more importantly, the release of new research and the emergence of new players in the field is helping increase the awareness of NASH and its complications and costs.

 

For more information on DRG’s assessment of the NASH market, please click here.

 

The more, the merrier

Activity in the pipeline for NASH drug treatments stepped up another notch or three in 2017 with numerous companies joining the hunt for a slice of the estimated multi-billion dollar future NASH market. Testing of Gilead’s selonsertib and Allergan’s cenicriviroc in Phase III trials (clinicaltrials.gov [NCT03053050 and NCT0305306, and NCT03028740, respectively]; accessed February 8, 2018) was commenced; these agents join Intercept Pharma’s obeticholic acid (Ocaliva) and Genfit’s elafibranor in this latter stage of development.

 

A stumble in the home strait?

However, the progress of obeticholic acid took several hits during 2017. First, a protocol change for its ongoing Phase III trial (clinicaltriasl.gov [NCT02548351]; accessed February 8, 2018) came to light, with the company announcing that the co-primary endpoint is now fibrosis improvement or NASH resolution rather than fibrosis improvement and NASH resolution. Second, the anticipated completion of enrollment for the trial was pushed back from H1 2017 to mid-2017; as of November 2017, enrolment was still ongoing. And to compound matters, the deaths of 19 patients being treated with the drug for its approved indication of primary biliary cholangitis has raised concerns about the safety. Overdosing of patients with liver impairment was determined to be the problem, but this led to the FDA requiring a black box warning to be inserted into Ocaliva’s prescribing information.

 

Two steps, forward one step back

Intercept are not the only company facing challenges. Cempra suspended development of solithromycin for NASH due to “unclear” efficacy (Cempra press release, February 28, 2017), and Astra Zeneca’s AZD4076 (RG-125) program was also halted.  Preliminary results for a Phase II trial of Immuron’s IMM-124E failed to demonstrate a significant difference versus placebo for effect on ALT levels (Immuron press release, July 10, 2017) and Allergan’s cenicriviroc did not demonstrate a significant difference versus placebo in the composite endpoint of reduction in fibrosis by at least one stage with no worsening of NASH (Allergan press release, September 22, 2017). However, the antifibrotic activity observed convinced the company to purse Phase III trials (clinicaltrials.gov [NCT03028740]; accessed February 8, 2018). Gilead’s GS-0976 had mixed results for markers of liver fat content and fibrosis (Gilead press release, October 24, 2017), and Galectin Therapeutics GR-MD-02 only provided significant improvement for hepatic venous pressure gradient in a subset of NASH cirrhosis patients (Galectin press release, December 5, 2017). Enrolment for Genfit’s Phase II trial of elafibranor has experienced delays (Genfit press release, April 24, 2017). Such delays are likely a reflection of the relatively low awareness of NASH, the low diagnosis rates, the asymptomatic nature of the disease, and the reluctance of patients to undergo liver biopsy.

 

New hopes

However, there were also many positives in terms of drug development. Phase II results for Madrigal Pharmaceuticals’ MGL-3196 achieved a significant reduction in liver fat plus improvements in liver enzymes and lipid profiles versus placebo after 12 weeks (Madrigal Pharmaceutical press release, December 6, 2017). Bristol-Myers Squibb (BMS)’s BMS-986036 also demonstrated a significant reduction in liver fat versus placebo after 16 weeks as well as improvements in biomarkers of fibrosis and liver injury (BMS press release, April 22, 2017). Furthermore, numerous additional Phase II trials kicked off, including those for Zydus’s saroglitazar, Inventiva’s lanifibranor (IVA-337), Can-Fite BioPharma’s CF-102, and Pfizer’s PF-05221304 (clinicaltriasl.gov [NCT03061721, NCT03008070, NCT02927314, and NCT03248882, respectively]; accessed February 8, 2018).

 

Bypassing biopsy

There is an important unmet need for new non-invasive diagnostics. Presently, liver biopsy is the gold standard for diagnosis. However, this procedure is invasive and many physicians and patients are often reluctant to undertake it, especially when treatment options are so limited. Nonetheless, as more advanced disease has worse outcomes, knowing the staging for NASH and fibrosis is critical for optimizing care and reducing the risk of complications. Experts in the field are offering guidance on best practices and trying to help practitioners decide when liver biopsy is required. The latest America Association for the Study of Liver Diseases (AASLD) guidelines provide a dedicated section on non-invasive diagnostics and how best to utilize currently available tools and resources. New technology is also being investigated with the hope of finding a test that would make NASH as easy to diagnose and monitor as diabetes or hypercholesterolemia. BMS announced collaboration with Nordic Bioscience to develop fibrosis biomarker technology (BMS press release, April 17, 2017), and ProSciento and OWL Metabolomics have also joined forces to develop a means of identifying NASH and NAFLD patients (Prosciento press release, June 7, 2017).

 

The road to drug approval may be bumpy, but 2017 can be seen as the year that the field of drug development for NASH really began to accelerate.

 

For more information on DRG’s assessment of the NASH market, please click here.

Relevant reports:

Non-alcoholic Steatohepatitis [ Landscape & Forecast | Disease Landscape & Forecast ]

Non-alcoholic Steatohepatitis [ Epidemiology | Americas Data ]

Non-alcoholic Steatohepatitis [ Epidemiology | Europe Data ]

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