Monoclonal antibodies for renal diseases: current concepts and ongoing treatments.

Review

Expert Opin. Biol. Ther. Downloaded from informahealthcare.com by University of Otago on 07/02/15 For personal use only.

Monoclonal antibodies for renal diseases: current concepts and ongoing treatments 1.

Introduction

2.

Materials and methods

3.

Monoclonal antibodies

4.

Conclusion

5.

Expert opinion

Domenico Santoro†, Vincenzo Pellicano`, Luca Visconti, Gianluca Trifiro`, Valeria Cernaro & Michele Buemi †

University of Messina, Department of Internal Medicine and Pharmacology, Messina, Italy

Introduction: In recent years, technological innovations in the field of molecular biology have provided new therapeutic options. In particular, human monoclonal antibodies (mAbs), initially used in the treatment of malignancies, have become a therapeutic tool for many other diseases. Most of the application of mAbs revealed encouraging findings to treat patients with immune-mediated glomerular diseases, for whom the standard protocols based on corticosteroids and non-specific immunosuppressants with heavy side effects have for decades been the only therapies. Area covered: Rituximab, an mAb directed against a specific antigen expressed on B lymphocytes, CD20 antigen, inducing a premature cell apoptosis became very important in the treatment of membranous glomerulonephritis, steroid-resistant nephrotic syndromes and membranoproliferative glomerulonephritis (MPGN). Another important mAb, eculizumab, is used successfully for treatment of atypical hemolytic uremic syndrome, C3 nephropathy and MPGN. Many other mAbs are now under premarketing investigation, such as adalimumab, daclizumab, fresolimumab, belimumab, tocilizumab, although some of these mAbs are already approved for different medical applications. Expert opinion: The availability of novel mAb may therefore constitute the basis for a revolution in the treatment of immune-mediated renal diseases. However, the cost for this therapy remains very high and represents a barrier for its widespread use. Keywords: glomerulonephritis, monoclonal, proteinuria, renal disease Expert Opin. Biol. Ther. [Early Online]

1.

Introduction

Many discoveries in the field of medicine have revolutionized the management of many chronic diseases, once considered fatal or difficult to treat. Among these, targeted immunotherapy certainly changed the face of Medicine as it was known. The concept of targeted immunotherapy was born in the first half of the twentieth century, when Paul Ehrlich had the brilliant idea of using monoclonal antibodies (mAbs) in the treatment of cancer. The first significant breakthrough came in 1975, when an innovative immunology technique was introduced: the ‘hybridoma’, described by Cesar Milstein and Georges K€ohler, responds to the possibility of producing a virtually unlimited quantity of identical and specific antibodies targeted to a single antigen called human mAbs or hmAbs [1]. Nowadays, we refer to targeted immunotherapy in case of treatment of diseases which determine induction, augmentation or suppression of the immune response based on the application of (h) mAbs. In particular, targeted immunotherapy exploits the ability of mAbs to bind irreversibly and specifically a molecular target, either as free protein or as a structure present on the cell surface, thus creating a 10.1517/14712598.2015.1045870 © 2015 Informa UK, Ltd. ISSN 1471-2598, e-ISSN 1744-7682 All rights reserved: reproduction in whole or in part not permitted

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D. Santoro et al.

Article highlights. .


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Human mAbs are specific antibodies targeted to a single antigen, either a free protein or a structure present on the cell surface. The binding between antibody and antigen is irreversible and results in the removal of the latter by the immune system. Initially, immunotherapy based on the use of mAbs has been developed for cancer treatment. Recently, its therapeutic indications have been potentially extended to the management of many immune-mediated diseases, including those affecting the kidney. This would allow to reduce the use and then the side effects of long-term therapy with steroids and other immunosuppressants. There is evidence of beneficial effects of rituximab in some glomerular diseases including membranous nephropathy, multi-relapsing minimal change disease and focal segmental glomerulosclerosis as well as in other autoimmune renal diseases (ANCA-associated vasculitis, lupus nephritis, mixed cryoglobulinemia). Eculizumab has been proved to be effective in the treatment of atypical hemolytic uremic syndrome, and it is currently under investigation in patients with C3 nephropathy and membranoproliferative glomerulonephritis. Some mAbs showed negative results (e.g., infliximab in ANCA-associated vasculitis or tocilizumab in lupus nephritis), whereas others (adalimumab, belimumab, fresolimumab and abatacept) seem to be beneficial in different glomerular diseases, especially in reducing proteinuria, as reported in small studies.

clinical trials from Phase I to Phase IV, on the efficacy and safety of biological drugs, specifically mAb-based therapies in the treatment of kidney disease, and to highlight the importance of identifying new therapeutic strategies as an alternative to standard therapies currently in use, as well as future prospects in this field of pharmacology. 2.

Materials and methods

Clinical studies were selected from the database of ClinicalTrials.gov, including all clinical trials, randomized and nonrandomized, open-label and blinded, placebo-controlled and single group assignment, both in progress and completed (Table 1). For the selection of the studies, a stepwise approach has been adopted as described in detail below. First phase: cross-search We performed the research through May 2014, therefore, all the results reported pertain to this date. In the database ClinicalTrials.gov, we have included the following keywords: 2.1

. renal; renal disease; chronic kidney disease; glomerular

disease; glomerulonephritis; syndrome; . monoclonal; biological,

nephritis;

nephrotic

This box summarizes key points contained in the article.

stable interaction that stimulates the immune system to attack and eliminate mAb targets. Over time, targeted immunotherapy has developed rapidly, especially with regard to its clinical use. Initially, targeted immunotherapy based on the use of mAbs has been developed as a possible cancer therapy. Recently, it became clear that mAbs possess multiple clinically relevant mechanisms of action, employable not only against cancer, but also against systemic diseases mediated by the immune system. Classically, in patients with chronic renal failure the therapy against the underlying renal disease was based on the use of corticosteroids and immunosuppressive drugs such as cyclophosphamide, azathioprine, cyclosporine, tacrolimus and mycophenolate mofetil. Such therapies expose the patient to the risk of relapsing and to potentially severe side effects, in particular for long-term corticosteroid therapy. The immunomodulatory properties of mAbs therefore may constitute the basis for new therapeutic strategies in many diseases. In some cases, mAbs, such as eculizumab or rituximab, have already replaced the traditional therapeutic approach based on corticosteroids, immunosuppressants and plasmapheresis. The aim of this task was to select ongoing and completed 2

which have been appropriately crossed with each other and entered into the search engine. These keywords were selected to be as closely as possible specific and selective to pursue our aim. Each association has produced a number of results of clinical trials related to those keywords; below, we list the associated keywords and the number of studies obtained: . . . . . . . . . . . . . .

renal -- biological: 897 renal disease -- biological: 830 chronic kidney disease -- biological: 197 glomerular disease -- biological: 29 glomerulonephritis -- biological: 14 nephritis -- biological: 20 nephrotic syndrome -- biological: 4 renal -- monoclonal: 196 renal disease -- monoclonal: 170 chronic kidney disease -- monoclonal: 28 glomerular disease -- monoclonal: 9 glomerulonephritis -- monoclonal: 7 nephritis -- monoclonal: 9 nephrotic syndrome -- monoclonal: 2

We were aware about a new employment of a specific mAb to treat some renal diseases: adalimumab. For this reason, we made out a new additional research to include adalimumab in our work, using the following keywords: ‘renal’ and

Expert Opin. Biol. Ther. (2015) 15(8)

Monoclonal antibody for renal disease

‘adalimumab’. Two clinical trials were obtained from this research and included in this paper: . renal -- adalimumab: 2

Second phase: selection A total of 2414 studies were obtained from the research, each of which has been analyzed in order to evaluate its suitability for the purpose of our work. We excluded studies that, in the various cross-searches, were repeated in others. Afterwards, trials which did not investigate the use of mAbs in the treatment of renal diseases were not considered. See Figure 1 for details on exclusion criteria. Out of the 2414 studies obtained by the initial cross-search, we selected only 32 studies that fulfilled the inclusion criteria of our research. Of these, only 17 have been completed while two (infliximab [ClinicalTrials.gov ID: NCT00368264] and ocrelizumab [ClinicalTrials.gov ID: NCT00626197]) were interrupted before completion (Table 1). Other 13 studies are still in progress at various stages of premarketing studies. Among the 17 completed studies, 5 were not available for consultation in any scientific site (PubMed, Google Scholar and others) (see Figure 1 for details).


2.2

Third phase: data synthesis A summary table has been drafted, in which all data regarding found trials have been reported. Table 1 lists all the 32 studies obtained from the second phase: each section of the table includes all studies related to their specific mAb. For each study, the most important parameters for the description of the trial have been highlighted. In the next section of paper, for each mAb a brief paragraph has been written, in which the most important pharmacological characteristics, relative studies, actual clinical applications and clinical trials have been reported. 2.3

3.

Monoclonal antibodies

Rituximab Rituximab is a chimeric mAb directed against the CD20 antigen, a ‘cluster of differentiation’ present on B cells and involved in cell cycle regulation, differentiation and activation of B-lymphocytes. Binding to this lymphocyte receptor in turn leads to a ‘down-regulation’ of the receptor and induction of apoptosis of CD20+ cells. In clinical practice, rituximab has been primarily used in the treatment of B-cell malignancies such as follicular lymphoma, widespread large B-cell lymphoma and chronic lymphocytic leukemia. However, due to its action on B cells, it also proves to be effective in the treatment of autoimmune cytopenias such as idiopathic thrombocytopenic purpura and hemolytic anemia, vasculitis and multiple sclerosis. Rituximab 3.1

was used as prophylaxis of transplant rejection, and in the treatment of Epstein--Barr virus-mediated complications [2]. The significant depletion of B cells, induced by rituximab treatment, triggered research to move towards the development of drugs for the treatment of kidney disease of autoimmune origin or with immune-mediated pathogenesis [3]. The studies and trials currently evaluating the effects of rituximab in nephrology include various renal diseases such as idiopathic membranous nephropathy (IMN), minimalchange disease (MCD), focal and segmental glomerulosclerosis (FSGS), renal involvement in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, childhood-onset, complicated, frequently relapsing nephrotic syndrome (FRNS) and steroid-dependent nephrotic syndrome (SDNS). The effect of rituximab has been studied in patients affected by IMN. Traditional regimens to treat IMN have included cyclophosphamide and cyclosporine in conjunction with corticosteroids, but all of these agents are characterized by significant toxicity. Recently, the M-type phospholipase A2 receptor (PLA2R) has been identified as a major antigenic target in IMN [4]. Autoantibodies directed against PLA2R are sensitive and specific for IMN. The anti-B-cell agent rituximab is a promising therapy for this disease, but biomarkers of early response to treatment currently do not exist. The study ‘Rituximab-Induced Depletion of Anti-PLA2R Autoantibodies Predicts Response in Membranous Nephropathy’ aimed at demonstrating that anti-PLA2R, as a potential marker of the immunological activity of IMN, might exhibit a different and more rapid response to rituximab treatment than clinical parameters such as proteinuria. The amount of anti-PLA2R was measured using western blot immunoassay in serial serum samples from a total of 35 patients treated with rituximab for membranous nephropathy in two distinct cohorts. Pretreatment samples from 25 of 35 (71%) patients contained anti-PLA2R, and these autoantibodies declined or disappeared in 17 (68%) of these patients within 12 months after rituximab administration. Those who demonstrated this immunologic response fared clinically better: 59 and 88% attained complete or partial remission by 12 and 24 months, respectively, compared with 0 and 33% among those with persistent anti-PLA2R levels. Changes in antibody levels preceded changes in proteinuria. One subject who relapsed during follow-up had a concomitant return of antiPLA2R. In summary, measuring anti-PLA2R levels by immunoassay may be a method to follow and predict response to treatment with rituximab in membranous nephropathy [5]. Rituximab effect on IMN was also evaluated by two other different groups of researchers. In 2012, Ruggenenti et al. demonstrated the beneficial effect of rituximab in 100 patients with membranous nephropathy treated with the mAb after a mean follow-up of 29 months. A response rate of 65% with a median time to response of 7 months was observed [6]. Fervenza et al. reported positive results with rituximab in another observational study conducted in North America.


