This state of the art section would not have existed 5 years ago. Replete with FDA approved and FDA not approved, humanized, synthetic or chimeric, monoclonal, polyclonal or fusion antibodies or receptors this group represents an immunologic cornucopia and a semantic and enuciating challenge. Spanning subcutaneous and intravenous routes, these agents run the gamut from the most expensive drug in the world, Eculizumab (more than the price of a 2014 fully loaded Lamborghini Aventador), to a still-in-research-phase but recently patented soluble CR1 receptor. The future of medicine is here in this bracket and one of these teams may very well bind their way to the final four.
Selection committee member for the Biologic Therapies Bracket:
Jonathan Hogan, MD
Assistant Professor of Medicine
Associate Program Director of the Fellowship Training Program
Division of Nephrology, Columbia University Medical Center
Dr. Hogan received his medical school and residency education at the University of Pennsylvania. He completed a fellowship in nephrology at Columbia University Medical Center, followed a Fellowship in Glomerular Diseases under the mentorship of Dr. Gerald Appel at the Glomerular Disease Center at Columbia University. His clinical interests are in the understanding and treatment of glomerular diseases in native and transplanted kidneys. He has written multiple peer-reviewed review articles and book chapters in this field, and is involved in multiple clinical studies in the treatment of glomerular disease.
Meet the competitors for the Biologics Bracket!
(1) Rituximab versus (8) Bortezemib
B cell depletion with the chimeric anti-CD20 monoclonal antibody rituximab is continuing to attract attention in kidney diseases such as systemic lupus erythematosus, vasculitis, and primary glomerulonephritis. Rituximab is probably the most versatile team in NephMadness 2014. Rituximab has been studied and used in multiple disciplines successfully. However, many of its uses are off label and very few instances exists in which rituximab is a first-line agent. However, some uncontrolled data have even demonstrated high response rates in treatment-refractory states. However, it is important to understand that rituximab is associated with toxicity and unique infections, and most importantly the optimal dosing of rituximab in renal disease requires careful attention. The nephrology world has seen the use of this agent beyond glomerular disease, such as antibody mediated rejection (AMR) in kidney transplantation and for desensitization procedure for transplant patients for removal of prior HLA antibodies. The three glomerular diseases that have been studied the most with rituximab are ANCA-associated vasculitis (AAV), idiopathic membranous nephropathy (iMN), and lupus nephritis. Let’s dig a little deeper into the literature.
While many single-center trials first demonstrated that rituximab may have a role in the treatment of AAV, the RAVE and RITUXIVAS trials are the two RCTs that really deserve significant mention. RAVE demonstrated that in patients with severe ANCA-associated vasculitis, rituximab therapy was not inferior to daily oral cyclophosphamide treatment (with both groups receiving steroids) for induction of remission, and may be superior in relapsing disease. The recently published RAVE follow-up demonstrated that a single course of rituximab was as effective as continuous conventional immunosuppressive therapy with oral cyclophosphamide followed by azathioprine for maintaining remissions over the course of 18 months. RITUXIVAS showed that rituximab-based regimen was not superior to standard intravenous cyclophosphamide for severe AAV with renal involvement. Although remission rates were high in both groups, the rituximab-based regimen was not associated with reductions in early severe adverse events. These studies have helped to at least give some traction for the use of anti-B cell therapy in ANCA vasculitis.
Now lets take a look at lupus nephritis. Rituximab has been shown (in uncontrolled case series) to be effective in refractory lupus nephritis. However, in the landmark 2012 LUNAR trial, while rituximab add-on therapy led to more responders and greater reductions in anti-dsDNA and C3/C4 levels compared to placebo, it did not improve clinical outcomes after 1-year of treatment. Similar to the AAV story, the matchup against classic lupus nephritis treatment was a draw to say the least.
With regard to IMN, rituximab is an exciting potential therapy. The mechanism of action of rituximab could be more specific than conventional cytotoxic therapy. This is because rituximab could potentially remove the deleterious B cells that produce the implicated anti-PLA2R antibody. However, it may be more advantageous to target the antibody-producing powerhouse plasma cells. A recent review published in CJASN evaluated all studies using rituximab in iMN (n=21). All of these studies were uncontrolled case reports or case series, and more than half of the published cases (50 of 85 cases) came from a single center where rituximab was used as primary immunosuppressive therapy for iMN. The results of ongoing RCTs will help to determine the role of rituximab in treating iMN.
Rituximab has a lot of name recognition and hype but so far hasn’t established a real track record in RCTs in nephrology with the exception of ANCA-vasculitis. For these reasons rituximab will have to overachieve to make it far in this year’s NephMadness tournament.
