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Novel Therapeutics for Management of Lupus Nephritis: What Is Next?

June 2023
Kidney Medicine 5(5):100688

DOI:10.1016/j.xkme.2023.100688

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Authors:

Sayali Bhalchandra Thakare

King Edward Memorial Hospital

Paolo Nikolai So

Piedmont Athens Regional Medical Center

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Lupus nephritis is a severe, organ-threatening manifestation of systemic lupus erythematosus. The current standard of care in the treatment of lupus nephritis is limited to broad-spectrum immunosuppressants, which have significant concerns of short- and long-term toxicity. With traditional approaches, kidney survival and patient outcomes have remained suboptimal. Robust research in the therapeutics of lupus nephritis has resulted in development of many novel drugs targeting specific inflammatory response pathways. Some newer agents have shown a definitive signal of benefit when added to standard of care. With the advent of precision medicine in nephrology, lupus nephritis treatment may undergo a shift toward incorporating approaches using these newer drugs and individualizing care of our patients. This review highlights major advances in management of lupus nephritis over the last 25 years and explores the ongoing trials of emerging therapies in lupus nephritis.

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Novel Therapeutics for Management of Lupus Nephritis:

What Is Next?

Sayali B. Thakare, Paolo Nikolai So, Sonia Rodriguez, Mohamed Hassanein, Edgar Lerma, and

Nasim Wiegley, on behalf of the GlomCon Editorial Team

Lupus nephritis is a severe, organ-threatening manifestation of systemic lupus erythematosus. The current

standard of care in the treatment of lupus nephritis is limited to broad-spectrum immunosuppressants, which

have signiﬁcant concerns of short- and long-term toxicity. With traditional approaches, kidney survival and patient

outcomes have remained suboptimal. Robust research in the therapeutics of lupus nephritis has resulted in

development of many novel drugs targeting speciﬁcinﬂammatory response pathways. Some newer agents have

shown a deﬁnitive signal of beneﬁt when added to standard of care. With the advent of precision medicine in

nephrology, lupus nephritis treatment may undergo a shift toward incorporating approaches using these newer

drugs and individualizing care of our patients. This review highlights major advances in management of lupus

nephritis over the last 25 years and explores the ongoing trials of emerging therapies in lupus nephritis.

2023 The Authors. Published by Elsevier Inc. on behalf of the National Kidney Foundation, Inc. This is an open access

article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Lupus nephritis (LN) develops in 40%-60% of patients

with systemic lupus erythematosus (SLE). The kidney

domain of SLICC/ACR (Systemic Lupus International

Collaborative Clinics/American College of Rheumatology)

Damage Index is associated with early mortality in SLE.

Hence, preventing kidney damage in SLE has long-term

prognostic implications. Currently used standard of care,

corticosteroids in combination with immunosuppressants,

has dramatically improved patient survival in LN (from 17%

at 5 years in untreated patients to 80% in those treated with

standard of care),

though not without the burden of drug

toxicities. Yet, 10%-30% of patients with LN progress to

kidney failure within 15 years.

This article provides an

overview of emerging therapies for LN and major random-

ized controlled trials (RCTs) involved in drug development.

NOVEL THERAPEUTIC TARGETS FOR LUPUS

NEPHRITIS

The diversity of immune response

in SLE and LN provides

many attractive biologic targets (Fig 1). Plasmacytoid den-

dritic cells are activated by signals from other immune cells

reacting to self-antigens. Interferon-alfa released from acti-

vated plasmacytoid dendritic cells serves as an ampliﬁer to

major axes of immune activation. Plasmacytoid dendritic

cells stimulate the production of other antigen-presenting

cells. They upregulate major histocompatibility complex II

and co-stimulatory molecules leading to the activation of T

cells. CD4 helper T cells, thus activated, produce a repertoire

of cytokines promoting autoreactive B-cell differentiation to

plasma cells. Plasma cells further drive higher auto-antibody

expression and immune complex formation in SLE and LN.

Delving into candidate drugs targeting these pathways is

arduous. A comprehensive study of clinical trials in LN

registered with ClinicalTrials.gov listsasmanyas126RCTs

initiated between 1998 and 2020, including those for 27

types of biological agents.

Among these, anti-inﬂammatory

agents act acutely by limiting immunologic damage,

making them useful as induction agents. Therapies that

target autoimmunity work toward attenuating disease ac-

tivity and thus prevent accruing damage from repeated

ﬂares.

Despite tremendous progress in unraveling the pathobi-

ology of LN, only a handful of drugs have shown mean-

ingful beneﬁts with acceptable side-effect proﬁles in phase 2

and 3 clinical trials (Table 1). Some of these agents have

received approval for use by regulatory agencies (Fig 1).

Belimumab, an anti-BAFF monoclonal antibody (mAb), was

the ﬁrst biological agent approved for SLE in 2011. After a

series of focused trials in patients with kidney involve-

ment,

belimumab was subsequently approved for LN in

December 2020. Voclosporin, a novel oral calcineurin in-

hibitor, was approved for LN in January 2021 based on

results from the AURORA trials.

25,26

The most recent

addition to the armamentarium of SLE is anifrolumab, an

anti-interferon-αmAb. Anifrolumab was approved for

moderate to severe SLE in August 2021, making it the only

new drug for SLE in over a decade. Anifrolumab is currently

undergoing a phase 3 trial in LN (Table 2).

Noting pre-

viously concluded trials helps gain perspective about the

impact of a given drug action on the pathogenic pathways

in LN. Table 1 outlines an updated list of concluded RCTs

that either failed to meet the primary endpoint, showed

unacceptable drug toxicity, or were terminated prematurely.

Remarkably, not all drugs demonstrating efﬁcacy in SLE

display replicable results in LN. The role of local immune

pathways, such as the intrarenal inﬂammatory cycle, inter-

stitial lymphocytic aggregates, or germinal centers within the

kidneys, may be implicated.

Therapeutic categories of drugs

evaluated in trials for patients with LN, such as B-cell ther-

apies and co-stimulatory blockade agents, are described.

B-CELL DIRECTED THERAPIES

B cells have a central role in the pathogenesis of LN and

are the most investigated axis for drug therapy.

Complete author and article

information provided before

references.

Correspondence to

S. B. ThakareS.B. Thakare

(thakare.sayali@gmail.com)

Kidney Med. 5(8):100688.

