On March 25, 2025 Kezar Life Sciences, Inc. (Nasdaq: KZR), a clinical-stage biotechnology company developing novel small molecule therapeutics to treat unmet needs in immune-mediated diseases, reported positive topline results from the PORTOLA Phase 2a clinical trial evaluating zetomipzomib, a novel, first-in-class selective immunoproteasome inhibitor, in patients with autoimmune hepatitis (AIH) and reported fourth quarter and year end 2024 financial results (Press release, Kezar Life Sciences, MAR 25, 2025, View Source [SID1234651404]).
"We are pleased to announce these exciting results from the PORTOLA trial, the first successful randomized study in treatment-refractory AIH," said Chris Kirk, CEO and co-founder of Kezar. "We are encouraged by the safety and efficacy data in this difficult-to-treat patient population, specifically durable and steroid-sparing remissions experienced by patients treated with zetomipzomib. We are eager to work with the FDA Division of Hepatology and Nutrition to remove the partial clinical hold and align on an appropriate trial design to demonstrate the clinical benefit of zetomipzomib in AIH. I’d like to thank the team at Kezar, the physicians and staff at our clinical trial sites, and most importantly, the patients and their caregivers, for their participation, sacrifice and hard work."
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"I am impressed by the totality of efficacy and safety data from the PORTOLA study," said Gideon Hirschfield, Chair of Autoimmune Liver Disease Research and Director of the Francis Family Liver Clinic, at the Toronto General Hospital. "Zetomipzomib represents a potent and targeted therapy for patients, and I believe these results will positively contribute to the design of a registrational trial of zetomipzomib in AIH, where patients are in need of better treatment options."
PORTOLA is a placebo-controlled, randomized, double-blind Phase 2a clinical trial evaluating the efficacy and safety of zetomipzomib in patients with AIH that are insufficiently responding to standard of care or
have relapsed from a previous CR. The trial enrolled 24 patients, randomized (2:1) to receive 60 mg of zetomipzomib or placebo in addition to background therapy for 24 weeks, with a protocol-suggested steroid taper. All patients were required to receive a starting daily steroid dose of 20-40 mg/day of prednisone (or budesonide equivalent) and physicians were encouraged to taper daily steroid usage to 5 mg/day consistent with AIH treatment guidelines established by the American Association for the Study of Liver Diseases (AASLD).
The primary efficacy endpoint of PORTOLA, which was not powered for efficacy, evaluated the proportion of patients who achieved a CR by Week 24, measured as normalization of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and Immunoglobulin G (IgG) values (if elevated at baseline), with steroid dose levels not higher than baseline. A key secondary endpoint was the proportion of patients who achieved a CR by Week 24 with a steroid dose of 5 mg/day or less. The PORTOLA trial included a pre-specified subgroup analysis of patients who were on steroid-based therapy at the time of screening, which represents a patient population with unmet medical needs for a potential future registrational study. Additional exploratory endpoints included changes in histologic assessment of AIH as measured in biopsies taken within six months of screening and repeated at Week 24 of the trial.
Summary of Topline Results
PORTOLA enrolled 24 patients as the ITT population. Consistent with the AASLD treatment goals, zetomipzomib treatment resulted in higher rates of complete biochemical responses (CR) combined with reduction of steroid dosage to 5 mg/day or less, compared to placebo. In the ITT population:
•Without regard to steroid taper, 50.0% (8 of 16) of zetomipzomib patients achieved a CR, compared to 37.5% (3 of 8) of placebo patients.
•31.3% (5 of 16) of zetomipzomib patients achieved both a CR and steroid taper to 5 mg/day or less, compared to 12.5% (1 of 8) of placebo patients.
•18.8% (3 of 16) of zetomipzomib patients achieved both a CR and complete steroid withdrawal to zero mg/day, compared to 0% (0 of 8) of placebo patients.
•Median duration of response in zetomipzomib patients achieving a CR was 27.6 weeks (including the ongoing open-label extension), and no disease flares were reported in any zetomipzomib-treated patient achieving CR. Disease flares were defined as a sustained increase in ALT values to 25% above the CR value or 1.25-fold higher than the upper limit of normal for more than one week and requiring a restart or increase in steroid dose.
In the pre-specified subgroup analysis, 21 of the 24 patients entered the study on a steroid-based therapy at the time of screening. One patient in the placebo arm and two patients in the zetomipzomib arm were not receiving steroids at screening. All patients on study were required to initiate treatment with an initial prednisone dose of 20–40 mg/day. Of the 21 patients in this subgroup analysis:
•Median steroid use at screening was 20 mg/day for patients enrolled in the zetomipzomib arm, compared to 10 mg/day in the placebo arm, indicating that the zetomipzomib-treated arm was more refractory than the placebo arm.
•Without regard to steroid taper, 57.1% (8 of 14) of zetomipzomib patients achieved a CR, compared to 28.6% (2 of 7) of placebo patients.
•35.7% (5 of 14) of patients on the zetomipzomib arm achieved a CR and steroid taper to 5 mg/day or less, compared to 0% (0 of 7) of placebo patients.
