The incidence of non-alcoholic steatohepatitis, or NASH, which refers to liver inflammation due to fat buildup in the liver, has risen dramatically over the last two decades because of growing prevalence of obesity, insulin resistance, diabetes and lipid disorders. Also called a “silent” liver disease, since the symptoms are not manifested in early stages, in some patients, NASH can also progress to fibrosis and cirrhosis over the years, with a high risk for liver failure and hepatocellular cancer.
In early stages of NASH, patients generally feel well. But once the disease is more advanced or cirrhosis develops, they begin to experience symptoms such as fatigue, weight loss, and weakness. A person with cirrhosis experiences fluid retention, muscle wasting, bleeding from the intestines, and liver failure.
An estimated 16 million Americans have NASH, according to reports. NASH is a more severe form of nonalcoholic fatty liver disease, or NAFLD. There is still no approved drug for treating NASH. Liver transplantation is the only option for NASH cirrhosis at this time. By 2020, NASH is projected to overtake hepatitis C as the leading cause of liver transplants in the U.S.
Let’s take a look at some of the companies developing NASH drugs. This is not necessarily an exhaustive list as we have limited the names to only phase II and phase III drug candidates.
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Allergan plc is evaluating Cenicriviroc, a once-daily, oral drug candidate, in a phase III trial, dubbed AURORA, in NASH patients with stage 2 to 3 liver fibrosis.
Initiated in April 2017, the AURORA trial is designed to enroll about 2,000 patients, and initial results are expected July 2019. The study is expected to be completed by July 2024.
Genfit SA is evaluating Elafibranor, an oral once-daily treatment, in a phase III trial, dubbed RESOLVE-IT, in patients with nonalcoholic steatohepatitis and fibrosis.
The RESOLVE-IT study was initiated in March 2016, and is expected to enroll 2,000 patients, with initial results slated for 2021.
The 18-month pre-planned safety review conducted by the Data Safety Monitoring Board in November 2017, found no safety issues that warranted any modifications in the conduct of the trial.
3. Gilead Sciences
Gilead Sciences Inc.’s Selonsertib, administered orally once daily, is in two phase III NASH trials called STELLAR 3 and STELLAR 4.
The STELLAR 3 trial is evaluating in Selonsertib in patients with NASH and bridging (F3) fibrosis.
The STELLAR 4 study is testing Selonsertib in patients with compensated cirrhosis due to NASH.
The STELLAR 3 trial was initiated in February 2017, and is designed to enroll 800 patients. Initial results are expected in January 2020, with study completion slated for October 2023.
Initiated in January 2017, the STELLAR 4 trial is also designed to enroll 800 participants, with initial results expected in January 2020, and study completion in October 2023.
4. Intercept Pharmaceuticals
Intercept Pharmaceuticals Inc. is evaluating once-daily, orally-administered Ocaliva as a potential treatment for NASH fibrosis in a phase III trial, dubbed REGENERATE.
Initiated in September 2015, the REGENERATE trial is designed to enroll approximately 2,000 NASH patients with stage 2 or stage 3 liver fibrosis. The interim analysis of the trial is expected in the first half of 2019, with study completion anticipated in October 2022.
A phase III trial of Ocaliva in NASH patients with cirrhosis that was originally scheduled by end of 2017 is now expected to commence this year.
Ocaliva was granted accelerated approval by the FDA for Primary Biliary Cholangitis in May 2016.
5. Boehringer Ingelheim
Germany-based privately-held Boehringer Ingelheim’s orally administered, once daily, BI 1467335 is under a phase IIa study in patients with NASH.
This trial was initiated in June 2016, and is designed to enroll 147 patients. Initial results from the study are expected in June 2018, with completion scheduled for July 2018.
6. Bristol-Myers Squibb
Bristol-Myers Squibb’s investigational treatment for NASH is a subcutaneously-injected drug, BMS-986036.
In a phase II trial in adults with NASH, the results of which were reported last April, BMS-986036 showed consistent improvement in fibrosis, liver stiffness and liver injury.
Bristol-Myers exclusively licensed the rights to BMS-986036 from Ambrx Inc.
7. Can-Fite BioPharma
Can-Fite BioPharma Ltd.’s experimental drug for NASH is an oral twice daily, Namodenoson, which is under a phase II study.
Initiated in November 2017, this study is designed to enroll approximately 60 patients with non-alcoholic fatty liver disease, with or without NASH. NAFLD is a precursor to non-alcoholic steatohepatitis.
8. Conatus Pharmaceuticals
Conatus Pharmaceuticals Inc’s drug candidate for NASH is known as Emricasan, and is being developed in collaboration with Novartis.
