[Translation] A Phase IIb, Randomized, Controlled, Double-Blind, Multicenter Study Comparing the Efficacy and Safety of Zetomipzomib (KZR-616) 30 mg or 60 mg versus Placebo in Patients with Active Lupus Nephritis

评估 Zetomipzomib 在活动性 III 或 IV 型（伴或不伴 V 型；III/IV +/-V 型）狼疮肾炎 (LN) 和单纯 V 型 LN 患者中的疗效和安全性。

[Translation]

To evaluate the efficacy and safety of zetomipzomib in patients with active class III or IV (with or without class V; class III/IV +/-V) lupus nephritis (LN) and isolated class V LN.

Start Date24 Apr 2024

Sponsor / Collaborator

Yunding Xinyao Pharmaceutical Technology Co., Ltd.

NCT05781750 / SuspendedPhase 2

A Phase 2b, Randomized, Controlled Double-blind, Multicenter Study Comparing the Efficacy and Safety of Zetomipzomib (KZR-616) 30 mg or 60 mg With Placebo in Patients With Active Lupus Nephritis

The purpose of this study is to assess the efficacy and safety of zetomipzomib (30 mg or 60 mg) compared with placebo in achieving renal response after 52 weeks of treatment in patients with active lupus nephritis (LN).

Start Date03 Nov 2023

Sponsor / Collaborator

Kezar Life Sciences, Inc.

NCT05569759 / Active, not recruitingPhase 2

A Randomized, Double-blind, Placebo-controlled, Phase 2a Study With Open-label Extension to Evaluate the Safety and Efficacy of Zetomipzomib (KZR-616) in Patients With Autoimmune Hepatitis

This is a Phase 2a, multi-center, placebo-controlled study in which patients with autoimmune hepatitis will receive zetomipzomib or placebo in addition to standard-of-care for 24 weeks; an optional open-label extension period allows patients to receive zetomipzomib (KZR-616) for an additional 24 weeks of treatment.

Start Date23 May 2023

Sponsor / Collaborator

Kezar Life Sciences, Inc.

100 Clinical Results associated with Zetomipzomib

100 Translational Medicine associated with Zetomipzomib

100 Patents (Medical) associated with Zetomipzomib

Literatures (Medical) associated with Zetomipzomib

01 Jan 2023·Frontiers in immunology

Zetomipzomib (KZR-616) attenuates lupus in mice via modulation of innate and adaptive immune responses.

Article

Author: Kirk, Christopher J. ; Fan, R. Andrea ; Muchamuel, Tony ; Anderl, Janet L. ; McMinn, Dustin L. ; Lowe, Eric ; Johnson, Henry W. B. ; Tuch, Brian B. ; Bomba, Darrin J. ; Millare, Beatriz

Zetomipzomib (KZR-616) is a selective inhibitor of the immunoproteasome currently undergoing clinical investigation in autoimmune disorders. Here, we characterized KZR-616 in vitro and in vivo using multiplexed cytokine analysis, lymphocyte activation and differentiation, and differential gene expression analysis. KZR-616 blocked production of >30 pro-inflammatory cytokines in human peripheral blood mononuclear cells (PBMCs), polarization of T helper (Th) cells, and formation of plasmablasts. In the NZB/W F1 mouse model of lupus nephritis (LN), KZR-616 treatment resulted in complete resolution of proteinuria that was maintained at least 8 weeks after the cessation of dosing and was mediated in part by alterations in T and B cell activation, including reduced numbers of short and long-lived plasma cells. Gene expression analysis of human PBMCs and tissues from diseased mice revealed a consistent and broad response focused on inhibition of T, B, and plasma cell function and the Type I interferon pathway and promotion of hematopoietic cell lineages and tissue remodeling. In healthy volunteers, KZR-616 administration resulted in selective inhibition of the immunoproteasome and blockade of cytokine production following ex vivo stimulation. These data support the ongoing development of KZR-616 in autoimmune disorders such as systemic lupus erythematosus (SLE)/LN.

