Introduction:

Many have commented that drug combinations represent the future of NASH therapeutics. As indicated by Pfizer’s recent announcement, large pharma companies are putting efforts toward the promise of combination therapy for NASH. These companies appear to be approaching combination therapy with two distinct strategies, stand alone and collaboration models, exemplified by Gilead and Pfizer/Novartis, respectively.

Why the emphasis on combinations?

There is a growing consensus that NASH results from excess free fatty acids generated from lipolysis in fat and de novo lipogenesis in the liver, with subsequent production of lipotoxic species which result in endoplasmic reticulum and oxidant stress, inflammasome activation, and fibrogenesis (Friedman, et. al., Nature Medicine 2018; 24:908–922). Additionally, it appears other factors may be involved in exacerbating the pathophysiology such as changes in the microbiome, liver delivery of gut-derived substances via increased intestinal permeability, and immune cell mechanisms. This complexity results in heterogeneity of disease phenotypes in humans.

Preclinical and early clinical data indicate potential for enhanced effect using a combination of drugs that target different pathways in NASH. The reported NASH clinical trials with positive effects of drug over placebo have often shown somewhat modest results, with a large percentage of patients who did not respond to therapy. Combination therapies targeting multiple pathways holds the promise of positive outcomes in higher percentages of patients in this heterogenous disorder.

How is large pharma approaching combination therapies?

While many companies are considering drug combinations, I will focus on the large companies with the most advanced programs that represent two different strategic approaches, Gilead and Pfizer/Novartis.

Gilead has three prominent drugs in NASH clinical development including selonsertib (Apoptosis signal-regulating kinase 1 (ASK1) inhibitor), GS-0976 (Acetyl CoA-Carboxylase (ACC) inhibitor) and GS-9674 (farnesoid X receptor (FXR) agonist). Each of these are in clinical trials, with selonsertib phase 3 trials reading out for NASH with advanced fibrosis and cirrhosis in the first half of 2019. Additionally, there is a large, seven-group, placebo-controlled, parallel group phase 2 trial (ATLAS; NCT03449446) underway using various combinations of each of the three drugs.

Novartis has been a primary mover in the area of collaboration between companies with NASH assets, including its partnership with Conatus and its pan-caspase inhibitor emricasan and a collaborative phase 2 trial with Allergan that combines the Novartis’ FXR agonist tropifexor and Allergan’s CCR2/CCR5 inhibitor cenicriviroc.

Adding to Novartis’ collaborative approach, the partnership announced between Pfizer and Novartis is a blockbuster in the field. In addition to tropifexor and emricasan, Novartis also has a SGLT 1/2 inhibitor (LIK06) in NASH development. The two companies will conduct both non-clinical and phase 1 clinical studies with the Novartis drugs and Pfizer’s NASH drugs, including an ACC inhibitor (PF-05221304, currently in phase 2), a diacylglycerol O-acyltransferase 2 (DGAT2) Inhibitor (PF-06865571, phase 1) and a ketohexokinase (KHK) Inhibitor (PF-06835919, phase 2).

Will combinations contain certain core drug classes?

It is notable that both Gilead and Pfizer/Novartis combination strategies include two similar classes of drugs, FXR agonists and ACC inhibitors. FXR agonists have taken a central role in NASH treatment because of multiple effects on NASH pathophysiology including hepatic fat and inflammation reduction, inhibition of anti-fibrosis, and reducing bacterial translocation from gut. Intercept Pharmaceutical’s phase 3 trial in pre-cirrhotic NASH with obeticholic acid reads out in 1H 2019 and will be a landmark study for the field. Positive results may solidify FXR agonists as a core component of combination therapy regimens.

ACC inhibitors target the key pathophysiology of increased free fatty acids in the liver, and there is some clinical data that they reduce liver fat. Additionally, there is emerging data suggesting that ACC inhibitors may influence fibrogenesis via effects on hepatic stellate cells. These findings have focused extra emphasis on this class of drugs.
There are other classes of drugs that may eventually be central components of combination therapies. Peroxisome proliferator-activated receptor (PPAR) agonists are very promising drugs in development, the most advanced being elafibranor (Genfit) which is in a phase 3 trial in NASH that reads out at the end of 2019. Another candidate as a central component of combination therapies is thyroid hormone receptor β agonists, for which the most advanced example is MGL-3196 from Madrigal Pharmaceuticals which has shown fairly relatively strong phase 2 clinical trial results.

Combination possibilities will evolve with additional clinical data, particularly emerging safety profiles and evidence of distinct efficacy parameters. I have not attempted to cover the full spectrum of drugs in development or combination possibilities. For the near future, Gilead and Pfizer/Novartis will lead in this space and define the landscape for the field.

What are the challenges with combination therapies?

Obtaining convincing pre-clinical animal model data to assess the efficacy of combination therapies could be challenging. Data in animal models is desirable to provide confidence in advancing combinations into clinical trials but may not always provide clear answers. The pathology in models is variable and the intensity of disease may not have enough dynamic range to allow assessment of combinations of multiple drugs, thus impairing rigorous statistical analysis. In the future, it is likely that some drug combinations will be evaluated in patients based on clinical data alone. The necessity of assessing safety of combinations in non-clinical studies when there is already clinical data will be an important discussion with regulatory agencies to avoid delays in clinical programs for lengthy animal studies with combinations.

Another significant challenge in combination therapies relates to the regulatory pathway for marketing approval. Currently, drugs part of a combination must each be shown to be efficacious alone, as well as in combination. The more straightforward situation is where one drug has marketing approval in NASH and a second experimental drug is added. Study designs would still have to show activity of the experimental drug alone. If there are two non-approved experimental therapies, one possible approach is to have phase 2b data showing a statistically significant effect on an appropriate endpoint with each agent, as well as a statistically significant improvement of the combination as compared to either single agent alone. In this situation, the company could seek agency approval to go into phase 3 with the combination alone, but this will take negotiation around each specific combination. Creative adaptive trial designs would be useful to explore in this situation and it will be critical for the industry to remain in close discussions with the regulatory agencies. Until there is regulatory agency experience with combination programs in NASH and clinical trial data, this represents an area of considerable risk for industry programs.

Finally, since NASH patient populations are heterogenous, the application of precision medicine in targeting appropriate patient subsets may be advantageous in advancing various combination therapies. These possibilities will be clarified with publication of additional studies with multiple categories of therapeutic agents, and continuing exploration of NASH pathophysiology and genetics.

Summary

The commitment by large pharma companies to evaluate combination therapies even before there is a single approved drug for NASH, is an exciting development. Combination therapy has advanced disease treatment in multiple areas of medicine including liver disease, most notably in the treatment of chronic viral hepatitis C. It is likely that the complex pathophysiology of NASH will also be amenable to combinatorial approaches. It is encouraging that this is being studied early in the game, hopefully compressing the timeframe to effective therapies for patients.

More information

For information on my consulting work and background please visit here: /consultants/peter-g-traber/

Additional blog posts by Peter G. Traber


Disclosure: From March 2011 through June 2018 the author was CEO and CMO of Galectin Therapeutics (NASDAQ: GALT), a company with a NASH development asset.

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