Published online June 14,

2023.

doi: 10.1016/

j.xkme.2023.100688

Kidney Med Vol 5 | Iss 8 | August 2023 | 100688 1

GlomCon Mini Review

Approaches include B-cell depletion (ie, rituximab,

obinutuzumab, ofatumumab, and ocrelizumab), anti-B-

cell activation (ie, belimumab, obexelimab, atacicept,

blisibimod, and ianalumab), co-stimulatory blockade (ie,

iscalimab, abatacept, ruplizumab, and dapirolizumab

pegol), and anti-plasma cell therapy (ie, bortezomib,

daratumumab, and ixazomib). Rituximab is the most

commonly used mAb for LN at present. Its popularity

arises from its ability to act as a steroid sparing agent

and from its observed efﬁcacy in refractory/relapsing

LN.

29,30

The 2012 LUNAR trial

failed to demonstrate

improvement in clinical outcomes, however post-hoc

analysis of the trial

showed that variability in pe-

ripheral B-cell depletion likely dictated outcomes, and a

complete, lasting peripheral depletion was associated

with complete response. Other controlled

and

observational studies

33,34

later did show beneﬁt of rit-

uximab as well compared to the standard of care. Rit-

uximab continues to be used in real world clinical

practice with promising newer data

supporting its use.

Obinutuzumab, a humanized anti-CD20 mAb (Fig 1),

achieves higher and more sustained B-cell depletion than

rituximab and received breakthrough therapy designa-

tion from the US Food and Drug Administration for LN

in 2019 based on the results of the NOBILITY trial.

However, BAFF levels increase with B-cell depletion.

Therefore, the sequential use of belimumab with ritux-

imab in the SynBioSe-2 trial (Fig 1) is evaluating syn-

ergistic inhibition of the repopulation of autoreactive B

cells. Long-lived autoreactive plasma cells are found in

the circulation and kidney interstitium and play a role in

ﬂares,

hence the rationale for using plasma cell-

Figure 1. Newer therapies for lupus nephritis. Abbreviations: BAFF, B-cell activating factor; BLM, Belimumab; CR, complete remis-

sion; CRR, complete renal response; eGFR, estimated glomerular ﬁltration rate; IFN, interferon; iv, intravenous; LN, lupus nephritis;

MAC, membrane attack complex; NET, neutrophil extracellular traps; PDC, plasmacytoid dendritic cell; PE, primary endpoint; PR,

partial remission; RCT, randomized controlled trial; RTX, rituximab; sc, subcutaneous; SOC, standard of care; UPCR, urinary

protein-creatinine ratio; vs, versus.

*All drugs were assessed as add-on to standard of care.

Thakare et al

2Kidney Med Vol 5 | Iss 8 | August 2023 | 100688

Table 1. Terminated Randomized Controlled Trials in Lupus Nephritis and Clinical Outcomes

Drug Mechanism of Action Trial Registration Phase Status

Trials with favorable outcomes

Filgotinib/lanraplenib Small molecule inhibitor of

JAK1/ATP-competitive

inhibitor of spleen tyrosine

kinase (SYK)

NCT03285711

(Class V LN)

2 Median reduction of 50.7%

in proteinuria at 16 wk for

ﬁglotinib, no beneﬁt with

lanraplenib6

Narsoplimab (OMS721) MASP-2 inhibitor mAb

(lectin pathway inhibitor)

NCT02682407 2 69%reduction of proteinuria

in 4/5 patients7

Trials with unfavorable outcomes

B-cell therapies

Rituximab Anti-CD20 mAb NCT00282347

(LUNAR)

3 Failed to meet the primary

endpoint, no safety signals8

Ocrelizumab Anti-CD20 mAb NCT00626197

(BELONG)

3 Early termination because of

higher incidence of serious

infections. Failed to meet

primary endpoint9

Atacicept Fusion protein between

TACI and Fc portion of IgG

NCT00573157

(APRIL-LN)

2/3 Terminated early owing to

severe infective

complications and

hypogammaglobulinemia10

Blisibimod Binds to BAFF and prevents

interaction with BAFF

receptors

NCT02514967

(CHABLIS7.5)

3 Terminated because of

failure of prior trial CHABLI

SC111

Bortezomib Proteasome inhibitor NCT01169857 4 Withdrawn because the

previous RCT in SLE did not

meet primary endpoint and

had higher adverse effects12

Ixazomib citrate Proteasome inhibitor NCT02176486 1 Terminated because of

insufﬁcient enrolment, no

safety concerns13

Co-stimulatory pathways

Abatacept Fusion protein binding to

CD80/86 resulting in

blockade of CD28 co-

stimulation

NCT00774852

(ACCESS)

NCT00430677

NCT01714817

(ALLURE)

2/3

Failed to meet the primary

endpoint, no safety signals14

Failed to meet the primary

endpoint, no safety signals15

Failed to meet the primary

endpoint, no safety signals16

BI-655064 Anti-CD40 mAb (co-

stimulatory blockade) for

maintenance therapy

NCT02770170

NCT03385564

(52-wk extension of

NCT02770170)

Effect size 15.2%and 9.1%

for 120-180 mg dose at 52

wk17

Results awaiting publication

Dapirolizumab pegol

(CDP7657)

PEGylated anti-CD40 Ab

fragment

NCT02804763 2 Failed to meet primary

endpoint, well tolerated,

smaller risk of

thromboembolic events18

Ruplizumab

(BG9588)

Anti-CD40L mAb (co-

stimulation blocker)

NCT00001789 2 Terminated because of

thromboembolic events19

Cytokine targeted therapies

AMG-811 Anti-IFN gamma NCT00818948 2 Favorable safety proﬁle and

PK but no clinical impact20

BIIB023 Human mAb against

TWEAK

NCT01499355

(ATLAS)

2 Prematurely terminated, no

clinical efﬁcacy21

Sirukumab

(CNTO-136)

Human IgG1k IL-6 mAb NCT01273389 2 Prematurely terminated,

neither increased efﬁcacy

nor acceptable safety

proﬁle, AE: mostly

infections22

Ustekinumab Anti-IL-17/23 mAb NCT03517722

(LOTUS)

3 Terminated in June 2020

because of lack of efﬁcacy in

interim analysis23

(Continued)

Kidney Med Vol 5 | Iss 8 | August 2023 | 100688 3

Thakare et al

depleting agents in LN. Bortezomib, a proteasome in-

hibitor, caused signiﬁcant neurotoxicity in patients with

LN, leading to the early termination of the trial

(Table 1). Finally, an immuno-proteosome inhibitor

(proteasome inducible by interferon-γ), KZR 616, is

currently being investigated with encouraging interim

results.

