Disease Analysis: Non-Alcoholic Steatohepatitis (NASH)
Author: Tim Blackstock
Publisher: Datamonitor Healthcare
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Disease Overview
Non-alcoholic fatty liver disease (NAFLD) is a hepatic condition closely associated with metabolic syndrome, and non-alcoholic steatohepatitis (NASH) is a segment of NAFLD. Both NAFLD and NASH patients display hepatic steatosis, and do not drink more than recommended guideline amounts of alcohol. Hepatocellular injury may or may not be present in NAFLD patients; however, NASH is characterized by the presence of hepatocellular injury marked by hepatic steatosis, inflammation, and/or fibrosis.
Latest key takeaways
- Non-alcoholic steatohepatitis (NASH) is characterized by chronic hepatic steatosis leading to inflammation and eventually fibrosis of the liver; it is commonly accepted as the hepatic manifestation of the metabolic syndrome. There are currently no disease-specific approved drug therapies for NASH in any of the major markets, which creates a significant unmet need considering the large prevalent population and expectations that NASH will become the leading indication for liver transplant in the US in the next few years.
- Development of a safe and efficacious pharmacotherapy has been hindered by the complicated and poorly understood pathophysiology of NASH. Moreover, due to the multifactorial nature of the disease, more than one pharmacotherapy is likely to be required for effective treatment. Consequently, there is a diverse range of modes of action in the pipeline and substantial interest in combination therapies.
- Datamonitor Healthcare estimates that in 2020, there were approximately 891.8 million prevalent cases of NASH worldwide in adults aged ≥20 years, and forecasts that number to increase to 965.4 million prevalent cases by 2027.
- In order for a drug candidate to gain accelerated approval by the US Food and Drug Administration (FDA), one of the following endpoints must be met: 1) improvement of ≥1 stage in fibrosis with no worsening of NASH; 2) improvement in NASH resolution with no worsening of fibrosis.
- While the FDA only requires achievement of one of the above endpoints, the European Medicines Agency (EMA) requires efficacy on both of these endpoints in a co-primary fashion, which could restrict or delay approvals in the five major European markets (France, Germany, Italy, Spain, and the UK). Notably, the EMA’s guidance is still in draft form, and therefore could be changed in response to industry lobbying before finalization.
- Given the lack of any marketed NASH therapies to date, the NASH market landscape is expected to grow dramatically over the forecast period, driven by new product approvals in the space.
- Despite obeticholic acid’s recent rejection by the FDA, Datamonitor Healthcare expects that the drug will be approved in Q1 2023 following Intercept’s anticipated NDA resubmission with additional data requested by the FDA. However, this still means the drug will lose its opportunity to monopolize the market for a significant period of time. While the FDA has described an imbalance in obeticholic acid’s risk/benefit profile as the reason for the drug’s rejection, increasing skepticism over the reliability of surrogate endpoints following large trial failures could have influenced its decision. It is also possible that the FDA is retrospectively raising the bar for accelerated approval (having previously agreed on the required surrogate endpoints for accelerated approval), and as obeticholic acid was the first NDA submitted in NASH, the FDA may be acting particularly cautiously to set a precedent for future NASH therapies.
- Although first approvals in the market will experience rapid uptake, the use of many novel agents will be restricted to F2/F3 NASH patients, reflecting the enrollment criteria of Phase III trials. High prices of new therapies will translate into high revenues; however, strict reimbursement criteria will limit market access for prohibitively priced therapies, including obeticholic acid, which is expected to have a premium price while it monopolizes the market. As a result, the off-label use of low-cost generic products, such as vitamin E and pioglitazone, will continue.
- The anticipated requirement for biopsy-confirmed NASH is expected to be the major barrier to treatment access. Therefore, in the short term, treatments will predominantly be prescribed by specialists such as gastroenterologists and hepatologists, which will limit the ease of accessibility of treatment.