01 Sep 2022·European journal of immunology

Effective therapy of polymyositis in mice via selective inhibition of the immunoproteasome

Article

Author: Kirk, Christopher J ; del Rio Oliva, Marta ; Basler, Michael ; Groettrup, Marcus

Abstract:

Polymyositis (PM) is a chronic autoimmune inflammatory myopathy resulting in muscle weakness. The limited approved therapies and their poor efficacy contribute to its comorbidity. We investigated the therapeutic use of ONX 0914 and KZR‐616, selective inhibitors of the immunoproteasome, in C protein‐induced myositis (CIM), a mouse model of PM that closely resembles the human disease. Diseased mice (day 13 postimmunization) were treated with 10 mg/kg ONX 0914, KZR‐616, or vehicle on alternate days until day 28. Endpoints included muscle strength assessed by a grip strength meter, serum creatine kinase activity, histology, and immunohistochemistry analysis. Treatment with ONX 0914 or KZR‐616 prevented the loss of grip strength in mice after CIM induction, while vehicle‐treated animals displayed progressive muscle weakness. Immunoproteasome inhibition lowered PM‐associated leukocyte infiltration of the muscle and prevented increased serum creatine kinase levels. LMP7‐deficient mice were resistant to CIM induction, as they showed no alterations in grip strength or creatine kinase (CK) levels or muscular alterations. In conclusion, selective inhibition of the immunoproteasome displays therapeutic efficacy in a preclinical mouse model of PM with suppression of muscle inflammation and preservation of muscle strength. Positive results from this study support the rationale for using KZR‐616 in clinical studies.

01 Aug 2022·Current opinion in pharmacology

Current and new targets for treating myositis

Review

Author: Oddis, Chester V ; Moghadam-Kia, Siamak

As treatment of refractory idiopathic inflammatory myopathies (IIM) has been challenging, there is growing interest in assessing new therapies that target various pathways implicated in the pathogenesis of IIM. In the largest clinical trial to date, rituximab was studied in adult and juvenile myositis, but the primary outcome was not met despite 83 percent of subjects with refractory myositis meeting the definition of improvement. The U.S. Food and Drug Administration (FDA) has recently granted approval to Octagam 10% immune globulin intravenous (IVIg), for the treatment of adult dermatomyositis based on impressive results from a double-blind placebo-controlled trial. Anti-tumor necrosis factor (anti-TNF) utility in IIM is not recommended and recent reports suggest this therapy may induce systemic autoimmune disease including myositis. Further, anti-IL6 therapy cannot be recommended as a recent trial of tocilizumab failed to reach its primary endpoint. Further studies are needed to assess the role of newer therapies such as abatacept (inhibition of T cell co-stimulation), sifalimumab (anti-IFNα), Janus kinase [JAK] inhibitors, apremilast (phosphodiesterase 4 inhibitor), and KZR-616 (selective inhibitor of the immunoproteasome) given their biological plausibility and encouraging recent small-case series results. The future of IIM therapy will depend on exploring biomarkers implicated in the etiopathogenesis of IIM, improvements in myositis classification based on serological and histopathological features, and well-designed controlled clinical trials using validated consensus outcome measures.

News (Medical) associated with Zetomipzomib

17 Oct 2024

·www.biospace.com

Kezar Life Sciences Announces Positive IDMC Safety Review of PORTOLA Trial of Zetomipzomib in Patients with Autoimmune Hepatitis and Provides PALIZADE Update