CO-STIMULATORY BLOCKADE AGENTS

CD40/CD40L and CD28/CD80/86 are attractive pathways

for therapeutic targets in immune-mediated disorders. A

trial involving an anti-CD40L antibody, ruplizumab, was

halted because of severe thromboembolic events.

polyethylene glycosylated anti-CD40 antibody fragment,

dapirolizumab pegol (CDP7657), was tested in LN with an

attenuated risk of thromboembolic events; however, the

trial did not meet the primary endpoint.

Because of

potential beneﬁts, nevertheless, a phase 3 RCT is in

progress.

Abatacept, a CD28/CD80 pathway blocker, failed to

meet the primary endpoint in 3 RCTs.

14-16

Because no

safety signals are reported and because abatacept is an

agent affecting autoimmunity, it might work better as

maintenance therapy. BI 655064

and Iscalimab,

both

humanized anti-CD40 mAbs, are also therapeutic candi-

dates currently under investigation.

OTHER POTENTIAL TARGET THERAPIES IN LN

These include but are not limited to cytokine-directed

therapies (ie, ustekinumab, sirukumab, BIIB023, AMG

811, secukinumab, and guselkumab), anti-complement

therapies (ie, ravulizumab, APL-2, iptacopan, and narso-

plimab) and miscellaneous (ie, kinase inhibitors, Fc re-

ceptor antagonists, and immune-proteasome inhibitors).

Itolizumab, anti-CD6 mAb, received fast-track designation

from the Food and Drug Administration for LN in

December 2019. Most of these agents showed efﬁcacy in

previous studies in SLE and are now being investigated for

LN.

Table 2 lists trials that are currently ongoing and are

expected to be completed in the near future. As we eagerly

await the results of these trials, optimizing the current

broad-spectrum therapy assumes prime importance. Ste-

roid reduction, a strategy incorporated into the current

guidelines of standard of care,

is one way toward making

therapy in SLE and LN safer.

CONCLUSIONS

The armamentarium of SLE is rapidly expanding. How-

ever, despite the steady engagement of resources from

basic sciences and clinical medicine, there is a long way to

go. Successful drug development often unfolds over many

years. To transform clinical care globally, beneﬁts from

scientiﬁc discoveries need to be made widely available and

affordable, which assumes the next level of the challenge

after the success of a clinical trial. Enthusiasm toward

emerging therapies is tempered by a realization that cur-

rent research focuses heavily on induction agents. More

studies are warranted for speciﬁc situations like membra-

nous LN, childhood-onset LN, maintenance therapy, and

antiphospholipid antibody syndrome. Precision medicine,

matching a given drug to the most responsive disease

phenotype, appears to be the future in LN (eg, ani-

frolumab in SLE patients with a high interferon signature).

Yet like never before, we could be poised to have plenty

more in the immediate future.

ARTICLE INFORMATION

GlomCon Editorial Team: A list of the GlomCon Editorial Team can

be found at: https://pubs.glomcon.org/editorial-team/.

Authors’Full Names and Academic Degrees: Sayali B. Thakare,

MD, DM, Paolo Nikolai So, MD, Sonia Rodriguez, MD, Mohamed

Hassanein, MD, Edgar Lerma, M D, and Nasim Wiegley, MD, on

behalf of the GlomCon Editorial Team

Authors’Afﬁliations: Department of Nephrology, Seth GSMC and

KEM Hospital, Mumbai, India (SBT); Private Practice, Manila,

Philippines (PNS); Division of Nephrology, University Health

Network, Toronto, ON, Canada (SR); Division of Nephrology and

Hypertension, University of Mississippi Medical Center, Jackson,

MI (MH); Section of Nephrology, University of Illinois at Chicago,

Chicago, IL (EL); and University of California Davis School of

Medicine, Sacramento, CA (NW).

Address for Correspondence: Address to Dr Sayali B. Thakare,

34A, AKD, Third ﬂoor, Old Building, KEM Hospital campus,

Acharya Dhonde Marg, Parel, Mumbai, Maharashtra, India,

400012. Email: thakare.sayali@gmail.com

Support: None.

Financial Disclosure: The authors declare that they have no

relevant ﬁnancial interests.

Table 1 (Cont'd). Terminated Randomized Controlled Trials in Lupus Nephritis and Clinical Outcomes

Drug Mechanism of Action Trial Registration Phase Status

Others

Abetimus sodium Tolerogen: reduces

production of double-

stranded DNA antibodies

NCT00089804

(ASPEN)

3 Terminated because of lack

of efﬁcacy

Deucravacitinib

(BMS-986165)

Selective tyrosine kinase

Tyk-2 inhibitor selectively

blocking the IL-17/23 and

IFN type I p/w

NCT03943147 2 Terminated because of

insufﬁcient enrolment

Abbreviations: AE, adverse effect; PK, pharmacokinetics.

4Kidney Med Vol 5 | Iss 8 | August 2023 | 100688

Thakare et al

Acknowledgments: Figure 1 was created using BioRender.com.

Prior Presentation: A modiﬁed version of this article was published

online at https://pubs.glomcon.org/lupus-nephritis-treatment-what-

is-next/ on October 20, 2022.

Peer Review: Received January 7, 2023. Evaluated by 2 external

peer reviewers, with direct editorial input from the Editor-in-Chief.

Accepted in revised form April 30, 2023.

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Others

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proteosome)

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1b/2 39 (LN-2) 2018-2022

Nipocalimab Fc receptor antagonist

(increases degradation of

IgG)

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Sirolimus mTOR inhibitor NCT04892212

(Single center)

2 20 2021-2023

Zanubrutinib Bruton tyrosine kinase

small molecule inhibitor

NCT04643470 2 200 2020-2023

Belimumab +rituximab Combination therapy NCT03747159

(SynBioSe-2)

2 70 2018-2025

Abbreviation: mAb, monoclonal antibody.

