Zetomipzomib as Add-on Therapy Lowers Kidney Inflammation: Data
Results show main efficacy goal of Phase 1b/2 MISSION trial was achieved
When given on top of standard therapy, zetomipzomib led to clinically significant reductions in urine protein levels, a marker of kidney impairment, in systemic lupus erythematosus (SLE) patients with active lupus nephritis, a severe form of lupus that causes kidney damage.
That’s according to full data from the now completed Phase 1b/2 MISSION trial (NCT03393013) and means that the study’s main efficacy goal has been achieved.
In agreement with previously reported top-line data, these benefits were accompanied by a reduction in kidney inflammation, which was sustained for three months after treatment was discontinued. SLE disease activity and biomarkers also eased.
“MISSION Phase 2 accomplished the goal of demonstrating that zetomipzomib, a first-in-class inhibitor of the immunoproteasome, has potent anti-inflammatory effects which result in clinically meaningful reductions in [urine protein levels] in patients who do not respond fully to standard-of-care therapies,” Noreen R. Henig, MD, chief medical officer of zetomipzomib developer Kezar Life Sciences, said in a press release.
The therapy also allowed a tapering of corticosteroid dosage without signs of immunosuppression.
“The anti-inflammatory effect is sustained following discontinuation of zetomipzomib, consistent with earlier data, and occurs without evidence of immunosuppression. Based on these exciting results, we believe zetomipzomib has the potential to be a long-term, steroid-sparing, broad immunomodulating treatment for patients with lupus nephritis,” Henig said.
The company plans a placebo-controlled trial to continue assessing zetomipzomib’s effectiveness at treating lupus nephritis and further dissect its mechanism of action in SLE and autoimmune hepatitis, an inflammatory liver disease.
“We are moving quickly to launch a multi-country randomized placebo-controlled study to evaluate zetomipzomib in patients with [lupus nephritis], as well as exploring the potential of the novel mechanism of action in diseases such as autoimmune hepatitis and systemic lupus erythematosus,” Henig said.
Samir V. Parikh, MD, associate professor of medicine at the Ohio State University Wexner Medical Center, presented the results in a poster presentation at the American Society of Nephrology’s (ASN) Kidney Week 2022 Annual Meeting, which ran Nov. 3–6 in Orlando, Florida. The poster was titled, “Zetomipzomib (KZR-616), A First-in-Class, Selective Immunoproteasome Inhibitor, Achieved Clinically Meaningful Renal Responses in Refractory or Hard-To-Treat Patients With Lupus Nephritis: Completed Phase 2 MISSION Study Results.”
Lupus nephritis and kidney damage
Lupus nephritis is a severe manifestation of lupus that causes kidney damage in SLE patients. Treating it usually involves medications that suppress the body’s immune response, such as corticosteroids, or target a single immune signal. Corticosteroids often lead to significant side effects and a single target approach is not always effective, however.
Proteasomes are protein complexes that degrade unnecessary or damaged proteins within cells. Immune cells carry a specific version of proteasomes, called immunoproteasomes, that play a key role in regulating their activity.
The use of broad proteasome inhibitors to reduce immune cell activity and inflammation has been a goal for treating several autoimmune diseases, including SLE and lupus nephritis, specifically. The lack of specificity toward immunoproteasomes could lead to immunity impairments and toxic effects, however.
Formerly known as KZR-616, zetomipzomib is a novel, first-in-class, selective immunoproteasome inhibitor developed to have broad therapeutic potential across multiple autoimmune diseases. It’s administered as a subcutaneous (under-the-skin) injection.
In preclinical studies using animal models of multiple autoimmune diseases, it showed broad anti-inflammatory effects without causing general immune system impairment.
Results of zetomipzomib trials
In a Phase 1 trial of healthy volunteers, zetomipzomib was deemed safe and well tolerated. Moreover, it selectively inhibited immunoproteasome function without the toxic side effects of current nonselective proteasome inhibitors.
The open-label MISSION trial consisted of two parts. In the Phase 1b part, increasing doses of zetomipzomib were given once weekly for 13 weeks (three months) along with standard lupus treatment to SLE patients with and without lupus nephritis. A total of 47 SLE patients, including two with active lupus nephritis, were followed for 12 more weeks. The main goal of this phase was to assess zetomipzomib’s safety and tolerability and determine the best dose for testing in Phase 2.