•21.4% (3 of 14) of patients on the zetomipzomib arm achieved a CR and complete steroid withdrawal to zero mg/day, compared to 0% (0 of 7) of placebo patients.
Safety
Treatment-emergent adverse events (TEAEs) were seen in all patients, with injection site reactions (ISRs) being the most commonly reported TEAE in both arms. Systemic injection reactions (SIRs), with onset occurring 8 to 24 hours post-dose and usually resolving within 48 hours, were all Grade 1 and Grade 2. SIRs are a protocol-defined set of specific adverse events (AEs) consisting of one or more of the following signs/symptoms: hypotension, tachycardia, nausea, vomiting, dizziness, headache, pyrexia, rigors and/or chills.
Three patients experienced treatment-emergent serious adverse events (SAEs): one in the placebo arm, a Grade 3 variceal bleeding with hematemesis and atrial fibrillation; and two in the zetomipzomib arm, a Grade 3 fever occurring after the Week 24 liver biopsy, and a Grade 3 influenza infection that fully resolved during study. All SAEs were considered unrelated to study treatment, and all three patients completed the double-blind treatment period. Infectious AEs were reported in 85.7% (6 of 7) of patients in the placebo arm and 56.3% (9 of 16) of patients in the zetomipzomib arm. One patient discontinued from the placebo arm for a UTI requiring antibiotic treatment prior to receiving a dose on study, and three patients discontinued on the zetomipzomib arm for a Grade 1 fatigue, Grade 2 hives and a Grade 2 AIH disease flare. The safety population (n=23) includes all patients who received at least one dose of study treatment:
Placebo Zetomipzomib
n=7 n=16
Adverse Events in Double-blind Treatment Period n (%) n (%)
Participants with at least 1 Treatment Emergent Adverse Event (TEAE) 7 (100.0) 16 (100.0)
Most common TEAE:
Injection Site Reaction (ISR) 4 (57.1) 15 (93.8)
Systemic Injection Reaction (SIR) 1 (14.3) 12 (75.0)
TEAE leading to study drug discontinuation 0 (0) 3 (18.8)
Grade 3 TEAE (no Grade 4 or 5 TEAEs reported) 1 (14.3)
3 (18.8)
Serious TEAE 1 (14.3) 2 (12.5)
Infectious TEAE 6 (85.7) 9 (56.3)
Grade ≥3 Infectious TEAE 0 (0) 1 (6.3)
Opportunistic Infections 0 (0) 0 (0)
Death 0 (0) 0 (0)
Financial Results
•Cash, cash equivalents and marketable securities totaled $132.2 million as of December 31, 2024, compared to $201.4 million as of December 31, 2023. The decrease was primarily attributable to cash used in operations to advance clinical-stage programs.
•Revenue decreased by $7.0 million in 2024 compared to 2023 due to the October 2023 upfront payment received under the collaboration and license agreement with Everest Medicines.
•Research and development (R&D) expenses for the fourth quarter of 2024 decreased by $6.6 million to $16.0 million, compared to $22.6 million in the fourth quarter of 2023. Full year R&D expenses decreased by $20.0 million to $65.7 million in 2024, compared to $85.7 million in 2023. This 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. The decrease was partially offset by the increased clinical trial costs related to the PALIZADE and PORTOLA trials.
•General and administrative (G&A) expenses for the fourth quarter of 2024 decreased by $0.3 million to $5.5 million compared to $5.8 million in the fourth quarter of 2023. Full year G&A expenses decreased by $3.1 million to $23.4 million in 2024, compared to $26.5 million in 2023. The decrease was primarily due to a decrease in legal and professional service expenses and non-cash stock-based compensation.
•Restructuring and impairment charges decreased by $4.7 million to $1.5 million in 2024, compared to $6.2 million in 2023. The decrease was primarily related to one-time severance-related costs made in 2023 and higher impairment costs recognized in 2023 than 2024 on the right-of-use asset for the vacated floor in the leased office facility and certain equipment no longer utilized.
•Net loss for the fourth quarter of 2024 was $20.2 million, or $2.77 per basic and diluted common share, compared to a net loss of $32.3 million, or $4.44 per basic and diluted common share, for the fourth quarter of 2023. Net loss for 2024 was $83.7 million, or $11.49 per basic and diluted common share, compared to a net loss of $101.9 million, or $14.04 per basic and diluted common share in 2023. The weighted-average shares used to compute net loss per basic and diluted common share have been retroactively adjusted to reflect the one-for-ten reverse stock split completed on October 29, 2024.
•Total shares of common stock outstanding was 7.3 million shares as of December 31, 2024, after taking into effect the one-for-ten reverse stock split completed on October 29, 2024.
Conference Call and Webcast
Kezar Life Sciences will host a webcast and conference call today, March 25, 2025, at 8:00 a.m. ET to discuss topline results from the PORTOLA Phase 2a clinical trial. To access the live audio webcast with slides and dial-in information as needed, please register here: View Source
A live webcast of the event can also be found on the Kezar website at View Source A replay of the event will be available for 90 days following the presentation.