Nonalcoholic steatohepatitis (NASH) became a buzzword when Intercept Pharmaceuticals (NASDAQ: ICPT) shares rocketed in January 2014. NASH is the most prevalent chronic liver disease affecting more than 10% of the adult population of the US. There are currently no drugs approved for NASH. Here is a min-review examining the NASH pipeline.
Intercept started this year’s NASH craze with positive results from the FLINT trial. Intercept’s lead candidate obeticholic acid (OCA), the 6α-ethyl derivative of chenodeoxycholic acid (CDCA), is a potent FXR agonist (EC50=99nM). The company is developing OCA for multiple indications including primary biliary cirrhosis (Phase III), NASH (Phase II), and primary biliary cirrhosis (Phase I).
In the FLINT trial, OCA (25 mg/day) was superior to placebo for improving liver histology according to the NAFLD Activity Score (45% vs. 21%, p=0.0002). OCA also significantly reduced serum liver enzymes including ALT, AST, and GGT. Unfortunately, the drug increased LDL-C (+9 vs. -8 mg/dL) and decreased HDL-C (-1 vs. +1 mg/dL), raising safety concerns about the long-term use. Moreover, OCA was associated with significant weight loss (-2.3 vs. 0 kg). Pruritus in the OCA group occurred more frequently (23% vs. 6%).
FXR is now one of the few clinically validated targets for NASH. German biotech Phenex Pharmaceuticals is developing FXR agonists as well. Px-102 and Px-104 are in Phase II development to treat NASH.
Galmed Pharmaceuticals (NASDAQ: GLMD) is an Israel-based biotech that raised $35 million in an IPO in March 2014. Galmed’s aramchol is a conjugate of cholic acid and arachidic acid initially designed to prevent the formation of cholesterol gallstones. In the 60-patient Phase IIb trial, high-dose aramchol (300 mg/day) significantly reduced liver fat content compared to placebo (-12.57% vs. +6.39%, p=0.02). However, Aramchol had no improvements in the levels of ALT or AST.
Galmed is currently prepared to initiate an out-US Phase IIb trial in NASH patients who also suffer from obesity and insulin resistance. The company will test higher doses and expects interim results in 2015H2. According to the latest pharmacokinetic data, higher doses (400 and 600 mg) were well tolerated.
Galectin Therapeutics (NASDAQ: GALT) is a biotech focused on discovery and development of galectin inhibitors. Galectin-3 is upregulated in liver fibrosis, renal fibrosis, and idiopathic pulmonary fibrosis (IPF), thereby establishing a rationale to treat fibrosis. Galectin currently has two galectin-3 inhibitors, namely GM-CT-01 and GR-MD-02, in clinical trials.
In June 2014, Galectin disclosed preclinical data from GR-MD-02 in preclinical model of NASH. GR-MD-02 significantly reduced ALT, AST and total bilirubin in plasma. Unfortunately, the drug at dose of 4 mg/kg showed no difference from a placebo in nearly all biomarkers in NASH patients. Shares of Galectin fell 61% on July 29, 2014. It remains to be seen whether additional benefits can be found with cohort 3 at dose of 8 mg/kg.
La Jolla Pharmaceutical (NASDAQ: LJPC) has completed a Phase II study of galectin-3 inhibitor GCS-100 in patients with chronic kidney disease. The company reported positive results in March 2014. Oddly, low dose (1.5 mg/m2) of GCS-100 is effective but a higher dose (30 mg/m2) is not. Here is Adam Feuerstein’s explanation: GCS-100 doesn’t really work at all. The so-called positive data is really just statistical noise because the standard deviation is too large. La Jolla’s NASH candidate LJPC-1010 is a more potent form of GCS-100 that can be given orally. The company intends to file an IND and begin a phase I trial in 2015H2.
In November 2014, Bristol-Myers Squibb (NYSE:BMY) signed an exclusive option agreement to acquire Galecto Biotech and its inhaled galectin-3 inhibitor TD139 for $444 million. TD139 complements BMS’ fibrosis pipeline which includes LPA1 receptor antagonist BMS-986020 for IPF.
