New Treatment Options for Lupus Nephritis Brad H. Rovin, MD Professor of Medicine and Pathology Division of Nephrology The Ohio State University Wexner Medical Center 1
The Clinical Trial Landscape Has Been Bleak… Drug Class Target Clinical Trial Status Abatacept-BMS CTLA4-Ig CTLA4-B7 Phase 2/3-FAILED Abatacept- CTLA4-Ig CTLA4-B7 Phase 2-FAILED ACCESS Laquinamod Small Molecule Inflammation Phase 2-ENCOURAGING but Development Discontinued Rituximab Monoclonal Antibody CD20 Phase 3-FAILED Sirukumab Monoclonal Antibody IL-6 Phase 2-FAILED Bortezomib Proteasome Inhibitor Plasma Cells Phase 4-STOPPED Anti-CD40 Ligand Monoclonal Antibody CD40 Ligand Phase 2-STOPPED Tabalumab Monoclonal Antibody BLyS Phase 3-FAILED Anti-TWEAK Monoclonal Antibody TWEAK Phase 2-FAILED
Lessons From Failed Trials Placebo + SOC Therapies: New LN/LN Flare Renal Response Pulse→High Dose Oral Corticosteroids Combined with: MMF or CYC • Timing of Biopsy • No Uniform • Definition of Renal Central vs Local Experimental Therapeutic Response Pathology Read • Expected Trial Outcomes Should • • No Consensus of Prolf vs Mem vs Mixed be Consistent with Where the Trial Duration • Novel Agent Acts in the LN Flare Duration of SLE/LN • Cycle Based on its Postulated No Data that and Cumulative Prior Mechanism of Action. Don’t Short-Term IS Therapy expect a maintenance drug to Response Predicts • Heterogeneity of LN induce remission… Long-Term Benefit • Heterogeneity of • • Is the target of the experimental Role of Histology Therapeutic Target therapeutic expressed in the in Defining Renal Expression kidney? Does this matter? Response 3
Case Study: Anti-IL6 (Sirukumab) in LN Patients with Class III or IV LN (Biopsy within 14 months) who still have active disease despite SOC induction and maintenance therapy Rovin et al, ASN, 2014 Potential pitfalls: • Long duration between biopsy and trial entry; what is being treated? • Serum/urine IL-6 levels were not measured at trial entry or during screening; is the target relevant? • The effect of previous/concomitant therapy on IL-6 was not taken into account 4
Anti-IL-6 Trial Results-Primary Outcome Sirukumab failed to improve proteinuria in the majority of treated patients Rovin et al, ASN, 2014 5 5
What Went Wrong? Possible Effects of Prior Therapy Were not Taken into Account in Trial Design In an older study it was shown that IL-6 levels decreased significantly in most LN patients who were treated with standard LN induction therapies. All of the sirukimab patients had been treated for some time before enrollment. It is possible that IL-6 was no longer important in ongoing renal injury in this cohort. Pre-tx Post- steroids/CYC Iwano et al, Clin Neph, 1993 6 6
The Presence of the Therapeutic Target Was not Verified at Trial Entry and When it Was Expression was LOW Urine IL-6 (pg/mmol Cr) Serum IL-6 (pg/ml) Responders (black) did not have the IL-6 was undetectable in the serum of all highest urine cytokine levels at the start sirukumab-treated patients before of trial; however urine IL-6 in the therapy. IL-6 levels rose in all treated responders dropped over time and patients and the responders (red) had the stayed low after therapy. largest increase. Sirukumab may work in individual patients-How to Identify? Rovin et al, ASN, 2014 7 7
What Else Went Wrong? IL-6 May Not be Involved in the Pathogenesis of LN in all Patients NR vs Normal Fold Change P-value IL6R 0.46 0.0001 IL6 signal transducer 0.46 0.0029 CR vs Normal Fold Change P-value IL6R 0.72 0.039 IL6 signal transducer 0.64 0.058 IL-6 signaling within the kidney was suppressed in these LN patients at renal flare-maybe IL-6 is not an ideal therapeutic target? Parikh et al, Lupus Sci Med, 2015 8
Currently Active LN Trials-Will These Succeed? Drug Class Target Clinical Trial Status Obintuzumab Monoclonal CD20 Phase 2 Antibody Rituxilup Monoclonal CD20 Phase 3 antibody Belimumab Monoclonal BLyS Phase 3 Antibody Rituximab/Belimumab Monoclonal CD20/BLyS Phase 2 Antibodies Voclosporin Calcineurin Calcineurin Phase 2 Inhibitor Anifrolumab Monoclonal Interferon α R1 Phase 2 Antibody Ixazomib Proteosome Plasma Cell Phase 1b inhibitor 9
B Cell Targeted Therapies (Déjà vu all over again?) 10