Bortezomib is an anti-myeloma agent that has recently entered the nephrology world via its use in kidney transplantation. Bortezomib is a proteosome inhibitor and has anti-plasma cell (antibody-producing cell) activity. In severe cases of antibody-mediated rejection that are potentially mediated by plasma cells, this agent has shown promise with good remission rates. What about other glomerular diseases? A recent case report demonstrated success of treatment with bortezomib in idiopathic membranous GN. Proteosome proteolysis is crucial for the degradation of the inhibitory protein (IkB) of nuclear factor kB (NF-kB), and hence, an interesting field of research has been developed with drugs having anti-proteasome activity, particularly in diseases with hyper-expression of NF-kB. Proteosome inhibitors are being adopted in pilot studies in antibody-mediated rejection and in AL amyloidosis. Other possible applications of bortezomib are in lupus, IgA nephropathy, idiopathic nephrotic syndrome and renal fibrosis. A basic science model of lupus nephritis showed attenuated kidney disease using bortezomib and there is an ongoing clinical trial in the use of this agent in proliferative lupus nephritis. Furthermore, a study is underway utilizing bortezomib in IgA nephropathy.
Bortezomib is a true star in the myeloma world. How will all of this success translate into the kidney realm? This will be a true test for bortezomib. If they can break through and provide a needed therapy for many kidney disease this will be a huge welcome to nephrologists and patients alike. Like many in this bracket, this is an upstart with talent and potential.
(3) Belimumab versus (6) Belatacept
Belimumab is a human monoclonal antibody that inhibits the B cell activating factor (BAFF). Belimumab has been approved for the use in systemic lupus. These drugs prevent B cell proliferation and hinder development into mature plasma cells with a resulting drop in antibody production. This mechanism of action is very well-suited to lupus whose pathophysiology is thought to involve autoantibody formation. The approval of belimumab was based on a 52-week study known as BLISS-52 trial published in Lancet in 2011. BLISS-52 enrolled 865 patients in 13 countries outside North America and randomized active lupus patients to 10mg/kg belimumab, 1 mg/kg belimumab, or placebo in addition to their standard lupus medications. Belimumab was administered IV 2 weeks apart for the first 2 doses, and then every 4 weeks. The study met primary endpoint and the response rates were 57.6%, 51.7% and 43.6% for belimumab 10 mg/kg, 1 mg/kg, and placebo, respectively. In addition to improvement in various clinical measurements of disease activity, patients were also able to reduce steroid dosages. Notably, the drug was well-tolerated and the safety profile, including the infection rate, was comparable to the placebo arm. What about patients with kidney disease and lupus? A post hoc analysis of the BLISS-52 trial showed that many indices of kidney involvement and serologic activity favored the belimumab. However, the differences seen between groups in a majority of kidney outcomes were not statistically significant. Among the 267 patients with CKD at baseline, those receiving mycophenolate mofetil or with serologic activity at baseline had greater improvement of kidney indices with belimumab. This suggests that there might be some kidney benefit with this agent but we have to keep in mind that severe lupus nephritis patients were excluded from the trial.
Belimumab has only made progress in lupus thus far. But again this is a biologic that has tremendous potential. I’m looking forward to the first round matchup with the belatacept.
Belatacept is a costimulatory blockade related antibody (CTLA-4 inhibitor). The BENEFIT trial published in the American Journal of Transplantation in 2010 put belatacept on the map. This trials aim was reducing the kidney damage commonly ascribed to calcineurin inhibitor toxicity in kidney transplant patients. Besides acute rejection rates early on, long-term kidney survival was significantly improved in the belatacept group than than calcineurin inhibitor group. The BENEFIT-EXT trial that followed showed that extended criteria kidney transplant recipients treated with belatacept achieved similar patient/graft survival, better kidney function, had an increased incidence of post transplant lymphoproliferative disorder, and exhibited improvement in the cardiovascular/metabolic risk profile versus cyclosporine-treated patients. At 3 years, immunosuppression with belatacept resulted in similar patient survival, graft survival and acute rejection, with better renal function compared with cyclosporine.
Belatacept has emerged as a true player in the kidney transplant arena. Calcineurin inhibitors are staples that help prevent rejection but unfortunately ravage the kidney. The use of this drug could really extend the life of the transplanted kidney. However, administration issues and cost make belatacept a difficult sell to the masses. Belatacept has great potential to go far in NephMadness 2014. The large clinical trials have been performed and now we as a nephrology community need to see where this drug fits into the transplant repertoire of drugs.
(5) Eculizumab vs. (4) Soluble CR1
Eculizumab is a recombinant humanized monoclonal antibody against C5 in the terminal complement cascade. It is FDA-approved for use in two disorders of the alternative complement system, paroxysmal nocturnal hemoglobuinuria (PNH) and atypical hemolytic uremic syndrome (aHUS). Similarly, in glomerular disease, interest in eculizumab lies in the treatment of the C3 glomerulopathies (C3 GN and dense deposit disease), a recently discovered group of disorders of the alternative complement pathway that result in C3 deposition on immunofluorescence and often times to a MPGN pattern on light microscopy. The largest published experience of eculizumab use in the C3 glomeruopathies was a case series of 6 patients (3 with C3 GN, 3 with DDD), three of whom had improvement in clinical parameters (serum creatinine or proteinuria), and in many cases, the soluble membrane attack complex (sMAC) level improved with therapy. The identification of patient-specific defects in the alternative complement pathway may help to determine which patients may benefit from this therapy.
