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Zetomipzomib, a first-in-class immunoproteasome inhibitor, for the treatment of SLE and LN

Dec 6, 2022
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Learning objective: After reading this article, learners will be able to cite a new development in systemic lupus erythematosus and lupus nephritis.

 Zetomipzomib, a first-in-class immunoproteasome inhibitor, was evaluated for tolerability, safety, and exploratory efficacy in patients with systemic lupus erythematosus (SLE) with/without concurrent lupus nephritis (LN) in the phase Ib/II MISSION study (NCT03393013).

Results from the phase II portion of the study were presented at the American Society of Nephrology (ASN) Kidney Week 2022 Annual Meeting in Orlando, FL.1

A total of 21 adult patients were included, eligible patients had a diagnosis of active LN (Class III or IV +/- Class V) with a 24-hour urine protein to creatinine ratio (UPCR) of ≥1.0 mg/mg, despite previous treatment with a corticosteroid and at least one immunosuppressive drug for 8 weeks or more. Patients received a subcutaneous 60 mg dose of zetomipzomib weekly for 24 weeks, with an initial dose of 30 mg, and were followed-up for 12-weeks to assess safety. The primary endpoint was the number of patients achieving ≥50% reduction in UPCR from baseline after treatment (overall renal response; ORR). Safety was measured by incidence of treatment-emergent adverse events (TEAEs).

Results 

Of the 21 patients who entered the study, 4 discontinued before the end of treatment. Efficacy was evaluated in the remaining 17 patients who completed treatment. The majority of the patients were female (90.5%) and the mean duration of SLE and LN was 9.7 years and 5.3 years, respectively. The most common TEAE was injection site reaction, experienced by 71.4% of patients, with serious TEAEs occurred in 2 (9.5%) patients (Table 1).

Table 1. Incidence of adverse events*

Adverse event, %

N = 21

Injection site reaction

71.4

TEAE leading to discontinuation

19.0

Grade 3 TEAE

28.6

Serious TEAE

9.5

Opportunistic infection

0

Death

0

TEAE, treatment-emergent adverse event.
*Adapted from Parikh et al.1

Overall renal response up to Week 37 is shown in Figure 1.

Figure 1. Overall renal response with zetomipzomib treatment*

CRR, complete renal response; ORR, overall renal response; UPCR, urine protein to creatinine ratios.

*Adapted from Parikh, et al.1

The median UPCR from baseline to Week 37 is shown in Figure 2.

Figure 2. UPCR from baseline to Week 37* 

UPCR, urine protein to creatinine ratios.

*Adapted from Parikh, et al.1

ORR at Week 25 varied across LN biopsy classes. The overall ORR was 64.7%, with 60%, 70%, and 50% of patients with pure Class III, pure Class IV, and Class III/IV + Class V achieving ORR, respectively.

Other efficacy results showed that:

  • Estimated glomerular filtration rate was stable through treatment and up to Week 37
  • At Week 13, 82.4% of patients had achieved a daily corticosteroid dose of ≤10 mg
  • The mean Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) reduced from 11.3 at baseline to 5.8 at Week 37

Conclusion

The authors highlighted that zetomipzomib may be an effective treatment add-on for patients with SLE and LN, with a favorable safety profile; 64.7% of patients achieved a reduction in UPCR of ≥50%, with many patients reducing their dose of corticosteroid.1 Renal responses remained consistent, regardless of LN class.1 However, the patient numbers in this study were low, additional studies with larger cohorts are planned to provide further efficacy and safety information in these patients.2

  1. Parikh SV, Furie R, Saxena A, et al. Zetomipzomib (KZR-616), a first-in-class selective immunoproteasome inhibitor for the treatment of lupus nephritis: preliminary results from the phase 2 MISSION study. Poster #TH-PO487. American Society of Nephrology Kidney Week 2022 Annual Meeting; Orlando, US.
  2. Kezar life sciences presents positive complete results from the MISSION phase 2 trial evaluating zetomipzomib in lupus nephritis at ASN’s Kidney Week 2022 Annual Meeting. https://www.businesswire.com/news/home/20221103005618/en/Kezar-Life-Sciences-Presents-Positive-Complete-Results-from-the-MISSION-Phase-2-Trial-Evaluating-Zetomipzomib-in-Lupus-Nephritis-at-ASN%E2%80%99s-Kidney-Week-2022-Annual-Meeting Published Nov 3, 2022. Accessed Nov 17, 2022.