zetomipzomib (KZR-616) / Kezar, Amgen, Everest Medicines - LARVOL DELTA

Targeting immunoproteasome-dependent β-catenin degradation as a therapeutic strategy in Relapsed/Refractory acute lymphoblastic leukemia (ASH 2025) - "Interestingly, treatment with M3258 (a selective PSMB8 inhibitor) did not interfere with β-cateninprotein degradation, suggesting that combined inhibition of both PSMB8 and PSMB9 is required forefficient inhibition...Likewise, genetic deletion of LEF1 rescued cellviability and caused resistance to Zetomipzomib and ONX-0914, highlighting the importance ofrepressive LEF1/β-catenin complexes in B- and T-ALL cells to suppress MYC. Our findings uncovered a previously unrecognized dependency of B- and T-ALL cells onimmunoproteasome-mediated β-catenin degradation to sustain MYC expression and survival... Our findings uncovered a previously unrecognized dependency of B- and T-ALL cells onimmunoproteasome-mediated β-catenin degradation to sustain MYC expression and survival. Targetingthe immunoproteasome, rather than the generic proteasome, offers a more selective strategy forlymphoid malignancies, with the potential for reduced off-target toxicity compared to..."

Acute Lymphocytic Leukemia • Hematological Malignancies • Immunology • Leukemia • Solid Tumor • T Acute Lymphoblastic Leukemia • Targeted Protein Degradation • T-cell Acute Lymphoblastic Lymphoma • CTNNB1 • MYC • PSMB10 • PSMB5 • PSMB8 • PSMB9 • TCF7

Targeting β-catenin nuclear export and protein degradation in high-risk acute lymphoblastic leukemia (ASH 2025) - "The combination of Selinexorwith GSK3B inhibition (LY2090314) or PSMB8/PSMB9 inhibition (Zetomipzomib/ONX0914) resulted insynergistic nuclear β-catenin accumulation in reporter cells...The identification of β-catenin as an XPO1 cargo protein and thenucleus as a shelter from protein degradation provide a mechanistic rationale for combining XPO1inhibition (selinexor, eltanexor) with GSK3B or immunoproteasome inhibition, which will support thedesign of forthcoming in vivo studies, including xenograft-based preclinical efficacy models in patient-derived B- and T-ALL xenografts. These findings identify β-catenin as a previously unrecognized and functionally significantcargo protein of XPO1 in B- and T-ALL... These findings identify β-catenin as a previously unrecognized and functionally significantcargo protein of XPO1 in B- and T-ALL. Our finding supports a promising combinatorial strategy for thetreatment of r/r ALL by co-targeting nuclear export and β-catenin protein..."

IO biomarker • Acute Lymphocytic Leukemia • B Acute Lymphoblastic Leukemia • Hematological Malignancies • Leukemia • Multiple Myeloma • T Acute Lymphoblastic Leukemia • Targeted Protein Degradation • PSMB8 • PSMB9 • XPO1

α-Aminoboronic Acid Moieties in Boro Dipeptides Modulate Proteasome Subunit Selectivity and Provide Access to Compounds with Potent Anticancer and Anti-Inflammatory Activity. (PubMed, J Med Chem) - "Although their cytotoxicity to cancer cells was not improved compared to bortezomib, selected compounds proved less toxic to noncancer cells and with anti-inflammatory activity comparable to that of zetomipzomib (KZR-616). The presented boro dipeptides with tailored P1 residues provide a basis for designing subunit-selective compounds with boronic acid as the warhead and optimized P2 and/or P3 positions."

Journal • Immunology • Oncology

Safety and Preliminary Efficacy of Zetomipzomib from the PALIZADE Phase 2b Clinical Trial in Patients with Lupus Nephritis (KIDNEY WEEK 2025) - P2 | "Fatalities were associated with possible pre-existing co-morbidities or underlying LN disease characteristics. Preliminary efficacy results indicate encouraging clinical activity in pts with Class III/IV ± V LN receiving 60 mg zeto."

Clinical • P2b data • Cardiovascular • Glomerulonephritis • Immunology • Infectious Disease • Inflammatory Arthritis • Lupus • Lupus Nephritis • Nephrology

Immunoproteasomes in Skeletal Muscle Pathologies: Emerging Roles, Conflicting Evidence, and Future Directions. (PubMed, Cells) - "Selective IMP inhibitors, such as ONX 0914 and KZR-616, display potent anti-inflammatory effects in preclinical models of autoimmune myositis and muscle atrophy. We emphasize the need for a deeper understanding of IMP-mediated mechanisms in skeletal muscle pathology and strategies combining selective inhibitors to enhance therapeutic efficacy while minimizing adverse effects. IMPs thus represent both a promising and potentially risky therapeutic target, with outcomes highly dependent on disease context."