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We are MedChem: The Frontiers in Medicinal Chemistry 2024

Article

Full-text available

Sep 2024
CHEMMEDCHEM

The Frontiers in Medicinal Chemistry (FiMC) is the largest international Medicinal Chemistry conference in Germany and took place from March 17th to 20th 2024 in Munich. Co‐organized by the Division of Medicinal Chemistry of the German Chemical Society (Gesellschaft Deutscher Chemiker; GDCh) and the Division of Pharmaceutical and Medicinal Chemistry of the German Pharmaceutical Society (Deutsche Pharmazeutische Gesellschaft; DPhG), and supported by a local organizing committee from the Ludwigs‐Maximilians‐University Munich headed by Daniel Merk, the meeting brought together approximately 225 participants from 20 countries. The outstanding program of the four‐day conference included 40 lectures by leading scientists from industry and academia as well as early career investigators. Moreover, 100 posters were presented in two highly interactive poster sessions.

In the Pursuit of Precision: Novel Target Therapies Revolutionizing SLE Care

Article

Full-text available

Jun 2024

Systemic lupus erythematosus (SLE) is a chronic, autoimmune, immune complex-mediated disease affecting mainly females at a young age. The disease etiology is still unknown, and different genetic and epigenetic factors related to disease onset and manifestations are being explored. The standard treatment regimen for SLE includes the long-term use of corticosteroids and non-specific immunosuppressive agents, often limited by co-morbidities or related side effects. However, recent advances in disease pathogenesis clarifying the role of inflammatory cytokines, chemokines, immune cells, and co-stimulation molecules have made a more practical, targeted approach possible, leading to personalized treatment strategies. This review summarizes current knowledge about SLE-targeted therapies in clinical practice.

Role of MCP-1 as an inflammatory biomarker in nephropathy

Article

Full-text available

Jan 2024

The Monocyte chemoattractant protein-1 (MCP-1), also referred to as chemokine ligand 2 (CCL2), belongs to the extensive chemokine family and serves as a crucial mediator of innate immunity and tissue inflammation. It has a notable impact on inflammatory conditions affecting the kidneys. Upon binding to its receptor, MCP-1 can induce lymphocytes and NK cells’ homing, migration, activation, differentiation, and development while promoting monocytes’ and macrophages’ infiltration, thereby facilitating kidney disease-related inflammation. As a biomarker for kidney disease, MCP-1 has made notable advancements in primary kidney diseases such as crescentic glomerulonephritis, chronic glomerulonephritis, primary glomerulopathy, idiopathic proteinuria glomerulopathy, acute kidney injury; secondary kidney diseases like diabetic nephropathy and lupus nephritis; hereditary kidney diseases including autosomal dominant polycystic kidney disease and sickle cell kidney disease. MCP-1 not only predicts the occurrence, progression, prognosis of the disease but is also closely associated with the severity and stage of nephropathy. When renal tissue is stimulated or experiences significant damage, the expression of MCP-1 increases, demonstrating a direct correlation with the severity of renal injury.

1202 Voclosporin for Lupus Nephritis: Results of the Two-year AURORA 2 Continuation Study

Conference Paper

Full-text available

Dec 2022

Background Voclosporin (VCS), a novel calcineurin inhibitor, was approved in the US in January 2021 for the treatment of adult patients with active lupus nephritis (LN) in combination with background immunosuppressive therapy. The Phase 3 AURORA 1 study showed that the addition of VCS to mycophenolate mofetil (MMF) and low-dose steroids in patients with LN significantly increased rates of complete renal response at 52 weeks. Here we report the results of the completed continuation study, AURORA 2, which assessed the long-term safety and tolerability of VCS compared to placebo in patients with LN receiving treatment for an additional 24 months following completion of the AURORA 1 study. Methods Key inclusion criteria for the parent AURORA 1 study included a diagnosis of biopsy-proven active LN (Class III, IV, or V ± III/IV), proteinuria ≥1.5 mg/mg (≥2 mg/mg for Class V) and estimated glomerular filtration rate (eGFR) >45 mL/min/1.73 m². Patients who completed AURORA 1 were eligible to enter AURORA 2 to continue on the same blinded therapy as at the end of AURORA 1 (either VCS or placebo twice daily in combination with MMF and low-dose steroids). Safety and tolerability were monitored, and eGFR, serum creatinine (SCr), and urine protein creatinine ratio (UPCR) were also assessed. Results In total, 116 and 100 patients in the VCS and control arms enrolled in AURORA 2. There were no unexpected safety signals in the VCS arm compared to control, with similar rates of serious adverse events reported in both arms (VCS [18.1%] vs. control [23.0%]; table 1). Eight patients in each arm experienced serious adverse events of infection; serious coronavirus infections were observed in two patients in the voclosporin arm and 5 patients in the control arm. There were 4 and 2 adverse events by preferred term of renal impairment reported in the VCS and control arms, respectively, none of which were considered serious, and no reports of acute kidney injury by preferred term in either arm. There were no deaths in the VCS arm during AURORA 2; four deaths were reported in the control arm (pulmonary embolism [n=1], coronavirus infection [n=3]). Mean eGFR and SCr levels remained stable through the end of AURORA 2. The difference between the VCS and control arms in LS mean change from baseline in eGFR was 2.7 mL/min/1.73 m² at 4 weeks following study drug discontinuation (figure 1). The mean reductions in UPCR observed in patients treated with VCS in AURORA 1 were maintained in AURORA 2 with no increase in UPCR noted at the follow-up visit 4 weeks after study drug discontinuation. Conclusion Voclosporin was well-tolerated over 3 years of treatment with no unexpected safety signals detected. Further, eGFR remained stable throughout the study period and the significant and meaningful reductions in proteinuria achieved in AURORA 1 were maintained. These data provide evidence of a long-term treatment benefit of VCS in patients with LN.View this table: • View inline • View popup Abstract 1202 Table 1 Overall Summary of Adverse Events • Download figure • Open in new tab • Download powerpoint Abstract 1202 Figure 1 LS Mean eGFR over Time. Analysis of AURORA 2 patients includes data from pre-treatment baseline of AURORA 1, 12 months in AURORA 1 and up to 25 months in AURORA 2 (including 4- week post-treatment visit). Renal function assessed with corrected eGFR (Chronic Kidney Disease Epidemiology Collaboration equation) using a prespecified ceiling of 90 mL/min/1.73 m2. Cl, confidence interval; eGFR, estimated glomerular filtration rate; FUP, follow-up visit (4-week post-treatment visit); LS Mean, least squares mean. Disclosures AS reports payments for Aurinia Pharmaceuticals Inc. speaker bureaus; primary investigator for Aurinia Pharmaceuticals Inc. clinical trials; advisory fees from Eli Lilly, AstraZeneca, GlaxoSmithKline and Kezar Life Sciences. YKOT reports research grants from commercial organizations including an unrestricted research grant from GlaxoSmithKline and Aurinia Pharmaceuticals Inc.; primary investigator for Aurinia Pharmaceuticals Inc. clinical trials; consultancy fees paid to institution from Aurinia Pharmaceuticals Inc., Novartis, GlaxoSmithKline, KezarBio, Vifor Pharma and Otsuka Pharmaceuticals. CC, NE, and HL are employees and shareholders of Aurinia Pharmaceuticals, Inc. HL is an employee and shareholder of Aurinia Pharmaceuticals, Inc. Data first presented by Saxena A et al. at the EULAR Congress June 1-4, 2022. Editorial support provided by MediComm Partners Ltd. Aurinia Pharmaceuticals Inc. provided funding for the study and presentation.

