Background/Purpose:

Proteasome inhibition is a standard of care for plasma cell malignancies. The first-generation inhibitor, bortezomib (BTZ), targets the constitutive proteasome and immunoproteasome and has been used in the treatment of Systemic Lupus Erythematosus and lupus nephritis (LN). However, BTZ therapy is associated with hematologic (thrombocytopenia, anemia, neutropenia) and constitutional (fatigue, peripheral neuropathy) adverse events (AEs). We report here the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of KZR-616, a first-in-class selective inhibitor of the immunoproteasome, in healthy volunteers (HV) following single or repeat subcutaneous (SC) or single intravenous (IV) administration (ACTRN12616001040459).

Methods:

Cohorts of HV (6 drug:2 placebo) received single SC or IV (30-minute infusion) doses or 4 weekly SC doses. Safety assessments, PK and PD were measured to Day 7 (SAD) or Day 28 (MAD). SAD cohorts included 7.5, 15, 30 and 60 mg (SC) and 7.5 and 15 mg (IV). MAD cohorts (all SC) included 30, 45, 60 mg and 2 intrasubject escalation cohorts with 1 dose at 30 mg and 3 subsequent doses at 45 mg. PK was measured by LC/MS². PD was measured using enzymatic and active site binding assays.

Results:

42 HV (31:11) were enrolled in 6 SAD cohorts. The most common AEs with SC administration were injection site reactions (ISRs), which were generally mild and transient. No clinically-significant laboratory or ECG abnormalities or dose limiting toxicities were observed in the SAD subjects.

Following SC administration, drug exposure increased dose proportionally and was characterized by rapid absorption (T_max 15 – 30 minutes) and clearance (T_1/2 ~2 hours). SC bioavailability was ~100%. Dose dependent and selective inhibition of the immunoproteasome exceeded 80% at ≥ 30 mg with significant recovery noted over 7 days. Constitutive proteasome inhibition was <37% in all cohorts.

40 HV (30:10) were enrolled in 5 SC MAD cohorts. In the initial cohort of 60 mg, an infusion reaction-like syndrome (chills, elevated heart rate, nausea) occurred ~8 hours after the first dose in 4 subjects. Further dosing in this cohort was withheld. Subsequent MAD cohorts (initiated at 30 mg) received prophylactic treatment with antihistamines +/- prednisone 1 hour prior to the first and second dose. No similar AEs occurred with repeat dosing of 30 or 45 mg. No clinically-significant laboratory or ECG abnormalities were seen in the remaining 4 MAD cohorts. ISRs did not increase in severity or frequency with repeat SC dosing, there were no AEs of peripheral neuropathy or infection, and 45 mg was well tolerated across 3 cohorts.

Consistent PK was noted following repeat administration and no drug accumulation was observed. At 45 mg, inhibition of 2 key subunits of the immunoproteasome, LMP7 and LMP2, was ~95% and ~70%, respectively.

Conclusion:

KZR-616 was well tolerated in HV and demonstrated consistent PK and PD. Selective immunoproteasome inhibition did not induce hematologic or constitutional toxicities associated with dual proteasome inhibitors. This study has identified candidate doses of KZR-616 to explore the safety, tolerability and efficacy of KZR-616 in patients with rheumatic diseases, such as LN, in an upcoming Phase 1b/2 study.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/kzr-616-a-selective-inhibitor-of-the-immunoproteasome-shows-a-promising-safety-and-target-inhibition-profile-in-a-phase-i-double-blind-single-sad-and-multiple-ascending-dose-mad-study-in-healt/