New Treatment Options for 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 CD20 Phase 3-FAILED 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 • Central vs Local Definition of Renal Pathology Read Experimental Therapeutic Response

• • Prolf vs Mem vs Mixed Expected Trial Outcomes Should • No Consensus of be Consistent with Where the Trial Duration • Duration of SLE/LN Novel Agent Acts in the LN Flare and Cumulative Prior Cycle Based on its Postulated • No Data that IS Therapy Mechanism of Action. Don’t Short-Term expect a maintenance drug to Response Predicts • Heterogeneity of LN induce remission… Long-Term Benefit

• Heterogeneity of • • Therapeutic Target Is the target of the experimental Role of Histology Expression therapeutic expressed in the in Defining Renal 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

4 taken into account Anti-IL-6 Trial Results-Primary Outcome

Sirukumab failed to improve proteinuria in the majority of treated patients

5 Rovin et al, ASN, 2014 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 6 Iwano et al, Clin Neph, 1993 The Presence of the Therapeutic Target Was not Verified at Trial Entry and When it Was Expression was

LOW

Cr)

/ml)

pg

mmol

/

6 ( 6

-

pg

6 ( 6

-

SerumIL Urine IL Urine

IL-6 was undetectable in the serum of all Responders (black) did not have the sirukumab-treated patients before highest urine cytokine levels at the start therapy. IL-6 levels rose in all treated of trial; however urine IL-6 in the patients and the responders (red) had the responders dropped over time and largest increase. stayed low after therapy. Sirukumab may work in individual patients-How to Identify? 77 Rovin et al, ASN, 2014 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?

8 Parikh et al, Lupus Sci Med, 2015 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 Monoclonal BLyS Phase 3 Antibody Rituximab/Belimumab Monoclonal CD20/BLyS Phase 2 Antibodies Voclosporin Calcineurin Calcineurin Phase 2 Inhibitor Monoclonal Interferon α R1 Phase 2 Antibody Ixazomib Proteosome Plasma Cell Phase 1b inhibitor

9 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.

12Goede et al NEJM 2014 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

13• CRR: PCR <0.5, eGFR >60 ml/min or if <60 no more than 20% ↑ 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 (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

15 Mysler et al., Arth Rheum, 2013 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

17 Dooley et al, Lupus, 2013 Anti-BLyS+Rituximab in LN-Supporting Evidence Deposition of auto-antibodies in non- immune mouse after CYC treatment; Blocked

by anti-BLyS

Control dsDNA Levels

- CYC-Treated

Placebo CYC CYC + Serumanti

αBAFF Treatment CYC DepositionFollowing

Ig 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 Glomerular

18 Kawabata et al. PLoS ONE 5(1): e8418. doi:10.1371/journal.pone.0008418 Calcineurin Inhibitors in LN

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 MMF 1g/d+TAC 4mg/d IV Pulse CYC 0.75g/m2

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

22 Mok et al, Ann Rheum Dis, 2015 Renal Responses and Adverse Events at 6 Months*

TAC All Patients MMF (N=76) TAC (N=74) p Class V MMF (N=12) p (N=16) CR 45 (59%) 46 (62%) 0.71 CR 6 (50%) 9 (56%) 0.09 PR 16 (21%) 20 (27%) PR 3 (25%) 7 (44%) NR 15 (20%) 8 (11%) NR 3 (25%) 0 (0%) CR (ACR)† 8 (11%) 10 (14%) 0.59 †Definition: creatinine clearance ≥90 mL/min+urine protein/creatinine <0.2+inactive urinary casts.

*There was no relationship between TAC level and Renal Response at 6 months

Adverse Events MMF TAC P Value Any Event 78% 93% 0.007 Zoster 18% 2.7% 0.003 Tremor 0% 20% <0.001 Reversible ↑ SCr by ≥30% 0% 14% 0.001

23 Mok et al, Ann Rheum Dis, 2015 Long-Term Renal Outcomes Using Tac Alone

Also: A decline in CrCl of ≥30% was seen in 13% of the MMF group and 24% of the TAC group, P=0.08

