In keeping with recent successes in treating lupus nephritis, such as the FDA approvals of belimumab and voclosporin, numerous ongoing trials are investigating novel lupus nephritis (LN) drugs targeting specific inflammatory response pathways. In a review published in Kidney Medicine, Sayali B. Thakare, MD, of King Edward Memorial Hospital in Mumbai, India, and colleagues summarized research efforts in drug development Here’s a selective list of ongoing trials:
- Daratumumab, an anti-CD38 monoclonal antibody that depletes plasma cells, is being evaluated in a phase 2 trial for its ability to safely induce complete or partial renal response in patients with active class 3 or 4 lupus nephritis (Clinicaltrials.gov, NCT04868838).
- Ianalumab (VAY736), an anti B-cell activating factor (BAFF) receptor monoclonal antibody, is being studied in a phase 3 trial in patients with active class 3 or 4 proliferative LN (with or without class 5) or pure class 5 membranous LN (Clinicaltrials.gov, NCT05126277). The primary endpoint is stable complete renal response, defined as estimated glomerular filtration rate (eGFR) of 90 mL/min/1.73 m2 or greater (or no less than 85% of baseline) and a 24-hour urinary protein to creatinine ratio (UPCR) less than 0.5 g/g.
- Obinutuzumab, an anti-CD20 monoclonal antibody aimed at B cell depletion, is under investigation for inducing complete renal response in patients with class 3 or 4 LN (with or without class 5) (Clinicaltrials.gov, NCT04221477).
- Iscalimab (CFZ533), an anti-CD40 monoclonal antibody, is being evaluated for safety and proteinuria reduction in patients with Class 3 or 4 LN (Clinicaltrials.gov, NCT03610516).
- Guselkumab, a monoclonal antibody that binds to human interleukin (IL)-23, was studied in the recently-completed phase 2 ORCHID-LN trial for its ability to reduce proteinuria (Clinicaltrials.gov, NCT04376827). Results are pending.
- Secukinumab, an anti-IL17A monoclonal antibody, is under investigation for its ability to induce complete renal response in patients with class 3 or 4 LN (with or without class 5) in the phase 2 SELUNE trial (Clinicaltrials.gov, NCT04181762).
- Pegcetacoplan (APL-2), which inhibits cleavage of C3 into C3a & C3b, is being studied for proteinuria reduction in patients with glomerulopathies, such as LN and IgA nephropathy in the phase 2 DISCOVERY trial (Clinicaltrials.gov, NCT03453619).
- Iptacopan (LNP023), a small molecule Factor B inhibitor, is under investigation for induction of complete renal response in patients with class 3 or 4 LN (with or without class 5) (Clinicaltrials.gov, NCT05268289).
- Ravulizumab, an anti-C5 IgG k monoclonal antibody, is being evaluated for proteinuria reduction in patients with proliferative LN or IgA nephropathy (IgAN) in the phase 2 SANCTUARY trial (Clinicaltrials.gov, NCT04564339).
- Anifrolumab, an anti-IFN-α already that is approved for systemic lupus erythematosus (SLE), is under investigation in the phase 3 IRIS trial for its ability to induce complete renal response in proliferative LN. Complete renal response is defined as an UPCR of 0.5 mg/mg or less, along with an eGFR of at least 60 mL/min/1.73m2 or no decrease from baseline of 20% or more (Clinicaltrials.gov, NCT05138133).
- Itolizumab, an anti-CD6 monoclonal antibody, is being studied in the phase 1b EQUALISE trial for treatment-emergent adverse events in patients with SLE with or without active proliferative LN (Clinicaltrials.gov, NCT04128579).
- KZR-616, a selective inhibitor of LMP7 & LMP2 in the immune proteosome, is being evaluated for safety and UPCR reduction in patients with SLE with or without active proliferative LN in the phase 1b/2 MISSION trial (Clinicaltrials.gov, NCT03393013).
- Nipocalimab, a Fc receptor antagonist that fosters degradation of IgG, is being tested for induction of complete renal response in patients with active proliferative LN in a phase 2 trial (Clinicaltrials.gov, NCT04883619).
- Sirolimus, an mTOR inhibitor, is under investigation for treatment of proteinuric flares in patients with proliferative LN in a phase 2/3 trial (Clinicaltrials.gov, NCT04892212). The primary endpoint is sustained renal response, defined as at least 50% proteinuria improvement, 24-hr urinary protein less than 1g, a serum creatinine no higher than 15% above baseline level, and no non-renal disease flare.
- Zanubrutinib, a Bruton tyrosine kinase small molecule inhibitor, is being studied for complete renal response in patients with active proliferative LN in a phase 2 trial (Clinicaltrials.gov, NCT04643470).
- is being further tested for its ability to target tissue-resident autoreactive B-cells in severe, active SLE, such as LN, in the phase 3 SynBioSe-2 trial (Clinicaltrials.gov, NCT03747159). The primary clinical outcome is the treatment failure rate at 104 weeks.
“The armamentarium of SLE is rapidly expanding,” Dr Thakare’s team concluded. “However, despite the steady engagement of resources from basic sciences and clinical medicine, there is a long way to go.”
They added: “Enthusiasm toward emerging therapies is tempered by a realization that current research focuses heavily on induction agents. More studies are warranted for specific situations like membranous LN, childhood-onset LN, maintenance therapy, and antiphospholipid antibody syndrome.”
Disclosure: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.
This article originally appeared on Renal and Urology News
Thakare SB, So PN, Rodriguez S, Hassanein M, Lerma E, Wiegley N; GlomCon Editorial Team. Novel therapeutics for management of lupus nephritis: What is next? Kidney Med. Published online June 14, 2023. 5(8):100688. doi:10.1016/j.xkme.2023.100688