Phase 2

Seven other drugs remain at the Pre-clinical Research phase (Phase 2). Phase 2 testing involves smaller samples because the safety of the compound at that point is not totally known.

Drugs in Phase 2 – Pre-clinical Research

GS-0976 – Manufactured by Gilead – GS-0976 is a 20mg oral tablet that inhibits Acetyl-CoA Carboxylase (ACC) to treat NASH by reducing liver fat levels and blocking the production of new liver fat.

In 2017, Gilead announced that GS-0976 has proven effective in improving liver fat content and noninvasive markers of fibrosis. Gilead awaits the completion of other Phase 2 tests before moving forward with the drug.

Cenicriviroc – Manufactured by Tobira (now part of Allergan) – After previously being investigated as a HIV drug, Allergan has transitioned Cenicriviroc toward treating NASH. The one-a-day oral medication operates as a dual antagonist for C-C chemokine receptors type 2 and 5, which help control the processes driving inflammation and fibrosis. In animal studies, Cenicriviroc has shown both anti-inflammatory and antifibrotic activity.

In 2017 Allergan and Novartis agreed to combine Novartis’s farnesoid X receptor with Allergan’s orally-administered Cenicriviroc for a Phase 2B study of the combination’s effectiveness in treating NASH. Over one year of study and a previous Phase 2B trial of Cenicriviroc found the treatment to improve fibrosis conditions without worsening NASH.

Emricasan – Manufactured by Conatus – Emricasan is an orally-administered pan-capase inhibitor that targets liver diseases by influencing the processes of apoptosis and inflammation. It has the ability to reduce elevated levels of serum ALT, AST, and capase mediated cleavage of cytokeratin-18 (CK18). Capase cleavage of CK18 produces a protein fragment called cCK18, which is a biomarker of apoptosis. Increased levels of cCK18 are associated with severity of NASH.

In 2017, Conatus partnered with Novartis to develop the treatment after Conatus announced the initiation of its Phase 2B clinical trail, ENCORE-LF. The study will test Emricasan’s effectiveness in treating patients with decompensated liver cirrhosis caused by NASH. Meanwhile, Conatus continues another ongoing Phase 2B trial, ENCORE-NF, which tests for improvements in NASH-caused fibrosis. Results from both studies will drop in 2019.

GR-MD-02 – Manufactured by Galectin – GR-MD-02 targets galectin proteins to treat liver diseases, including NASH. Specifically, the orally-administered drug goes after galectin-3, an important protein in the pathogenesis of fatty liver disease and fibrosis. When the drug binds to the protein, it impedes its function. Animal testing has shown that this disruption has led to positive effects through the reversal of liver fibrosis and cirrhosis.

In 2016, Galectin announced that GR-MD-02’s Phase 2A trial NASH-FX, a study that looked into the treatment’s effectiveness in improving fibrosis conditions, did not meet its primary and secondary endpoints. However, its principal trail, NASH-CX, which looks into GR-MD-02’s effectiveness in treating NASH patients with liver cirrhosis, remains ongoing. Results will come in 2017.

Leucine + Metformin + Sildenafil – Manufactured by NuSirt – Pharmaceutical manufacturer NuSirt is currently exploring the possibility of using leucine, metformin, and sildenafil to reduce the symptoms of NAFLD and NASH. L-leucine, an allosteric Sirt1 activator, produces synergistic effects when combined with metformin and sildenafil to reverse mild fatty liver disease symptoms on the AMPK-eNOS-Sirt1 pathway. The drug increases fatty acid oxidation, reduces lipogenic gene expression, decreases inflammatory markers. However, these results have only been shown to occur in animals. A trial in which scientists administered the drug to mice found the treatment resulted in a marked reduction of fibrogenesis and inflammation.

NuSirt has completed a Phase 2 study of the drug’s effectiveness and results are forthcoming.

Tipelukast – Manufactured by MediciNova – Tipelukast is an orally-administered compound that aims to reduce fibrotic and inflammatory activity through antagonizing and inhibiting various factors in these processes. These avenues include antagonizing the leukotriene (LT) receptor, inhibiting phosphodiesterase (PDE) 3 and 4, inhibiting 5-lipoxygenase (5-LO), down-regulating LOXL2, collagen type 1, and TIMP-1, genes that promote fibrosis, and down-regulating CCR2 and MCP-1, genes that promote inflammation.

In preclinical trials, one-a-day treatment resulted in significantly reduced fibrosis area in animal subjects. Based on these results, the FDA has approved a Phase 2 clinical trail of Tipelukast in treating NASH.

Volixibat (SHP-626) – Manufactured by Shire – The FDA has given Volixibat Fast Track status. The drug acts as a one-a-day pill that inhibits the apical sodium dependent bile acid transporter (ASBT).

Currently, Shire is recruiting individuals for its Phase 2 study into the treatment’s effectiveness for adults with NASH.