Nephritis Brad H. Rovin, MD Professor of Medicine and Pathology - - PowerPoint PPT Presentation

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

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Drug Class Target Clinical Trial Status

Abatacept-BMS CTLA4-Ig CTLA4-B7 Phase 2/3-FAILED Abatacept- ACCESS CTLA4-Ig CTLA4-B7 Phase 2-FAILED 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

The Clinical Trial Landscape Has Been Bleak…

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Placebo Experimental Therapeutic

+ SOC Therapies: Pulse→High Dose Oral Corticosteroids Combined with: MMF or CYC Renal Response New LN/LN Flare

• Timing of Biopsy
• Central vs Local

Pathology Read

• Prolf vs Mem vs Mixed
• Duration of SLE/LN

and Cumulative Prior IS Therapy

• Heterogeneity of LN
• Heterogeneity of

Therapeutic Target Expression

• No Uniform

Definition of Renal Response

• No Consensus of

Trial Duration

• No Data that

Short-Term Response Predicts Long-Term Benefit

• Role of Histology

in Defining Renal Response

• Expected Trial Outcomes Should

be Consistent with Where the Novel Agent Acts in the LN Flare Cycle Based on its Postulated Mechanism of Action. Don’t expect a maintenance drug to induce remission…

• Is the target of the experimental

therapeutic expressed in the kidney? Does this matter?

Lessons From Failed Trials

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Case Study: Anti-IL6 (Sirukumab) in LN

Rovin et al, ASN, 2014

Patients with Class III

• r IV LN (Biopsy

within 14 months) who still have active disease despite SOC induction and maintenance therapy 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

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Anti-IL-6 Trial Results-Primary Outcome

Rovin et al, ASN, 2014

Sirukumab failed to improve proteinuria in the majority of treated patients

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What Went Wrong? Possible Effects of Prior Therapy Were not Taken into Account in Trial Design

Iwano et al, Clin Neph, 1993 Pre-tx Post- steroids/CYC

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.

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Rovin et al, ASN, 2014

The Presence of the Therapeutic Target Was not Verified at Trial Entry and When it Was Expression was LOW

IL-6 was undetectable in the serum of all sirukumab-treated patients before

• therapy. IL-6 levels rose in all treated

patients and the responders (red) had the largest increase. Responders (black) did not have the highest urine cytokine levels at the start

• f trial; however urine IL-6 in the

responders dropped over time and stayed low after therapy. Serum IL-6 (pg/ml) Urine IL-6 (pg/mmol Cr) Sirukumab may work in individual patients-How to Identify?

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What Else Went Wrong? IL-6 May Not be Involved in the Pathogenesis of LN in all Patients

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 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

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Drug Class Target Clinical Trial Status Obintuzumab Monoclonal Antibody CD20 Phase 2 Rituxilup Monoclonal antibody CD20 Phase 3 Belimumab Monoclonal Antibody BLyS Phase 3 Rituximab/Belimumab Monoclonal Antibodies CD20/BLyS Phase 2 Voclosporin Calcineurin Inhibitor Calcineurin Phase 2 Anifrolumab Monoclonal Antibody Interferon α R1 Phase 2 Ixazomib Proteosome inhibitor Plasma Cell Phase 1b

Currently Active LN Trials-Will These Succeed?

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B Cell Targeted Therapies (Déjà vu all over again?)

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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?

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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

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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% ↑

• 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

RITUXILUP – Supporting Evidence

Condon MB, et al. Ann Rheum Dis. 2013, Porter et al ASN 2014

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High-Dose Pulse Steroids-Important to Rituxilup Success?

• BELONG: Renal Responses as a function of pulse corticosteroid dose

Methylprednisolone Dose (Day 1) Placebo Ocrelizumab <500 mg 38% 63% 500-<1000 mg 50% 65% ≥1000 mg 74% 72%

Mysler et al., Arth Rheum, 2013

• The pulse MP in the RITUXILUP trial may provide sufficient anti-

inflammatory activity to allow MMF and Rituximab to kick-in and control disease

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Belimumab (Anti-BLyS, BAFF) in LN

• GSK Belimumab: Placebo or Belimumab + SOC (MMF
• r 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

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Anti-BLyS for Treatment of LN-Supporting Evidence

Dooley et al, Lupus, 2013

• 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

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Kawabata et al. PLoS ONE 5(1): e8418. doi:10.1371/journal.pone.0008418

Control

Anti-BLyS+Rituximab in LN-Supporting Evidence

Glomerular Ig Deposition Following CYC Treatment

Serum anti-dsDNA Levels

CYC-Treated CYC + anti-BAFF Placebo CYC CYC + αBAFF

• 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

Deposition of auto-antibodies in non- immune mouse after CYC treatment; Blocked by anti-BLyS

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Calcineurin Inhibitors in LN

CNIs as Part of a Multi-Target Induction Regimen

Liu et al, Ann Int Med, 2015

LN IV MP 500mg/d X3d Oral Steroid Taper 0.6mg/kg/d IV Pulse CYC 0.75g/m2 MMF 1g/d+TAC 4mg/d Complete Renal Remission

N=368

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 Liu et al, Ann Int Med, 2015 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) Skin/soft tissue infection 1 (0.6) Epilepsy 1 (0.6) Septicemia 1 (0.6) Doubling SCr 1 (0.6) 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)

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CNIs Alone as LN Induction Therapy

Mok et al, Ann Rheum Dis, 2015 CRR defined as proteinuria <1g/d 81% of patients were Class III/IV Mean follow-up was 61 months

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All Patients MMF (N=76) TAC (N=74) p CR 45 (59%) 46 (62%) 0.71 PR 16 (21%) 20 (27%) NR 15 (20%) 8 (11%) CR (ACR)† 8 (11%) 10 (14%) 0.59

†Definition: creatinine clearance ≥90 mL/min+urine protein/creatinine <0.2+inactive urinary casts.

Renal Responses and Adverse Events at 6 Months*

Mok et al, Ann Rheum Dis, 2015

Class V MMF (N=12) TAC (N=16) p CR 6 (50%) 9 (56%) 0.09 PR 3 (25%) 7 (44%) NR 3 (25%) 0 (0%) *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

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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

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Long-Term Renal Outcomes of Cyclofa-Lune Trial

Zavada, et al, Lupus, 2012 and 2014

• 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 to CSA Similar to CYC

No statistically significant differences between CyC or CyA at any time point

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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

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Targeting the Proteosome, complement, and IFNα WHY? Answers from intra-renal gene expression

Parikh et al, Lupus Sci Med, 2015

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Proteosome Inhibitors

Hainz et al, Nephron Exp Nephrol, 2011

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

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The Alternative Complement Pathway is Highly Up- Regulated in LN

C3 convertase components; ↑ alternative pathway activation Complement regulators; ↓ alternative pathway activation

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

Emerging drug: Eculizumab

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Pathway Analysis of Serial LN Biopsies

Pathway analysis demonstrates that NR do not achieve control of their interferon pathway.

• 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

Anifrolumab, an Anti-Interferon Alpha Receptor Monoclonal Antibody, in Moderate to Severe SLE

Furie et al, ACR Meeting, San Francisco, 2015

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.

• 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

• r 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

CONCLUSION