Journal • Review • Immunology • Inflammation • Muscular Atrophy • Muscular Dystrophy • Myositis • Sarcopenia

Efficacy and Safety Results of Zetomipzomib from the PALIZADE Phase 2b Clinical Trial in Patients with Lupus Nephritis (ACR Convergence 2025) - P2 | "Safety analysis of enrolled pts indicated overall similar safety profiles between zeto dosed at 30 mg and 60 mg, and these findings are consistent with previous studies of zeto in LN. Preliminary efficacy data from a treatment evaluable population with Class III/IV ± V LN in the PALIZADE trial offer encouraging activity in pts receiving a 60 mg dose of zeto."

Clinical • P2b data • Cardiovascular • Glomerulonephritis • Immunology • Infectious Disease • Inflammatory Arthritis • Lupus • Lupus Nephritis • Nephrology • Renal Disease

ANALYSIS OF CIRCULATING BIOMARKERS IN THE RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED PORTOLA PHASE 2A STUDY EVALUATING ZETOMIPZOMIB, A SELECTIVE IMMUNOPROTEASOME INHIBITOR, IN PATIENTS WITH AUTOIMMUNE HEPATITIS (AASLD 2025) - P2 | "In the PORTOLA Phase 2a study, zeto administration resulted in notable alterations in biomarker activity across both the innate and adaptive immune systems that correlated with clinically relevant biochemical responses in AIH. Circulating biomarker changes following zeto treatment were consistent with previous reports from clinical studies in patients with SLE. These findings provide intriguing starting points for further mechanistic studies and validation in the AIH population."

Biomarker • Clinical • P2a data • Autoimmune Hepatitis • Hepatology • Immunology • Inflammation • Inflammatory Arthritis • Lupus • Systemic Lupus Erythematosus • TGFB1

ZETOMIPZOMIB, A FIRST-IN-CLASS SELECTIVE IMMUNOPROTEASOME INHIBITOR, DEMONSTRATES STEROID SPARING BIOCHEMICAL REMISSION IN PATIENTS WITH RELAPSED OR INSUFFICIENTLY RESPONDING AUTOIMMUNE HEPATITIS IN A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, PHASE 2A STUDY (AASLD 2025) - P2 | "Pts (N=24, intention-to-to-treat [ITT] population) were randomized (2:1) to zeto 60 mg or PBO s.c. weekly (QW) for 24 Ws in conjunction with 20 – 40 mg prednisone equivalent/day. Zetomipzomib treatment was associated with a favorable safety profile and showed promising efficacy in achieving steroid-sparing CR in a difficult-to-treat population of pts with AIH."

Clinical • P2a data • Autoimmune Hepatitis • Fibrosis • Hepatology • Immunology • Inflammation • Inflammatory Arthritis • Lupus • Systemic Lupus Erythematosus

Zetomipzomib and the PORTOLA Trial: A Transformative Step Forward in Autoimmune Hepatitis (AIH) (AASLD 2025) - "This session will present findings from the Phase 2a PORTOLA trial evaluating zetomipzomib, a first-in-class selective immunoproteasome inhibitor, in autoimmune hepatitis. Attendees will hear insights on the study design and clinical outcomes, followed by expert discussion on the potential role of immunoproteasome inhibition in advancing treatment for this challenging disease."

Autoimmune Hepatitis • Hepatology • Immunology • Inflammation

Kezar Life Sciences Announces FDA Has Lifted Partial Clinical Hold on PORTOLA Phase 2a Trial Evaluating Zetomipzomib for the Treatment of Patients with Autoimmune Hepatitis (Businesswire) - "Kezar Life Sciences...announced that the Division of Hepatology and Nutrition of the U.S. Food and Drug Administration (FDA) has lifted the partial clinical hold on the completed PORTOLA Phase 2a clinical trial evaluating zetomipzomib, a first-in-class selective immunoproteasome inhibitor, in patients with autoimmune hepatitis (AIH)....The company met with the Independent Data Monitoring Committee (IDMC) for the previously terminated PALIZADE clinical trial to review the safety profile of zetomipzomib. The IDMC has provided Kezar with recommendations for conducting future clinical trials in LN. Based on this feedback and internal analysis of safety data across all clinical studies involving zetomipzomib, Kezar plans to respond to the FDA Division of Rheumatology and Transplant Medicine with a request to lift the clinical hold on zetomipzomib in LN."