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D. Santoro et al.

Table 1. Table of medical trials on new biological therapies for renal diseases. Pharmaceutical Trial category and drug


Rituximab

Drug administration period

Design

No. of patients

Inclusion criteria

NCT00748644 MAINRITSAN: Study of the efficacy of rituximab for maintenance treatment in systemic ANCAassociated vasculitis: prospective, multicenter, controlled, randomized comparative study of rituximab versus azathioprine

1) Rituximab: 500 mg doses for a total of 5 infusion plus 1 mg/kg/day of corticosteroids; 2) Azathioprine 2 mg/kg/day for 12 months plus 1 mg/kg/day of corticosteroids

Phase III, interventional randomized, open-label, parallel assignment efficacy study

117

1) Wegener’s granulomatosis or microscopic polyangiitis complying or kidney-limited disease with or without detectable ANCA; 2) Achieved remission using a treatment combining corticosteroids and an immunosuppressive agent according to current French guideline 3) Age between 18 and 65 years

NCT01731561 Comparison study of two rituximab regimens in the remission of ANCA associated vasculitis (MAINRITSAN 2)

1) Rituximab (arm A): infusion will be performed at days 1 and 15, months 6, 12 and 18 (i.e., a total of 5 infusions), at the dose of 500 mg at a fixed dosage; 2) Rituximab (arm B): infusion will be performed at day 1, patients will receive new 500 mg rituximab infusions either if CD19 are > 0/mm3, or if ANCA are positive again or if ANCA titer significantly raises every 3 months Rituximab 375 mg/m2 intravenous infusion, 1 ml/kg/h, progressively increased up to 4 ml/kg/h according to drug tolerability

Phase III, interventional, randomized, parallel assignment, Open-label study

166

1) Granulomatosis with polyangiitis or microscopic polyangiitis complying or kidney-limited disease with or without detectable ANCA at the time of diagnosis or relapse, and at remission

Phase III, interventional, single group assignment, open-label study

20

1) Histological diagnosis of MCD or FSGS or mesangial proliferative GN; 2) Steroid-dependent or multirelapsing NS

NCT00981838 NEMO: a prospective, sequential study to assess the efficacy of rituximab therapy in maintaining remission of NS after steroid and immunosuppressive therapy withdrawal in patients with steroiddependant or multirelapsing minimal change disease or FSGS NCT00275613 Pilot study The rituximab dose is 1000 mg (1 g) of rituximab for MPGN given as an i.v. infusion every 2 weeks for 2 doses (days 1 and 15)

NCT00556192 Can targeted elimination of B-cell depletion therapy and/or combination therapy restore peripheral B-cell abnormalities in SLE?

1) Rituximab of 1000 mg given 2 weeks apart; methylprednisolone 250 mg i.v. be given followed by prednisolone 30 mg/day; 2) Rituximab of 1000 mg given 2 weeks apart; methylprednisolone 250 mg i.v. be given followed by prednisolone 30 mg/day; cyclophosphamide 500 mg/m2; 3) Cyclophosphamide (50 -- 100 mg/ day); azathioprine (up to 2.5 mg/kg/ day) for maintenance up to 12 months; oral prednisolone 0.5 mg/ kg/day (up to 30 mg daily) for 4 weeks, tapered by 5 mg every 2 weeks thereafter until 5 mg/day for the rest of the study period

10 Phase I, interventional single group assignment, open-label study

1) MPGN biopsy-proven; 2) Urinary protein to creatinine ratio > 1.0 in a 24-h urine collection; 3) Systolic blood pressure < 140 mmHg for at least 75% of readings (3 months before the enrollment); 4) GFR ‡ 25 ml/min

Phase II, interventional, randomized, parallel assignment, double-blind study

1) Biopsy confirmed active proliferative LN; 2) Proteinuria ‡ 2g/day; 3) Elevated anti-double-stranded (anti-dsDNA) level at BL; 4) Activity index of ‡ 6

20

The new terminology for “Wegener’s granulomatosis” adopted in May 2011 is “granulomatosis with polyangiitis (GPA)”. ACR: American College of Rheumatology; AE: Adverse event; anti-dsDNA: Anti-double-stranded; aHUS: Atypical hemolytic uremic syndrome; ANA: Antinuclear remission; CRR: Complete renal response; DDD: Dense deposit disease; FSGS: Focal segmental glomerulosclerosis; ISN/RPS: International Society of Nephrology/Renal glomerulonephritis; NS: Nephrotic syndrome; PD: Pharmacodynamics; PK: Pharmacokinetics; p.o.: By mouth; PR: Partial remission; PRR: Partial renal response; producing Escherichia coli hemolytic-uremic syndrome; TMA: Thrombotic microangiopathy; uPCR: Urinary protein/creatinine ratio.

4



Outcome measures

Objectives or hypothesis

Date Start


Primary: Number of major relapse (BVAS > 10) in each group at the end of the maintenance treatment Secondary: mortality rate, number of minor relapses

Primary: Number of relapses at 28 months

Comparison between azathioprine (conventional therapy) and rituximab in patients with systemic ANCA-associated vasculitis, in remission (achieved with an induction treatment combining corticosteroids and an immunosuppressant, mainly intravenous pulses of cyclophosphamide, and plasma exchanges and/or polyvalent immunoglobulins when indicated) after the first flare of the disease (new diagnosis) or after a relapse The aim of this study is to assess the efficacy of a rituximab regimen based on rate of ANCA and CD19 lymphocytes for maintenance treatment in systemic ANCA-associated vasculitis

To be finished

October 2008

November 2012

February 2018

Status

Result

June 2013

This study has been completed

No study results posted on ClinicalTrials.gov Results found on PubMed

No

This study is ongoing, but not recruiting participants

No study results posted on ClinicalTrials.gov for this study

April 2011



No study results posted on ClinicalTrials.gov for this study Results found on PubMed No study results posted on ClinicalTrials.gov for this study

Completed

Primary: Recurrence of NS (time frame: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months) Secondary: The dose of immunosuppressive therapy to prevent further NS relapses

The study is primarily aimed at evaluating April 2009 whether rituximab may maintain stable NS remission after tapering and withdrawal of steroid and immunosuppressive therapy in patients with MCD or FSGS and steroiddependent or multirelapsing NS

Primary: change in urinary protein excretion at 6 months Secondary: changes in the GFR, in SCr, in urinary protein excretion at 3, 9 and 12 months

Selective B lymphocyte depletion will result in disappearance of pathogenic antibodies and induce remission of proteinuria in patients with idiopathic MPGN

November 2005

March 2009


Primary (at week 48): 1) eGFR > 90 mil/min/1.73 m2; 2) Urinary protein:; 3) Urinary creatinine ratio < 0.2; 4) Inactive urinary sediment

Evaluate the safety and efficacy of antiCD20 mAb, rituximab, used as 1. monotherapy, 2. in combination with cyclophosphamide, in the treatment of proliferative LN, as compared with standard immunosuppressive therapy with cyclophosphamide and azathioprine

June 2006

December 2009


antibody; ANCA: Anti-neutrophil cytoplasmic antibody; aPL: Antiphospholipid; b.i.d.: Twice a day; BL: Baseline; CKD: Chronic kidney disease; CR: Complete Pathology Society; i.v.: Intravenous; LN: Lupus nephritis; MCD: Minimal-change disease; MMF: Mycophenolate mofetil; MPGN: Membranoproliferative PT: Plasma therapy; SLE: Systemic lupus erythematosus; SAE: Serious adverse events; s.c.: Subcutaneous; Scr: Serum creatinine; STEC-HUS: Shiga-toxin


5

Table 1. Table of medical trials on new biological therapies for renal diseases (continued). Pharmaceutical Trial category and drug


Design

No. of patients

Inclusion criteria

1) Rituximab: 1 cycle of rituximab (4 i.v. infusions): day 0: 375 mg/m2 day 7: 375 mg/m2 day 14: 375 mg/m2 day 21: 375 mg/m2; 2) Rituximab (2 cycles): first cycle of rituximab (4 i.v. infusions): day 0: 375 mg/m2 day 7: 375 mg/m2 day 14: 375 mg/m2 day 21: 375 mg/m2 Second cycle of rituximab (4 i.v., infusions, 6 months later) 1) Rituximab, 1000 mg intravenously on days 1, 15, 168 and 182; 2) Placebo

Phase III, interventional, randomized, parallel assignment, open-label study

36

1) Patient with active LN, previously treated with cyclophosphamide and mycophenolate (sodium or mofetil), who have not received rituximab in the previous year; 2) Age between 18 and 70 years

Phase III, interventional, randomized, parallel assignment, double-blind treatment study

144

1) Diagnosis of SLE; 2) Diagnosis of ISN/RPS 2003 class III or IV LN, with either active or active/chronic disease 3) Proteinuria; 4) Age between 16 and 75 years

Rituximab infused i.v. on day 1 and day 15 at a dose of 375 mg/m2 up to a maximum of 1000 mg per dose in children and at a dose of 1000 mg on day 1 and day 15 in adults

Phase II, interventional, single group assignment, open-label study

20

1) FSGS involving native kidneys with a diagnostic biopsy performed within the last 3 years; 2) Proteinuria ‡ 3.0 g 3) eGFR > 40 ml/min; 4) Age between 6 and 80 years

NCT00626197 A randomized, doubleblind, placebo controlled, parallel-group, multicenter study to evaluate the efficacy and safety of two doses of ocrelizumab in patients with WHO or ISN class III or IV nephritis due to SLE NCT01221181 Eculizumab therapy for DDD and C3 nephropathy

1) Ocrelizumab, studied in two doses: 400 mg and 1 g

Phase III, interventional, randomized, parallel assignment double-blind treatment study

381

1) Age 16 years or above; 2) Diagnosis of SLE; 3) Active LN

Eculizumab 900 mg i.v. one a week for 4 weeks, 1200 mg i.v. week 5, then 1200 mg i.v. every 2 weeks through week 53

Phase I, interventional, non-randomized, single group assignment, open-label study

Not specified

1) Biopsy-proven DDD or C3 nephropathy; 2) Age > 18 3) Proteinuria > 1000 mg/day 4) uPCR > 1.0

NCT01410916 Safety and efficacy study of eculizumab in STEC-HUS

Eculizumab 300, 600, 900 or 1200 mg will be administered intravenously

Phase II and Phase III, interventional, single group assignment, open-label study

Not specified

1) Patient has been diagnosed with STEC-HUS; 2) Age > 2 months (body weight > 5 kg)


NCT01765842 Comparison of the efficacy of two rituximab treatment regimens in patients with lupus nephropathy resistant to conventional treatments

