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

 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*

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

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

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.

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