Gilead's Multiple NASH Combination Therapies Fail to Meet Primary Endpoint in Phase II ATLAS Trial

News Event

Today, Gilead Sciences announced the Phase 2 clinical trial results of a study named ATLAS for NASH. This trial enrolled 392 NASH patients with severe fibrosis (F3-F4) and compared the effects on improving fibrosis among an ACC2 inhibitor firsocostat, an FXR receptor agonist cilofexor, their dual-drug combination, as well as each combined separately with the ASK1 inhibitor selonsertib versus placebo. After 48 weeks of treatment, none of the treatment groups showed a significant increase in the proportion of patients achieving no worsening of NASH and at least one-stage improvement in fibrosis, thus failing to meet the primary endpoint of the trial. However, some secondary endpoints demonstrated partial improvements, with detailed data to be presented at future academic conferences.

Drug Source Analysis

Apart from Intercept’s FXR receptor agonist obeticholic acid (OCA, brand name Ocaliva), which in a Phase 3 trial this February doubled the proportion of patients with at least a one-stage improvement in fibrosis after 18 months of treatment (23% in the high-dose group vs. 12% in the control group), progress in improving fibrosis in the NASH field has been limited. Even the low-dose OCA group failed to achieve a statistically significant difference compared with placebo. However, several drugs, particularly thyroid hormone receptor agonists, have shown promising effects in improving hepatic steatosis. Cilofexor, acquired by Gilead Sciences from the German biopharmaceutical company Phenex for $470 million, is considered a me-too drug given that OCA paved the way; however, because its mechanism of action has been validated, it is likely to be a core component of combination therapies. Firsocostat was purchased from Nimbus for $1.2 billion; ACC2 is a well-established target for weight loss. ASK1 is a stress-regulatory protein. Selonsertib has already failed in two Phase 3 trials as a monotherapy this year, and adding it to other mechanistic agents has clearly not yielded substantial improvements. Thus, these combinations address different aspects of NASH and can be regarded as a multi-pronged attack on the disease.

NASH is currently the most prevalent disease amenable to technical intervention. Although multiple mechanisms may improve prognosis by addressing hepatic steatosis, fibrosis, and inflammation, this also underscores the heterogeneity and complexity of the disease. Theoretically, such a complex condition is difficult to control with single-target drugs; therefore, combination therapies should be more effective. While combination therapies may enhance efficacy, they also increase the likelihood of adverse effects, with a greater potential for additive side effects in diseases with complex pathogenesis. Since the toxicity of most small-molecule drugs originates from the liver, and NASH is a liver disease, the risk of drug-drug interactions increases alongside monotherapy-related side effects, thereby limiting the tolerated dosage. Most importantly, although the ultimate successful treatment is most likely to involve drug combinations, this does not mean that a brute-force approach using permutations and combinations is the optimal strategy for identifying these winning regimens. Although Cilofexor can be considered a validated target-specific drug and serve as a backbone for combination therapy, its efficacy is modest and its side effects are severe. While it can serve as a focal point, this necessitates that other components assume greater responsibility. Typically, a more effective strategy involves first identifying smaller, suitable patient populations for each monotherapy, and then systematically optimizing combinations to expand the eligible population. However, this requires a sufficient understanding of the pathology and reliable biomarkers for patient stratification, whereas NASH currently remains a broad, heterogeneous mix.

Gilead Sciences reaped substantial profits from its hepatitis C drugs, and it would have been an ideal outcome for the company to carve out a significant niche in NASH, the largest liver disease market following hepatitis C. However, NASH is indeed a highly complex disease. In addition to the current targets, LOXL2, caspases, and Galectin have also failed in proof-of-concept (POC) trials. These successive failures may erode the patience and confidence of Gilead and its investors, with experts predicting that the company may gradually withdraw from this field. A current trend involves exiting common mass-market diseases and entering rare diseases with relatively clearer mechanisms and lower payment barriers. Sanofi has just announced its exit from diabetes and cardiovascular diseases, and Amgen earlier withdrew from the central nervous system (CNS) therapeutic area. Gilead has also made significant investments in autoimmune diseases, hematologic malignancies, and CAR-T therapies. Coupled with other recent challenges, although Gilead has invested heavily in NASH over the past few years—acquiring nearly all novel mechanistic drug candidates available—it is possible that the company will make a decisive move to abandon its NASH program.

Original Title: Exclusive | Gilead’s Multiple NASH Combination Therapies Fail in Phase II Clinical Trials