By Dr. Sayali B. Thakare
Assistant Professor
Seth GSMC and KEM Hospital
Mumbai, India

Figure 1. Newer Therapies for Lupus Nephritis

Delving into candidate drugs targeting these pathways is arduous. A comprehensive study of clinical trials in LN registered with ClinicalTrials.gov enlists as many as 126 RCTs initiated between 1998 and 2020, including those for 27 types of biological agents. Amongst these, anti-inflammatory agents act acutely by limiting immunological damage, making them useful as induction agents. Therapies that target autoimmunity work towards attenuating disease activity and thus prevent accruing damage from repeated flares. 

Despite tremendous progress in unraveling the pathobiology of LN, only a handful of drugs have shown meaningful benefits with acceptable side-effect profiles in phase 2 and 3 clinical trials (Table 1). Some of these agents have received approval for use by regulatory agencies (Figure 1). Belimumab, an anti-BAFF monoclonal antibody, was the first biological agent approved for SLE in 2011. After a series of focused trials in patients with renal involvement, Belimumab was subsequently approved for LN in December 2020. Voclosporin, a novel oral calcineurin inhibitor (CNI), was approved for LN in January 2021. The most recent addition to the armamentarium of SLE is Anifrolumab, an anti-IFN-α (interferon-alpha) monoclonal antibody (mAb). Anifrolumab was approved for moderate to severe SLE in August 2021, making it the only new drug for SLE in over a decade. Anifrolumab is currently undergoing a phase 3 trial in LN (Table 2). Noting previously concluded trials helps gain perspective about the impact of a given drug action on the pathogenic pathways in LN. Table 1 outlines an updated list of concluded RCTs that either failed to meet the primary endpoint, showed unacceptable drug toxicity or were terminated prematurely.

Table 1. Terminated Randomized Controlled Trials in Lupus Nephritis and Clinical Outcomes

Remarkably, not all drugs demonstrating efficacy in SLE display replicable results in LN. The role of local immune pathways, such as the intra-renal inflammatory cycle, interstitial lymphocytic aggregates, or germinal centers within the kidneys, may be implicated. Therapeutic categories of drugs evaluated in trials for patients with LN, such as B-cell therapies and co-stimulatory blockade agents, are described.

(1) B-cell Directed Therapies

B-cells have a central role in the pathogenesis of LN and are the most investigated axis for drug therapy. Approaches include B-cell depletion (i.e., Rituximab, Obinutuzumab, Ofatumumab, Ocrelizumab), anti-B-cell activation (i.e., Belimumab, Obexelimab, Atacicept, Blisibimod, Ianalumab), co-stimulatory blockade (i.e., Iscalimab, Abatacept, Ruplizumab, Dapirolizumab pegol), and anti-plasma cell therapy (i.e., Bortezomib, Daratumumab, Ixazomib). Obinutuzumab, a humanized anti-CD20 monoclonal antibody (Figure 1), achieves higher and more sustained B-cell depletion than Rituximab and received breakthrough therapy designation from FDA for LN in 2019 based on the results of the  NOBILITY trial. However, BAFF levels increase with B-cell depletion. Therefore, the sequential use of Belimumab with Rituximab in the SynBioSe-2 trial (Figure 1) is evaluating synergistic inhibition of the repopulation of autoreactive B-cells. Long-lived autoreactive plasma cells are found in the circulation and renal interstitium and play a role in flares; hence the rationale for using plasma cell-depleting agents in LN. Bortezomib, a proteasome inhibitor, caused significant neurotoxicity in patients with LN leading to the early termination of the trial (Table 1). Finally, an immuno-proteosome inhibitor (proteasome inducible by IFN-gamma), KZR 616, is currently being investigated with encouraging interim results.

(2) Co-stimulatory Blockade Agents

CD40/CD40L and CD28/CD80/86 are attractive pathways for therapeutic targets in immune-mediated disorders. A trial involving an anti-CD40L antibody, Ruplizumab, was halted due to severe thromboembolic events. A PEGylated anti-CD40 Ab fragment, Dapirolizumab Pegol (CDP7657), was tested in LN with an attenuated risk of thromboembolic events; however, the trial did not meet the primary endpoint. Due to potential benefits, nevertheless, a phase III RCT is in progress.

Abatacept, a CD28/CD80 pathway blocker, failed to meet the primary endpoint in three RCTs. Since no safety signals are reported and being an agent affecting autoimmunity, Abatacept might work better as  maintenance therapy. BI 655064 and Iscalimab, both humanized anti-CD40 mAbs, are also therapeutic candidates currently under investigation.

(3) Other Potential Target Therapies in LN

These include but are not limited to, cytokine-directed therapies (i.e., Ustekinumab, Sirukumab, BIIB023, AMG 811, Secukinumab, Guselkumab), anti-complement therapies (i.e., Ravulizumab, APL-2, Iptacopan, Narsoplimab) and miscellaneous (i.e., kinase inhibitors, Fc receptor antagonist, immune-proteasome inhibitor). Itolizumab, anti-CD6 mAb, received fast-track designation from the FDA for LN in December 2019. Most of these agents showed efficacy in previous studies in SLE and are now being investigated for LN. Table 2 enlists trials that are currently ongoing and are expected to be completed in the near future. As we eagerly wait for the results of these trials, optimizing the current broad-spectrum therapy assumes prime importance. Steroid reduction, a strategy incorporated into the current guidelines of SOC, is one way toward making therapy in SLE and LN safer. 

Table 2. Ongoing Randomized Controlled Trials of Newer Agents in Lupus Nephritis

The armamentarium of SLE is rapidly expanding. However, despite the steady engagement of resources from basic sciences and clinical medicine, there is a long way to go. Successful drug development often unfolds over many years. In order to transform clinical care globally, benefits from scientific discoveries need to be made widely available and affordable, which assumes the next level of the challenge after the success of a clinical trial. 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. Precision medicine, matching a given drug to the most responsive disease phenotype, appears to be the future in LN (e.g., Anifrolumab in SLE patients with a high IFN signature). Yet like never before, we might be poised to have plenty more in the immediate future.