New developments in systemic lupus erythematosus

Article

Full-text available

Dec 2021
Rheumatology

In this review, the results of recent and ongoing clinical trials in patients with SLE are discussed. After many unsuccessful trials in the past decade, belimumab was the first biologic specifically designed for SLE that met its primary end point. At the same time, studies on the pathophysiology of SLE have further elucidated the pathways involved in the disease, which has led to the identification of new possible therapeutics and has encouraged the initiation of new trials. These new drugs include biologics that target B cells, T cells and type 1 interferons, and small molecules that inhibit kinases. Other therapeutics aim to restore immunological balance by restoring tolerance. Results from phase II and even phase III trials are promising and it is likely that some of the therapeutics discussed will receive approval in the following years. Hopefully, this will allow for more tailor-made medicine for SLE patients in the future.

B-cell depletion with obinutuzumab for the treatment of proliferative lupus nephritis: a randomised, double-blind, placebo-controlled trial

Article

Full-text available

Oct 2021
ANN RHEUM DIS

Objective: Randomised trials of type I anti-CD20 antibodies rituximab and ocrelizumab failed to show benefit in proliferative lupus nephritis (LN). We compared obinutuzumab, a humanised type II anti-CD20 monoclonal antibody that induces potent B-cell depletion, with placebo for the treatment of LN in combination with standard therapies. Methods: Patients with LN receiving mycophenolate and corticosteroids were randomised to obinutuzumab 1000 mg or placebo on day 1 and weeks 2, 24 and 26, and followed through week 104. The primary endpoint was complete renal response (CRR) at week 52. Exploratory analyses through week 104 were conducted. The prespecified alpha level was 0.2. Results: A total of 125 patients were randomised and received blinded infusions. Achievement of CRR was greater with obinutuzumab at week 52 (primary endpoint, 22 (35%) vs 14 (23%) with placebo; percentage difference, 12% (95% CI -3.4% to 28%), p=0.115) and at week 104 (26 (41%) vs 14 (23%); percentage difference, 19% (95% CI 2.7% to 35%), p=0.026). Improvements in other renal response measures, serologies, estimated glomerular filtration rate and proteinuria were greater with obinutuzumab. Obinutuzumab was not associated with increases in serious adverse events, serious infections or deaths. Non-serious infusion-related reactions occurred more frequently with obinutuzumab. Conclusions: Improved renal responses through week 104 were observed in patients with LN who received obinutuzumab plus standard therapies compared with standard therapies alone. Obinutuzumab was well tolerated and no new safety signals were identified. Trial registration number: NCT02550652.

Comprehensive Analysis of Clinical Trials Registration for Lupus Nephritis Therapy on ClinicalTrials.gov

Article

Full-text available

Jun 2021

Objective: Clinical trials are the most effective method for evaluating therapeutic strategies. The purpose of this study was to comprehensively assess the characteristics of trials on lupus nephritis (LN) and provide a reference for LN treatment and research. Methods: Registered therapeutic trials on drug interventions for LN were obtained from ClinicalTrials.gov up to December 3, 2020. The general characteristics, methodological characteristics, detailed characteristics, investigated drugs, eligibility criteria, and outcome measures of these trials were analyzed. Results: A total of 126 eligible trials were evaluated, and these trials mainly investigated the initial treatment of adult proliferative LN. Half of the trials enrolled <50 participants, and 70.7% of the trials lasted for 6–24 months. In total, 95.2% of trials adopted an interventional study design. Of intervention trials, 56.6% were in phase 2 or phase 3, 76.7% were randomized, 77.5% employed a parallel assignment, and 41.7% were masked. The eligibility criteria and outcome measures of the included trials varied and involved a variety of indicators. Chemical agents and biologics are the most widely studied immunotherapies, of which mycophenolate mofetil, tacrolimus, and rituximab are the most studied. In addition, some trials studied cell transplantation treatment. Conclusions: The majority of clinical trials for LN therapy registered on ClinicalTrials.gov investigated the initial treatment of adult proliferative LN, and most of these trials were randomized, parallel assigned, and insufficiently masked interventional trials with small scale, short duration, various eligibility criteria, and outcome measures. We hope that more large-scale, long-term multicenter, and high-quality RCT trials with standardized inclusion criteria/exclusion criteria and treatment effect evaluation systems will be conducted and that more energy and funding will be put into exploring biological products and stem cell therapies. In addition, trials for membranous LN, childhood-onset LN, and maintenance phase LN are needed to establish optimal treatment strategies.