Complement receptor-1 (CR1) inhibits both C3 and C5 convertases of the classical and alternative complement cascade. It has been shown that recombinant soluble CR1 (sCR1) effectively blocks complement activation in vitro and in vivo. Therefore, it has been postulated that sCR1 may be a useful treatment in patients with a dysregulated complement activation such as in dense deposit disease. sCR1 acts by targeting C3 convertase and thus would affect the alternative complement cascade more proximally than eculizumab and possibly preventing the deposition of C3 in glomeruli and halt disease progression. A recent paper in the JCI showed that aCR1 was capable of restoring complement function in 2 patients with mutations in the complement factor H-related (CFHR) gene cluster. sCR1 was found to stop activation of the alternative complement pathway in one patient with dense deposit disease and ESRD. A basic science study utilizing soluble CR1 during cardiopulmonary bypass showed some promise in reducing complement activation and subsequent organ damage. Its utility in affecting clinical disease will depend on further study. Soluble CR1 is truly a diaper dandy of the group. This is almost completely untested but we are in desperate need of novel therapy that target the complement cascade.
(7) ACTHar gel vs. (2) Abatacept
Just like belatacept in kidney transplantation, abatacept is an inhibitor of co-stimulatory molecule CD80 (a.k.a. B7-1) in T-cell signaling. It has been approved for use in RA for patients that fail TNF alpha inhibition. In a NEJM case series recently, the authors described six cases and how this agent helped improve proteinuria. Taking a step further, they found that post-transplant, not all proteinuric FSGS stained for B7-1 in the kidney biopsy. They only treated the B7-1 positive FSGS strain with this agent to show response. A table in the NEJM paper shows the 5 patient characteristics. Four patients were post-transplant FSGS and had failed rituximab. Two of the four responded to just one dose of 10 mg/kg of abatacept and the two remaining needed 2 doses of 10 mg/kg. This is remarkable that just few doses put the disease in remission. They had 36-48 follow up data on all of them and still in remission. The patient 5 was a nontransplanted primary FSGS case which was B7 positive and also responded to this agent but required monthly dosages for a year. Given transplant patients are on other agents that target the immune system, one dose might be sufficient compared to native FSGS. In addition, there is some interest in the role of this agent in lupus nephritis and diabetic nephropathy.
ACTHar gel is a 39-amino acid peptide form of the naturally occuring adrenocorticotropic hormone (ACTH). ACTHar gel works by stimulating the adrenal cortex to secrete cortisol, corticosterone and aldosterone. ACTHar gel was popularized in the 1960s for the treatment of a variety of conditions (in fact, 19 FDA-approved indications exist!). ACTHar gel was initially approved by the FDA in 1950 and, similar to other corticosteroids, is indicated for numerous autoimmune, allergic and inflammatory conditions in adults. Believe it or not, ACTHar gel is the only FDA approved “treatment” for nephrotic syndrome. Here is the exact indication from the FDA:
“Inducing a diuresis or a remission of proteinuria in the nephrotic syndrome without uremia of the idiopathic type or that due to lupus erythematosus.”
Currently, it has re-emerged since 2009 as a potential treatment for refractory proteinuric diseases. In a small prospective trial that included patients with idiopathic membranous nephropathy and minimal change disease, ACTHar gel showed promise in inducing remission of proteinuria in refractory disease. Prior to that, the landmark paper by Bomback et al showed that in 21 patients with nephrotic syndrome of various etiologies, that ACTHar gel was capable of achieving remission. However, this was an uncontrolled study. Pontecelli performed a vigorous RCT with synthetic ACTH in membranous nephropathy in 2006 pitting ACTHar gel against his own Pontecelli regimen and found ACTHar gel to be non inferior. What about its use in FSGS? The largest experience is a recent case series of mostly steroid-resistant and steroid-dependent patients. This suds showed that 29% of patients experienced a remission with ACTHar gel therapy. However, given its significant cost ($28,000 a vial) and high frequency of steroid-like side effects, more data is needed to determine the role that syntheic ACTH will play in the treatment of FSGS or other glomerular diseases. A search query in clinical trials suggest ongoing or completed trials in use of this agent in lupus nephritis, diabetic nephropathy and resistant nephrotic syndrome. ACTHar gel is an interesting opponent. They have FDA approval for a condition that is hard to earn. This is mainly because this indication was earned before rigorous randomized trials and safety data were required for such approval. That being said. ACTHar gel is gaining popularity in a world where case reports and series still predominate the landscape. ACTHar gel will be a team to watch in NephMadness as clinical trials are only now being performed.
-Written and Edited by Kenar Jhaveri and Jonathan Hogan