Future of Lupus Treatments Looks Brighter With Multiple Promising Therapeutic Approaches

Ianalumab ‘Double Blocking’ B Cells

Another way could be to develop more potent B-cell–depleting drugs, as Nancy Agmon-Levin , MD, head of the Clinical Immunology, Angioedema and Allergy Unit, Lupus and Autoimmune Diseases Clinic, at Sheba Medical Center, Tel Aviv University in Tel Aviv, Israel, reported during one of the clinical abstract sessions at EULAR 2024.

Dr. Agmon-Levin presented data on 67 individuals with SLE who had participated in a multicenter phase 2 study of ianalumab, a fully human immunoglobulin (Ig) G1 monoclonal antibody that results in a “double blocking of the B-cell lineage.”

Ianalumab targets the B-cell–activating factor receptor (BAFFR), but what makes it distinct from other BAFF-targeting drugs is that it has had a fructose molecule removed from its Fc portion, which renders it more likely to trigger antibody-dependent cellular cytotoxicity.

“This is a B-cell depletion therapy,” Agmon-Levin said, but it also blocks BAFFR-mediated survival of B cells, so the subsequent recuperation process of BAFFR-expressing B cells is affected, leading to continued B-cell depletion.

The phase 2 study she presented consisted of an initial 28-week, double-blind period, during which time participants had been randomly allocated to receive either subcutaneous injections of ianalumab 300 mg or a matching placebo every 4 weeks. This was followed by a 24-week, open-label period where all participants were treated with ianalumab, and then an off-treatment, minimal follow-up period that lasted up to 68 weeks, with continued data collection for safety.

The primary outcome measure was a composite of meeting criteria for the SLE Responder Index 4 and a sustained reduction in corticosteroid use at 28 weeks. This was achieved in 15 of the 34 (44.1%) people treated with ianalumab vs only 3 (9.1%) of the 33 people who had been given a placebo.

Dr. Agmon-Levin reported that the effect on this outcome was sustained to the end of the open-label period, at 1 year, in 15 (45.5%) of 33 participants who had continued treatment with ianalumab and achieved in 13 (40.6%) of 32 participants who had switched from placebo to ianalumab treatment.

Moreover, longer durations of treatment were associated with a host of improved outcomes, Dr. Agmon-Levin said: “Treatment was improved along the 52 weeks, and we can see from the LLDAS [Lupus Low Disease Activity State], DORIS [Definition Of Remission In SLE], and SRI-6 and -8 that as you continue the therapy, you improve the outcomes.”

The potential benefits of ianalumab in the treatment of SLE and lupus nephritis will now be further examined in the phase 3 SIRIUS-SLE1 , SIRIUS-SLE2, and SIRIUS-LN trials, which are estimated to provide initial results in 2027 and complete in early 2029 or 2030.
 

Targeting Plasma Cells With Daratumumab

Another drug showing signs that it might be useful as a treatment for SLE is daratumumab, as Tobias Alexander, MD, of Charité — Universitätsmedizin Berlin, reported during one of the late-breaking abstract sessions at EULAR 2024.

“Daratumumab is a human, first-in-class anti-CD38 antibody that efficiently depletes plasma cells,” Dr. Alexander said. CD38 is both a receptor and an enzyme, and while it is found on the surface of most immune cells, it’s particularly expressed by plasma cells, he added.

Daratumumab is not a total newcomer, however, as it’s already approved for the treatment of multiple myeloma under the trade name Darzalex. The rationale for using it in SLE comes from two case reports, Dr. Alexander explained. The first, published in 2020 in The New England Journal of Medicine, involved two patients with severe and life-threatening lupus who were given off-label treatment for a period of 4 weeks and experienced good clinical and serologic responses. The second, published last year in Nature Medicine, involved six patients with refractory lupus nephritis, five of whom had a clinical response at 6 months.

“On this background, we conducted an investigator-initiated trial, which was an open-label, single-center, proof-of-concept study,” Dr. Alexander said. A total of 10 female patients whose ages ranged from 24 to 43 years were included in the phase 2 trial that was dubbed DARALUP. For inclusion, all had to have a Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) of four or more for clinical manifestations, have been treated with at least two prior disease-modifying drugs to no avail, and be anti–double-stranded DNA (anti-dsDNA) antibody positive. Dr. Alexander reported that the median baseline SLEDAI-2K score was 12 and ranged from 8 to 20, with the number of prior therapies ranging from two to nine.

Daratumumab was given at a dose of 1800 mg via subcutaneous injection every week for 8 weeks. This is the same dose that is used to treat multiple myeloma, Dr. Alexander explained, although the dosing is not stopped. The reason for stopping after 8 weeks in the current trial was to be able to see what happened once the treatment was stopped. The follow-up was for 36 weeks.

Dr. Alexander reported that there was a “very dramatic and significant” effect on the primary endpoint of a reduction in anti-dsDNA antibody levels, decreasing from a median of 166.3 U/mL at baseline to 61.1 U/mL at week 12 (P = .002). Alongside, there was a reduction in the SLEDAI-2K score from 12 to 4 within 12 weeks, which was sustained at the 36-week follow-up assessment. Improvements in skin, joint, kidney, and level of proteinuria were also seen.

Although all patients experienced adverse events, none were serious. Infections and infestations (mostly nasopharyngitis, COVID-19, and gastroenteritis) were the most common, experienced by 80% of the participants; 70% had injection site reactions or fatigue, 60% had gastrointestinal symptoms, 50% had a fall of IgG < 5 g/L, 40% had headache, and 20% had back pain.

“This is a positive trial. I think we could demonstrate that [daratumumab] produced very strong, rapid, and durable clinical improvements,” Dr. Alexander said. “We think that targeting CD38 is relevant; plasma cells had been depleted based on the reduction of anti-dsDNA antibodies,” he added.

From the audience, however, Peter Nash, MBBS, of Griffith University in Brisbane, Australia, questioned whether the results could be attributed to “a steroid effect” because patients had been treated with oral dexamethasone throughout the study.

Dr. Alexander noted that steroid use had been part of the treatment schedule but acknowledged it was a possible confounder.

“I think we can be confident that [daratumumab] had a major effect on plasma cells decreasing…because we see that also the vaccine titers decreased,” Dr. Alexander said. “Time will tell, but even more important is the durability of the responses over time, which you don’t achieve under steroids.”