Phase 2b clinical trial seeks SLE patients with lupus nephritis

Kezar Life Sciences is enrolling patients to test zetomipzomib

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by Lindsey Shapiro |

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PALIZADE, a Phase 2b clinical trial of Kezar Life Sciences’ investigational therapy zetomipzomib, is still enrolling systemic lupus erythematosus (SLE) patients with active lupus nephritis, a severe lupus complication that causes kidney damage.

The launch of the placebo-controlled PALIZADE trial (NCT05781750) earlier this year followed the completion of the open-label Phase 1b/2 MISSION trial (NCT03393013), where zetomipzomib was found to safely ease disease activity in lupus nephritis patients and across various patient subgroups.

Recruitment is ongoing at eight U.S. sites, with an enrollment target of 279 adults with active lupus nephritis.

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The PALIZADE trial, along with another being conducted in people with autoimmune hepatitis, is intended to, “demonstrate zetomipzomib’s potential to be a steroid-sparing, immunomodulating treatment for multiple autoimmune conditions,” John Fowler, co-founder and CEO of Kezar, said in a press release.

Lupus nephritis usually is treated with immune-suppressing medications, such as corticosteroids or other immunosuppressants.

However, corticosteroids are accompanied by significant side effects with long-term use, and other immunosuppressants often target a single immune signal, which is not always effective.

Zetomipzomib was formerly known as KZR-616

Formerly known as KZR-616, zetomipzomib is a selective inhibitor of immunoproteasomes — protein complexes that play an important role in regulating immune function. When immunoproteasomes are inhibited, so is the activity of multiple signaling pathways involved in inflammation and immune cell activation that have been implicated in autoimmunity.

That’s why zetomipzomib is expected to have broad anti-inflammatory effects that could be of benefit for various autoimmune diseases, including SLE patients with lupus nephritis, and reduce the need for corticosteroids.

Its potential in lupus nephritis patients was tested in the Phase 1b/2 MISSION trial. After a first, dose-finding part involving 47 SLE patients with or without lupus nephritis, 21 patients with active lupus nephritis were enrolled in its Phase 2 portion.

All of these participants had a urine protein-to-creatinine ratio (UPCR) of at least 1 mg/mg at the study’s start. This ratio is an indicator of kidney health, where higher values indicate worse kidney function.

Participants received weekly under-the-skin injections of zetomipzomib for about six months on top of standard therapies (corticosteroids and other immunosuppressants). The dose of the first injection was 30 mg, and 60 mg thereafter. After treatment ended, patients were followed until week 37 (about nine months).

Trial results demonstrated that 64.7% of the patients achieved an overall renal response rate (ORR) after six months, defined as having a UPCR reduction of at least 50% since the study’s start (baseline), meeting the trial’s main goal. This was accompanied by a mean 53% reduction in corticosteroid use. By week 37, 88.2% of the participants had reached ORR.

Moreover, 41.2% achieved a complete renal response (CRR) by week 29, defined as a UPCR of 0.5 mg/mg or less, preserved kidney function — as measured by the estimated glomerular filtration rate — and a daily dose of corticosteroids equivalent to 10 mg or less of prednisone, and no use of prohibited medications.

Drops in UPCR were associated with reductions in urinary CD163 levels, a biomarker of active kidney inflammation. Reductions in clinical measures of SLE disease activity also were observed.

Later analyses indicated the benefits of zetomipzomib were maintained across key patient subgroups, including in Hispanic/Latino participants, patients with different degrees of nephritis severity, and in patients with very high protein levels in the urine (UPCR of at least 3 mg/mg).

Zetomipzomib was tolerated well, with no signs of immunosuppression. Most side effects were mild or moderate.

In PALIZADE, participants will be assigned randomly to receive zetomipzomib (30 or 60 mg) or a placebo once weekly for a year, alongside standard background therapy, followed by a one-month safety follow-up.

Background therapy will include mycophenolate mofetil (sold as CellCept) and optional treatment with into-the-vein methylprednisolone, followed by oral steroids. Over the first 16 weeks (about four months), there will be a mandatory tapering of oral corticosteroids to a dose of 5 mg per day or less.

The main efficacy goal is to determine the proportion of patients who achieve a CRR at week 37. Secondary goals related to UPCR reductions, corticosteroid use, measures of SLE disease activity, and life quality also will be evaluated.

The PALIZADE trial is expected to finish in 2026.