The NASH Pipeline: Replete With Targets And New Compounds

The numerous different targets of investigational drugs for the treatment of NASH suggest the jury is still out on which mechanism of action is most likely to prove effective against the condition. Ireland’s Afimmune is the latest company wanting to advance an investigational drug for the disorder into late-stage clinical studies.

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The anatomy of a liver

Many targets and drugs are being evaluated for the treatment of non-alcoholic steatohepatitis (NASH), a form of non-alcoholic fatty liver disease (NAFLD), but no one really knows which will turn out best for patients.

There is even a possibility researchers could turn to combinations of drugs with different mechanisms of action in order to produce an effective therapy, like hepatologists have done with another liver disease, hepatitis C infection.

In total, there are more than a dozen compounds in late-stage clinical development for the condition, according to Informa Pharma Intelligence’s pipeline databases, Biomedtracker and Pharmaprojects, ranging from fatty acid derivatives to monoclonal antibodies and chemokine inhibitors (see table 1).

The lead product, Intercept Pharmaceuticals Inc.’s Ocaliva (obeticholic acid), was approved in the US in June for another liver-related condition, primary biliary cholangitis, in combination with ursodeoxycholic acid (UDCA), in adult patients with an inadequate response to UDCA, or who are unable to tolerate UDCA. (Also see "Ocaliva OK'd; Will NASH Success, Acquisition Be Next For Intercept?" - Scrip, 29 May, 2016.) It is also awaiting approval for this indication in the EU. (Also see "Full Data For Intercept's Liver Disease Drug Show Rivals Where To Differentiate" - Scrip, 18 Aug, 2016.)

Patient enrolment in Intercept's Phase III REGENERATE study of Ocaliva in patients with NASH is expected to be completed in the first half of 2017, for an interim analysis in 2019; its Phase II CONTROL study is expected to complete patient enrollment by the end of 2016.

NASH could be a lucrative opportunity for the pharmaceutical and biotech industry because of its high prevalence. A recent report from Datamonitor Healthcare analysts found there were around 50m patients with NASH globally, with the number of patients expected to increase 13.9% by 2035. (Also see "Fatty Liver Diseases: A Public Health Concern, But Market Opportunity" - Scrip, 17 Aug, 2016.)

Table 1. Selected Investigational NASH Therapies in Advanced Clinical Studies

Product	Company	Activity	Stage
Ocaliva (obeticholic acid)	Intercept Pharmaceuticals Inc.	farnesoid X receptor agonist	Phase III
elafibranor	Genfit SA	PPAR alpha, delta modulator	Phase III RESOLVE-IT study started in March 2016
Aramchol	Galmed Pharmaceuticals Ltd.	ATP-binding cassette transporter 1 inhibitor	Phase IIb ARREST study.
cenicriviroc	Tobira Therapeutics Inc.	chemokine receptor 5 antagonist	Phase IIb
emricasan	Conatus Pharmaceuticals Inc.	caspase inhibitor	Phase IIb
remogliflozin etabonate	Islet Sciences Inc.	SGLT inhibitor	Phase IIb
simtuzumab	Gilead Sciences Inc.	lysyl oxidase-like 2 targeting mAB	Phase IIb
ARX618	Bristol-Myers Squibb Co., Ambrx Inc.	fibroblast growth factor 21 variant	Phase II
GRI-0621	GRI Bio. Inc.	NKT 1 inhibitor	Phase II
GR-MD-02	Galectin Therapeutics Inc.	galectin-3 protein inhibitor	Phase II
GS-4997	Gilead Sciences	apoptosis signal regulating kinase 1 inhibitor	Phase II
IMM-124E	Immuron Ltd.	unknown	Phase II
tipelukast (MN-001)	MediciNova/Kyorin Pharmaceutical Co. Ltd.	leukotriene inhibitor	Phase II
MSDC-0602K	Octeta Therapeutics	mTOT (mitochondrial target of thiazolidinediones)	Phase II
NC101	Naia Ltd.	GLP-1 receptor agonist	Phase II
Px104	Gilead Sciences/Phenex Pharmaceuticals AG	farnesoid X receptor agonist	Phase II
volixibat (SHP626)	Shire PLC	ileal bile acid transporter inhibitor	Phase II
TEV-45478	Teva Pharmaceutical Industries Ltd.	not disclosed	Phase II
LJN-452	Novartis AG	farnesoid X receptor agonist	Phase II

Source: Biomedtracker and Pharmaprojects.

A further compound, Afimmune's DS102 (15-hydroxyeicosapentaenoic acid), is expected to join the list of hopeful projects in last-stage clinical studies for NASH later this year, when a Phase IIa study is planned. In Phase I studies, DS102 was well-tolerated, the company reports.

Afimmune is a new company recently spun out of Dublin-based DS Biopharma (formerly Dignity Sciences Ltd.). DS102 also has potential in fibrotic pulmonary disorders, and will be evaluated for the treatment of chronic obstructive pulmonary disorder (COPD) by Afimmune.

For its part, DS Biopharma, a privately held company, will concentrate on the development of potential anti-inflammatory products, like DS107 in atopic dermatitis and pruritus, and DS109 for acne. Phase IIb studies with topical and oral DS107 are planned for later in 2016, while DS109 should also enter the clinic for inflammatory skin disorders by the end of the year.

This story was updated on August 30, 2016 to correct the timing of the interim analysis of Intercept's Phase III REGENERATE study. Intercept is expecting trial enrolment completion for REGENERATE in 1H 2017 for an interim analysis in 2019. The original story said the interim analysis was expected in the first half of 2017.