NCT00282347 LUNAR: A Phase III, randomized, double-blind, placebocontrolled, multicenter study to evaluate the efficacy and safety of rituximab in subjects with ISN/RPS class III or IV LN NCT01573533 A pilot study to assess the efficacy of rituximab therapy in patients with treatment resistant idiopathic FSGS: Integrating an assessment of the relevance of soluble urokinase receptor and activation of podocyte b3 integrin

Ocrelizumab

Eculizumab



Outcome measures


Date

Status

Result

Start

To be finished

Completed

December 2015

No

This study is currently recruiting participants


January 2013



No



No

The study was suspended early

No study results posted on ClinicalTrials.gov Partial results found on PubMed

No


No study results posted on ClinicalTrials.gov

June 2012



Primary: 1) (GFR) ‡ 60; 2) Proteinuria £ 0.5 g/24 h; 3) Serum albumin > 3 g/ dl; 4) Inactive urine sediment

The hypothesis is that the alternative procedure (a second cycle of rituximab) will reduce the relapse rate of LN and the consequent deterioration of renal function. Besides it will reduce health care expenses (hospitalization, medication, hemodialysis and renal transplantation)

November 2012

Primary: Percentage of Participants Who Achieved a Complete Renal Response (CRR), a Partial Renal Response (PRR), or no Renal Response (NRR) at Week 52

A study to evaluate the efficacy and safety of rituximab in combination with mycophenolate mofetil (MMF) compared with placebo in combination with MMF in subjects diagnosed with ISN/RPS 2003 class III or IV LN

January 2006

Primary: changes in proteinuria (at 12 months) defined as: Complete remission (proteinuria < 0.5 g/day) Partial remission (improvement in proteinuria by > 50% and to a level between 0.5 and 3.5 g/day) Incomplete remission (improvement in proteinuria equal to or > 50%, but residual proteinuria still > 3.5 g/day) Primary: achievement of a CRR or a PRR

The purpose of this study is to determine whether rituximab therapy is safe and effective in treating patients with the kidney condition, FSGS, which is no longer responsive to traditional therapies

October 2013

Study designed to evaluate the efficacy and safety of ocrelizumab added to SOC (corticosteroid plus one of two immunosuppressant regimens) compared with placebo added to SOC in patients with WHO or ISN class III or IV LN

February 2008

August 2010 The goals will be to determine whether Primary: number of treatment leads to an improvement in subjects with complete remission of proteinuria, up kidney function, defined by remissions of proteinuria and improvements in eGFR to 1 year after therapy and to improvement in histologic Secondary: change in parameters, including percentage of nonproteinuria level up to 1 affected glomeruli, interstitial fibrosis, year after therapy intensity of C3 staining of immunofluorescence and amount of electron dense deposits by electron microscopy This protocol is designed to collect safety July 2011 Primary: improvement in systemic TMA & vital organ and efficacy data on patients who have involvement at 8 weeks of been or will be treated with eculizumab treatment defined as either for STEC-HUS, in the context of the 2011 STEC-HUS epidemic in Germany complete or partial responder based on hematologic normalization /improvement & clinically important improvement in vital organs: brain, kidney and thrombosis

November 2015

December 2015


Table 1. Table of medical trials on new biological therapies for renal diseases (continued).


Pharmaceutical Trial category and drug


Design

No. of patients

Inclusion criteria

NCT01770951 A retrospective, observational, non-interventional trial to assess eculizumab treatment effect in patients with aHUS

Not specified

Retrospective, observational, non-interventional trial

30

1) Male or female patients of any age who have been diagnosed with aHUS; 2) Received at least one dose of eculizumab for the treatment of aHUS between 2007 and 2009 outside this controlled clinical trial

NCT00838513 An openlabel, multicenter controlled clinical trial of eculizumab in adult patients with plasma therapy-sensitive aHUS

Eculizumab Intravenously administered 900 mg once per week for 4 weeks, 1200 mg on week 5 then 1200 mg every 2 weeks thereafter

Phase II, interventional, non-randomized, single group assignment, open-label study

15

1) Male or female patients ‡ 18 years of age who have been diagnosed with aHUS; 2) Patients must be receiving PT for aHUS and must be observed to receive ‡ 1 PT treatment every 2 weeks and no more than 3 PT treatments/week (at an unchanged frequency) for at least 8 weeks before first dose of eculizumab

NCT00844545 An openlabel, multicenter controlled clinical trial of eculizumab in adult patients with plasma therapy-sensitive aHUS



16

1) Male or female patients ‡ 18 years of age who have been diagnosed with aHUS; 2) Screening platelet count, < 150 109/l and at least 25% lower than the average remission platelet count

NCT00844844 An openlabel, multicenter controlled clinical trial of eculizumab in adolescent patients with plasma therapy-resistant aHUS



1

NCT00844428 An openlabel, multicenter controlled clinical trial of eculizumab in adolescent patients with plasma therapy-sensitive aHUS



5

1) Male or female patients from 12 and up to 18 years weighing ‡ 40 kg who have been diagnosed with aHUS; 2) Screening platelet count, < 150 109/l and at least 25% lower than the average remission platelet count 1) Male or female patients from 12 and up to 18 years weighing ‡ 40 kg who have been diagnosed with aHUS; 2) Patients must be receiving PT for aHUS and must be observed to receive ‡ 1 PT treatment every 2 weeks and no more than 3 PT treatments/week (at an unchanged frequency) for at least 8 weeks before first dose of eculizumab

1) Patient body weight ‡40 kg: initial phase 900 mg weekly 4 and maintenance phase 1200 mg at week 5; then 1200 mg every 2 weeks; 2) Patient body weight 30 < 40 kg : initial phase 600 mg weekly 2 and maintenance phase 900 mg at week 3; then 900 mg every 2 weeks NCT01665391 A study of 1) Fresolimumab 1 mg/kg total body fresolimumab in patients weight administered i.v.; 2) Fresolimumab 4 mg/kg total body with steroid-resistant weight administered i.v.; 3) Placebo primary FSGS administered to match active treatment group

Phase II, interventional, single group assignment, open-label study

10 patients

1) Biopsy-proven primary MPGN; 2) Creatinine clearance > 20 ml/min 3) Proteinuria persistently exceeding 3.5g in adults or exceeding 40 mg/h/m2 in children; 4) Persistently low C3 levels and high C5 levels in at least two consecutive evaluations

Phase II, multicenter, double-blind, parallel dosing, randomized study

Not specified

1) Biopsy-proven diagnosis of primary FSGS including all histological subtypes; 2) eGFR ‡ 30 ml/min 3) Urinary total protein/creatinine ratio ‡ 3 mg protein/mg creatinine

NCT02093533 Evaluating the morphofunctional effects of eculizumab in MPGN

Fresolimumab


Outcome measures


Date


Start

Primary: Overall safety and tolerability of eculizumab based on adverse events of special interest/adverse drug reactions and additional adverse events, through 26 weeks Primary: TMA event-free status is defined as the absence for at least 12 weeks of 1) decrease in platelet count of > 25% from the platelet count pre-PT BL set point; 2) PT while the patient is receiving eculizumab and; 3) new dialysis Secondary: PK and PD of eculizumab in patients with aHUS Primary: assess the effect of eculizumab to reduce TMA as measured by platelet count change from BL during the treatment period (26 weeks) in patients with PT-resistant aHUS (protocol defined) Primary: assess the effect of eculizumab to reduce TMA as measured by platelet count change from BL during the treatment period (26 weeks) Primary: Assess the effect of eculizumab on TMA event-free status (26 weeks) defined as the absence for at least 12 weeks of 1) decrease in platelet count of > 25% from the platelet count pre-PT BL set point; 2) PT while the patient is receiving eculizumab, and; 3) new dialysis Assess the effect of eculizumab to reduce TMA as assessed by hematologic normalization Primary: proteinuria changes from BL at weeks 1, 12, 24, 36, 48 and 72 Secondary: terminal complement complex (sC5b-9) levels, GFR and time to disease progression Primary: percentage of patients achieving PR or CR in urinary protein Secondary: number of patients reporting AEs, SAEs and medical events of interest

To be finished

Status

Result

Completed

The objective of this retrospective trial is to assess safety and efficacy of eculizumab in aHUS patients treated outside of an Alexion-sponsored controlled clinical trial

August 2009

November 2010



The purpose of this study is to determine whether eculizumab is safe and effective in the treatment of adult patients with plasma therapy-sensitive aHUS.

July 2009

December 2013



The purpose of this study is to determine whether eculizumab is safe and effective in the treatment of adult patients with plasma therapy-resistant aHUS

May 2009

July 2013



The purpose of this study is to determine whether eculizumab is safe and effective in the treatment of adolescent patients with plasma therapy-resistant aHUS.

July 2009

December 2013



The purpose of this study is to determine whether eculizumab is safe and effective in the treatment of adolescent patients with plasma therapy-resistant aHUS

May 2009

July 2013



In recent case reports eculizumab, an mAb that binds to C5 to prevent formation of the membrane attack complex, is a safe and effective therapy

March 2014

March 2016

No



Compare the achievement of a PR or CR in urinary protein:creatinine ratio in patients treated with fresolimumab versus placebo and compare the safety profile of patients treated with fresolimumab versus placebo

August 2012

June 2014

No






1) Fresolimumab 1 mg/kg, i.v. infusion on day 0 and monitored over 24 h. Post-infusion for safety up to 112 days; 2) Fresolimumab 2 mg/ kg, i.v. infusion on day 0 and monitored over 24 h. Post-infusion for safety up to 112 days; 3) Fresolimumab 4 mg/kg, i.v. infusion on day 0 and monitored over 24 h. Post-infusion for safety up to 112 days; 4) Fresolimumab 0.3 mg/kg, i.v. infusion on day 0 and monitored over 24 h. Post-infusion for safety up to 112 days NCT00753103 Study to Infliximab 5 mg/kg i.v. infusion at investigate the safety and weeks 0, 2, 6 and 10 of study PLUS efficacy of infliximab as standard immunosuppressive therapy additional therapy in the treatment if ANCAassociated vasculitis


NCT00464321 Safety study of GC1008 (fresolimumab) in patients with FSGS of single doses of GC1008 in patients with treatment-resistant idiopathic FSGS

Infliximab

BIIB023

Daclizumab

Belimumab

Design

No. of patients

Inclusion criteria

Phase I, interventional, non-randomized, single group assignment, open-label study

16

1) GFR ‡ 25 ml/min; 2) Urinary total protein: creatinine ratios > 200 mg/mmol; 3) Biopsy confirmed as idiopathic FSGS

Phase II, interventional, non-randomized, parallel assignment, open-label study

37

.Either newly diagnosed or relapsed ANCA-associated vasculitis (Wegener’s granulomatosis, microscopic polyangiitis, renal limited vasculitis

NCT00368264 AntiTNF-a chimeric mAb (infliximab) and azathioprine in patients suffering from SLE with WHO class V glomerulonephritis

1) Azathioprine; (2 mg/kg) plus four infusions of infliximab (5 mg/kg) 2) Azathioprine (2 mg/kg) plus four placebo infusions

Phase II and III, Not double-blind, ran- specified domized, placebo-controlled, multicenter trial

1) SLE (ACR criteria fulfilled) with biopsy-proven membranous glomerulonephritis (WHO class V); 2) Proteinuria > 3 g/day) 3) SCr: 1.5 times the upper limit of normal range

