Disease Analysis: Non-Alcoholic Steatohepatitis (NASH)
Publisher: Datamonitor Healthcare
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Disease Overview
The diagnosis of non-alcoholic fatty liver disease (NAFLD) requires evidence of hepatic steatosis and the lack of secondary causes of liver fat accumulation such as substantial alcohol consumption, long-term use of a steatogenic medicine, or monogenic hereditary disorders. NASH is a more advanced form of NAFLD where there is liver inflammation with hepatocyte injury, which can lead to
hepatic fibrosis. Although the presence of fibrosis is not required for a diagnosis of NASH, fibrosis is present in over 80% of NASH patients. For this reason, NASH patients are often further segmented by their fibrosis stage. Detection of fibrosis is important as it is linked to worse outcomes for patients.
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 2021, there were approximately 903 million prevalent cases of NASH worldwide in adults aged ≥20 years, and forecasts that number to increase to 965 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 previous rejection by the FDA, Datamonitor Healthcare expects that the drug will be approved in Q2 2023 following Intercept’s anticipated New Drug Application (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.
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
32 KEY REGULATORY EVENTS
32 Intercept Withdraws EU NASH Drug Filing But May Retry
32 Intercept Plans To Refile OCA For NASH At US FDA With Consensus Reads Of Patient Biopsies
33 PROBABILITY OF SUCCESS
34 LICENSING AND ASSET ACQUISITION DEALS
34 Novo Nordisk Moves Into NLRP3 Space With Ventus Agreement
34 Sino Biopharm Gets China Rights To Inventiva’s Phase III NASH Drug
34 NeuroBo Will Help Advance Dong-A Candidates For NASH, Obesity, Type 2 Diabetes
35 Juntendo Researchers Will Evaluate MOA Of MediciNova’s Tipelukast
35 Intercept Offloads Ex-US Business To Advanz, May Be Doubling Down On NASH In US
35 PathAI And GlaxoSmithKline Announce Multi-Year Partnership
36 Merck And Aligos Expand Collaboration To Develop Oligonucleotide Therapies For NASH
36 Sciwind Licenses Global Rights To Develop Sanofi’s GIP Receptor Agonists
36 Arrowhead Gets $120m From GSK For First-In-Class NASH RNAi Candidate
36 RNAi Returns To Spotlight As Novo Nordisk Swoops For Dicerna
37 Asia Deal Watch: D&D Pharmatech Signs Licensing And Development Agreement With Shenzhen Pregene For DD01
38 CLINICAL TRIAL LANDSCAPE
40 Sponsors by status
40 Sponsors by phase
41 Recent events
47 DRUG ASSESSMENT MODEL
47 Farnesoid X receptor (FXR) agonist
48 Stearoyl-coenzyme A desaturase 1 (SCD1) inhibitor
49 Thyroid hormone β-selective agonists
50 Fibroblast growth factor (FGF) analogs
50 Glucagon-like peptide-1 (GLP-1) agonists
51 Peroxisome proliferator-activated receptor (PPAR) agonists
52 Structurally engineered fatty acid (SEFA)
52 Endogenous metabolic modulator (EMM)
53 Prodrug of bioidentical testosterone
53 Fatty acid synthase (FASN) inhibitor
53 AMP-activated protein kinase (AMPK) activator
54 Regimens
56 MARKET DYNAMICS
58 FUTURE TRENDS
59 Payer restrictions will limit market access for prohibitively priced first-generation NASH agents
59 Obeticholic acid’s advantage of monopolizing the market has been reduced following its CRL
60 Increased competition from new product launches will shape the NASH market
60 GLP-1 agonists will experience rapid uptake in diabetic NASH patients
60 Use of combination therapies will be restricted to severe patients due to prohibitive pricing
61 No therapy for F4 NASH patients on the horizon
61 NASH outcomes data to drive future market growth
62 CONSENSUS FORECASTS
63 RECENT EVENTS AND ANALYST OPINION
63 Denifanstat for NASH (November 3, 2022)
64 Ocaliva for NASH (September 30, 2022)
65 AXA1125 for NASH (September 29, 2022)
66 Efruxifermin for NASH (September 13, 2022)
68 PXL065 for NASH (August 30, 2022)
69 Ocaliva for NASH (July 7, 2022)
71 Pemvidutide for NASH (June 6, 2022)
73 HU6 for NASH (February 9, 2022)
74 Icosabutate for NASH (November 15, 2021)
76 Aramchol for NASH (November 1, 2021)
78 MET642 for NASH (October 21, 2021)
80 KEY UPCOMING EVENTS
81 KEY OPINION LEADER INSIGHTS
81 NASH market
81 Obeticholic acid
81 Resmetirom
81 FGF analogs
82 Combination therapies
82 Endpoints
82 Prescribing trends
82 F4 patients
83 Pricing
83 Biopsies and non-invasive tools
85 UNMET NEEDS
85 Pharmacological treatment
85 Clinical trials in advanced NASH patients
85 Non-invasive diagnostic tools
87 BIBLIOGRAPHY
90 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
33 Figure 6: Probability of success in the endocrine pipeline
38 Figure 7: Clinical trials in NAFLD
38 Figure 8: Top 10 drugs for clinical trials in NAFLD
39 Figure 9: Top 10 companies for clinical trials in NAFLD
39 Figure 10: Trial locations in NAFLD
40 Figure 11: NAFLD trials status
41 Figure 12: NAFLD trials sponsors, by phase
47 Figure 13: Datamonitor Healthcare’s drug assessment summary for NASH
56 Figure 14: Current dynamics in NASH
56 Figure 15: Market opportunity in NASH
57 Figure 16: Threat of substitution in NASH
57 Figure 17: Payer pressure/buyer power in NASH
58 Figure 18: Future trends in NASH: growth drivers
59 Figure 19: Future trends in NASH: growth resistors
64 Figure 20: Denifanstat for NASH (November 3, 2022): Phase IIb – FASCINATE-2
66 Figure 21: AXA1125 for NASH (September 29, 2022): Phase IIb – EMMPACT
68 Figure 22: Efruxifermin for NASH (September 13, 2022): Phase IIb – HARMONY (Biopsy-Confirmed)
71 Figure 23: Ocaliva for NASH (July 7, 2022): Phase III – REGENERATE
73 Figure 24: Pemvidutide for NASH (June 6, 2022): Phase I – ALT-801-101 (Australia)
76 Figure 25: Icosabutate for NASH (November 15, 2021): Phase IIb – ICONA
79 Figure 26: MET642 for NASH (October 21, 2021): Phase IIa – NASH Patients (US)
80 Figure 27: 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
62 Table 6: Forecasted global sales, by drug ($m), 2022–26
63 Table 7: Denifanstat for NASH (November 3, 2022)
64 Table 8: Ocaliva for NASH (September 30, 2022)
65 Table 9: AXA1125 for NASH (September 29, 2022)
67 Table 10: Efruxifermin for NASH (September 13, 2022)
69 Table 11: PXL065 for NASH (August 30, 2022)70 Table 12: Ocaliva for NASH (July 7, 2022)
72 Table 13: Pemvidutide for NASH (June 6, 2022)
74 Table 14: HU6 for NASH (February 9, 2022)
75 Table 15: Icosabutate for NASH (November 15, 2021)
77 Table 16: Aramchol for NASH (November 1, 2021)
78 Table 17: MET642 for NASH (October 21, 2021)
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