Raptor Pharmaceuticals (NASDAQ: RPTP) is developing RP103 (delayed-release cysteamine bitartrate) for Huntington’s disease, nonalcoholic fatty liver disease in children, and Leigh syndrome. Cysteamine has been approved for the treatment of nephropathic cystinosis under the trade name PROCYSBI. The bulk of NASH patients are adults, which make it less of market potential. The company is conducting a Phase IIb trial under a cooperative agreement with NIH. In 2010, Raptor conducted a Phase IIa clinical trial in adolescent patients with NASH. 7 of 11 patients achieved a greater than 50% reduction in ALT levels. AST levels were decreased by an average of 41%.
After being a dominant player in the hepatitis C market, Gilead Sciences (NASDAQ:GILD) is now eyeing to the next big liver disease market. In 2010, Gilead acquired Arresto Biosciences for $225 million and added an anti-LOXL2 mAb called simtuzumab (formerly AB0024) to the pipeline. LOXL2 is an important enzyme that promotes the cross-linking of collagen fibers, which can contribute to tumors and fibrosis. The failure in pancreatic cancer is a minor setback for the project, but simtuzumab may show its worth in NASH. Interim Phase II data may occur in 2015H2.
French-based GENFIT (OTC: GNFTF) is developing dual PPAR α/δ agonist GFT505 for NASH. In previous Phase II trials, GFT505 significantly reduced fasting plasma triglycerides (-21%) and LDL-C (-13%), as well as GGT (-30.4%), and ALT (-20.5%). Results from the pivotal phase IIb trial are expected in 2015Q1.
Emricasan (IDN-6556, PF-03491390) of Conatus Pharmaceuticals (NASDAQ: CNAT) is a first-in-class, orally active pan-caspase inhibitor. Caspases are important enzymes in cells for apoptosis. Emricasan inhibits all caspases, decreasing liver injury and fibrosis. The compound was originally discovered by Idun Pharmaceuticals. Pfizer acquired Idun for $298 million in 2005 and then licensed it to Conatus for $19.25 million in 2010. In fact, Conatus was founded by the executive management team of Idun. The original patent covering emricasan (WO0001666) will expire soon. Don’t worry, the company has filed an additional patent (WO2008068615) to protect the crystal form of emricasan.
In 2007, the FDA placed a clinical hold on emricasan after Pfizer’s scientists observed inflammatory infiltrates which might contribute the formation of tumors. Pfizer discontinued the program in 2008. Luckily, these infiltrates, observed in mice, were not observed in any other species. Conatus conducted a 6-month carcinogenicity study in mouse model and found there was no evidence of drug-related tumorgenicity, which led the FDA to hand them green light in January 2013.
Conatus is testing emricasan in multiple indications including liver cirrhosis, liver failure and NASH. To date, the drug has been studied in over 500 subjects. In Phase IIb trial, emricasan significantly reduced ALT and AST levels in patients with hepatitis C. Conatus initiated a 40-patient Phase II NASH trial in March 2014. Top-line results are expected in 2015Q1.
In May 2014, Shire (NASDAQ: SHPG) acquired Lumena Pharmaceuticals for $260 million in cash. Lumena brings to Shire two ASBT inhibitors called LUM001 and LUM002 which reduce bile acid absorption and have the potential to improve liver function. Shire intends to test LUM002 in a Phase II trial in patients with NASH.
Tobira Therapeutics’ lead product, cenicriviroc, is a first in class dual inhibitor of CCR2 and CCR5 being originally evaluated for the treatment of HIV. Recently, the company initiated a Phase II proof of concept study in patients with NASH.
In 2012, GNI Group in-licensed Asia/Australia rights to caspase inhibitor EP1013 (F573) from EpiCept Corporation (merged with Immune Pharmaceuticals (NASDAQ: IMNP)) for $12 million. Shanghai Genomics, a wholly owned subsidiary of GNI Group, filed an IND application for liver failure in China in February 2014.
For hepatitis C, a simple blood test is enough to yield clear results, whereas NASH is far more complex. The uncertainty from the FDA also creates risks for investors. Drug makers are waiting for the FDA to outline what means a meaningful improvement for NASH patients, in other words, to identify clinically meaningful endpoints for NASH.
Although only a Phase II trial, Gilead employs event free survival as primary clinical endpoint which is the gold standard for demonstrating clinical benefit. Other companies, represented by Intercept, use NAFLD Activity Score to measure the primary outcome.
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