Emricasan is under the following trials:
— A phase IIb trial of Emricasan in reducing hepatic venous pressure gradient in patients with compensated or early decompensated liver cirrhosis caused by nonalcoholic steatohepatitis, and severe portal hypertension, dubbed ENCORE-PH. Top-line results from this trial are expected in October 2018. — A phase IIb clinical trial of Emricasan evaluating potential improvements in fibrosis and steatohepatitis in patients with fibrosis caused by NASH, dubbed ENCORE-NF. Top line results are expected in the first half of 2019. — A phase IIb clinical trial of Emricasan in NASH cirrhosis patients, dubbed ENCORE-LF. Top-line results are expected in the second half of 2019.
9. Cirius Therapeutics
Privately-held Cirius Therapeutics, previously known as Octeta Therapeutics, is developing a treatment for NASH, which goes by the name MSDC-0602K, an oral, once-daily next-generation small molecule.
MSDC-0602K is under a phase 2b study for the treatment of patients with NASH and liver fibrosis, dubbed EMMINENCE trial.
Initiated in July 2016, EMMINENCE is designed to enroll 380 participants. The trial is expected to be completed in July 2019.
10. Galectin Therapeutics Inc.
Galectin Therapeutics Inc. has completed testing GR-MD-02 in a phase IIb clinical trial in NASH cirrhosis patients.
In the phase IIb trial, dubbed NASH-CX, GR-MD-02 was administered as infusion every other week for 52 weeks, for a total of 26 doses. About half of the NASH cirrhosis patients in the trial had esophageal varices and the other half of the subjects were without esophageal varices.
The NASH-CX trial missed the primary endpoint of reaching statistical in reducing hepatic venous pressure gradient, when the total group of patients was considered. However, a statistically significant and clinically meaningful effect of GR-MD-02 was observed on the primary endpoint measurement of HVPG in the subgroup of NASH cirrhosis patients without esophageal varices.
The Company plans to advance GR-MD-02 into phase III testing.
11. Galmed Pharmaceuticals
Galmed Pharmaceuticals Ltd. is evaluating Aramchol, a once-daily, oral drug, in a phase IIb clinical trial in patients with biopsy proven NASH who are overweight or obese, and who are pre-diabetic or type-II-diabetic.
The trial, dubbed, ARREST, was initiated in January 2015, and has enrolled 240 patients. Patients enrolled in the ARREST Study have advanced NASH with more than 60% having fibrosis in stages 2 and 3. Top line data from this study are expected in the second quarter of 2018.
Aramchol is also being studied in a proof-of-concept phase IIa clinical trial designed in up to 50 patients with HIV-associated NAFLD and lipodystrophy. The study, dubbed ARRIVE, has enrolled 50 patients, and top line data is expected in the first quarter of 2018.
12. Gemphire Therapeutics
Gemphire Therapeutics Inc.’s experimental drug for NASH is known as Gemcabene.
A phase IIa proof-of-concept clinical trial of Gemcabene in adults with FPL, a rare genetic disorder characterized by an abnormal distribution of fatty tissue, which can lead to a variety of metabolic abnormalities including NASH was initiated in December 2017.
This study is expected to enroll 8 FPL patients with elevated triglycerides and NAFLD, and top line results from the trial are expected in the second half of 2018.
Immuron Limited is testing IMM-124E, an oral, three-times-daily drug candidate, in a phase II trial in patients with any stage biopsy-proven NASH.
Initiated in December 2014, the phase II trial enrolled 133 participants. The primary endpoint is the change in liver fat content confirmed by MRI, and change in ALT.
Top line data from the IMM-124E phase II trial in NASH is expected in Q1, 2018.
In addition to the adult NASH study, IMM-124E is also being evaluated in a phase II study in children with pediatric NAFLD. Top line results from this study are expected in 4Q, 2018.
Privately-held Inventiva’s once-daily oral drug candidate Lanifibranor is under a phase IIb study in patients with NASH.
The study, dubbed NATIVE, was initiated in February 2017, with a target enrollment of 225 patients. Initial results from the study are expected in January 2019, with the study slated for completion in February 2019.
15. Madrigal Pharmaceuticals
Madrigal Pharmaceuticals Inc.’s once-daily oral MGL-3196 is under a phase II study in patients with biopsy-proven NASH.
Initiated in September 2016, the study enrolled 125 patients 18 years of age and older. Top-line results from the study that were reported in December 2017, revealed statistically significant improvement in the relative decrease in liver fat in patients treated with MGL-3196 compared with placebo at 12-weeks.
The trial is ongoing, and safety and efficacy will again be assessed at 36-weeks. The study is expected to be completed in April 2018.