- Clinical trials focusing on F4 patients with compensated cirrhosis remain an area of unmet need. Companies are reluctant to pursue programs in this space as cirrhosis has predominantly been viewed as irreversible; however, given that these patients are closely associated with negative hepatic outcomes, effective interventions remain an important unmet need.
- Another challenge that will remain once the first therapy is approved for NASH is how to measure a treatment benefit in the commercial setting, as using biopsies will not be feasible on such a large scale; however, there are no reliable non-invasive replacements yet available.
- Numerous high-impact upcoming events for drugs in the NASH space are expected during 2022, including an FDA presubmission meeting on obeticholic acid, and clinical trial data from the most advanced drug candidates.
CONTENTS
8 OVERVIEW
8 Latest key takeaways
10 DISEASE BACKGROUND
10 Definition
10 Symptoms
10 Diagnosis
12 Patient segmentation
14 TREATMENT
16 EPIDEMIOLOGY
16 Prevalence methodology
19 PIPELINE DRUGS
31 KEY REGULATORY EVENTS
31 Intercept Withdraws EU NASH Drug Filing But May Retry
31 Intercept Plans To Refile OCA For NASH At US FDA With Consensus Reads Of Patient Biopsies
31 Intercept Wants More Time to Address EMA’s Questions Over Its NASH Treatment
32 Intercept Might Not Refile NASH NDA In 2021
32 Intercept Commits To Resubmitting NASH NDA, But Analysts See Conflicting Signs
32 NASH Drug Development Questions? US FDA Has Many Of The Answers
32 Intercept’s NASH Plans For Better Alignment With FDA
34 PROBABILITY OF SUCCESS
35 LICENSING AND ASSET ACQUISITION DEALS
35 Sciwind Licenses Global Rights To Develop Sanofi’s GIP Receptor Agonists
35 Arrowhead Gets $120m From GSK For First-In-Class NASH RNAi Candidate
35 RNAi Returns To Spotlight As Novo Nordisk Swoops For Dicerna
35 Asia Deal Watch: D&D Pharmatech Signs Licensing And Development Agreement With Shenzhen Pregene For DD01
36 Cyclerion Moves On From Praliciguat With Out-License To Akebia
37 CLINICAL TRIAL LANDSCAPE
39 Sponsors by status
39 Sponsors by phase
40 Recent events
46 DRUG ASSESSMENT MODEL
46 Farnesoid X receptor (FXR) agonists
47 Stearoyl-coenzyme A desaturase 1 (SCD1) inhibitor
48 Thyroid hormone β-selective agonists
48 Fibroblast growth factor (FGF) analogs
49 Glucagon-like peptide-1 (GLP-1) agonist
50 Peroxisome proliferator-activated receptor (PPAR) agonists
51 Structurally engineered fatty acid (SEFA)
51 Endogenous metabolic modulator (EMM)
51 Prodrug of bioidentical testosterone
51 Fatty acid synthase (FASN) inhibitor
52 AMP-activated protein kinase (AMPK) activator
52 Thiazolidinedione
52 Regimens
54 MARKET DYNAMICS
56 FUTURE TRENDS
57 Payer restrictions will limit market access for prohibitively priced first-generation NASH agents
57 Obeticholic acid’s advantage of monopolizing the market has been eliminated following its CRL
58 Increased competition from new product launches will shape the NASH market
58 GLP-1 agonists will experience rapid uptake in diabetic NASH patients
58 Use of combination therapies will be restricted to severe patients due to prohibitive pricing
59 No therapy for F4 NASH patients on the horizon
60 CONSENSUS FORECASTS
61 RECENT EVENTS AND ANALYST OPINION
61 HU6 for NASH (February 9, 2022)
62 Icosabutate for NASH (November 15, 2021)
