KZR-616 Shows Early Promise in Treatment of Active SLE

Patricia Inacio, PhD avatar

by Patricia Inacio, PhD |

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KZR-616, a selective immunoproteasome inhibitor, is safe, well-tolerated, and effectively reduces disease activity in patients with active systemic lupus erythematosus (SLE), preliminary Phase 1b data show.

The findings were presented at the European League Against Rheumatism (EULAR) 2019 Annual Meeting in Geneva, Switzerland, in a poster titled, “Treatment of systemic lupus erythematosus patients with the immunoproteasome inhibitor KZR-616: results from the first two cohorts of an open-label phase IB dose escalation trial.

Proteasomes are protein complexes that work to degrade unnecessary or damaged proteins within cells, making them crucial for cell health and survival. Because of this key role, drugs preventing the proteasome from working have been extensively used for killing cancers, particularly multiple myeloma.

In lupus, researchers have attempted to use proteasome inhibitors as a means to reduce active immune cells and inflammation, but results have been disappointing and associated with too much toxicity. This is likely because proteasomes are present in all cells.

Interestingly, a specific proteasome — the immunoproteasome — is present in immune cells only, and a selective inhibitor of this protein complex is thought to result in a broad anti-inflammatory response without compromising normal immunity, significantly reducing toxic effects.

KZR-616, developed by Kezar Life Sciences, is the first immunoproteasome inhibitor reaching clinical trials, and is expected to work not only in lupus but also in other autoimmune and inflammatory diseases.

Research using animal models of multiple autoimmune diseases showed that selective inhibition of the immunoproteasome was anti-inflammatory while enabling normal immune responses to occur.

A Phase 1a clinical trial using healthy volunteers also showed that KZR-616, injected into the skin, was safe, well-tolerated, and selectively inhibited immunoproteasome function, without the toxic side effects of current non-selective proteasome inhibitors.

Now, researchers are studying KZR-616 in patients with active SLE, with or without lupus nephritis (a kidney inflammation caused by lupus).

Ongoing and recruiting participants, the MISSION Phase 1b/2 trial (NCT03393013) consists of two parts. The Phase 1b trial is testing two KZR-616 doses — 45 mg and 60 mg — given along with standard lupus treatment, to assess its safety and tolerability and determine the best dose for further testing.

At the meeting, researchers presented preliminary results from the first two cohorts of the Phase 1b trial. Among the 13 patients included to date, eight received the 45 mg dose and five received the 60 mg dose. The treatment was carried out for 13 weeks, with 12 weeks of follow-up.

At the time of enrollment, all patients had active disease — defined as an SLE Disease Activity Index (SLEDAI) score of 4 or higher despite stable immunosuppressant, antimalarial, and/or corticosteroid therapy. After 13 weeks of treatment, 33% and 67% of patients in the lowest and highest dose, respectively, showed a reduction in SLEDAI scores of 4 points or more.

The 45 mg dose was safe and well-tolerated. Only mild side effects were seen, the most common being nausea and skin reactions and severe itching at the injection site.

Despite its efficacy, the 60 mg dose was stopped because all patients experienced vomiting within eight to 24 hours after the first dose.

“Presenting our first in-patient data with KZR-616, our novel selective immunoproteasome inhibitor, is an important milestone for Kezar and represents the culmination of several years of our team’s research and developmental efforts,” Niti Goel, Kezar’s chief medical officer, said in a press release. “We are encouraged by the safety, tolerability, and potential efficacy seen thus far in the MISSION trial.”

The Phase 2 part of the trial is recruiting patients with active proliferative lupus nephritis in Australia, Colombia, Mexico, and the United States. This trial is a randomized, placebo-controlled, double-blind study that will continue to test the safety and efficacy of KZR-616 given as 30 mg and 45 mg doses to patients receiving mycophenolate and prednisone. For more information, see the trial’s page.