Kezar Life Sciences Faces FDA Setback for Autoimmune Hepatitis Drug, Explores Strategic Alternatives
Key Insights
Kezar Life Sciences was unable to align with the FDA on a registrational trial for zetomipzomib in autoimmune hepatitis (search) after the agency cancelled a scheduled Type C meeting and requested additional hepatic impairment studies.
The FDA's requirements would delay future zetomipzomib trials by approximately 2 years and mandate 48-hour patient monitoring in clinical research units, which could hinder enrollment.
Despite positive Phase 2a PORTOLA trial results showing 36% of steroid-dependent patients achieved biochemical remission with zetomipzomib versus 0% with placebo, the company is now exploring strategic alternatives.
Kezar Life Sciences announced it has been unable to reach alignment with the FDA on a potential registrational clinical trial for zetomipzomib in autoimmune hepatitis (search) (AIH), prompting the company to initiate a strategic review process with TD Cowen to explore alternatives for maximizing shareholder value.
The FDA Division of Hepatology and Nutrition cancelled a Type C meeting that was previously scheduled with Kezar in the fourth quarter to discuss a proposed study in AIH. In their written response, the FDA requested that Kezar conduct a stand-alone study to define the pharmacokinetics of zetomipzomib in subjects with significant hepatic impairment prior to initiating another clinical trial in AIH, despite Kezar's plan to exclude AIH patients with significant hepatic impairment from the proposed registration-enabling study.
Regulatory Challenges Create Development Delays
The interim study required by the FDA would delay future trials of zetomipzomib in AIH by approximately 2 years. Additionally, the FDA has mandated that future clinical trials include 48-hour patient monitoring in a clinical research unit, which Kezar believes would likely hinder patient enrollment and participation.
"We are incredibly disappointed with the unusual decision by the FDA to cancel our Type C meeting, which we had hoped would allow us to align on key clinical trial parameters for a potentially registration-enabling study of zetomipzomib in patients with AIH, a population with significant unmet medical need and currently without FDA-approved therapies," said Chris Kirk, PhD, CEO of Kezar Life Sciences.
Kezar had submitted a comprehensive report to the FDA integrating safety, efficacy and pharmacology data across more than 300 patients and healthy volunteers enrolled in zetomipzomib clinical trials, along with a risk mitigation plan for outpatient monitoring modeled after approved injectable therapeutics.
Promising Clinical Results Despite Regulatory Setbacks
Despite the regulatory challenges, zetomipzomib demonstrated encouraging results in the Phase 2a PORTOLA trial, the first successfully completed randomized clinical trial in patients with refractory or relapsed AIH. In steroid-dependent patients, 36% of those treated with zetomipzomib achieved biochemical remission and were able to taper their daily steroid dose to AASLD treatment guideline levels of ≤ 5 mg/day, compared to 0% in the placebo group.
No patients achieving a complete response with zetomipzomib experienced flares during treatment, including those continuing therapy in the open-label extension. The drug was generally well-tolerated, with the most common adverse events being mild to moderate injection site reactions, and fewer infections reported in the zetomipzomib group relative to placebo-treated patients.
Addressing Significant Unmet Medical Need
Autoimmune hepatitis (search) affects approximately 100,000 individuals in the United States, predominantly women, with females affected four times as often as males. The rare chronic disease occurs when the immune system attacks the liver, causing inflammation and tissue damage that severely impacts patients' physical health and quality of life.
Currently, there are no FDA-approved therapeutics specifically for AIH, and few industry-sponsored clinical trials exist. Standard treatment involves lifelong use of corticosteroids (search) and immunosuppressive agents, resulting in increased risk of infections, malignancies, diabetes, osteoporotic fractures and cataracts. If left untreated, AIH can lead to cirrhosis (search), liver failure (search) and hepatocellular carcinoma (search).
Novel Mechanism of Action Shows Promise
Zetomipzomib is a novel, first-in-class, selective immunoproteasome (search) inhibitor with broad therapeutic potential across multiple autoimmune diseases. Preclinical research demonstrates that selective immunoproteasome inhibition results in a broad anti-inflammatory response in animal models of several autoimmune diseases while avoiding immunosuppression.
Biomarker analysis from the PORTOLA trial showed that zetomipzomib administration led to meaningful changes across both innate and adaptive immune pathways in patients with AIH. Reductions in immunoglobulins, B cells and monocytes, along with increases in regulatory T cells, were observed in participants achieving a complete response.
Strategic Review and Financial Position
In connection with evaluating strategic alternatives, Kezar will implement a restructuring plan including workforce reduction and other cost-containment measures while retaining employees essential for supporting value creation. As of September 30, 2025, the company's cash, cash equivalents and marketable securities totaled approximately $90.2 million.
The company's Board of Directors has also extended its limited duration stockholder rights plan to protect shareholder interests and ensure fair participation in the strategic review process. The Rights Plan will automatically expire following the certification of voting results from the company's 2026 annual meeting, unless stockholders approve its continuation.