63 Aramchol for NASH (November 1, 2021)
65 MET642 for NASH (October 21, 2021)
66 LPCN 1144 for NASH (August 25, 2021)
68 ALT-801 for NASH (June 16, 2021)
70 TERN-101 for NASH (June 14, 2021)
73 Multiple Drugs for NASH (May 24, 2021)
75 CORT118335 for NASH (May 6, 2021)
76 Efruxifermin for NASH (March 22, 2021)
79 KEY UPCOMING EVENTS
80 KEY OPINION LEADER INSIGHTS
80 NASH market
80 Obeticholic acid
80 Resmetirom
80 FGF analogs
81 Combination therapies
81 Endpoints
81 Prescribing trends
81 F4 patients
82 Pricing
82 Biopsies and non-invasive tools
84 UNMET NEEDS
84 Pharmacological treatment
84 Clinical trials in advanced NASH patients
84 Non-invasive diagnostic tools
86 BIBLIOGRAPHY
88 APPENDIX
LIST OF FIGURES
18 Figure 1: Trends in prevalent cases of NASH, 2018–27
19 Figure 2: Overview of pipeline drugs for NASH in the US
19 Figure 3: Pipeline drugs for NASH, by company
20 Figure 4: Pipeline drugs for NASH, by drug type
20 Figure 5: Pipeline drugs for NASH, by classification
34 Figure 6: Probability of success in the endocrine pipeline
37 Figure 7: Clinical trials in NAFLD
37 Figure 8: Top 10 drugs for clinical trials in NAFLD
38 Figure 9: Top 10 companies for clinical trials in NAFLD
38 Figure 10: Trial locations in NAFLD
39 Figure 11: NAFLD trials status
40 Figure 12: NAFLD trials sponsors, by phase
46 Figure 13: Datamonitor Healthcare’s drug assessment summary for NASH
54 Figure 14: Current dynamics in NASH
54 Figure 15: Market opportunity in NASH
55 Figure 16: Threat of substitution in NASH
55 Figure 17: Payer pressure/buyer power in NASH
56 Figure 18: Future trends in NASH: growth drivers
57 Figure 19: Future trends in NASH: growth resistors
63 Figure 20: Icosabutate for NASH (November 15, 2021): Phase IIb – ICONA
66 Figure 21: MET642 for NASH (October 21, 2021): Phase IIa – NASH Patients (US)
68 Figure 22: LPCN 1144 for NASH (August 25, 2021): Phase II – LiFT (Biopsy-Confirmed NASH)
70 Figure 23: ALT-801 for NASH (June 16, 2021): Phase I – SAD/MAD (Australia)
73 Figure 24: TERN-101 for NASH (June 14, 2021): Phase IIa – LIFT
75 Figure 25: Aldafermin for NASH (May 24, 2021): Phase IIb – ALPINE2/3
76 Figure 26: CORT118335 for NASH (May 6, 2021): Phase IIa – Probable Nonalcoholic Steatohepatitis
78 Figure 27: Efruxifermin for NASH (March 22, 2021): Phase IIa – BALANCED
79 Figure 28: Key upcoming events in NASH
LIST OF TABLES
13 Table 1: Fibrosis staging in NAFLD using the Brunt et al. system adapted by the NASH CRN Pathology Committee
14 Table 2: Guideline recommendations on lifestyle interventions
15 Table 3: Summary of pharmacological recommendations for NASH/NAFLD from US, EU, and Japanese guidelines
17 Table 4: Prevalent cases of NASH, 2018–27
21 Table 5: Pipeline drugs for NASH in the US
60 Table 6: Forecasted global sales, by drug ($m), 2022–26
61 Table 7: HU6 for NASH (February 9, 2022)
62 Table 8: Icosabutate for NASH (November 15, 2021)
64 Table 9: Aramchol for NASH (November 1, 2021)
65 Table 10: MET642 for NASH (October 21, 2021)
67 Table 11: LPCN 1144 for NASH (August 25, 2021)
69 Table 12: ALT-801 for NASH (June 16, 2021)
71 Table 13: TERN-101 for NASH (June 14, 2021)
73 Table 14: Multiple Drugs for NASH (May 24, 2021)
76 Table 15: CORT118335 for NASH (May 6, 2021)
77 Table 16: Efruxifermin for NASH (March 22, 2021)
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