NCT01499355 ATLAS: a study to evaluate the efficacy, safety, and tolerability of BIIB023 in subjects with LN

Background therapy including oral steroids (prednisone or equivalent) and mycophenolate mofetil PLUS: 1) i.v. infusion of BIIB023 low dose; 2) i.v. infusion of BIIB023 high dose; 3) i.v. infusion of placebo

Phase II, interventional, multicenter, randomized, doubleblind, placebocontrolled study

Not specified

Documented diagnosis of SLE according to current ACR criteria. At least 4 ACR criteria must be documented, 1 of which must be a positiveANA, anti-Sm, or anti-dsDNA antibody

NCT01930890 Study to evaluate the long-term safety, efficacy, and immunogenicity of BIIB023 in subjects with LN NCT00040248 A randomized trial examining the use of daclizumab in Wegener’s granulomatosis

1) BIIB023 (other name: anti-TWEAK [TNF-related Weak Inducer of Apoptosis]) low dose (3 mg/kg) or high dose (20 mg/kg) i.v. infusion

Phase II, a doseblinded, 2-dose level, parallelgroup, multicenter, long-term extension study Phase II, interventional

175 (estimated)

Patients who completed study ‘ATLAS’ through week 52 and did not discontinue BIIB023 or placebo

75

NCT01639339 Study to evaluate the efficacy and safety of belimumab plus standard of care versus placebo plus standard of care in adult subjects with active LN

1) Belimumab plus standard therapy; belimumab administered 10 mg/kg on days 0, 14, 28 and then every 28 days thereafter through week 100; 2) Placebo plus standard therapy

1) Diagnosis of Wegener’s granulomatosis based on clinical characteristics and histopathologic and/or angiographic evidence of vasculitis; 2) Age 18--75 years 3) Presence of glomerulonephritis defined by red blood cell casts and proteinuria or renal biopsy showing necrotizing glomerulonephritis in the absence of immune deposits 1) Clinical diagnosis of SLE by ACR criteria; 2) Biopsy confirmed active LN; 3) Autoantibody-positive

Daclizumab, 1 mg/kg i.v. on day 0, week 2, week 4 and every month thereafter for a total of 18 months (20 doses)

Phase III, 464 randomized, double-blind, placebo-controlled, parallel assignment study


Outcome measures


Date


Start

To be finished

Status

Result

Completed

Primary: To determine safety and tolerability of single dose infusions of GC1008 in patients with treatment-resistant idiopathic FSGS and nephrotic range proteinuria up to 2 years

This study will investigate whether May 2007 GC1008, an antibody which neutralizes TGF-b, is safe in treating patients with the disease called FSGS. The highest dose without excessive side effects will be investigated. Tests will determine how long GC1008 is in the body and how it is excreted

February 2010



Primary: Time to clinical remission (Birmingham Vasculitis Activity Score 0 or 1)

The purpose of this study is to determine whether infliximab (monoclonal antiTNF-a antibodies) are safe and effective in the treatment of ANCA-associated vasculitis

January 2003

July 2006


Primary: Comparison of time needed to reduce proteinuria to 1.5 g/day or less between the infliximab plus azathioprine and the azathioprine-only group

The combination of four infusions of infliximab with azathioprine will be faster than azathioprine alone in reducing proteinuria to < 1.5 g/day in patients with active LN WHO class V (proteinuria > 3 g/day)

September 2006

June 2009

Primary: proportion of subjects who achieve renal response (complete or partial) at week 52; Secondary: proportion of subjects with uPCR > 3.0 mg/mg at day 1, who achieve uPCR < 1.0 mg/mg at week 52

The primary objective of the study is to assess the efficacy of BIIB023 as an addon treatment to background therapy compared with placebo in combination with background therapy in the treatment of subjects with active, biopsyproven LN Subjects who complete this study through week 52 will be offered the option to enter an extension study under a separate protocol This is an extension study for all participants who completed study ‘ATLAS’ through week 52 and did not discontinue BIIB023 or placebo

July 2012

September 2016

No

Interrupted before completion (failure to recruit patients with membranous LN not previously treated with azathioprine) This study is currently recruiting participants

No study results posted on ClinicalTrials.gov for this Study Results found on PubMed No study results posted on ClinicalTrials.gov for this study

November 2013

January 2019

No

Enrolling by invitation


May 2005



No



Primary: number of participants that experience AEs and SAEs

Not provided

Primary: Number of participants with a renal response at week 104

This study will examine the safety and effectiveness of daclizumab (also called Zenapax or anti-CD25) in patients with Wegener’s granulomatosis, a type of vasculitis (blood vessel inflammation). Wegener’s granulomatosis can affect many parts of the body, including the brain, nerves, eyes, sinuses, lungs, kidneys, intestinal tract, skin, joints, heart and other sites The purpose of this study is to evaluate the efficacy, safety and tolerability of belimumab in adult patients with active LN

June 2002

July 2012

September 2017



D. Santoro et al.




Design

No. of patients

Inclusion criteria

Adalimumab

NCT00814255 Novel therapies for resistant FSGS (FONT II): Phase II clinical trial

1) Adalimumab 24 mg/m2 (maximum dose 40 mg) s.c. q14 days; 2) Lisinopril p.o. 10--20 mg/day Losartan p.o. 25--50 mg/day Atorvastatin p.o. 10--20 mg/day; 3) Galactose 0.2 g/ kg/dose (maximum dose 15 g) p.o. b.i.d.

Phase II, randomized, open-label, parallel assignment study

23

1) Primary FSGS confirmed by renal biopsy; 2) Failure to respond to prior therapy; 3) Age 1--65 years at onset of proteinuria and at time of randomization

NCT00193648 Pilot studies of novel therapies to treat resistant FSGS

1) Adalimumab 24 mg/m2 to a maximum of 40 mg/dose every other week for the entire treatment period; 2) Rosiglitazone by oral administration Milatuzumab will be administered s.c. at 3 different dose levels once or twice weekly for 4 weeks

Phase I, randomized parallel assignment open-label safety study Phase Ib, interventional, single group assignment, open-label study Phase II, randomized, double-masked, placebo-controlled, multicenter study

21

1) Primary FSGS confirmed by renal biopsy; 2) eGFR ‡ 40 ml/min/1.73 m2 3) Age 2--42 years at onset of proteinuria and at time of randomization 1) Diagnosis of SLE by ACR revised criteria (meets ‡ 4 criteria); 2) Positive ANA (titer ‡ 1:80) at study entry 3) Age > 18; 4) Scr < 2.5 mg/dl, proteinuria < 3.5 g/day 1) Protein Z with CKD presumed due to diabetes type I or type II; 2) Proteinuria/creatinine ratio ‡ 800 mg/g; 3) eGFR 20 -- 60 ml/min; 4) SCr from 1.3 -- 3.3 mg/dl (F) and 1.5 -- 3.5 mg/dl (M)

Milatuzumab

NCT01845740 A Phase Ib study of milatuzumab administered s.c. in patients with active SLE

LY2382770

NCT01113801 Study to evaluate the safety and renal efficacy of LY2382770 (TGF-b antibody) in patients with diabetic kidney disease due to type I or type II diabetes NCT00046774 Clinical trial of immunotherapy of MRA, a humanized anti-IL 6 receptor mAb, in patients with SLE

Tocilizumab

Abatacept

ALXN1007

NCT01714817 Study to evaluate the efficacy and safety of BMS-188667 (abatacept) or placebo on a background of mycophenolate mofetil and corticosteroids in the treatment of subjects with active class III or IV LN NCT02128269 Phase IIa trial of ALXN1007 for the treatment of non-criteria manifestations of aPL syndrome

1) LY2382770 (TGF-b antibody): s.c. injection (2--10--50 mg) given monthly for 12 months; 2) Placebo: s.c. injection given monthly for 12 months

30

400 (estimated)

Subjects will be treated with biweekly infusions of one of three doses (2, 4 or 8 mg/kg) of MRA for 12 weeks and followed for 8 weeks after the last dose

Phase I, interventional, single group assignment, open-label, doseascending clinical trial

23

1) Abatacept 30 mg/kg injection by intravenous on days 1, 15, 29 and 57, followed by a weight-tiered dose approximating 10 mg/kg injection by intravenous every 4 weeks, Mycophenolate mofetil 1.5 g tablet by mouth and Prednisone up to 60 mg tablet by mouth daily for 104 weeks placebo plus mycophenolate mofetil and prednisone ALXN1007 10 mg/kg i.v. q 2 weeks per 12 doses

Phase III, interventional, parallel assignment, randomized, doubleblind, placebocontrolled study

400


20

1) Must fulfill at least 4 of the criteria for SLE as defined by the ACR; 2) CKD criteria: i) < 30% increase in creatinine compared with lowest level during treatment ii) proteinuria £ 1.5 times the BL before treatment iii) £ 2+ cellular casts in the urinary sediment (on a scale of 0--4), and iv) Extra-renal disease activity does not exceed 10 on the non-renal components of the SELENA-SLEDAI score 1) Biopsy within 12 months prior to screening visit indicating active Class III or IV proliferative lupus glomerulonephritis (lupus effecting your kidney); 2) uPCR ‡ 1.0 at screening; 3)Scr £ 3 mg/dl (i.e., £ 265 µmol/l); 4) Potential subjects must have active LN

1) Patients with a persistent and clinically significant aPL profile; 2) aPL-nephropathy (diagnosed by kidney biopsy within 12 months of screening); 3) Urine protein to creatinine ratio > 1.0 at the time of the screening

The new terminology for “Wegener’s granulomatosis” adopted in May 2011 is “granulomatosis with polyangiitis (GPA)”. ACR: American College of Rheumatology; AE: Adverse event; anti-dsDNA: Anti-double-stranded; aHUS: Atypical hemolytic uremic syndrome; ANA: Antinuclear remission; CRR: Complete renal response; DDD: Dense deposit disease; FSGS: Focal segmental glomerulosclerosis; ISN/RPS: International Society of Nephrology/Renal glomerulonephritis; NS: Nephrotic syndrome; PD: Pharmacodynamics; PK: Pharmacokinetics; p.o.: By mouth; PR: Partial remission; PRR: Partial renal response; Escherichia coli hemolytic-uremic syndrome; TMA: Thrombotic microangiopathy; uPCR: Urinary protein/creatinine ratio.

