Mar. 25 at 11:51 AM
$KZR Kezar Life Sciences reports topline results from PORTOLA trial
Kezar Life Sciences reported topline results from the PORTOLA Phase 2a clinical trial evaluating zetomipzomib, a selective immunoproteasome inhibitor, in patients with autoimmune hepatitis and reported fourth quarter and year end 2024 financial results. 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, aspartate aminotransferase and Immunoglobulin G values, 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. PORTOLA enrolled 24 patients as the ITT population. Consistent with the AASLD treatment goals, zetomipzomib treatment resulted in higher rates of complete biochemical responses 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% of zetomipzomib patients achieved a CR, compared to 37.5% of placebo patients; 31.3% of zetomipzomib patients achieved both a CR and steroid taper to 5 mg/day or less, compared to 12.5% of placebo patients; 18.8% of zetomipzomib patients achieved both a CR and complete steroid withdrawal to zero mg/day, compared to 0% of placebo patients; median duration of response in zetomipzomib patients achieving a CR was 27.6 weeks, 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% of zetomipzomib patients achieved a CR, compared to 28.6% of placebo patients; 35.7% of patients on the zetomipzomib arm achieved a CR and steroid taper to 5 mg/day or less, compared to 0% of placebo patients; 21.4% of patients on the zetomipzomib arm achieved a CR and complete steroid withdrawal to zero mg/day, compared to 0% of placebo patients.
Treatment-emergent adverse events were seen in all patients, with injection site reactions being the most commonly reported TEAE in both arms. Systemic injection reactions, 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 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: 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% of patients in the placebo arm and 56.3% 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 includes all patients who received at least one dose of study treatment.
