Rituximab and Other Therapies for SLE

Although biotherapies for systemic lupus erythematosus (SLE) started 15 years ago, few have proceeded to completion. For now, only Belimumab has approved for SLE, but is highly expensive with only modest outcomes.

A report in Joint Bone Spineconveys which biotherapies offer the most potential.

The French study, which appears in the September 21 online issue of the journal, is based on reviews of Phase II and Phase III studies indexed in PubMed, the abstracts of EULAR and ACR meetings, and ongoing trials registered on clinicaltrials.gov.

Rituximab

Rituximab is a chimeric human monoclonal antibodythat selectively targets CD20+ B cells and causes their depletion. It was initially developed as a treatment for B-cellmalignancies. Two trials were conducted with the goal of complete or partial remission of the kidney disease, but neither trial met its primary outcome.

EXPLORER was a double-blind trial on patients with systemic lupus erythematosus, but no active renal or neurological issues. Its researchers utilized British Isles Lupus Assessment Group (BILAG) assessments, establishing BILAG A indicated high disease activity in at least one domain, while BILAG B indicated moderate activity in two or more. Its 257 patients were randomized to receive rituximab or placebo in addition to their current treatment and to high-dose prednisone for the first 10 weeks. There was no clinical difference in response rates: patients on placebo showed a 28.4% response, with 29.6% for those actually on rituximab.

In another trial, LUNAR, 144 patients with lupus nephritis (Class III or IV) received both mycophenolate mofetil and prednisone, then some also received rituximab while others the placebo. Neither group achieved the primary outcome; i.e., complete or partial remission of kidney disease.

A more current CD20 trial against lupus nephritis features obinutuzumab. It is considered far stronger than rituximab, because it is fully humanized and features stronger antibody-dependent cytotoxicity. Reports are pending.

On the Positive Side of Rituximab

Despite neither LUNAR nor EXPLORER showing totally positive results for rituximab, the authors suggest re-examining its potential benefits for systemic lupus erythematosus. Specifically, they point to the fact that in post-EXPLORER analysis, rituximab seemed to have potential to prevent severe SLE flares. Additionally, in both trials the authors ascertained robust effects on both anti-dsDNA titers and B-cell counts. They also determined there are at least observational studies reaffirming rituximab safety and efficacy specific to systemic lupus erythematosus treatment.

Less Impressive B-Cell Hunter

Like rituximab, epratuzumab is a B-cell antagonist, this one specifically targeting CD22. But unlike rituximab, its Phase III trials showed little significance.

A Phase IIb trial, EMBLEM, seemed promising:  cumulative dosages of 2,400 mg/month aided moderate-to-severe systemic lupus erythematosus. But Phase III trials EMBODY-1 and -2 offered less encouragement.

EMBODY studies inclusion required patients with active SLE to present either one BILAG A score or at least two BILAG B scores in dermatological, musculoskeletal or cardiopulmonary domains.

Patients scoring positively on BILAG A for renal or central nervous system involvement were also among those excluded.

Several drugs have been tested employing type I interferons (IFNs) approach. Among the trials in this report, two utilized monoclonal antibodies fighting IFN-a:  rontalizumab and sifalimumab.

Here is a very brief summary of some therapies under study. For more details on the results of these studies, please click here:

Efficacy of biotherapies targeting CD20 and CD22 in systemic lupus erythematosus.

Rituximab:  No difference in complete or partial renal remission rate at W52 between the placebo arm and rituximab arm (45.8% versus 56.9%, respectively, for the global response; P = 0.18)

Ocrelizumab:  No significant difference in global renal response at W48 between the placebo arm and the ocrelizumab 400 and 1000 mg arms (54.7, 66.7, and 67.1%, respectively)

Epratuzumab:  No difference in the BICLA response at W48 between the placebo

Efficacy of biotherapies targeting the BLyS/APRIL system in systemic lupus erythematosus.

Belimumab:  SRI-4 response rate at W52 significantly higher than with placebo (44%) with 1 mg/kg (51%) or 10 mg/kg (58%): P = 0.0129 and P = 0.0006, respectively

Belimumab (BLISS-76):  SRI-4 response rate at W52 significantly higher than with placebo (33.5%) with 10 mg/kg (43.2%; P = 0.017) but no significant difference with 1 mg/kg (40.6%; P = 0.089) No significant difference at W76

Belimumab (BLISS-SC):  SRI-4 response rate at W52 significantly higher than with placebo (48.7%) with 200 mg (61.4%; P = 0.0009)

Tabalumab (ILLUMINATE -1):  No difference for the SRI-5 response rate at W52 between the placebo (29.3%), 120 mg SC/2 weeks (31.8%) and a dose of 120 mg SC/4 weeks (35.2%): P > 0.05

Tabalumab (ILLUMINATE -2):  SRI-5 response rate at W52 significantly higher than with placebo (27.7%) with 120 mg SC/2 weeks (38.4%; P = 0.002) but no significant difference with 120 mg SC/4 weeks (34.8%; P = 0.051)

Blisibimod (PEARL-SC):  SRI-5 response rate at W24 not better than pooled placebo (35.3%) with 100 mg SC/weeks (32.3%): P = 0.603 and a dose of 200 mg SC once weekly (43.5%; P = 0.154) or 200 mg SC every 4 weeks (35.9%; P = 0.925)

Atacicept (APRIL-SLE):  Proportion of patients with a BILAG A or B flare by W52 similar with atacicept 75 mg and placebo (58 and 54%, respectively; P = 0.543).

Efficacy of biotherapies targeting type 1 interferons in systemic lupus erythematosus.

Rontalizumab (ROSE):  Proportion of patients with a BILAG score improvement, no new BILAG A, and no more than 1 new BILAG B 41.8% with placebo 45.5% with rontalizumab

Sifalimumab (MEDI-545): SRI-4 response at W52 significantly better than placebo (45.4%) with 1200 mg (59.8%; P = 0.031)

Anifrolumab (MEDI-546):  SRI-4 response on D169 + prednisone < 10 mg/d and ≤baseline dose, maintained between D85 and D169: significantly higher proportion vs. the placebo (17.6%) with 300 mg (34.3%; P = 0.014)

References:

Biotherapies in systemic lupus erythematosus: New targets.Joint Bone Spine. 2016 Sep 20. pii: S1297-319X(16)30123-3. doi: 10.1016/j.jbspin.2016.07.004. https://www.ncbi.nlm.nih.gov/pubmed/27663753