12



Outcome measures


Date


Start

To be finished

Status

Result

No study results posted on ClinicalTrials.gov for this study Result of its relative Phase I study found on PubMed No study results posted on ClinicalTrials.gov for this study No study results posted on ClinicalTrials.gov for this study No study results posted on ClinicalTrials.gov for this study

Completed

Primary: reduction in proteinuria at 6 months by > 50% of the value at the time of screening and changing in eGFR, compared with value at enrollment

Test whether adalimumab and/or galactose can safely reduce proteinuria (abnormal amounts of protein in the urine) and protect kidney function better than standard treatment for patients with FSGS

December 2008

February 2014


Primary: Safety and tolerance of medications at 16 weeks of treatment period Secondary: reduction in proteinuria Primary: Safety of the s.c. administered milatuzumab and efficacy

The hypothesis are that two novel agents -- TNF-a antagonist and a PPARg agonist -- can be administered safely to patients with resistant FSGS

July 2005

October 2007


The purpose of this study is to evaluate the efficacy, safety and tolerability of milatuzumab in patients with active SLE

August 2014

November 2015

No

This study is not yet open for participant recruitment

July 2014

No


July 2007


No study results posted on ClinicalTrials.gov for this study Results found on PubMed

Primary: Change in SCr from BL to 12 month end point; Secondary: change in uPCR from BL to 12 month end point

July 2010 The primary objective is to determine if LY2382770, administered monthly for 1 year, is more effective than placebo at slowing the progression of diabetic kidney disease in patients treated with an angiotensin-converting enzyme inhibitor or an angiotensin II receptor blocker

Primary: safety/tolerance of MRA in patients with SLE

This study will examine the safety and effects of the mAb MRA in patients with SLE

September 2002

Primary: Proportion of subjects achieving complete response of renal disease following 52 weeks of treatment, where complete response is a composite end point based on renal function, proteinuria, urine sediment and corticosteroid dose Primary: To evaluate the safety and tolerability of i.v. ALXN1007 based on the incidence and severity of treatment-emergent AEs and SAEs

The purpose of this study is to evaluate (abatacept) for treatment of LN when used on a background of Cellcept (mycophenolate) and prednisone (corticosteroids)

January 2013

July 2019

No



The primary purpose of this study is to evaluate the safety and tolerability of i.v. ALXN1007 in persistently aPL-positive patients with at least one of the following non-criteria manifestations of APS: aPL-nephropathy, skin ulcers and/or thrombocytopenia

April 2014

July 2017

No



antibody; ANCA: Anti-neutrophil cytoplasmic antibody; aPL: Antiphospholipid; b.i.d.: Twice a day; BL: Baseline; CKD: Chronic kidney disease; CR: Complete Pathology Society; i.v.: Intravenous; LN: Lupus nephritis; MCD: Minimal-change disease; MMF: Mycophenolate mofetil; MPGN: Membranoproliferative PT: Plasma therapy; SLE: Systemic lupus erythematosus; SAE: Serious adverse events; s.c.: Subcutaneous; Scr: Serum creatinine; STEC-HUS: Shiga-toxin producing


13

D. Santoro et al.

Associated keywords and number of studies obtained renal – biological: 897 renal disease – biological: 830 chronic kidney disease – biological: 197 glomerular disease – biological: 29 glomerulonephritis – biological: 14 nephritis – biological: 20 nephrotic syndrome – biological: 4 renal – monoclonal: 196 renal disease – monoclonal: 170 chronic kidney disease – monoclonal: 28 glomerular disease – monoclonal: 9 glomerulonephritis – monoclonal: 7 nephritis – monoclonal: 9 nephrotic syndrome – monoclonal: 2 renal – adalimumab: 2

Trials found on ClinicalTrials.gov


2414

Exclusion criteria: 1) studies carried out on populations of patients in renal replacement therapy (hemodialysis, peritoneal dialysis); 2) studies carried out on populations of patients with malignancy (primary or metastatic) of the kidney; 3) studies carried out on transplant patients (patients pre-transplant in end stage renal disease suitable for transplantation) both for donors and for recipients (studies on the suitability for transplantation); 4) studies conducted on treatment with biologic agents (erythropoietin, vitamin D, etc ...), but not of interest for our research focused on monoclonal antibodies; 5) repeated studies

Trials excluded from the research 2382

Suitable trials 32

Included trials 32

Unfound, uncompleted or still ongoing studies 20

Relative completed studies found 12

Figure 1. Flowchart of studies selection and exclusion criteria.

Of 20 patients treated with 4 weekly courses of rituximab repeated after 6 months, the authors showed a total response rate of 80% [7]. Another area of research for new use of rituximab is ANCA-associated vasculitis with renal involvement. In their 14

article on the Maintenance of Remission using Rituximab in Systemic ANCA-associated Vasculitis (MAINRITSAN) trial, Guillevin et al. reported that rituximab prevented relapse of ANCA-associated vasculitis better than azathioprine. Patients with newly diagnosed or relapsing granulomatosis with




microscopic polyangiitis, or renal-limited ANCA-associated vasculitis in complete remission after a cyclophosphamideglucocorticoid regimen were randomly assigned to receive either 500 mg of rituximab on days 0 and 14 and at months 6, 12 and 18 after study entry or daily azathioprine until month 22. The primary end point was the rate of major relapse at month 28. The 115 enrolled patients (87 granulomatosis with polyangiitis, 23 microscopic polyangiitis and 5 renal-limited ANCA-associated vasculitis) received azathioprine (58 patients) or rituximab (57 patients). At month 28, major relapse had occurred in 17 patients in the azathioprine group (29%) and in 3 patients in the rituximab group (5%). In conclusion, more patients with ANCA-associated vasculitis had sustained remission at month 28 with rituximab than with azathioprine [8]. The NEMO study (ClinicalTrials.gov ID: NCT00981838) was primarily aimed at evaluating the incidence of recurrences in patients with multi-relapsing nephrotic syndrome (NS), suffering from MCD and FSGS. In particular, this was a prospective, multicenter, case-controlled study, which was aimed to determine whether rituximab maintained remission of the NS after discontinuation of steroids and other immunosuppressants. The comparison was made among the incidence of recurrences observed in the previous year with rituximab administration. Other considered parameters were the amount of steroids and immunosuppressive drugs necessary to achieve and maintain remission of NS over the previous year and the effects of treatment on clinical and laboratory findings. The treatment was well tolerated and after 1 year from the start of rituximab therapy, all patients were in remission and half had never presented any recurrence of disease. Compared with the previous year, the total number of relapses in the group and the annualized relapse rate per patient were significantly reduced after treatment with rituximab. The same result was also reported when comparing the rate of recurrence observed within 2 years before rituximab administration to the relapse rate occurring within 2 years after treatment. This extension of the follow-up period showed that the protective effect of rituximab against the recurrence of NS is long lasting. Moreover, growth, body mass index and blood pressure were significantly improved in the subset of children, as an expression of the regression of the side effects of chronic use of steroids. Renal function had improved in all subjects, especially in children and in patients with FSGS. These results suggest that rituximab is helping in limiting the long-term complications of NS and related immunosuppressive treatments, which are often devastating especially in children, and allows patients to maintain sustained remission without immunosuppression in most cases [9]. In another trial (ClinicalTrials.gov ID: NCT00275613), the effect of rituximab in membranoproliferative glomerulonephritis (MPGN) was studied. The MPGN is an immunecomplex disease with a relatively poor prognosis, for which no curative treatment in adults has been established so far. The hypothesis of the authors of this study was that the

disease would respond positively to a depletion of B cells through the use of rituximab. The primary outcome used as a parameter for the success or failure of the trial was the change in proteinuria. Before treatment, the mean urinary excretion of protein was around 3.9 ± 2.0 g/day. After administration of rituximab, proteinuria decreased significantly in all patients. The difference was statistically significant (p < 0.05) at 6, 9 and 12 months, but not at 3 months. The lowest mean urinary excretion of protein was 1.4 ± 1.4 g/day at 9 months. Two complete remissions and three partial remissions were found in six enrolled patients. Creatinine clearance did not change significantly during the study and no adverse events were recorded. In conclusion, rituximab reduced proteinuria in patients with MPGN type I, but did not affect the improvement in eGFR in a year. This study suggests that B cells may play a role in this disease and that further studies are needed to better understand the pathogenesis of the disease and the effects of the drug [10]. Another important study is that one of rituximab for Childhood-onset Refractory Nephrotic Syndrome Study Group. Minimal change NS is the most common form of the disorder, for which steroid therapy is effective for most patients. Those who respond well rarely progress to chronic renal failure, but up to half develop FRNS or SDND. The Japanese group investigated the efficacy and safety of rituximab in young patients with FRNS and SDNS. Fifty-two patients (from 2 to 18 years old) were enrolled for this double-blind, randomized, placebo-controlled trial. Of 52 patients who underwent randomization, 48 received the assigned intervention (24 were given rituximab and 24 placebo). Patients were followed-up for 1 year. The primary end point was the relapse-free period. Safety end points were frequency and severity of adverse events. The median relapse-free period was significantly longer in the rituximab group (267 days) than the placebo group (101 days). Regarding serious adverse events, there was no statistically significant difference between rituximab and placebo groups. In conclusion, the Japanese group has shown that the relapse-free period increases with rituximab in patients with childhood-onset, complicated FRNS and SDNS. Adverse events were generally mild and the frequency of serious adverse events did not differ significantly between groups, demonstrating that rituximab is safe and effective for at least 1 year of treatment in a multicenter, double-blind, randomized, placebo-controlled trial [11]. Another area in which rituximab was tested in terms of efficacy and safety is lupus nephritis (LN) and, more broadly, in systemic lupus erythematosus (SLE). One trial found in the cross search (ClinicalTrials.gov ID: NCT00556192) evaluated the effects of rituximab in the treatment of LN in terms of efficacy and safety of rituximab, as either monotherapy or in combination with cyclophosphamide, in comparison with the standard immunosuppression based on cyclophosphamide and azathioprine. More specifically, 20 patients enrolled in the study were randomized into three


15


D. Santoro et al.

groups, as described in Table 1. We have no results of this study so far. The second randomized controlled trial (RCT) was the Lupus Nephritis Assessment With Rituximab (LUNAR) trial (ClinicalTrials.gov ID: NCT00282347), which evaluated the efficacy of rituximab compared with placebo in combination with standard-of-care therapy in 144 patients with proliferative LN. Treatment with rituximab was associated with the successful depletion of B cells in 99% of patients and ameliorating of serological markers of active lupus. Despite this improvement, again there was no significant difference in overall renal response rates or clinical efficacy at 1 year between placebo (45.8%) and treatment arms (56.9%) of the trial (p = 0.18) [12]. However, before concluding that rituximab is not a good therapy for SLE, a careful evaluation of the design of the LUNAR trial (and others like EXPLORER trial [ClinicalTrials.gov ID: NCT00137969]), which did not consider renal function as one of the study outcomes, is necessary. With regard to disease severity, a high percentage of included patients were likely to have mild-to-moderate SLE with no history of poor response to standard therapies. This observation, in itself, may explain why rituximab was not superior to the other drugs in these predominantly non-complicated patients. Considering concomitant therapies, the high doses of corticosteroids permitted in both arms of these trials could have lead to significant differences not being apparent in a short-term evaluation. In addition, the possible synergistic effect of rituximab in combination with immunosuppressive agents (cyclophosphamide or mycophenolate), suggested by some authors to have significant advantages in complicated, refractory SLE cases, was not evaluated in these RCTs [13,14]. Ocrelizumab Another anti-CD20 mAb is ocrelizumab, a (h) mAb. Ocrelizumab is undergoing Phase III clinical trials for rheumatoid arthritis (RA) and LN, and Phase II trials for multiple sclerosis and hematological tumours. Previously, ocrelizumab was also being developed for the treatment of SLE and neuromyelitis optica [15]. Ocrelizumab has shown clinical efficacy and safety in a recently reported trial in patients with RA [16]. This drug was studied in two doses (400 mg and 1 g) in the Study to Evaluate Ocrelizumab in Patients With Nephritis Due to SLE (BELONG) trial (ClinicalTrials.gov ID: NCT00626197) that included 381 patients with severe LN. However, the trial was suspended early due to the detection of a severe infection-related safety signal in the treatment arm. Nonetheless, the report from the BELONG trial showed a trend towards a better response in the ocrelizumab 400 mg (62%) and 1 g (64%) treatment arms compared with placebo (51%), thus suggesting there is a potential for the use of this drug in SLE [17]. Despite the results, ocrelizumab has not been further studied. 3.2

