South San Francisco-based biotech Kezar Life Sciences (NASDAQ: KZR) announced topline results from its Phase IIa PORTOLA trial evaluating zetomipzomib for the treatment of autoimmune hepatitis (AIH).
At the same time, the company also reported financial results for the fourth quarter and full year ending December 31, 2024.
The PORTOLA trial assessed the safety, tolerability and preliminary efficacy of zetomipzomib in patients with AIH who are either refractory to or intolerant of standard therapy.
AIH is a rare, chronic disease in which the immune system attacks the liver. This can cause inflammation and potentially lead to liver damage over time.
Managing AIH typically requires lifelong maintenance therapy to prevent relapse and avoid severe complications. Without treatment, the disease can progress to cirrhosis, liver failure or hepatocellular carcinoma.
In the US, AIH affects an estimated 100,000 people, with cases on the rise. The exact cause remains unknown, though the condition affects women at a rate four times higher than men.
Current standard treatment relies on long-term immunosuppression with corticosteroids. Their use can lead to serious and often life-altering side effects, such as diabetes, osteoporosis and cataracts.
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Zetomipzomib is a first-in-class selective immunoproteasome inhibitor. According to Kezar, preclinical studies have shown that selectively inhibiting the immunoproteasome triggers a broad anti-inflammatory response in animal models of various autoimmune diseases without causing immunosuppression.
In the PORTOLA trial, zetomipzomib demonstrated a favorable safety profile and showed promising clinical activity.
The trial included 24 relapsed, steroid-dependent AIH patients. Patients received either 60 mg of zetomipzomib or placebo alongside standard background therapy for 24 weeks, following a protocol-recommended steroid taper.
All participants began treatment with a daily steroid dose of 20 mg to 40 mg of prednisone (or an equivalent dose of budesonide). Physicians were encouraged to taper the dose to 5 mg/day in accordance with the American Association for the Study of Liver Diseases (AASLD) guidelines for AIH management.
Among the 21 out of 24 patients on steroid-based therapy, 36% (five of 14) of patients treated with zetomipzomib achieved a complete biochemical response (CR) and steroid taper to 5 mg/day or less. None of the seven patients achieved a CR in the placebo group.
Among all 24 patients, 31% (five of 16) of zetomipzomib patients achieved both a CR and steroid taper (≤5 mg/day). Only one of eight patients achieved it among the placebo patients.
The median duration of response in zetomipzomib patients achieving a CR was 27.6 weeks, including the ongoing open-label extension (OLE).
No disease flares were reported in any patients administered zetomipzomib who achieved CR during the study.
A significant proportion of patients achieved reductions in key liver enzyme levels, including ALT and AST.
Improvements in these markers and achieving a CR by Week 24 made up the primary efficacy endpoint of the study.
There were no new safety signals, and most treatment-emergent adverse events were mild to moderate in severity.
“We are very encouraged by the results of the PORTOLA study, which suggest zetomipzomib has the potential to offer a meaningful therapeutic option for patients with autoimmune hepatitis — a population that currently faces limited treatment alternatives,” said John Fowler, CEO of Kezar Life Sciences.
“These data support further development, and we look forward to discussing next steps with regulatory authorities.”
Related: Hansa Biopharma Shares Positive Imlifidase Phase II Study Data in Rare Autoimmune Disorder
Kezar’s Q4 and Full-Year 2024 Financial Highlights
In addition to the trial data, Kezar also reported its fourth-quarter and full-year earnings in the announcement.
Total cash, cash equivalents and marketable securities amounted to approximately $132.2 million. This was down from $201.4 million as of December 31, 2023.
The company said the decrease was mainly due to cash used in operations to advance clinical-stage programs.
R&D expenses for Q4 2024 amounted to $16.0 million. This was a decrease of $6.6 million from $22.6 million in the same quarter of 2023.
Full-year R&D expenses were down by $20.0 million to $65.7 million in 2024, compared to $85.7 million in 2023.
Kezar said the decrease was primarily due to the “company’s strategic restructuring in October 2023 to prioritize its clinical-stage programs, reducing personnel-related costs and spending in its early-stage research activities, and a $5.0 million milestone payment made in 2023 under Kezar’s exclusive license agreement with Onyx Therapeutics.”
Kezar noted the decrease was partially offset by the increased clinical trial costs of PALIZADE and PORTOLA.
Net loss for Q4 was $20.2 million and $94.2 million for the full year.
The company anticipates presenting updated data from both programs at upcoming scientific and medical conferences in 2025.
In late September 2024, Kezar paused dosing and enrollment for its Phase IIb PALIZADE lupus study of zetomipzomib after four patient deaths in the Philippines and Argentina. A few weeks later, the company decided to terminate the study entirely and focus on the drug in AIH.
Due to questions around the lupus trial, the FDA placed a second, but partial, clinical hold on the PORTOLA trial.
However, according to Fierce Pharma, analysts at William Blair noted the hold was not just because of the PORTOLA trial. They said there were “potential concerns of some placebo patients among the four patients yet to roll over in the OLE, who could be subject to safety risk upon initiating zetomipzomib treatment.”
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