PORTOLA Phase 2a clinical trial in patients with autoimmune hepatitis (AIH) to continue without modification following review by Independent Data Monitoring Committee (IDMC); reiterating guidance of topline data in first half 2025 PALIZADE Phase 2b clinical trial in patients with active lupus nephritis (LN) will be discontinued; focusing resources on clinical development of zetomipzomib in AIH SOUTH SAN FRANCISCO, Calif.--(BUSINESS WIRE)--Kezar Life Sciences, Inc. (Nasdaq: KZR), a clinical-stage biotechnology company developing novel small molecule therapeutics to treat unmet needs in immune-mediated diseases, today announced key clinical development updates. The IDMC overseeing the PORTOLA Phase 2a clinical trial of zetomipzomib in patients with AIH recommended that the trial may proceed without modification following its third scheduled meeting. The IDMC examined safety data from all patients enrolled in the trial, including data from patients who completed the blinded treatment period and continued to the open-label extension portion of the trial which includes an additional 24 weeks of treatment. Three members of the IDMC, including the committee chair, are also members of the IDMC overseeing the PALIZADE study of zetomipzomib in LN. To date, no Grade 4 or 5 serious adverse events (SAEs) have been observed in the PORTOLA trial which is being conducted at clinical sites in the United States. Kezar has completed enrollment of PORTOLA and plans to report topline data in the first half of 2025. Kezar has also made the strategic decision to terminate the PALIZADE Phase 2b clinical trial in patients with active LN and focus clinical development efforts of zetomipzomib in AIH, a rare disease with a significant unmet medical need. PALIZADE was recently placed on clinical hold following the recommendation of the IDMC after its assessment of four Grade 5 (fatal) SAEs that occurred in patients enrolled in the Philippines and Argentina (including one patient on placebo). Kezar will unblind the trial and perform a full investigation into all safety events from the study. As of termination, 84 patients were enrolled, and Kezar will report available data from PALIZADE at a later date. “The IDMC recommendation to continue the PORTOLA trial without modification strengthens our confidence in the potential for zetomipzomib to be a meaningful treatment for patients living with autoimmune hepatitis,” said Chris Kirk, PhD, Kezar’s Chief Executive Officer. “While we are disappointed to discontinue our development program in LN, we would like to thank the investigators, patients and their families for their participation in the PALIZADE trial. This decision was difficult given the favorable safety pro clinical activity data we have presented from the MISSION study and rapid enrollment to PALIZADE. However, a focused development effort in AIH extends our cash runway and provides flexibility as we work to bring zetomipzomib forward as a treatment for patients living with this life-threatening disease.” Kezar’s unaudited cash position is approximately $148 million, including cash, cash equivalents and marketable securities, as of September 30, 2024. This cash estimate is a preliminary estimate and based on information currently available to management, and this estimate could change. About PORTOLA 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. The study has completed enrollment of 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. The primary efficacy endpoint will measure the proportion of patients who achieve a complete biochemical response 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. About Autoimmune Hepatitis Autoimmune hepatitis (AIH) is a rare chronic disease in which the immune system attacks the liver and causes inflammation and tissue damage, severely impacting patients’ physical health and quality of life. Lifelong maintenance therapy is required to avoid relapse and burdensome adverse effects. If left untreated, AIH can lead to cirrhosis, liver failure and hepatocellular carcinoma. In the United States, AIH affects approximately 140,000 individuals, with incidence rates increasing. The cause of this condition remains unclear, with females affected four times as often as males. Currently, standard of care treatment for AIH is chronic, immunosuppressive treatment with corticosteroids that frequently cause life-altering side effects, including diabetes, osteoporotic fractures and cataracts. There is a significant need for treatment regimens that reduce or remove the need for chronic immunosuppression from using corticosteroids. About Kezar Life Sciences Kezar Life Sciences is a clinical-stage biopharmaceutical company developing novel small molecule therapeutics to treat unmet needs in immune-mediated diseases. For more information, visit , and follow us on LinkedIn , Facebook , Twitter and Instagram . Cautionary Note on Forward-looking Statements This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Words such as “may,” “will,” “can,” “should,” “expect,” “believe,” “plans,” “potential,” “anticipate” and similar expressions (as well as other words or expressions referencing future events, conditions or circumstances) are intended to identify forward-looking statements. These forward-looking statements are based on Kezar’s expectations and assumptions as of the date of this press release. Each of these forward-looking statements involves risks and uncertainties that could cause Kezar’s future results or performance to differ materially from those expressed or implied by the forward-looking statements. Forward-looking statements contained in this press release include, but are not limited to, statements about the nature, frequency and severity of adverse events; the design, progress and outcome of Kezar’s clinical trials; Kezar’s ability to report data from its clinical trials on expected timelines, if at all; and Kezar’s ability to extend its cash runway. Many factors may cause differences between current expectations and actual results, including those factors that are discussed in Kezar’s filings with the U.S. Securities and Exchange Commission, including the “Risk Factors” contained therein. Except as required by law, Kezar assumes no obligation to update any forward-looking statements contained herein to reflect any change in expectations, even as new information becomes available. Contacts Investor and Media Contact: Gitanjali Jain Senior Vice President, Investor Relations and External Affairs Kezar Life Sciences, Inc. gjain@kezarbio.com