MediciNova Inc. is testing orally administered MN-001 in a phase II trial in patients with NASH.
Initiated in March 2016, this study is designed to enroll 40 patients. The study is expected to be completed in March 2018.
17. Mitsubishi Tanabe
Japan-based Mitsubishi Tanabe Pharma Corp. is evaluating oral, once-daily MT-3995 in a phase II trial in patients with NASH.
This study was initiated in September 2016, and is designed to enroll 40 patients. Initial trial results are expected in March 2018, with the study scheduled for completion in April 2019.
18. NGM Biopharmaceuticals
Privately-held NGM Biopharmaceuticals Inc.s investigational NASH therapy is NGM282, a once-daily subcutaneous injectable, under a phase II dose finding trial for 12 weeks in patients with histologically confirmed NASH.
This 12-week study is an expansion trial, and it replicates the original phase II NASH trial in duration and eligible patient population. The expansion study includes the evaluation of lower dose levels of NGM282, as well as a histological assessment after 12 weeks of treatment in a subset of patients receiving a 3 milligram daily dose. Biopsy data from this study are expected in the first quarter of 2018.
NGM Bio is backed by The Column Group, Merck, Prospect Ventures, Topspin Partners, Rho Ventures, Tichenor Ventures and other investors.
Novartis AG has three drug candidates for NASH.
Tropifexor, a once-daily, oral compound, is under a phase II trial, dubbed FLIGHT-FXR. Initiated in August 2016, FLIGHT-FXR is designed to enroll 345 patients. Initial results from the study are expected in December 2018, with the study expected to be completed in July 2019.
Another drug candidate of Novartis being tested for NASH is LMB763, a once-daily, oral compound, which is also under a phase II study. This study was initiated in October 2016, and is designed to enroll 100 patients. The study is expected to be completed in August 2019.
LIK066, a once-daily, oral compound, is also under a phase II study in patients with non-alcoholic steatohepatitis. Initiated in October 2017, this study is designed to enroll 110 patients, with completion slated for April 2019.
20. Novo Nordisk
Novo Nordisk A/S’ subcutaneously administered once daily Semaglutide is under a phase II study in adult patients with NASH.
This study was initiated in November 2016, and is designed to enroll 372 patients. Initial results from the study are expected in November 2019, with the study completion anticipated in January 2020.
Pfizer Inc.’s oral drug candidate PF-05221304 is under a phase IIa trial in adult subjects with Nonalcoholic Fatty Liver Disease.
This study was initiated in August 2017, and is designed to enroll 360 patients. Initial results from the study are expected in February 2019. The trial is slated for completion in March 2019.
Shire plc is evaluating once daily, orally-administered Volixibat in a phase II study for the treatment of NASH with liver fibrosis in adults.
The study, initiated in July 2016, is designed to enroll 266 patients, and is expected to be completed in July 2020.
Taiwan-based TaiwanJ Pharmaceuticals is testing twice daily oral dosing of JKB-121 in a phase II study for the treatment of NASH.
Initiated in August 2015, the trial achieved target enrollment of 66 patients last January. Results from the study, due in December 2017, have not yet been announced.
24. Viking Therapeutics Inc.
Viking Therapeutics Inc. is evaluating oral, once-daily VK2809 in a phase II trial in patients with primary hypercholesterolemia and non-alcoholic fatty liver disease.
Initiated in August 2016, this study is designed to enroll 80 patients. Results from the trial are expected in the first half of 2018.
25. Zydus Cadila
India-based Zydus Cadila is evaluating once-daily oral experimental therapy Saroglitazar Magnesium in a phase II trial in patients with NASH.
This study was initiated in April 2017, and is designed to enroll 104 patients with Nonalcoholic Fatty Liver Disease and/or NASH.
Initial results from the study are expected in February 2018, with the study scheduled for completion in June 2018.
Given the rising obesity epidemic, the incidence of NAFLD/NASH is also expected to increase in the near future. According to market research firm GlobalData, the NASH space across the seven major markets of the U.S., France, Germany, Italy, Spain, the UK, and Japan, is set to rise from $618 million in 2016 to around $25.3 billion by 2026, representing a very rapid compound annual growth rate of 45%.
Although there are a number of investigational NASH therapies in various stages of development, there is no approved drug yet for this silent killer. However, the fact that the race to develop an effective drug against NASH has reached the home stretch, with 4 drug candidates in phase III stage of the trial, is welcome news for patients. The very earliest a NASH drug could hit the market is 2021, assuming all goes well as planned.
Who will make it to the finish line and who will abandon the race? Only time will tell.
Date: November 5, 2018