24 Mok et al, Ann Rheum Dis, 2015 Long-Term Renal Outcomes of Cyclofa-Lune Trial • CYC plus steroids vs CSA plus steroids • 18 months of IV then oral CYC as induction and maintenance • 18 months of oral CSA as induction and maintenance • Proliferative LN • N=40 patients; mainly Caucasian Response CYC CSA CYC CSA CYC CSA Complete Response 24% 26% 14% 37% - - Complete + Partial Response 52% 43% 38% 58% - - Follow-up 9 mo 9 mo 18 mo 18 mo 7.4 yr 8.3 yr 50% ↑ in SCr - - - - 16% 11% Doubling of SCr - - - - 10% 10% ESRD - - - - 5% 5% SCr last follow-up (umol/l) - - - - 71 63 Proteinuria last follow-up (g) - - - - 0.5 0.4 Adverse Events Similar Similar to CSA to CYC 25 No statistically significant differences between CyC or CyA at any time point Zavada, et al, Lupus, 2012 and 2014 Final Thoughts on Calcineurin Inhibitors in LN • Tac + MMF was superior to CYC for LN induction • Tac alone was equivalent to MMF and CYC for LN induction Caveats

• Mainly studied in Asian cohorts However vocolosporin, a next generation CNI will be tried in a multi-racial cohort, as an add on to MMF SOC • Correlation between CNI level and renal outcome not clear • Long-term outcomes need to be explored in more patients of more diverse ethnic/racial backgrounds • CNIs have moderate toxicity • CNIs can reduce proteinuria by non-immune mechanisms; this could mask ongoing renal inflammation suggesting the usual definitions of renal response may not apply 26 Targeting the Proteosome, complement, and IFNα

WHY? Answers from intra-renal gene expression

27 Parikh et al, Lupus Sci Med, 2015 Proteosome Inhibitors Proteasome inhibitors kill plasma cells and block NF-kB activation, so could theoretically target inflammation directly by decreasing pro- inflammatory cytokines and also indirectly by decreasing auto- antibody production.

Emerging drug: Ixazomib

28 Hainz et al, Nephron Exp Nephrol, 2011 The Alternative Complement Pathway is Highly Up- Regulated in LN

mRNA expression of components of the alternative complement pathway in the kidney at flare

C3 convertase components; ↑ alternative pathway activation

Complement regulators; ↓ alternative pathway activation

Emerging drug:

29 Pathway Analysis of Serial LN Biopsies • Patients with LN were biopsied at diagnosis • Biopsy repeated after SOC induction therapy (8 months) • Patients who had a complete renal response (CRR) and those who had no response (NR) were identified clinically • Changes in intra-renal transcript expression from the first biopsy to the repeat biopsy were measured and compared

Pathway analysis demonstrates that NR do not achieve

30control of their interferon pathway. Anifrolumab, an Anti-Interferon Alpha Receptor Monoclonal Antibody, in Moderate to Severe SLE Seropositive mod-sev non-renal SLE despite SOC were randomized and received placebo or qMonth ANIFR (300mg, 1000mg) for 48 weeks. Patients were stratified by SLEDAI, steroid dose, IFN gene signature (4-gene expression assay, high or low). Primary endpoint was SLE Responder Index (SRI) with sustained steroid reduction (<10 mg/d) at DAY 169.

RESULTS (1000 mg dose was no more effective; similar SAE profile, more H. Zoster in ANIFR Arms) Outcome Variable N Placebo N (%) ANIFR 300 mg N (%) Odds Ratio P SRI+Steroid Taper 305 18 (17.6) 34 (34.1) 2.38 0.014 IFN sig HIGH 229 10 (13.2) 27 (36) 3.55 0.004 IFN sig LOW 76 8 (30.8) 7 (29.6) 0.96 0.95 SRI+Taper DAY 365 305 26 (25.5) 51(51.5) 3.08 <0.001 CLASI (50% ↓) 77 8 (31%) 17 (63%) 4.5 0.013 28-Joint Count (50%↓) 131 18 (48.6) 32 (69.6) 2.67 0.038

CONCLUSION: ANIFR significantly reduced extra-renal disease activity compared to placebo across multiple clinical endpoints. Enhanced effects in IFN HIGH patients support the pathobiology of treatment strategy. Lack of dose response may be due to nearly similar degrees of IFN gene signature inhibition with both doses.

Furie et al, ACR Meeting, San Francisco, 2015 CONCLUSION • Trial design has potentially contributed to the failure of several promising LN therapies. • Many of the currently active trials target B-cells. Whether B-cell depletion is best applied during induction or maintenance is still to be determined. • Results from the CNI studies in Asia appear promising but long-term outcome data are needed and CNIs must be tested in more diverse populations. • There are good theoretical reasons to look at proteosome inhibitors and anti-complement agents in LN. • There are good theoretical reasons plus positive clinical data to look at alpha-interferon antagonists in LN