DSMB • FDA event • Autoimmune Hepatitis • Lupus Nephritis

Immunoproteasome Inhibitor (KZR-616) Desensitization and Maintenance Therapy in Highly Sensitized Non-Human Primates (WTC 2025) - "*Purpose: Immunoproteasome inhibitors (IPI), selectively targeting hematopoietic cells, exhibit lower toxicity than conventional PIs. Desensitization with IPI therapy was well tolerated in highly sensitized rhesus monkeys. This study demonstrates that IPI-based desensitization effectively reduces DSA. While IPI alone did not extend graft survival, its combination with belatacept yielded prolonged graft survival."

Clinical • Antibody-mediated Rejection • CD4

A Study of Zetomipzomib (KZR-616) in Patients With Autoimmune Hepatitis (PORTOLA) (clinicaltrials.gov) - P2 | N=24 | Completed | Sponsor: Kezar Life Sciences, Inc. | Trial completion date: Aug 2025 ➔ Apr 2025 | Active, not recruiting ➔ Completed

Trial completion • Trial completion date • Autoimmune Hepatitis • Immunology • Inflammation

Kezar Life Sciences Reports First Quarter 2025 Financial Results and Provides Business Update (Businesswire) - "Kezar is responding to the information request from the FDA Division of Hepatology and Nutrition to resolve the partial clinical hold on the PORTOLA Phase 2a clinical trial."

FDA event • Autoimmune Hepatitis

Targeting the ubiquitin-proteasome pathway in systemic lupus erythematosus. (PubMed, Expert Rev Clin Immunol) - "Bortezomib and the selective immunoproteasome inhibitors, ONX-0914 and zetomipzomib, ameliorate renal disease in murine lupus models...Thalidomide and lenalidomide are effective in refractory cutaneous lupus but again limited by their off-target effects. A phase II RCT of iberdomide shows favorable results in SLE, especially chronic and subacute cutaneous lesions. These molecules should be further explored in larger clinical trials of renal and cutaneous SLE."

Journal • Review • Cutaneous Lupus Erythematosus • Glomerulonephritis • Immunology • Inflammatory Arthritis • Lupus • Lupus Nephritis • Nephrology • Renal Disease • Systemic Lupus Erythematosus • Targeted Protein Degradation • CRBN

Kezar Life Sciences...Reports Fourth Quarter and Year End 2024 Financial Results (GlobeNewswire) - "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....The decrease was partially offset by the increased clinical trial costs related to the PALIZADE and PORTOLA trials."

Commercial • Autoimmune Hepatitis • Lupus Nephritis

Kezar Life Sciences Announces Positive Topline Results from the PORTOLA Phase 2a Trial Evaluating Zetomipzomib for the Treatment of Patients with Autoimmune Hepatitis (AIH) and Reports Fourth Quarter and Year End 2024 Financial Results (Businesswire) - P2a | N=24 | PORTOLA (NCT05569759) | Sponsor: Kezar Life Sciences, Inc. | "Zetomipzomib treatment results in steroid-sparing biochemical remissions in accordance with AASLD treatment guidelines in a difficult-to-treat, refractory AIH patient population; In relapsed, steroid-dependent AIH patients, of the 21 of 24 entering screening on steroid-based therapy, 36% (5 of 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; In the intention-to-treat (ITT) population, 31% (5 of 16) of zetomipzomib patients achieved a CR and steroid taper (≤5 mg/day), compared to 1 of 8 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 during study."

P2a data • Autoimmune Hepatitis

Kezar Life Sciences to Present Topline Results from the PORTOLA Phase 2a Trial Evaluating Zetomipzomib for the Treatment of Patients with Autoimmune Hepatitis on March 25, 2025 (Businesswire) - "Kezar Life Sciences, In...today announced that it will present topline results from the PORTOLA Phase 2a trial evaluating zetomipzomib for the treatment of patients with autoimmune hepatitis (AIH) on Tuesday, March 25, 2025, at 8:00 a.m. ET."

P2a data • Autoimmune Hepatitis

Kezar Life Sciences to Present at Virtual KOL Event Hosted by William Blair on Zetomipzomib Clinical Development in Autoimmune Hepatitis and Provide a Safety Update from the PALIZADE Trial for Lupus Nephritis on February 27, 2025 (Businesswire) - "The event will feature Aparna Goel, MD, a general transplant and hepatologist at Stanford University, who will discuss the burden of autoimmune hepatitis (AIH) on patients, current treatments and unmet needs, and expectations for how the treatment landscape will evolve in coming years. Zung To, SVP of Clinical Development, will also provide an overview of the PORTOLA Phase 2a clinical trial of zetomipzomib in patients with AIH. Kezar has completed enrollment of PORTOLA and plans to report topline data in the first half of 2025. Rachel Peterson, MD, Head of Clinical Immunology, will provide a safety update from the PALIZADE Phase 2b clinical trial of zetomipzomib in patients with active LN, which was discontinued and unblinded in October 2024."

