FRI0196 TREATMENT OF SYSTEMIC LUPUS ERYTHEMATOSUS PATIENTS WITH THE IMMUNOPROTEASOME INHIBITOR KZR-616: RESULTS FROM THE FIRST 2 COHORTS OF AN OPEN-LABEL PHASE 1B DOSE ESCALATION TRIAL
Authors: Richard Furie, Darrin Bomba, Maria Dall’era, Massiel Prieto, Janet Anderl, Jinhai Wang, Christopher Kirk, Niti Goel
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Nonspecific proteasome inhibitors, e.g., bortezomib (BTZ), target both the constitutive and immuno- proteasomes and are standard of care for multiple myeloma. While BTZ has been used to treat refractory systemic lupus erythematosus (SLE) and lupus nephritis (LN), it is associated with adverse events (AEs) that limit its broad use. KZR-616, a first-in-class selective inhibitor of the immunoproteasome, is highly active and well tolerated in murine SLE<sup>1</sup>. In a Phase (Ph) 1 healthy volunteer (HV) study, KZR-616 subcutaneously (SC) at 30 and 45 mg weekly (QW) was shown to be safe, be well tolerated and achieve the target level of immunoproteasome inhibition<sup>2</sup>. We report here the preliminary safety and efficacy of KZR-616 in the Ph 1b portion of Study KZR–616–002 in active SLE patients (pts) (NCT03393013). <h3>Objectives</h3> The 1° objective of this first-in-patient study is to assess the safety and tolerability of KZR–616. The 2° objectives are to evaluate pharmacokinetics (PK) and determine the KZR-616 doses for the Ph 2 portion of the study. Pharmacodynamics (PD) and efficacy are also being assessed. <h3>Methods</h3> This open-label multicenter dose escalation trial enrolled SLE pts (per Systemic Lupus International Collaborating Clinics Classification Criteria) with SLE Disease Activity Index (SLEDAI) ≥4 despite stable background immunosuppressant, antimalarial, and/or corticosteroid (≤20 mg prednisone equivalent) therapy. Patients received KZR-616 at 45 mg (Cohort 1) or 60 mg (Cohort 2) SC QW through Week 13 (W13) with 12 weeks of follow up. Cohort 2a is currently enrolling pts using intrapatient dose escalation from 30 to 60 mg. Safety data include AEs, vitals, electrocardiograms and laboratory tests. Efficacy measures include the SLEDAI, Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI), 28 tender (T) and swollen (S) joint counts (JC), Physician Global Assessment (PhGA), and Patient Global Assessment (PtGA) in evaluable pts (receive ≥1 month of KZR-616; non-evaluable pts can be replaced). <h3>Results</h3> We enrolled 13 pts: 8 in Cohort 1, 5 in Cohort 2. The pts were 100% female; Baseline (BL) median SLEDAI was 10.0. All pts received at least 1 dose of KZR-616. In each cohort, 3 pts withdrew due to withdrawal of consent prior to W13. Overall, the 45 mg dose was well tolerated with no SAEs; all AEs were mild in intensity. The most common AEs were injection site erythema (62.5%), nausea (25%), and injection site pruritus (25%).Cohort 2 (60 mg) enrollment was halted, as all pts experienced vomiting within ∼8-24 hours (h) of their first dose, which typically resolved within 24 h. One pt had an SAE of thrombotic microangiopathy. Two pts permanently reduced their dose to 45 mg. After 2 doses at 45 mg, another pt successfully re-escalated to 60 mg. In Cohort 2a (n=5 to date), there has been 1 SAE of localized herpes zoster. In pts, PK and PD were similar to that achieved for the same doses in HV<sup>1</sup>. Efficacy data for evaluable pts are shown in the table. Two (33%) and 2 (67%) evaluable pts in Cohorts 1 and 2, respectively, had a SLEDAI improvement of ≥4 points from BL at W13. <h3>Conclusion</h3> KZR-616 dosed at 45 mg SC QW appears to be safe and well tolerated and showed evidence of disease suppression at W13 in active SLE pts on stable background therapy. The Ph 2 doses in the first randomized placebo-controlled trial with KZR-616 in active LN pts on mycophenolate and prednisone will be 30 and 45 mg. Efforts are ongoing to evaluate KZR–616 doses ≥60 mg using step–up dosing. <h3>References</h3> [1] Muchamuel, et al. ARD 2018. 77:A685. [2] Lickliter, et al. ARD 2018. 77:A1413. <h3>Disclosure of Interests</h3> Richard Furie Grant/research support from: Biogen, UCB Pharma, but not in the last 12 months, Consultant for: Biogen, UCB Pharma, but not in the last 12 months, Darrin Bomba Shareholder of: Stockholder in Kezar Life Sciences, Employee of: Employee of Kezar Life Sciences, Maria Dall'Era Grant/research support from: University has received funds to serve as a site on this clinical study, Consultant for: On Data Monitoring Committee for Janssen, Biogen, and Genentech; on Steering Committee for EMD Serono., Massiel Prieto Grant/research support from: Site has received funds to conduct this clinical trial, Janet Anderl Shareholder of: Stockholder in Kezar Life Sciences, Employee of: Employee of Kezar Life Sciences, Jinhai Wang Shareholder of: Shareholder in Kezar Life Sciences, Employee of: Employee of Kezar Life Sciences, Christopher Kirk Shareholder of: Shareholder and option holder in Kezar Life Sciences, Consultant for: Consultant for Amgen, Employee of: Employee of Kezar Life Sciences, Niti Goel Shareholder of: Own stock options in Kezar Life Sciences., Employee of: Corporate officer of Kezar Life Sciences.