Phase 2

17 Oct 2024

·www.biospace.com

Kezar Cuts Lupus Program After Patient Deaths, Focuses on Autoimmune Hepatitis

Earlier this month, Kezar Life Sciences announced that the mid-stage test of zetomipzomib in lupus nephritis had been placed on an FDA clinical hold. Now, that program is being terminated. Kezar Life Sciences is discontinuing a lupus program after four patient deaths occurred during a Phase IIb trial and will focus on developing the same drug in autoimmune hepatitis. Earlier this month, Kezar announced that the mid-stage study of zetomipzomib in lupus nephritis had been placed on an FDA clinical hold. The regulatory action came after the company reported four patient deaths in the Phase IIb PALIZADE trial. Other serious adverse events were reported as well that “showed a similar proximity to dosing.” Kezar voluntarily suspended enrollment and began looking at mitigation strategies for the drug. Now, an independent data monitoring committee that had been examining the PALIZADE trial and the Phase IIa PORTOLA trial of zetomipzomib in hepatitis has recommended that the lupus program be suspended. Kezar will proceed with the hepatitis study and expects a readout in the first half of 2025, according to a Thursday press release. Kezar noted that one of the deaths that occurred in the PALIZADE study was in a patient who had received a placebo. The trial was conducted in Argentina and the Philippines. The trial will be unblinded and a full investigation will be conducted into the safety events, the company said. At the time the study was terminated, 84 patients were enrolled. Kezar promised to release available data at a later time. CEO Chris Kirk said Kezar’s decision was a difficult one, as the company had seen a favorable safety pro clinical activity in an earlier trial called MISSION. The PALIZADE trial also enrolled very quickly. “However, a focused development effort in AIH [autoimmune hepatitis] extends our cash runway and provides flexibility as we work to bring zetomipzomib forward as a treatment for patients living with this life-threatening disease,” Kirk said. The data committee recommended that the PORTOLA trial proceed without modification after examining all safety data from the patients enrolled in the trial. No serious adverse events rated grade 4 or higher, which would indicate a death, have occurred in the PORTOLA trial which is being conducted in the U.S. In other news, Kezar has rejected an unsolicited bid from Concentra Biosciences to acquire the biotech. The offer had been to buy all outstanding shares for $1.10 apiece, plus a contingent value right. Kezar has decided that the value significantly undervalues the company and zetomipzomib. Concentra, meanwhile, has moved to acquire 9.9% of Kezar’s common stock. Kezar has adopted a stockholder rights plan, also known as a “poison pill” defense, to protect against any party buying a controlling stake through the open market without paying stockholders their due. The rights plan does not block a more traditional buyout, even from Concentra, if the board deems it in the best interests of shareholders, Kezar noted. Kezar’s shares were trading at 80 cents on the Nasdaq Capital Market Thursday morning, down more than 9% from the prior close. Concentra is owned by Tang Capital, a life sciences-focused investment firm. The company has made many attempts over the years to buy out struggling biotechs, most recently succeeding in acquiring Theseus Pharmaceuticals. Similar buyouts offered to LianBio, Rain Oncology and Atea Pharmaceuticals were unsuccessful.