16

Infliximab Infliximab is the second most widely investigated mAb in clinical trials. Infliximab is a chimeric mAb directed against TNF-a. Its mechanism of action is to selectively bind TNF-a, which is involved in the inflammatory response, inhibiting its functions at the cellular level. The actions of TNF-a significantly differ, depending on the concentration and the place of actions, whether local or systemic [6]. Often, however, the production of antibodies against the biological molecules is a cause of resistance to therapy. The therapy, therefore, is effective only in 60% of subjects, either for production of anti-infliximab antibodies and for the presence of particular genetic polymorphisms in the population in the promoter of the TNF-a gene [18,19]. Therefore, infliximab could expose patients to tuberculosis infection [20]. It was approved in August 1998 by the US FDA for the treatment of two important disorders: inflammatory bowel diseases (Crohn’s disease and ulcerative colitis) and rheumatic diseases (ankylosing spondylitis, psoriatic arthritis and RA), diseases whose common element was found to be an increased production of TNF-a [21]. TNF-a is implicated in the pathogenesis of ANCAassociated vasculitis. Currently, immunosuppressive therapy of these diseases is accompanied by considerable morbidity and mortality. On the basis of this pharmacological mechanism, it was suggested that infliximab may help in the control of ANCA-associated vasculitis. It has been hypothesized that causal environmental factors in individuals with genetic predisposition may stimulate Th1 lymphocytes to produce pro-inflammatory cytokines such as TNF-a, which induce the migration and on-site degranulation of polymorphonuclear cells to the endothelium, thus causing immune-mediated kidney damage. In line with that, the use of infliximab has been proposed to potentially reduce TNF-a levels in patients with ANCA-associated vasculitis. The ‘ACTIVE study’ (ClinicalTrials.gov ID: NCT00753103) was conducted to assess efficacy and safety of inflixiamb and whether infliximab could improve renal function in nephritis caused by ANCA-associated vasculitis, in addition to traditional therapy (combined use of corticosteroids and cyclophosphamide), which improves patient’s survival but is charged with high morbidity and mortality. The experimental group (group 1) was formed by patients with active vasculitis who received infliximab in addition to standard immunosuppressive therapy (prednisolone, methylprednisolone and azathioprine or mycophenolate mofetil instead of azathioprine in patients not tolerant to the drug) as described in Table 1. Instead, the control group (group 2) received only the standard therapy. The addition of infliximab did not have a significant impact on outcomes evaluated in this study [22]. In brief, this study has not shown any clear clinical benefit of the addition of infliximab to standard therapy for ANCA-associated vasculitis, suggesting 3.3



that inhibition of TNF-a may have no effect on renal function. A second study on infliximab in the treatment of renal SLE with WHO class V glomerulonephritis (ClinicalTrials.gov ID: NCT00368264) was prematurely terminated (failure to recruit patients with membranous LN not previously treated with azathioprine). Eculizumab Eculizumab is another biological drug belonging to synthetic mAb class. Eculizumab is a (h) IgG mAb, an anti-C5 antibody that specifically binds the human complement factor C5 and prevents its cleavage by the C5 convertase, thus avoiding the formation of the C5b-9 terminal complement [23]. Eculizumab was first used for paroxysmal nocturnal hemoglobinuria treatment, a rare genetic disorder characterized by episodes of complement-mediated intravascular hemolysis and hemoglobinuria (more pronounced during the hours of sleep), associated with a high risk of thrombosis; venous thrombosis is the leading cause of death from respiratory complications such as massive pulmonary embolism [24]. Over time, it became clear that eculizumab could be used in the treatment of atypical hemolytic uremic syndrome (aHUS), a rare condition characterized by acute renal failure, microangiopathic thrombosis, hemolytic anemia and thrombocytopenia. In most cases the etiology is unknown. Recent studies have shown that aHUS may be associated with impairment in the regulation of the alternative complement pathway that would lead to a deficient cell protection and inadequate complement activation against platelets and endothelial cells, causing vascular damage particularly in kidneys. Accordingly, it became reasonable to treat these patients with a drug that would block the activation of the complement, to prevent or reduce kidney damage. Recently, different clinical trials have reported the efficacy of eculizumab also in the treatment of aHUS. In the completed studies, eculizumab showed remission in a case of congenital aHUS and in an adult with recurrent post-transplant aHUS. In adult patients, a single dose of eculizumab proved to be effective in maintaining remission for 8 months [25,26]. The most important studies on eculizumab effects on aHUS patients were conducted by a French group led by Legendre. In two prospective Phase II trials, patients with aHUS, who were 12 years of age or older, received eculizumab for 26 weeks and during long term extension phases. Patients with low platelet counts and renal damage (in trial 1) and those with renal damage but no decrease in the platelet count of more than 25% for at least 8 weeks during plasma exchange or infusion (in trial 2) were recruited. The primary end points included a change in the platelet count (in trial 1) and thrombotic microangiopathy event-free status (no decrease in the platelet count of > 25%, no plasma exchange or infusion and no initiation of dialysis) (in trial 2). After discontinuation of plasma exchange or infusion and initiation of eculizumab


3.4

treatment, there were continuous, time-dependent increases in the eGFR from baseline to week 26. In both trials, improvement in the eGFR was accompanied by a decrease in proteinuria in patients with baseline proteinuria of grade 1+ or higher. In addition, in trial 1, dialysis was discontinued in four of five patients (80%) who had required dialysis at the time of initiation of eculizumab, and these patients remained dialysis-free throughout eculizumab treatment. In conclusion, these two clinical studies suggest that long-term eculizumab treatment is effective in patients with aHUS, with earlier intervention associated with a greater clinical benefit [27]. In the typical forms of HUS (90% of cases) associated with gastrointestinal infections, bacteria and many viruses have been proposed as possible causative agents. In particular, some strains of Escherichia coli (strain O157:H7) or Shigella dysenteriae were held to be responsible, as capable of producing special exotoxins (verotoxins), which in turn may induce the activation of neutrophils and damage the endothelial cells [28]. Currently, there are several both completed and ongoing studies, exploring the use of eculizumab in the treatment of HUS. One of these studies, ‘Safety and Efficacy Study of Eculizumab in Shiga-Toxin Producing Escherichia Coli Hemolytic-Uremic Syndrome’ (ClinicalTrials.gov ID: NCT01410916) aims to treat typical HUS, in children older than 2 months, with eculizumab. The Phase III trial was completed at the end of 2013 and still no results are available. There are other trials testing eculizumab in the treatment of glomerular diseases such as membrane-proliferative glomerulonephritis (MPGN) and dense deposit disease (DDD). The first study called ‘EAGLE’ (ClinicalTrials.gov ID: NCT02093533) has suggested that eculizumab is a drug capable to stop or induce remission in patients with MPGN. This study is still recruiting patients, so at the moment results are not available. The second study (ClinicalTrials.gov ID: NCT01221181) is intended to test eculizumab for the treatment of DDD, also called type II MPGN. DDD most commonly affects children between 5 and 15 years. The spontaneous remissions are rare and about 50% of individuals undergo ESRD within 10 years from diagnosis. This open-label study aims to demonstrate the efficacy and safety of eculizumab in patients with DDD and to determine whether eculizumab treatment leads to an improvement in renal function, defined by the proteinuria and eGFR, and an amelioration of histological parameter. The study is still ongoing. Daclizumab Daclizumab is a (h) mAb that acts by binding its specific antigen, CD25, the a-subunit of the receptor for IL-2 shown on the cell membrane of T lymphocytes. The expression of the IL-2 receptor has been associated with inflammation and/or neoplasms, lymphoid malignancy, autoimmune diseases and allograft rejection [29]. Daclizumab was originally used to prevent rejection in organ transplantation, especially in kidney transplantation. 3.5


17


D. Santoro et al.

The purpose of the pharmacological treatment with daclizumab is to saturate the receptors for IL-2 and prevent the activation of T cells, thus avoiding the synthesis of antibodies against the transplanted organ. The use of daclizumab was also recently introduced in a clinical Phase II for the treatment of multiple sclerosis, demonstrating that daclizumab is effective in reducing the contrast-enhancing lesions. These results provided the first evidence of the long-term efficacy and safety of treatment with daclizumab and support its further clinical development in other areas [30]. Common adverse events, reported in clinical trials with a frequency of at least 10%, include insomnia, tremor, headache, high blood pressure, shortness of breath, gastrointestinal side effects and edema [31]. In nephrology, this drug was tested in patients with Wegener’s granulomatosis (WG). The aim of the current standard treatment is to control inflammation. In most cases, the treatment consists in a combination of corticosteroids (e.g., prednisone) and another immunosuppressant drug such as cyclophosphamide, azathioprine or methotrexate. Using a high dosage regimen of prednisone in combination with cyclophosphamide, more than 90% of patients improve the clinical outcomes, and 75% can achieve long-term remissions. Unfortunately, 50% of these patients experience a reactivation and relapsing of the disease. Recurrence of WG is usually sensitive to the same treatment that induced remission, but at higher doses [32]. A clinical trial (ClinicalTrials. gov ID: NCT00040248) was aimed to test the safety and efficacy of daclizumab as an add-on treatment with methotrexate for maintenance of remission induced by standard therapy with cyclophosphamide and glucocorticoids in patients with WG and active glomerulonephritis. In this study, all patients initially received daily cyclophosphamide and glucocorticoids, and, once reached the remission, cyclophosphamide was replaced by methotrexate as maintenance therapy. Although the study is completed, there are no data available on the results of this study so far. Belimumab Belimumab is a (h) mAb produced synthetically, whose target antigen is represented by B-cell activating factor (BAFF) also known as B-lymphocyte stimulator; in particular, binding this molecule, belimumab inhibits its functions [33]. The signaling, activated by BAFF and its specific receptor, BAFF-R, stimulates B cells to enter into proliferation and, to the other side, to avoid apoptosis. B lymphocytes are responsible not only for a part of the normal immune response, but also for the exaggerated response that occurs in aggressive autoimmune diseases such as SLE, but also in RA and Sj€ogren’s syndrome and Waldenstr€om disease [34], for which belimumab is employed. In April 2010, belimumab was submitted to the FDA and the EMA as a potentially new drug for the treatment of a disease with systemic involvement which is SLE. This request was based mainly on clinical improvement and amelioration of 3.6