Previously reported Phase 1b data showed three months with once weekly zetomipzomib up to a dose of 75 mg was safe and well tolerated. Efficacy measures, including a reduction in urine protein levels, were seen in two patients with lupus nephritis with doses higher than 45 mg.
In Phase 2, adults with active lupus nephritis received zetomipzomib, first at a dose of 30 mg (week 1), followed by 60 mg, for a total of 24 weeks (around six months). It was injected subcutaneously, once weekly, and given on top of standard therapies. These included corticosteroids (used by all patients) and at least one immunosuppressive medication — either mycophenolate mofetil (95.2%), hydroxychloroquine (66.7%), and azathioprine (9.5%).
Patients’ 24-hour urine protein to creatinine ratio (UPCR) at the start of the study (baseline) was 1 milligram per milligram (mg/mg) or higher. Creatinine is an indicator of kidney function.
Patients were evaluated at week 25, but were followed for an additional 12 weeks. The study lasted 37 weeks (almost nine months).
The main efficacy goal of the Phase 2 part was to assess the proportion of patients achieving an overall renal response (ORR), which was defined as having a reduction of 50% or more in UPCR by week 25.
The number of patients achieving a complete renal response (CRR) was a key secondary efficacy goal. CRR was defined by a UPCR value of 0.5 or less, which denotes an absolute reduction in protein levels in the urine, along with preserved kidney function, as measured by the estimated glomerular filtration rate (eGFR). In order to achieve CRR, patients had to be on a low dose of corticosteroids (prednisone/prednisone equivalent dose of 10mg or less) and not resort to prohibited medications.
Exploratory endpoints included measures of SLE disease activity, such as the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K), Physician Global Assessment, and Patient Global Assessment scores.
Seventeen of the 21 SLE patients with active lupus nephritis in Phase 2 completed treatment and were followed until the study’s end at 37 weeks. Four discontinued the trial before the end of treatment.
By week 25, 64.7% achieved an ORR, the main efficacy goal. This was accompanied by a 53% mean reduction in corticosteroid standard of care use.
Results of follow-up
During follow-up, 94.1% of patients reached ORR by week 29, and 88.2% by week 37. Also, 70.6% achieved an UPCR of 0.7 or less by the end of the study.
CRR was achieved by 35.3% of patients after treatment, according to all the pre-established criteria. This percentage increased to 41.2% by week 29, which was maintained to the end of the study.
Mean eGFR remained stable throughout the study. Also, the drop in UPCR across the study correlated with a reduction in the urinary levels of CD163, a biomarker of active kidney inflammation.
According to Kezar, these findings agree with a scenario of active inflammation in lupus nephritis patients at the study’s start, despite standard-of-care therapy. Most importantly, it supports the benefits of zetomipzomib at easing inflammation.
Most patients (82.4%) were using a low dose of corticosteroids (10 mg or less) by week 13, despite no pre-defined tapering off protocol. Doses of immunosuppressive agents used as part of the standard therapy regimen remained stable throughout the study.
These benefits were accompanied by easing of other SLE manifestations, as shown by a reduction in the SLEDAI-2K scores, which fell from a mean of 11.3 at the study’s start to 6.5 after treatment, and to 5.8 by the study’s end.
Physician Global Assessment scores also dropped from a mean of 57.2 (baseline) to 23.9 (week 25) and to 16.2 (study’s end). Reductions also were seen in Patient Global Assessment scores, which dropped from a mean of 23.6 at baseline to 10.7 at week 25, reaching 6.6 by the study’s end.
Of the 12 patients with abnormally high levels of anti-nuclear antibodies that target double stranded DNA (anti-dsDNA), a hallmark of SLE, 10 saw their levels either decrease or normalize by week 25. These levels were maintained in nine patients until the study’s end.
Safety data showed zetomipzomib was well tolerated throughout the study with no signs of immunosuppression. No additional safety signals were detected and side effects were generally mild to moderate, consistent with those previously reported. No opportunistic or severe infections were reported.
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