Phase 2Acquisition

09 Oct 2024

·endpts.com

Kevin Tang's Concentra swoops in on another struggling biotech, offering to buy Kezar

Concentra Biosciences, a shell company from Tang Capital, wants to buy another biotech that has found itself in a bind. Kevin Tang’s shop told Kezar Life Sciences’ board on Tuesday that it is willing to pay $1.10 per share to buy out the Bay Area biotech. The move comes just days after Kezar stopped its Phase 2b clinical trial in lupus nephritis after four patients died. The trial was then put on official hold by the FDA this week. Kezar’s share price $KZR spiked 22% to 91 cents apiece in post-market trading after Concentra’s proposal became public. Kezar had closed Tuesday at 74 cents per share. The biotech debuted as a public company at $15 per share in June 2018. Tang Capital owns 9.9% of Kezar’s outstanding shares. The investor has bought more than six million shares in Kezar since Sept. 30, according to an SEC filing . Concentra’s non-binding proposal also comes with the potential for further payments. If the deal goes through and Concentra is able to out-license or sell Kezar’s experimental drugs and intellectual property, then shareholders could get 80% of those net proceeds. In his letter to the board, Tang said Concentra “has funds immediately available to execute this transaction.” “Concentra has the expertise and resources to maximize the value of the CVR for the benefit of Kezar shareholders,” Tang wrote. “This may include, if appropriate, completing PORTOLA, an ongoing Phase 2a study of zetomipzomib in patients with autoimmune hepatitis.” Concentra has had a mixed bag of success. Atea Pharmaceuticals and LianBio rejected the shell company’s unsolicited bids last year. Theseus Pharmaceuticals and Jounce Therapeutics , meanwhile, both went with the takeover bids. DNA sequencing company Singular Genomics was also targeted by Concentra last month. Tang wants to hear back from Kezar by the close of business on Oct. 18. Otherwise, the offer will expire, he wrote in the letter. A Kezar spokesperson didn’t immediately respond to an Endpoints News inquiry. The 2015 Amgen spinout has had a string of setbacks in the past 12 months. In August, Kezar stopped enrolling patients in a Phase 1 solid tumor trial. Last October, it laid off 41% of its staff, swapped CEOs and ended preclinical R&D to keep the lights on. At the end of June, the company had $164 million in cash, equivalents and marketable securities.

Phase 1Phase 2AcquisitionIPO

100 Deals associated with Zetomipzomib

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Hepatitis, Autoimmune	Phase 2	US	Kezar Life Sciences, Inc.	23 May 2023
Autoimmune Haemolytic Anaemias	Phase 2	US	Kezar Life Sciences, Inc.	01 Jul 2020
Autoimmune Haemolytic Anaemias	Phase 2	AU	Kezar Life Sciences, Inc.	01 Jul 2020
Autoimmune Haemolytic Anaemias	Phase 2	IT	Kezar Life Sciences, Inc.	01 Jul 2020
Autoimmune Haemolytic Anaemias	Phase 2	PL	Kezar Life Sciences, Inc.	01 Jul 2020
Autoimmune Haemolytic Anaemias	Phase 2	RU	Kezar Life Sciences, Inc.	01 Jul 2020
Purpura, Thrombocytopenic, Idiopathic	Phase 2	US	Kezar Life Sciences, Inc.	01 Jul 2020
Purpura, Thrombocytopenic, Idiopathic	Phase 2	AU	Kezar Life Sciences, Inc.	01 Jul 2020
Purpura, Thrombocytopenic, Idiopathic	Phase 2	IT	Kezar Life Sciences, Inc.	01 Jul 2020
Purpura, Thrombocytopenic, Idiopathic	Phase 2	PL	Kezar Life Sciences, Inc.	01 Jul 2020

Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT05781750 (PALIZADE, Company_Website) Manual	Phase 2	Lupus Nephritis	-	zetomipzomib 30 mg	lwbanzjbts(yecifhkoal) = four fatal, or grade 5, serious adverse events among participants in the Philippines and Argentina, according to the release. lckljaetxt (rdzdtljyjg )	Negative	01 Oct 2024
NCT05781750 (PALIZADE, Company_Website) Manual	Phase 2	Lupus Nephritis	-	zetomipzomib 60 mg		Negative	01 Oct 2024
NCT04628936 (CTgov)	Phase 2	Dermatomyositis	18	KZR-616	pprlrzlnyv(orfyoxlmxj) = ezehnnzyaa fyenrtlcgc (sfxplhuftg, qzpteegqfs - ijdmtjisfe) View more	-	05 Jun 2024
NCT04033926 (PRESIDIO, CTgov)	Phase 2	Dermatomyositis	25	Zetomipzomib (Arm A: Period 1 (Zetomipzomib))	rccmprrgvg(tqwjhsyydj) = etwsmarler ibudzprgfb (feidokclao, hhzgoehejo - pomyldwaul) View more	-	03 Jan 2024
NCT04033926 (PRESIDIO, CTgov)	Phase 2	Dermatomyositis	25	Placebo (Arm B: Period 1 (Placebo))	rccmprrgvg(tqwjhsyydj) = gbyngkprra ibudzprgfb (feidokclao, dvvweqmvmx - xnifouxvgl) View more	-	03 Jan 2024
MISSION (EULAR2023)	Phase 2	Lupus Nephritis uCD163	21	Zetomipzomib 60mg	aetdzapvwz(zpikrqzeov) = ddpnyklnho dyziwhkpwb (drtihdxhoa )	Positive	31 May 2023
NCT03393013 (MISSION, EULAR2023)	Phase 2	Lupus Nephritis proteinuria \| urinary CD163	21	Zetomipzomib 60 mg SC QW	uujmogyaps(bvarmerrnl) = wdxcisxpjf agyojwdveh (ugcxdbuqne ) View more	-	31 May 2023
NCT03393013 (MISSION, ASN2022) Manual	Phase 2	Lupus Nephritis	5	KZR-616	qnurqpqhjk(pidhhjetpn) = zlnmitqrwl uyybnvghud (rluvgirdsp ) View more	Positive	03 Nov 2022
NCT03393013 (MISSION, Biospace) Manual	Phase 2	Lupus Nephritis	17	Zetomipzomib	bslceikruc(dlqmhnedal) = lwkbmqzmxs qgfynkccoz (eesuuklvpf ) View more	Positive	27 Jun 2022
NCT04033926 (PRESIDIO, BusinessWire) Manual	Phase 2	Dermatomyositis \| Polymyositis	25	Zetomipzomib (Zetomipzomib+Zetomipzomib+placebo)	pyrpakokvi(scgzthskgv) = icipemoqkq toevedpxvj (klnasfpfin ) View more	Negative	03 May 2022
NCT04033926 (PRESIDIO, BusinessWire) Manual	Phase 2	Dermatomyositis \| Polymyositis	25	Zetomipzomib (Zetomipzomib+placebo+Zetomipzomib)	pyrpakokvi(scgzthskgv) = seqlkiavgm toevedpxvj (klnasfpfin ) View more	Negative	03 May 2022
NCT03393013 (MISSION, BusinessWire) Manual	Phase 1	Systemic Lupus Erythematosus	47	Zetomipzomib	uenjtsflvj(ivmahmebad) = dbpuppjvju fmnngscwyg (vqpiewycep ) View more	Positive	02 Jun 2021

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