18

specific biomarkers found in two pivotal Phase III trials in patients with SLE, BLISS-52 and BLISS-76, which collectively have involved 1684 patients [35]. The efficacy of belimumab for treating SLE was evaluated in the study BLISS-52. Adult patients with SLE and SLEspecific autoantibody positive (ANA or anti-double-stranded DNA [anti-dsDNA]) treated with the stable treatment regimen with fixed doses of prednisone (up to 40 mg/day) were included in the trial. The combination of belimumab with standard therapy resulted in a response rate greater than placebo after 52 weeks. It must be emphasized that patients with severe nephritis or central nervous system (CNS) involvement were excluded from the study [36]. Although efficacy and safety have been proved in the treatment of SLE, the exclusion of patients with LN in this study did not allow us to consider belimumab as a suitable drug for the treatment of patients with active LN. For this reason, in 2012, the BLISS-LN study (ClinicalTrials.gov ID: NCT01639339) was started, which is still ongoing and is currently recruiting adult patients with active LN. The purpose of this study is to evaluate the efficacy, safety and tolerability of belimumab in adult patients with active LN. The first data will be available in 2017. Nevertheless, the encouraging results obtained in the BLISS-52 and BLISS-76 studies suggest that in the future belimumab may be used as a treatment for patients with active nephritis associated with SLE. Fresolimumab Fresolimumab is a fully recombinant (h) mAb directed against the human TGF-b (type I, II and III). TGF-b, a cytokine often overexpressed in several malignancies, appears to play an important role in promoting growth, progression and tumor cell migration. Fresolimumab inhibits the activity of all isoforms of TGF-b, which may lead to the inhibition of the growth and migration of cancer cells as well as of tumorinduced angiogenesis [37]. Fresolimumab has not yet received FDA approval, but already several clinical trials are taking care of its possible application areas: oncology, rheumatology and so on. Recently, its use in nephrology has been postulated, in particular in the fight against an idiopathic glomerular disease such as FSGS. In particular, since the TFG-b appears to be involved in the development and progression of FSGS, some clinical trials have been conducted to understand if fresolimumab could be employed in the treatment of this disease. These studies are: ‘A Phase I, Multicenter, Open-label, Dose-escalating Study of Single Doses of GC1008 in Patients With Treatment-Resistant Idiopathic FSGS’ (ClinicalTrials.gov ID: NCT00464321) and ‘A Phase II, Multicenter, Double-Blind, Parallel Dosing, Randomized Study of Fresolimumab or Placebo in Patients With Steroid-Resistant Primary Focal Segmental Glomerulosclerosis’ (ClinicalTrials.gov ID: NCT01665391). Both these studies have completed enrollment but are currently in progress, so there are no available data. 3.7




3.8

Tocilizumab

Tocilizumab is a (h) mAb directed against the receptor for IL-6 (IL-6R), a cytokine that plays an important role in the immune response and is implicated in the pathogenesis of autoimmune diseases, multiple myeloma and certain types of cancer (e.g., prostate cancer) [38]. It is a mAb mainly used for the treatment of RA and systemic juvenile idiopathic arthritis, a severe form of RA that affects children [39]. Regarding possible pharmacological interactions, it has been reported that the plasma levels of simvastatin were reduced by 57% after a single dose of tocilizumab. The most common adverse effects of tocilizumab observed in clinical trials were: upper respiratory tract infections (more than 10% of patients) as nasopharyngitis (common cold), headache and increased blood pressure (at least 5%). The enzyme alanine transaminase was found higher in at least 5% of patients, but in most cases with no symptoms [40]. The Phase I study ‘Tocilizumab in SLE’ (ClinicalTrials.gov ID: NCT00046774) is aimed to evaluate the safety of the IL-6R inhibition and to collect preliminary data on the clinical and immunological efficacy of tocilizumab in patients with SLE. The levels of anti-dsDNA have reported a median decrease of 47% in patients belonging to the experimental group with a dose of 4 mg/kg body weight and 8 mg/kg, with a 7.8% decrease of their levels of IgG. One patient was withdrawn from the study because of neutropenia. Infections occurred in 11 patients; none was associated with neutropenia. These changes, together with a significant decrease in the frequency of circulating plasma cells, suggest a specific effect of tocilizumab. Five patients enrolled in the study had renal involvement. All of them presented chronic glomerulonephritis mainly characterized by proteinuria, which has not changed during the study. In conclusion, this pilot study provides the first data showing that tocilizumab can effectively block the effects of IL-6 in patients with SLE. The improvements in markers of inflammation, clinical manifestations and serological activity of lupus are encouraging and should be further explored in controlled studies, but by now there is no evidence on the efficacy of tocilizumab in LN [41]. Abatacept Abatacept is a mAb produced to suppress the activity of T lymphocyte cells. This antibody is designed to bind two T-cell membrane receptors, CD80 (know as B7-1) and CD86, thereby preventing T cell activation [42]. Abatacept is able to selectively modulate a key costimulatory signal required for full activation of T lymphocytes expressing CD28. Full activation of T lymphocytes requires two signals that are provided by antigen-presenting cells: the recognition of a specific antigen by a T-cell receptor (signal 1) and a second, costimulatory signal. One of the major costimulatory pathways involves the binding of CD80 and CD86 molecules on the surface of antigen-presenting cells to the CD28 receptor on T cells 3.9

(signal 2). Abatacept selectively inhibits this costimulatory pathway by specifically binding CD80 and CD86 [43]. In 2005, the FDA approved abatacept as an alternative treatment to standard therapy of RA and in 2008 the approval was extended to children older than 6 years of age with juvenile idiopathic arthritis. Some evidence and case reports highlighted that abatacept may block the progression of FSGS [44]. In this study, Abatacept induced partial or complete remission of proteinuria in a group of five patients B7-1-positive at glomerular level, suggesting that B7-1 may be a useful biomarker for the treatment of some glomerulopathies. These data indicate that abatacept may stabilize b1-integrin activation in podocytes and reduce proteinuria in patients with B7-1-positive glomerular disease. The authors, however, concluded that a large-scale clinical trial is needed to demonstrate drug efficacy in this indication of use, and especially in kidney disease characterized by the expression of the molecule B7-1 on podocytes [45]. In October 2012 the trial started: ‘Efficacy and Safety Study of Abatacept to Treat Lupus Nephritis’ (ClicalTrials. gov ID: NCT01714817). The purpose of this study is to evaluate the efficacy of abatacept use for the treatment of LN, as add-on to standard therapy based on mycophenolate mofetil and corticosteroids. The study is expected to enroll 400 patients with active LN with proliferative glomerulonephritis (class III or IV), to be divided into two randomized groups: experimental and control group. The experimental group will receive abatacept as indicated in Table 1. The primary outcome is the proportion of subjects who achieve complete response of kidney disease after 52 weeks of treatment, measured as improvement in renal function, reduced proteinuria and improved urinary sediment. The study is still ongoing. Adalimumab Adalimumab is a (h) mAb which is directed towards the TNF-a. It is approved by the FDA as anti-inflammatory agent to treat adults with RA, ankylosing spondylitis, Crohn’s disease or psoriasis and children with juvenile idiopathic arthritis [46-48]. Despite increasing use of this agent, there is little information about the effect of anti-TNF-a agents in renal disorders [49]. Production of TNF-a is enhanced in cultured peripheral blood mononuclear cells obtained from children with steroid-resistant NS and FSGS [50,51]. Expression of the cytokine is also increased within the renal parenchyma of patients with FSGS and TNF-a immunoreactivity correlates with the extent of interstitial fibrosis [52]. Finally, TNF-a causes endothelial cell injury and increases glomerular permeability in vitro [53]. Taken together, these findings support a role of TNF-a in mediating proteinuria and renal fibrosis in FSGS. Currently, there are two studies, both completed but in different trial phase, dealing with adalimumab in renal disease. The first one, ‘Novel Therapies for Resistant FSGS (FONT 3.10


19


D. Santoro et al.

II): Phase II Clinical Trial’ (ClinicalTrials.gov ID: NCT00814255) tested whether adalimumab and/or galactose can safely reduce proteinuria and protect kidney function better than standard treatment for patients with FSGS. There are no results of this study, but the previous and complete Phase I study of this project was found: ‘Report of the FONT (Novel Therapies for Resistant FSGS) Study Group’. FONT trial aimed to assess the pharmacokinetics, tolerability and safety of adalimumab in FSGS. Patients with primary FSGS resistant to current treatment regimens are at high risk of progression to end-stage kidney disease. Antifibrotic agents, such as TNF-a antagonists, are a promising strategy to slow or halt the decline in renal function, based on preclinical and clinical data. Ten patients were assigned to adalimumab with 20% having collapsing, 10% cellular, 20% tip and 50% not otherwise specified lesions. Nine participants completed the 16-week treatment period and underwent all of the laboratory evaluations. eGFR, proteinuria and pharmacokinetic assessment after initial dosing and steady state were measured. In the nine patients who completed the 16-week treatment period, four achieved at least a 50% reduction in proteinuria, with the decline beginning at week 2 and reaching a nadir at week 16. In no case, the urinary protein excretion declined to normal. Pharmacokinetic assessment demonstrated increased clearance of adalimumab in patients with resistant primary FSGS and validated the need for evaluating the disposition of novel therapies in this disease to define appropriate dosing regimens. The study provides a rationale to evaluate efficacy of adalimumab as an antifibrotic agent for resistant FSGS in Phase II/III clinical trials [54]. The second study was ‘Pilot Studies of Novel Therapies to Treat Resistant FSGS’ (ClinicalTrial.gov ID: NCT00193648). The hypothesis is that two novel agents, TNF-a antagonist and PPARg agonist, can be administered safely to patients with resistant FSGS. The aims of this Phase I study were first to assess the safety and tolerability of TNF-a antagonist and a PPARg agonist in patients with resistant FSGS, and then to conduct a pharmacokinetic assessment of the selected agents to enable selection of medication regimens for investigation in a randomized Phase II study. The results of this study are not yet available. Recently, a beneficial effect of adalimumab has been reported in a patient with membranous glomerulonephritis, who received this mAb for simultaneous presence of psoriasis, followed by a disappearance of psoriatic skin lesions and remission of nephritic syndrome [55]. However, there are no started trials on this specific topic. 3.11

Other biological drugs BIIB023

3.11.1

BIIB023 is a (h) mAb directed against a particular molecule belonging to the superfamily of TNF, called TWEAK (TNF-like weak inducer of apoptosis). TWEAK is a multifunctional cytokine that controls many cellular activities including proliferation, migration, differentiation, apoptosis, 20

angiogenesis and inflammation, by binding Fn14, a highly inducible cell surface receptor. Recent studies have indicated that the TWEAK-Fn14 intracellular signaling may contribute to the pathogenesis of cancer, stroke and autoimmune diseases. Fn14 is expressed in different organs, including kidneys; therefore, it is conceivable that some of these chemokines induced by TWEAK are critical in the pathogenesis of LN [56]. High levels of TWEAK molecules in urine are observed in patients with active LN. The urine analysis showed that the urinary TWEAK levels in patients with biopsy-proven LN were significantly higher than those found in SLE patients without renal involvement in healthy subjects [57]. The inhibition of TWEAK/Fn14 signaling has been proven to be effective in several animal models of inflammatory diseases, suggesting that the BIIB023-induced selective blockade of TWEAK may be clinically useful in LN. The clinical trial ‘BIIB023 Long-Term Extension Study in Subjects With Lupus Nephritis’ has been thought as an extension of the previous study, called ‘ATLAS’. The primary objective of ATLAS (Clinical Trials ID: NCT01499355) is to evaluate and compare the efficacy of BIIB023 as an addon treatment with standard therapy (mycophenolate mofetil and prednisone) versus placebo in patients with active LN. Moreover, the experimental group will be further divided into two subgroups, each of which will receive anti-TWEAK in different doses (Table 1). The secondary objective is to evaluate the safety and tolerability of BIIB023 compared with placebo in this study population. Participants who complete the study at week 52 can enter the extension of the study in a separate protocol. The primary objective of this extension study (Clinical Trials ID: NCT01930890) is to assess the longterm safety and tolerability of BIIB023 in patients with LN. Participants admitted from the previous ATLAS study will be followed-up for 108 weeks. The subjects who received low dose or high dose of BIIB023 in the previous study will continue to receive the same dosage, always in addition to therapy. Instead, participants who received the placebo in the ATLAS study will be randomized to receive either high or low doses of BIIB023, always in addition to background therapy. Both of these studies are still in the experimental phase (Phase II), and the results are expected by 2019. Milatuzumab Milatuzumab is a (h) mAb targeting tumors that express the CD74 antigen. CD74 has been reported to regulate chemoattractant migration of macrophages and dendritic cells, while the role of CD74 on peripheral naive and memory B cells also expressing CD74 remains unknown. The study evaluated the influence of milatuzumab on B-cell proliferation, chemoattractant migration and adhesion molecule expression. Milatuzumab leads to modestly reduced proliferation, alterations in migration and adhesion molecule expression preferentially of CD27-naive B cells. Thus, it may be a candidate antibody for the autoimmune disease therapy by modifying B-cell 3.11.2