Clinical • P2 data • Autoimmune Hepatitis • Lupus Nephritis

A Study of Zetomipzomib (KZR-616) in Patients with Active Lupus Nephritis (PALIZADE) (clinicaltrials.gov) - P2 | N=84 | Terminated | Sponsor: Kezar Life Sciences, Inc. | N=279 ➔ 84 | Trial completion date: Jul 2026 ➔ Nov 2024 | Suspended ➔ Terminated | Trial primary completion date: May 2026 ➔ Nov 2024; Sponsor Decision.

Enrollment change • Trial completion date • Trial primary completion date • Trial termination • Glomerulonephritis • Immunology • Inflammatory Arthritis • Lupus • Lupus Nephritis • Nephrology

Zetomipzomib (KZR-616), a First-in-Class Selective Immunoproteasome Inhibitor, Demonstrated Improvements in SLE/LN Disease Measures and Biomarkers in Patients with Highly Active SLE or Nephrotic Range Proteinuria in the Open-label Phase 1b/2 MISSION Study (ACR Convergence 2024) - P1/2 | "Results from this subgroup analysis suggest that treatment with zetomipzomib 60 mg once weekly is effective across multiple organ systems in patients with highly active SLE as well as in those with nephrotic range proteinuria (UPCR ≥3)."

Biomarker • Clinical • P1/2 data • Inflammatory Arthritis • Musculoskeletal Diseases • Nephrology • Renal Disease • CD163

Kezar Life Sciences Announces Clinical Hold of Zetomipzomib IND for Treatment of Lupus Nephritis (Businesswire) - "Kezar Life Sciences...announced that it was informed via teleconference with the U.S. Food and Drug Administration (FDA) that the zetomipzomib Investigational New Drug (IND) application for the treatment of lupus nephritis (LN) has been placed on clinical hold. This action follows Kezar’s communication to the FDA that Kezar was voluntarily suspending enrollment and dosing in its Phase 2b PALIZADE clinical trial of zetomipzomib in patients with active LN at the recommendation of the trial’s Independent Data Monitoring Committee (IDMC)....The FDA indicated that they will provide an official clinical hold letter to Kezar within 30 days....'At this time, our zetomipzomib IND for the treatment of autoimmune hepatitis is unaffected'."

FDA event • Autoimmune Hepatitis • Lupus Nephritis

A Study of Zetomipzomib (KZR-616) in Patients With Active Lupus Nephritis (PALIZADE) (clinicaltrials.gov) - P2 | N=279 | Suspended | Sponsor: Kezar Life Sciences, Inc. | Recruiting ➔ Suspended

Trial suspension • Glomerulonephritis • Immunology • Inflammatory Arthritis • Lupus • Lupus Nephritis • Nephrology

Kezar’s ongoing Phase 2a PORTOLA clinical trial of zetomipzomib in patients with autoimmune hepatitis has completed enrollment and remains active at this time (Businesswire) - "To date, no Grade 4 or 5 SAEs have been observed in the PORTOLA clinical trial."

Enrollment closed • Autoimmune Hepatitis

Kezar Life Sciences Reports First Quarter 2024 Financial Results and Provides Business Update (Businesswire) - "PALIZADE Phase 2b clinical trial of zetomipzomib in patients with active lupus nephritis actively enrolling; reiterating guidance of topline data in mid-2026. PORTOLA Phase 2a clinical trial of zetomipzomib in patients with autoimmune hepatitis actively enrolling; reiterating guidance of topline data in mid-2025."

P2a data • P2b data • Autoimmune Hepatitis • Immunology • Lupus Nephritis

Kezar Life Sciences Announces Cessation of Enrollment and Dosing in the Phase 2b PALIZADE Trial of Zetomipzomib in Active Lupus Nephritis Patients (Businesswire) - "Kezar Life Sciences...today announced the voluntary cessation in enrollment of new patients and dosing of ongoing patients in the Phase 2b PALIZADE clinical trial, pending further evaluation....To date, 84 patients have been enrolled in the PALIZADE trial, and patient safety data are reviewed by an Independent Data Monitoring Committee (IDMC)....Kezar’s decision to pause enrollment and dosing on PALIZADE enables time to evaluate the totality of data regarding the SAEs and determine next steps and potential risk mitigation strategies. The Company has notified all study investigators and is notifying regulatory authorities, including the U.S. Food and Drug Administration (FDA) and the European Medicines Agency, of its decision. At this time, a formal Investigational New Drug clinical hold has not been issued. If Kezar receives a clinical hold letter from the FDA, it will review the content and determine next steps."

Trial suspension • Lupus Nephritis