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- Zetomipzomib treatment results in steroid-sparing biochemical remissions in accordance with AASLD treatment guidelines in a difficult-to-treat, refractory AIH patient population.<\/i><\/li>\n
- In relapsed, steroid-dependent AIH patients, of the 21 of 24 entering screening on steroid-based therapy, 36% (5 of<\/i>14) of zetomipzomib-treated patients achieved a complete biochemical response (CR) and clinically significant steroid taper to 5 mg\/day or less, compared to 0 of 7 of placebo patients.<\/i><\/li>\n
- In the intention-to-treat (ITT) population, 31% (5 of 16) of zetomipzomib patients achieved a CR and steroid taper (\u22645 mg\/day), compared to 1 of 8 placebo patients.<\/i><\/li>\n
- 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 during study.<\/i><\/li>\n
- Favorable safety profile was observed during the 6-month, blinded treatment period.<\/i><\/li>\n
- Cash, cash equivalents and marketable securities totaled $132 million as of December 31, 2024<\/i><\/li>\n<\/ul>\n
SOUTH SAN FRANCISCO, Calif.–(BUSINESS WIRE<\/a>)–Kezar Life Sciences, Inc.<\/a> (Nasdaq: KZR), a clinical-stage biotechnology company developing novel small molecule therapeutics to treat unmet needs in immune-mediated diseases, today 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.\n<\/p>\n
\n\u201cWe are pleased to announce these exciting results from the PORTOLA trial, the first successful randomized study in treatment-refractory AIH,\u201d said Chris Kirk, CEO and co-founder of Kezar. \u201cWe 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\u2019d 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.\u201d\n<\/p>\n
\n\u201cI am impressed by the totality of efficacy and safety data from the PORTOLA study,\u201d said Gideon Hirschfield, Chair of Autoimmune Liver Disease Research and Director of the Francis Family Liver Clinic, at the Toronto General Hospital. \u201cZetomipzomib 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.\u201d\n<\/p>\n
\nPORTOLA 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).\n<\/p>\n
\nThe 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.\n<\/p>\n
Summary of Topline Results<\/span><\/b><\/p>\n
\nPORTOLA 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:\n<\/p>\n
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- \nWithout 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.\n<\/li>\n
- \n31.3% (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.\n<\/li>\n
- \n18.8% (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.\n<\/li>\n
- \nMedian 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.\n<\/li>\n<\/ul>\n
\nIn 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\u201340 mg\/day. Of the 21 patients in this subgroup analysis:\n<\/p>\n
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- \nMedian 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.\n<\/li>\n
- \nWithout 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.\n<\/li>\n
- \n35.7% (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.\n<\/li>\n
- \n21.4% (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.\n<\/li>\n<\/ul>\n
Safety<\/span><\/b><\/p>\n
\nTreatment-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.\n<\/p>\n
\nThree 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:\n<\/p>\n
- In relapsed, steroid-dependent AIH patients, of the 21 of 24 entering screening on steroid-based therapy, 36% (5 of<\/i>14) of zetomipzomib-treated patients achieved a complete biochemical response (CR) and clinically significant steroid taper to 5 mg\/day or less, compared to 0 of 7 of placebo patients.<\/i><\/li>\n
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