functions [58]. Milatuzumab is the first anti-CD74 antibody that has started premarketing clinical studies for the treatment of multiple myeloma, non-Hodgkin’s lymphoma and chronic lymphocytic leukemia. Due to its effectiveness in reducing and modulating the function of B cells, milatuzumab is still under study in the treatment of SLE. The study ‘A Phase Ib Study of Milatuzumab Administered Subcutaneously in Patients With Active SLE’ (ClinicalTrials.gov ID: NCT01845740) is aimed to evaluate if milatuzumab may help in the control of SLE and all its clinical manifestations (cutaneous lupus erythematosus, discoid lupus erythematosus, CNS lupus vasculitis and lupus nephritis). Milatuzumab will be given subcutaneously at different dose schemes, once or twice weekly, for 4 weeks. The period of study treatment lasts 4 weeks. Then patients will be followed for disease activity for at least 12 weeks. If patients respond to the study drug, they may be eligible for one course of retreatment, again followed by 12 weeks of follow-up. Patients who show a response will continue to be followed at time points up to 1 year after treatment to assess how long the response lasts. This study is not yet open for participant recruitment. ALXN1007 ALXN1007 is the code name for a new therapeutic agent designed to regulate the complement inflammatory pathway. This is a novel anti-inflammatory antibody designed to target severe and ultra-rare inflammatory disorders. ‘An Open-Label Proof of Concept Phase IIa Trial of ALXN1007 for the Treatment of Non-criteria Manifestations of Antiphospholipid Syndrome (APS)’ (ClinicalTrials.gov ID: NCT02128269) is the name of the trial referring to one of the first applications of this new drug in nephrology. The primary outcome of the still ongoing study is to evaluate the safety and tolerability of intravenous ALXN1007 in persistently antiphospholipid-positive patients with at least one of the following non-criteria manifestations of APS: antiphospholipidnephropathy, skin ulcers and/or thrombocytopenia. The time frame established to gather results is a treatment period of 24 weeks and follow-up period of 12 weeks. 3.11.3

LY2382770 Diabetic nephropathy is characterized by renal hypertrophy, thickening of basement membranes and accumulation of extracellular matrix in the glomerular mesangium and in the interstitium. Previous investigations have shown that high glucose concentration increases TGF-b1 mRNA expression in mesangial and proximal tubule cells and treatment with anti-TGF-b antibody (LY2382770) results in the prevention of the effects of high glucose on cell growth (e.g., induction of cellular hypertrophy) and the stimulation of collagen biosynthesis [59]. The study ‘A Randomized, Double-Masked, PlaceboControlled, Multicenter, Phase II Study to Evaluate the Safety and Renal Efficacy of LY2382770 in Patients With Diabetic Kidney Disease Due to Type I or Type II Diabetes’ is aimed 3.11.4

to evaluate efficacy and safety of this new drug in patients with diabetic kidney disease. The primary objective of the study is to test the hypothesis that in diabetic kidney disease patients, treated with ACE inhibitors or angiotensin II receptor blockers, LY2382770 administered for 1 year is more effective than placebo at slowing the progressive loss of kidney function, as measured by serum creatinine change from baseline. Although this study has been completed, results are not yet publicly available. 4.

Conclusion

mAbs, initially developed for cancer treatment, are now increasingly available for the therapy of a wide range of diseases that are mediated by the immune system. The standard protocols based on corticosteroids and non-specific immunosuppressants, heavily limited by side effects, have represented for decades the only therapies for patients with immunemediated glomerular diseases. The growing availability of novel mAbs may constitute the basis for a revolution in the treatment of immune-mediated renal diseases, thus reducing all the side effects related to long-term therapy with steroid and other immunosuppressants. The other side of the coin is the cost of this therapy that is very high and represents a very critical barrier for their widespread use. 5.

Expert opinion

For many years, patients with immuno-mediated glomerular disease have been treated with chemotherapy regimen protocols mostly based on cyclophosphamide, azathioprine and steroids. A threefold increase has been estimated in cancer risk in patients following such chemotherapy [60]. The actual option of mAbs has opened new frontiers and new hopes for the treatment of immuno-mediated glomerular disease. Rituximab, a chimeric mAb against the CD20 antigen on B cells, has been able to reduce proteinuria in some immuno-mediated glomerular diseases such as membranous nephropathy, multi-relapsing minimal change disease and focal segmental glomerulosclerosis [6,61]. Moreover, it has been successfully used in other autoimmune renal diseases, such as ANCA-associated vasculitis, LN and mixed cryoglobulinemia [62]. Another mAb, eculizumab, has been proved to be effective in the treatment of aHUS, while the use in C3 nephropathy and MPGN is currently under investigation [63,64]. In particular, the use of eculizumab has completely changed the clinical history of aHUS. In the past, patients affected by such disease underwent treatments with plasmapheresis and immunosuppressive drugs without having great results. Other mAbs showed negative results. This is the case of infliximab (ClinicalTrials.gov ID: NCT00753103) that did not show significantly beneficial effects in ANCA-associated


21


D. Santoro et al.

vasculitis as compared with standard therapy. Another negative example is tocilizumab (ClinicalTrials.gov ID: NCT00046774) for the treatment of LN. However, in other cases, trials were not completed at the time this analysis was carried out. Small studies are revealing the efficacy of other mAbs such as adalimumab (anti-TNF-a) [65], belimumab (anti-B-lymphocyte stimulator), fresolimumab (anti-TGF-b) [66], abatacept (CTLA4Ig) [67], in different glomerular diseases, including FGSG and LN, especially in reducing proteinuria. These encouraging results and the growing availability of novel mAbs selectively targeting cytokines, inflammatory mediators and different lymphocyte populations will expand the number of immune-mediated glomerular diseases that can be treated with these new drugs. One of the problems that are encountered in patients treated with biologicals, including mAbs, is represented by the so-called ‘drug-induced hypersensitivity reactions’ that have increased in the last years, compromising the safety of patients. The clinical presentation of hypersensitivity reactions to biological agents ranges from mild cutaneous manifestations to life-threatening reactions. Rapid desensitization could represent a procedure that enables selected patients to receive the full treatment dose in a safe way, in spite of their immediate hypersensitivity reaction to the drug, and protects them against anaphylaxis. In future, the interest will be directed to the advent of the biosimilars of mAbs. Even if newer mAbs are under evaluation, patent expiries and patient demand have fueled the development of biosimilars, which may have up to 40% lower price than reference products. Therefore, the development of biosimilars may lead to a substantial decrease of the costs of biological therapy of immune-mediated diseases, thus assuring the sustainability of the national health systems and allowing the treatment of a Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.

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Frenzel L. Novel uses of rituximab. Rev Prat 2013;63(10):1349-53

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Evans R, Salama AD. Update on rituximab: an established treatment for all immune-mediated kidney diseases? Nephron Clin Pract 2014;126:97-109

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5.

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..

much larger number of patients. A previous drug utilization study [68] on the epoetin use in a general population of Southern Italy (about 650,000 inhabitants) in the years 2010--2011 demonstrated that if biosimilars would have accounted for much larger proportion of the total use of epoetins (40 vs 2%), up to 1.2 million euro yearly would have been saved only concerning this drug class. Although efficacy and safety of biosimilars have to be demonstrated as comparable to the reference product on the basis of the premarketing studies presented to the regulatory agencies, yet minor differences (e.g., amount of glycosylation) in the protein structure that may ultimately affect in vivo activity between biosimilars and reference products may occur due to the complexity of the production process. Nevertheless, the same considerations hold true in case of major changes in the production process of reference products. Given the complexity of mAbs and their relevant immunogenicity, this issue should be carefully considered. Little changes in protein conformation may alter function, insolubility or increase immunogenicity that is a major determinant to loss of clinical efficacy in patients who undergo biological treatments [69]. mAbs represent complex therapeutic proteins for which the alteration of biological function is a great risk in case of protein modification [70]. For all these reasons, short- and long-term post-marketing surveillance for safety and immunogenicity of biosimilars and different lots of originator mAbs is strongly required.

Declaration of interest The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.

Beck LH Jr, Fervenza FC, Beck DM, et al. Rituximab-induced depletion of anti-PLA2R autoantibodies predicts response in membranous nephropathy. J Am Soc Nephrol 2011;22(8):1543-50 This study showed that measuring anti-PLA2R levels may be a useful method to follow and predict response to treatment with rituximab in patients with membranous nephropathy. Ruggenenti P, Cravedi P, Chianca A, et al. Rituximab in idiopathic membranous nephropathy. J Am Soc Nephrol 2012;23:1416-25 In this study, the authors showed for the first time, in a large cohort of high-risk patients with idiopathic


membranous nephropathy the efficacy of rituximab. 7.

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Fervenza FC, Abraham RS, Erickson SB, et al. Mayo nephrology collaborative group: rituximab therapy in idiopathic membranous nephropathy: a 2-year study. Clin J Am Soc Nephrol 2010;5:2188-98 This study showed no difference in terms of proteinuria between patients treated with four doses of RTX versus RTX at 1 g every 2 weeks. Guillevin L, Pagnoux C, Karras A, et al. Rituximab versus azathioprine for maintenance in ANCA-associated


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disease: A joint Italian Society of Rheumatology (SIR), Italian Society of Dermatology (SIDeMaST), and Italian Group of Inflammatory Bowel Disease (IG-IBD) position paper. Autoimmun Rev 2014;13(7):751-5


Affiliation

Domenico Santoro†1,2, Vincenzo Pellicano`2, Luca Visconti2, Gianluca Trifiro`2, Valeria Cernaro2 & Michele Buemi2 † Author for correspondence 1 University of Messina, Department of Internal Medicine and Pharmacology, AOU G.Martino PAD C; Via Consolare Valeria, 98100 Messina, Italy Tel: +39 090 2212331; Fax: +39 090 2212331; E-mail: [email protected] 2 University of Messina, Department of Clinical and Experimental Medicine, Messina, Italy


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Current concepts on monoclonal gammopathies.

Current concepts on monoclonal gammopathies.

Cisplatin and renal injury; current concepts.

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Current concepts in ophthalmology. Retinal vascular diseases.

Current concepts of renal proximal tubular function.

Autoimmune diseases: overview and current concepts of pathogenesis.

Monoclonal antibodies in renal transplantation: a review.

Monoclonal antibodies to renal cancer antigens.

Therapeutic monoclonal antibodies for respiratory diseases: Current challenges and perspectives, March 31 - April 1, 2016, Tours, France.

Current Concepts and Ongoing Research in the Prevention and Treatment of Open Fracture Infections.

Current concepts in bone metastasis, contemporary therapeutic strategies and ongoing clinical trials.

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Current Concepts for Patellar Dislocation.

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