A Study of KZR-616 in Patients With SLE With and Without Lupus Nephritis

This was a Phase 1b/2, open-label, multi-center study in which patients received zetomipzomib administered as a SC injection weekly for either 13 weeks (Phase 1b) or for 24 weeks (Phase 2). In both phases, safety assessments continued for up to 12 weeks following the last dose of zetomipzomib.

Phase 1b was an open-label, multiple dose escalation study designed to evaluate the safety and tolerability of escalating doses of zetomipzomib when administered in addition to standard-of-care therapy in patients with SLE with or without nephritis. For each cohort, at least 6 patients were to be enrolled to assure the availability of at least 4 evaluable patients. Decisions to escalate, expand, or decrease the dose level or dosing frequency following the first 4 weeks of dosing for at least 4 evaluable patients in a cohort were made following review by a data monitoring committee (DMC).

The zetomipzomib formulations and doses administered by cohort in Phase 1b were:

• Cohort 1: zetomipzomib frozen maleate, 45 mg weekly × 13 weeks
• Cohort 2: zetomipzomib frozen maleate, 60 mg weekly × 13 weeks
• Cohort 2a: zetomipzomib frozen maleate, 30 mg weekly × 2 weeks, followed by 45 mg weekly × 2 weeks, followed by 60 mg weekly × 9 weeks
• Cohort 2b: zetomipzomib lyophile, 30 mg weekly × 1 week, followed by 60 mg weekly × 12 weeks
• Cohort 2c: zetomipzomib lyophile, 30 mg weekly × 1 week, followed by 60 mg weekly × 12 weeks (tolerability strategies cohort)
• Cohort 3: zetomipzomib lyophile, 30 mg weekly × 1 week, followed by 75 mg weekly × 12 weeks

The Phase 2 portion of the open-label study was designed to evaluate the renal response, safety, and tolerability of a single dose level (60 mg) of zetomipzomib administered weekly in addition to standard therapy in patients with active proliferative lupus nephritis (LN) (Class III or IV, with or without Class V disease) with a UPCR ≥1.0. Patients must have been on standard therapy for LN including at least 1 immunosuppressive agent. Zetomipzomib was administered as a SC injection weekly for 24 weeks (including a step up from an initial Week 1 dose of 30 mg).

Key Inclusion Criteria:

Phase 1b:

• Fulfilled the 2012 Systemic Lupus International Collaborating Clinics (SLICC) classification for SLE
• Had a positive antinuclear antibody (ANA) titer, anti-double stranded DNA (dsDNA) antibody titer, or a positive anti-Smith antibody titer
• Had active SLE (as indicated by Systemic Lupus Erythematosus Disease Activity Index 2000 [SLEDAI-2K] score ≥4), and
• Had received at least 1 prior therapy for SLE

Phase 2:

• Had active proliferative LN (Class III or IV, with or without Class V disease)
• Had a UPCR ≥1.0 measured in 24-hour urine collection
• Had a histologic diagnosis of LN on renal biopsy within the prior 2 years; for biopsies > 1 year before the Screening visit, one of the following must also be present at screening: low C3, low C4, or anti-ds-DNA elevated to above normal range
• Fulfilled the 2012 SLICC classification for SLE
• Had a positive ANA titer, anti-dsDNA antibody titer, or anti-Smith antibody titer, and
• Were currently receiving ≥1 immunosuppressive agent at a stable dose and route of administration for ≥8 weeks. If the patient is also on corticosteroids then must be on a stable dose for ≥ 2 weeks prior to Baseline

Key Exclusion Criteria:

Phase 1b:

• Current or medical history of:

• Central nervous system manifestations by autoimmune disease
• Overlapping autoimmune condition that may affect study assessments/outcomes
• Antiphospholipid syndrome with history of thromboembolic event of within the 52 weeks prior to Screening
• Malignancy of any type, with exceptions for in situ cancer that has been completely excised and certain cancers >5 years ago
• Positive test at Screening for HIV, hepatitis B/C
• Major surgery within 4 weeks before signing informed consent form or planned major surgery during the study period

Phase 2:

• Current or medical history of:

• Central nervous system manifestations of SLE
• Overlapping autoimmune condition that may affect study assessments/outcomes
• Antiphospholipid syndrome with history of thromboembolic event of within the 52 weeks prior to Screening
• Malignancy of any type within the last 5 years, with exceptions for appropriately excised and cured cervical carcinoma in situ or excised basal or squamous cell carcinomas of the skin
• Has received dialysis within the 52 weeks prior to Screening
• Positive test at Screening for HIV, hepatitis B/C
• Major surgery within 12 weeks before signing informed consent form or planned major surgery during the study period
• Use of investigational therapy or device, and/or participation in an investigational trial <8 weeks or 5 half-lives, whichever is longer, prior to Baseline; Patients who participated in Phase 1b of KZR-616-002 are excluded from Phase 2