By: Tanya Casimiro, PhDAs the first Phase III data in non-alcoholic steatohepatitis (NASH) begin to be released, the next 12 months will prove crucial to understanding which drivers will shape the NASH market. Key questions of interest to stakeholders will be answered, such as:
- Which mechanism of action (MoA) or combination will provide the best efficacy profile?
- Can an indirect MoA reverse fibrosis?
- Will a non-invasive diagnosis be able to replace biopsy, possibly increasing early detection?
- Will the Phase III data, expected to read out imminently, be robust enough that payers will not impose prescription restrictions?
The leading MoA has not yet been established; several players are trying to get to the top spot
NASH is a histological categorization of nonalcoholic fatty liver disease (NAFLD), defined by the presence of more than 5% haptic steatosis and inflammation with hepatocyte ballooning. The presence of fibrosis is not required for diagnosis, but without treatment, NASH-induced fibrosis can progress to cirrhosis, liver failure and liver cancer.
Currently, monotherapies dominate the development landscape and numerous MoAs continue to be investigated. Lead compounds in development (listed in the table below) directly target fibrosis or symptoms of NASH, which could indirectly limit fibrosis by inhibiting disease progression.
Table: Lead MoAs in NASH by Clinical Development Phase
|MoA||FXR agonists||PPAR agonists||CCR2 and CCR5 inhibitors||ASK1 inhibitors|
|Acronym definition||Farnesoid X receptor (FXR)||Peroxisome proliferator-activated receptor (PPAR)||C-C chemokine receptor type 2 (CCR2), CCR type 5 (CCR5)||Apoptosis signal-regulating kinase 1 (ASK1)|
|Target||Bile acid synthesis||Blood glucose and lipid levels||Fibrosis||Inflammation|
|Relevance||This MoA acts to reverse NASH symptoms and is also being tested for indirect reversal of fibrotic activity||This MoA acts to reverse NASH symptoms and is also being tested for indirect reversal of fibrotic activity||This MoA is a direct reversal agent for fibrotic activity||This MoA acts to improve inflammation, and as a result, is expected to reverse fibrotic activity|
|Highest phase of development||III||III||III||III|
Another interesting target is the glucagon-like peptide 1 receptor (GLP-1R). Drugs targeting GLP-1R have been developed for diabetes and obesity indications. GLP-1R agonists may prove relevant as patients with NASH often have obesity and diabetes as comorbidities1. Phase II data presented at EASL 2018 showed that a GLP-1R agonist could normalize ALT levels, a measurement of liver damage2.
Phase III data readouts are expected in 2019 and will likely have a key role in determining which of these MoAs will be considered best in class. Both the FXR agonists and PPAR agonists are aiming to reverse fibrosis with an indirect MoA. While fibrosis reversal may be a difficult endpoint by which to prove efficacy, it is a primary concern for patients and healthcare providers. As a result, medicines that target late-stage fibrosis are likely to gain the earliest acceptance from payers.
Single treatment versus combination – the best-in-class treatment approach is yet to be determined
Due to the range of symptoms contributing to a final diagnosis, it is unlikely that a single MoA will work for all patients – as such, combination therapies may provide an exciting approach.
Although further back in development (Phase II), a combination approach will likely provide a more efficacious treatment for NASH and fibrosis by targeting multiple MoAs. At EASL 2018, proof-of-concept data showed an ASK1 inhibitor and an ACC inhibitor combination improved hepatic steatosis, liver biochemistry and fibrosis markers3,4.
Diagnosis remains a hurdle, but solutions are in the pipeline
Liver biopsy is the guideline standard for diagnosis. As was established by the Phase II FLINT trial, the leading Phase III trials for treating NASH (REGENERATE, REVERSE, RESOLVE-IT, AURORA, STELLAR 3 and 4) require a baseline biopsy in the inclusion criteria and follow-up biopsies, most commonly at 12 or 18 months. Liver biopsies pose risks that include bleeding, infection and accidental injury to nearby organs. If a NASH treatment is approved, patients with early signs of the condition may be resistant to undergoing a biopsy, and payers may be resistant to reimbursing without a biopsy.
A non-invasive diagnostic test may increase the diagnosis rates for both early- and late-stage NASH. Non-invasive techniques to monitor progress have gained prominence; both MRI diagnostics and proteomics platforms are in development. Serum protein and liver breakdown biomarkers also are being identified and tested.
Payers may be the last hurdle to entry
Even with biomarkers to identify the best candidates for treatment, reimbursement may prove to be a challenge. The FDA and payers will expect to see conclusive data connecting the dots between early-stage NASH and long-term health outcomes. Additionally, NASH may be considered a lifestyle disease by payers. When sofosbuvir for HCV was launched, payers imposed prescription restrictions5. These restrictions were dependent on a patient’s drug-use status, HIV co-infection status and severity of disease progression. For NASH as well, payers could require prescription restrictions. If patients have the option to undergo cognitive behavior therapy or disease-modification therapies to reverse the condition, payers could argue that NASH treatments are not worthy of premium pricing status or refuse to cover them.
The top spot is still up for grabs
The NASH landscape is in flux; the endpoints, the leading drug candidates, the followers and the new entrants appear to be changing by the month. Numerous treatments are progressing in development, but the market is still anyone’s game.
- Hazlehurst, J. M. “Non-alcoholic Fatty Liver Disease and Diabetes.” Metabolism – Clinical and Experimental, Vol. 65, no. 8 (2016): 1096-1108.
- Newsome, P., et al. “The Effect of Semaglutide on Liver Enzymes in Subjects with Obesity and Elevated Alanine Aminotransferase: Data from a Randomised Phase 2 Trial.” Journal of Hepatology, Vol. 68 (2018): S365-S604.
- Lawitz, E., et al. “Proof of concept study of an apoptosis-signal regulating kinase (ASK1) inhibitor (selonsertib) in combination with an acetyl-CoA carboxylase inhibitor (GS-0976) or a farnesoid X receptor agonist (GS-9674) in NASH.” Journal of Hepatology, Vol. 68 (2018): S37–S64.
- US National Library of Medicine. Identifier NCT02781584, “Safety, Tolerability, and Efficacy of Selonsertib, GS-0976, and GS-9674 in Adults With Nonalcoholic Steatohepatitis (NASH).” Clinicaltrials.gov. https://clinicaltrials.gov/ct2/show/NCT02781584?term=NCT02781584&rank=1 (accessed July 2, 2018).
- Barua, S, et al. “Restrictions for Medicaid Reimbursement of Sofosbuvir for the Treatment of Hepatitis C Virus Infection in the United States.” Annals of Internal Medicine, Vol. 163(3) (2015): 215-223.