Obinutuzumab for treatment of Class III/IV LN (NOBILITY) • Biopsy Proven ISN/RPS Class III, IV, or III/IV+V LN, excludes RPGN • Primary End Point – Complete renal remission at 52 weeks • Concerns: Trial design similar to LUNAR • Optional Repeat Biopsy at 52 weeks • Does the study drug deplete B cells in kidney tissue? • Do patients who achieve CRR also achieve a histologic remission? 11
Did LUNAR Fail Because of Incomplete B Cell Depletion and Will NOBILITY be Successful? Glyco-engineered, humanized, Type II monoclonal antibody against CD20 that targets the extracellular loop of the CD20 transmembrane antigen expressed on the surface of B cells Increased sensitivity to antibody- dependent-cellular-cytotoxicity Study Rationale: Obinutuzumab has been studied in Lymphoma and CLL and has been shown to more completely suppress circulating B cells by high-sensitivity flow and has been shown to deplete B-cells in tissue. Goede et al NEJM 2014 12
RITUXILUP: Open Label Multi-Center RCT Comparing MMF + Rituximab vs MMF + Steroids to Treat LN • Non-inferiority trial • Primary endpoint: CRR at week 52 with no need for PO steroid • CRR: PCR <0.5, eGFR >60 ml/min or if <60 no more than 20% ↑ 13
RITUXILUP – Supporting Evidence • Single center cohort study with long-term follow up • Biopsy-proven active ISN/RPS class III, IV or class V LN if not already on steroids • RPGN and CNS lupus excluded • 2 doses of rituximab (1g) plus methylprednisolone (500mg) on days 1 and 15 • Maintenance with MMF (500mg BID – titrated up to level (1.4- 2.4mg/L) • NO ORAL STEROIDS Condon MB, et al. Ann Rheum Dis. 2013, Porter et al ASN 2014
High-Dose Pulse Steroids-Important to Rituxilup Success? • BELONG: Renal Responses as a function of pulse corticosteroid dose Methylprednisolone Dose Placebo Ocrelizumab (Day 1) <500 mg 38% 63% 500-<1000 mg 50% 65% ≥1000 mg 74% 72% • The pulse MP in the RITUXILUP trial may provide sufficient anti- inflammatory activity to allow MMF and Rituximab to kick-in and control disease Mysler et al., Arth Rheum, 2013 15
Belimumab (Anti-BLyS, BAFF) in LN • GSK Belimumab: Placebo or Belimumab + SOC (MMF or Euro-Lupus CYC and steroids for induction; MMF or AZA maintenance, respectively) for 2 years • ITN CALIBRATE: Phase II Open-Label RCT comparing Belimumab + steroids versus steroids alone in patients with proliferative LN treated with CYC + Rituximab for Induction; here induction is Rituximab (1g) + IV CYC (750 gm) at week 0 and 2, followed by randomization to placebo or belimumab at week 4 16
Anti-BLyS for Treatment of LN-Supporting Evidence • Post hoc analysis of anti-BLyS trials • Compared rates of renal flare in anti-BLyS-treated patients to patients treated with placebo • Addition of anti-BLyS to SOC seemed to prevent renal flares in SLE patients in a dose-dependent fashion Dooley et al, Lupus, 2013 17
Anti-BLyS+Rituximab in LN-Supporting Evidence Deposition of auto-antibodies in non- immune mouse after CYC treatment; Blocked by anti-BLyS Glomerular Ig Deposition Following CYC Treatment Control Serum anti-dsDNA Levels CYC-Treated Placebo CYC CYC + αBAFF CYC + anti-BAFF • Killing B cells by any drug (e.g CYC or Ritux ) ↑ Serum BLyS (BAFF) levels • Reconstitution of B cells in a high BLyS (BAFF) environment fosters auto-reactive B cells, even in a non-autoimmune mouse • Anti-BlyS prevents this and may help sustain renal response 18 Kawabata et al. PLoS ONE 5(1): e8418. doi:10.1371/journal.pone.0008418
Calcineurin Inhibitors in LN 19 19
CNIs as Part of a Multi-Target Induction Regimen LN IV MP 500mg/d X3d Oral Steroid Taper 0.6mg/kg/d N=368 IV Pulse CYC 0.75g/m 2 MMF 1g/d+TAC 4mg/d Complete Renal Remission Liu et al, Ann Int Med, 2015
Repeat Biopsy Findings and Adverse Events Multi-Target Therapy (n=14) Cyclophosphamide Therapy (n=9) Initial Biopsy Week 24 Biopsy Initial Biopsy Week 24 Biopsy Activity Index 11.5 2 11.5 3 Chronicity Index 1 2 1 3 ADVERSE EVENTS Multitarget n (%) Cyclophosphamide n (%) Serious 13 (7.2) 5 (2.8) Pneumonia 7 (3.9) 1 (0.6) Zoster 2 (1.1) 1 (0.6) URI 2 (1.1) 0 Skin/soft tissue infection 0 1 (0.6) Epilepsy 1 (0.6) 0 Septicemia 0 1 (0.6) Doubling SCr 1 (0.6) 0 More patients in the multitarget group than the IVCY group dropped out as a result of adverse events (5.5% vs 1.7%, P =0.086) Liu et al, Ann Int Med, 2015
CNIs Alone as LN Induction Therapy 81% of patients were Class III/IV CRR defined as proteinuria <1g/d Mean follow-up was 61 months Mok et al, Ann Rheum Dis, 2015 22
Recommend
More recommend