POS0687 A RANDOMISED DOSE RANGING, PLACEBO-CONTROLLED, PHASE II STUDY ASSESSING THE EFFICACY AND SAFETY OF BI 655064, AN ANTAGONISTIC ANTI-CD40 ANTIBODY, IN PATIENTS WITH LUPUS NEPHRITIS

Article

Full-text available

Jun 2021

Background In patients with SLE, activation of the CD40–CD40L pathway results in stimulation and proliferation of B cells and other inflammatory cell types. The subsequent generation of autoantibodies and their deposition in the kidney, as well as activation of myeloid and resident kidney cells, result in local inflammation and eventually, kidney injury. Thus, CD40 is an appealing therapeutic target in lupus nephritis (LN). BI 655064 is a humanised anti-CD40 monoclonal antibody that blocks the CD40 pathway in a nanomolar range and downregulates activated B cells. Objectives To assess the efficacy and safety over 52 weeks of three doses of subcutaneous BI 655064 compared with placebo, as add-on to mycophenolate and steroids, in patients with active proliferative LN (ClinicalTrials.gov number: NCT02770170 ). Methods Overall, 121 patients with LN were randomised, double blind, in a 2:1:1:2 ratio to placebo or BI 655064 120 mg, 180 mg or 240 mg, and received a weekly loading dose for the first 3 weeks, followed by dosing every 2 weeks for the 120 and 180 mg doses, and weekly (120 mg) for the 240 mg group. Key inclusion criteria included an active ISN/RPS class III or IV (±V) renal biopsy within 3 months prior to screening and a screening protein/creatinine ratio of ≥1 mg/mg. Randomisation was stratified based on race (Asian vs non-Asian) and screening protein/creatine (UP/UC) ratio (<3 vs ≥3). The primary efficacy endpoint was complete renal response (CRR), defined as 24 h proteinuria <0.5 g/day and stable eGFR at Week 52. Results The placebo response in this trial was higher than expected (48.3%; Table 1); none of the BI 655064 doses increased rates of CRR at Week 52 compared with placebo. However, CRR at Week 52 based on creatinine-adjusted proteinuria, assessed using spot urine, showed a better response in the 180 mg group (50%) vs placebo (42.5%), and the 180 mg dose showed a greater change from baseline over time vs placebo from Week 4. Time to CRR was shorter in the 180 mg group (17.3 weeks) vs placebo (20.4 weeks). The 180 mg group also showed improvement vs placebo in total SLEDAI (SELENA) and its subscores. The unexpected high placebo response prompted a post hoc analysis evaluating confirmed CRR (cCRR), whereby confirmation of the endpoint was required at both Weeks 46 (penultimate visit on treatment) and 52. A 15.2% higher cCRR in the 180 mg group (44.3%) vs placebo (29.1%) was observed (p=0.26). While based on a small sample size, there were more reports of infection-related severe and serious adverse events and neutropenia in the 240 mg group compared with placebo. Of note, in those who experienced neutropenia, a clinical impact (e.g. increase in infections) was not established. Aside from these observations, safety data were comparable across treatment groups. Larger decreases from baseline were observed in the percentage of CD27−IgD−CD95+, CD27−IgD+CD95+, CD27+IgD+CD95+ and CD27+IgD−CD95+ B-cell subsets in the 180 and 240 mg groups compared with placebo. Treatment-emergent anti-drug antibodies (ADAs) were detected in five patients treated with BI 655054, all at low titre, and in one who received placebo; ADAs had no impact on pharmacokinetics or safety. Conclusion The trial did not meet its primary CRR endpoint. However, when confirmation of CRR was required at both Weeks 46 and 52, the resultant decrease in the placebo response generated an effect size of 15.2% and 9.1% in favour of 180 mg and 240 mg BI 655064, respectively. Table 1. Efficacy endpoints at Week 52 Placebo (n=40) BI 655064 120 mg (n=21) 180 mg (n=20) 240 mg (n=40) Observed CRR, n 20 8 9 18 Adjusted* CRR, % 48.3 38.3 45 44.6 Observed cCRR, n 13 5 9 16 Adjusted* cCRR, % 29.1 22.5 44.3 38.2 Mean change from baseline in SLEDAI Total score −6.5 −6.1 −9.7 −8.2 Non-renal score −1.4 −3.0 −2.8 −3.1 Renal score −5.1 −3.7 −6.8 −5.0 Clinical score −5.7 −3.9 −7.9 −6.5 CRR based on 24 h proteinuria; cCRR based on UP/UC (spot urine) at Weeks 46 and 52. *Logistic regression model including treatment and the covariates race and proteinuria at screening. Disclosure of Interests David Jayne Consultant of: DRJ has received consulting fees from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline Research & Development Ltd, Novartis, and Roche, Juergen Steffgen Employee of: JS is employed by Boehringer Ingelheim., Juanita Romero-Diaz Consultant of: JRD has received research consulting fees from Boehringer Ingelheim, Hirofumi Amano Grant/research support from: HA has received research grants from Boehringer Ingelheim, Kajohnsak Noppakun Consultant of: KN has received honoraria from Boehringer Ingelheim, Novartis, Roche, Jansen, AstraZeneca, Otsuka Pharmaceuticals, Astellas Pharma, Abbott, Sanofi and Novo Nordisk, Grant/research support from: KN has received research grants from Boehringer Ingelheim, GlaxoSmithKline Research & Development Ltd, Visterra Inc., Kalbe Genexine Biologics, Aurinia Pharmaceuticals Inc., and Omeros Corporation., Harold Michael Gomez Speakers bureau: HMG has received speaker’s fees for Pfizer, MSD, Unilab, Astellas Pharma, AstraZeneca, GlaxoSmithKline Research & Development Ltd, and Aurinia Pharmaceuticals Inc., Rhona Recto: None declared, Valérie Belsack Employee of: Boehringer Ingelheim, Nora Fagan Employee of: Boehringer Ingelheim, Steven Padula Employee of: Boehringer Ingelheim, Ivette Revollo Employee of: Boehringer Ingelheim, Jing Wu Employee of: Boehringer Ingelheim, Sudha Visvanathan Employee of: Boehringer Ingelheim, Richard Furie Consultant of: RF has received research consulting fees, Grant/research support from: RF has received clinical trial support

Phase 2, Randomized, Placebo-Controlled Trial of Dapirolizumab Pegol in Patients with Moderate-to-Severe Active Systemic Lupus Erythematosus

Article

Full-text available

May 2021

Objective: To evaluate dose-response, efficacy and safety of dapirolizumab pegol (DZP) in patients with systemic lupus erythematosus (SLE). Methods: Adults with moderately to severely active SLE (SLEDAI-2K score ≥6 and ≥1 BILAG A or ≥ 2 BILAG B domain scores), receiving stable corticosteroid (≤40 mg/day prednisone-equivalent), antimalarial, or immunosuppressant drugs were included. Patients with stable lupus nephritis (proteinuria ≤2 g/day) not receiving high-dose corticosteroids or cyclophosphamide were permitted entry. Randomized patients received placebo or intravenous DZP (6/24/45 mg/kg) and standard-of-care (SOC) treatment every 4 weeks to week 24, after which patients received only SOC to week 48. The primary objective was to establish a dose-response relationship based on week 24 BILAG-Based Composite Lupus Assessment (BICLA) responder rates. Results: All DZP groups exhibited improvements in clinical and immunological outcomes vs placebo at week 24; however, BICLA responder rates did not fit pre-specified dose-response models (best-fitting model [Emax]: p= 0.07). Incidences of serious treatment-emergent adverse events across DZP groups were low and similar to placebo. Following DZP withdrawal, SLEDAI-2K, physician's global assessment (PGA), BILAG, and Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) scores stabilized; BICLA and SLE Responder Index (SRI-4) responder rates declined (likely due to interventions with disallowed escape medications), BILAG flares increased, and immunologic parameters returned towards baseline. Conclusions: Although the primary objective was not met, DZP appeared to be well tolerated, and patients exhibited improvements across multiple clinical and immunological measures of disease activity after 24 weeks relative to placebo. The potential clinical benefit of DZP warrants further investigation.

A Prospective Study on Long-Term Clinical Outcomes of Patients With Lupus Nephritis Treated With an Intensified B-Cell Depletion Protocol Without Maintenance Therapy

Article

Full-text available

Feb 2021

Background we aim to investigate the safety and efficacy of an intensified B-cell depletion induction therapy (IBCDT)without immunosuppressive maintenance regimen compared to standard of care in biopsy-proven Lupus Nephritis (LN). Methods Thirty patients were administered an IBCDT (4 weekly Rituximab 375mg/m2 and 2more doses after 1&2 months;2 infusions of 10 mg/kg cyclophosphamide (CYC),3 methylprednisolone pulses), followed by oral prednisone (tapered to 5 mg/day by the 3rd month). No immunosuppressive maintenance therapy was given. Thirty patients matched for LN class and age were selected as controls: 20 received 3 methylprednisolone pulses days followed by oral prednisone and mycophenolate mofetil (MMF) 2-3 g/day, while 10 were given the Euro Lupus CYC. Results At 12 months, complete renal remission was observed in 93% of patients on IBCDT, in 62.7% on MMF, and in 75% on CYC (p=0,03); the dose of oral prednisone was lower in the IBCDT group (mean±SD 2.9±5.0mg/dl) than MMF (10.5±8.0 mg/day,p<0.01) or CYC group (7.5±9.0mg/day,p<0.01). Mean follow-up after treatment was 44.5 months (IQR 36–120months), 48.6 months (IQR36–120months), and 45.3 (IQR36–120months) for IBCDT, MMF and CYC, respectively. At their last follow-up visit, we observed no significant differences in proteinuria and serum creatinine, nor in the frequency of new flares among the three groups. Conclusion In biopsy proven LN, the IBCDT without further immunosuppressive maintenance therapy was shown to be as effective as conventional regimen of MMF or CYC followed by a 3-year maintenance MMF regimen. Moreover, the use of IBCDT was associated with a marked reduction of glucocorticoid cumulative dose.

Efficacy and safety of an anti‐CD20 monoclonal antibody, rituximab, for lupus nephritis: A meta‐analysis

Article

Nov 2021

Background The efficacy and safety of rituximab (RTX) for lupus nephritis are still a controversial issue. Methods We systematically searched MEDLINE, EMBASE, and the Cochrane Library databases for all clinical controlled studies. Results Six studies with 588 patients were included in our meta-analysis. RTX increased total renal remission rates (TR, odds ratio [OR] 2.16, 95% CI 1.31 to 3.55, P = .003) and complete renal remission rate (CR, OR 2.42, 95% CI 1.18 to 4.94, P = .02) compared with the control group. Subgroup analyses showed that rituximab was more effective at increasing the rate of TR and CR for lupus nephritis patients compared with mycophenolate mofetil (TR, OR 4.6, 95% CI 1.29 to 16.47, P = .02; CR, OR 2.56, 95% CI 1.19 to 5.47, P = .02) and cyclophosphamide (TR, OR 2.89, 95% CI 1.31 to 6.40, P = .009; CR, OR 2.75, 95% CI 1.19 to 6.4, P = .02). Rituximab also had advantage in reducing Systemic Lupus Erythematosus Disease Activity Index score (–2.49, 95% CI –3.77 to –1.22, P = .0001). There were no significant differences between the RTX group and control group on the change of proteinuria (–0.36 g/d, 95% CI –0.71 to –0.00 g/d, P = .05) and serum creatinine (0.13 mg/dL, 95% CI –0.15 to 0.42 mg/dL, P = .36). RTX treatment did not increase the risk of adverse events compared to the control group. Conclusions This study provides clear beneficial effects of RTX in patients with lupus nephritis. In addition, RTX therapy did not increase the risk of adverse events compared to the control group.

POS0695 KZR-616, A SELECTIVE IMMUNOPROTEASOME INHIBITOR FOR THE TREATMENT OF SYSTEMIC LUPUS ERYTHEMATOSUS: RESULTS FROM THE COMPLETED DOSE ESCALATION PHASE 1B PORTION OF THE MISSION STUDY

Article

Jun 2021

Background KZR-616 is a first-in-class selective inhibitor of the immunoproteasome, which is active in >15 autoimmune disease models, including murine models of systemic lupus erythematosus (SLE)/lupus nephritis (LN). 1,2,3 Selective inhibition of the immunoproteasome modulates both innate and adaptive immune effector cells, resulting in reduced inflammatory T helper cell subsets (Th1 and Th17), increased regulatory T cells, and decreased plasma cells and autoantibodies. KZR-616 was well tolerated in two healthy volunteer studies of 100 subjects receiving up to 75 mg subcutaneously (SC). Target levels of immunoproteasome inhibition were observed at doses ≥30 mg. 3,4 KZR-616 is currently in Phase 2 studies for several autoimmune indications, including the ongoing Phase 2 portion of the MISSION Study (KZR-616-002; NCT0339013) in patients with LN. Objectives Results of the completed MISSION Phase 1b dose escalation portion of the study are reported. Methods In the open-label, multicenter, dose escalation Phase 1b portion, SLE patients (per SLICC Classification Criteria) with SLEDAI ≥4 despite stable background immunosuppressant, anti-malarial, and/or corticosteroid therapy were administered weekly KZR-616 subcutaneously at doses of 45 mg (cohort 1), 60 mg (cohort 2), 60 mg following step-up doses of 30 mg and 45 mg (cohort 2a), 60 mg following a step-up dose of 30 mg (cohorts 2b, 2c) or 75 mg following a step-up dose of 30 mg (cohort 3) for 13 weeks with follow-up through Week 25 (W25); a lyophilized formulation was used for cohorts 2b, 2c and 3. The disease activity measures assessed were: SLEDAI-2K, Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI), 28 tender and swollen joint counts, Physician and Patient Global Assessments, and Patient Assessment of Pain. Safety and tolerability were assessed in the safety population (patients receiving at least one dose of KZR-616). Results The Phase 1b portion of MISSION enrolled 47 SLE patients, including 2 patients with active proliferative LN. The most common treatment-emergent adverse events (TEAE) were injection site reactions, which were mostly mild. Infections occurred at a low rate, and there were no reports of peripheral neuropathy, prolonged hematologic AEs, or clinically significant laboratory abnormalities. No discontinuations were observed in cohorts 2b and 2c; no serious AEs were reported in cohort 3 and TEAEs were consistent with those reported in earlier cohorts. Mean values of all measures of disease activity improved in evaluable patients who completed the 13-week treatment period, and improvements were generally maintained at W25. All patients with elevated anti-double-stranded DNA antibody (anti-dsDNA) levels at baseline (n=7) had a reduction in levels with 3 of 7 experiencing a >50% reduction in their levels. Two of two patients with active proliferative LN had a >50% reduction in UPCR and experienced reductions in SLEDAI-2K scores as well as anti-dsDNA levels. Exposure to KZR-616, similar to that reported in healthy volunteers, was dose-proportional across doses, and no accumulation was observed. Conclusion KZR-616 SC, once weekly for 13 weeks up to 75 mg, appears to be safe and well-tolerated in patients with active SLE on stable background therapy in the MISSION Phase 1b. At doses ≥45mg, efficacy was noted, including improvements in proteinuria in two of two patients with LN and serologic improvement in all 7 patients with quantifiable levels of anti-dsDNA antibodies at baseline. KZR-616 60 mg SC weekly for 24 weeks is currently being evaluated in the MISSION Phase 2 in patients with LN. Based on the results of MISSION, inhibition of the immunoproteasome with KZR-616 represents a novel strategy to treat autoimmune diseases. References [1]Basler M et al. Clin Exp Rheumatol 2015 (suppl 92);S74. [2]Muchamuel T et al. Ann Rheumatol Dis 2018;77(suppl 2);685. [3]Muchamuel T et al. ASN 2020 Virtual Conference. [4]Snyder B et al. ACR/ARP 2019 Annual Meeting. [5]Fan RA et al. ACR/ARP 2019 Annual Meeting. Acknowledgements Kezar Life Sciences acknowledges the support of site investigators and patient participants in the MISSION study Disclosure of Interests Richard Furie Consultant of: Genentech;Kezar Life Sciences, Grant/research support from: Kezar Life Sciences, SV Parikh Consultant of: Aurinia Pharmaceuticals, BMS, GlaxoSmithKline, and Kezar Life Sciences, Grant/research support from: Aurinia Pharmaceuticals;EMD-Serono, Jinhai Wang Shareholder of: Kezar Life Sciences, Employee of: Kezar Life Sciences, Darrin Bomba Shareholder of: Kezar Life Sciences, Employee of: Kezar Life Sciences, Richard Leff Employee of: Kezar Life Sciences [part-time], Christopher Kirk Shareholder of: Kezar Life Sciences, Employee of: Kezar Life Sciences -- full-time employee, Noreen Henig Shareholder of: Kezar Life Sciences, Employee of: Kezar Life Sciences

Efficacy and safety of voclosporin versus placebo for lupus nephritis (AURORA 1): a double-blind, randomised, multicentre, placebo-controlled, phase 3 trial

Article

May 2021
LANCET

Background Voclosporin, a novel calcineurin inhibitor approved for the treatment of adults with lupus nephritis, improved complete renal response rates in patients with lupus nephritis in a phase 2 trial. This study aimed to evaluate the efficacy and safety of voclosporin for the treatment of lupus nephritis. Methods This multicentre, double-blind, randomised phase 3 trial was done in 142 hospitals and clinics across 27 countries. Patients with a diagnosis of systemic lupus erythematosus with lupus nephritis according to the American College of Rheumatology criteria, and a kidney biopsy within 2 years that showed class III, IV, or V (alone or in combination with class III or IV) were eligible. Patients were randomly assigned (1:1) to oral voclosporin (23·7 mg twice daily) or placebo, on a background of mycophenolate mofetil (1 g twice daily) and rapidly tapered low-dose oral steroids, by use of an interactive web response system. The primary endpoint was complete renal response at 52 weeks defined as a composite of urine protein creatinine ratio of 0·5 mg/mg or less, stable renal function (defined as estimated glomerular filtration rate [eGFR] ≥60 mL/min/1·73 m² or no confirmed decrease from baseline in eGFR of >20%), no administration of rescue medication, and no more than 10 mg prednisone equivalent per day for 3 or more consecutive days or for 7 or more days during weeks 44 through 52, just before the primary endpoint assessment. Safety was also assessed. Efficacy analysis was by intention-to-treat and safety analysis by randomised patients receiving at least one dose of study treatment. The trial is registered with ClinicalTrials.gov, NCT03021499. Findings Between April 13, 2017, and Oct 10, 2019, 179 patients were assigned to the voclosporin group and 178 to the placebo group. The primary endpoint of complete renal response at week 52 was achieved in significantly more patients in the voclosporin group than in the placebo group (73 [41%] of 179 patients vs 40 [23%] of 178 patients; odds ratio 2·65; 95% CI 1·64–4·27; p<0·0001). The adverse event profile was balanced between the two groups; serious adverse events occurred in 37 (21%) of 178 in the voclosporin group and 38 (21%) of 178 patients in the placebo group. The most frequent serious adverse event involving infection was pneumonia, occurring in 7 (4%) patients in the voclosporin group and in 8 (4%) patients in the placebo group. A total of six patients died during the study or study follow-up period (one [<1%] patient in the voclosporin group and five [3%] patients in the placebo group). None of the events leading to death were considered by the investigators to be related to the study treatments. Interpretation Voclosporin in combination with MMF and low-dose steroids led to a clinically and statistically superior complete renal response rate versus MMF and low-dose steroids alone, with a comparable safety profile. This finding is an important advancement in the treatment of patients with active lupus nephritis. Funding Aurinia Pharmaceuticals.