NephMadness 2014 • Biologics • First Round Results

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Rituximab versus Bortezomib

Winner: Rituximab

Rituximab versus bortezomib was a tough battle. Both agents are borrowed from our oncology colleagues. They also affect similar cell types. For ritux it’s the B cell and for bortez it is the plasma cell. They have really made a significant addition to the nephrology drug arsenal in transplantation. Bortezomib is an anti-plasma cell agent that has made some progress in acute kidney rejection but unfortunately we are still awaiting its widespread use in glomerular diseases. On the other hand, rituximab has the upper hand in both transplantation and glomerular diseases. Let’s take a look at some adverse effects regarding both these agents. While cardiac arrest and anaphylactic reactions have been reported with rituximab, the major concern is development of progressive multifocal leukoencephalopathy (PML). PML, although rare, has been reported in patients treated with rituximab in both cancer and with lupus. Whether this is a drug effect or a net immunosuppression effect is hard to differentiate. Infectious complications are common with rituximab as well. What about bortezomib? Bortezomib is associated with peripheral neuropathy in 30% of patients. Occasionally, this neuropathy can be painful. It seems to be a side effect of proteasome inhibitors. The myelosuppressive side effects of bortezomib appear to be minor. Rituximab advances to the next round given the vast use of this agent in the nephrology world for various disorders. However, there is hope for bortezomib for the future as reducing the production of pathologic antibodies via plasma cells sounds like an attractive approach to a number of glomerular diseases. Bortezomib is a team for the future, but unfortunately the future is not yet here. We have more experience with rituximab but this could be the peak of its run.

Belimumab versus Belatacept

Winner: Belatacept

A post-hoc analysis of the BLISS-52 trial showed that many indices of kidney involvement and serologic activity favored the use of belimumab in patients with lupus. Remember belimumab works by inhibiting B cell activation by blocking the B cell activating factor (BAFF). However, the differences seen between groups (mycophenolate vs. mycophenolate + belimumab) in a majority of kidney outcomes were not statistically significant. This suggested 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. It is possible that in patients with more severe kidney involvement with lupus that belimumab might be more effective. On the other hand, belatacept is on a roll in kidney transplantation. And this is where the difference was made in NephMadness 2014. A quick search of ongoing clinical trials shows several ongoing studies on use of belatacept in transplantation. Calcineurin inhibitors allowed us to think of “steroid free” protocols in transplantation. While belatacept has provided the potential for “calcineurin free” protocols? What is most common cause of CKD in the post transplantation world? That would be calcineurin inhibitor toxicity. Has the era begun for calcineurin-free care? Belatacept clearly wins this round to match up against the almighty rituximab.

Eculizumab versus Soluble CR1

Winner: Eculizumab

This was an interesting match-up. Complement inhibition versus complement inhibition. However, you have a more specific inhibition with soluble CR1. Soluble CR1’s youth and inexperience really showed against the almighty eculizumab. Eculizumab has taken the nephrology and hematology world by storm. With cases of Shiga toxin–associated HUS even treated, such a record landed this drug in NEJM and puts it right in the spotlight. The cases had such great recovery. Furthermore, NEJM also published a letter on a case of refractory MPGN, but it is the atypical HUS syndromes where this agent made its home. Soluble CR1 has a long way to go still as it is currently only being evaluated in basic science models. Great concept and more specific, but eculizumab takes this one with a landslide victory.

ACTHar gel versus Abatacept

Winner: ACTHar Gel

Abatacept made its big splash into the nephrology scene in 2013 in this NEJM paper. Success was seen in patients with glomeruli that stained positive for B7-1 in a variety of nephrotic diseases. While this agent is very specific and showing great promise in glomerulonephritis and posttransplant glomerulonephritis, ACTHar Gel upset this promising agent. One of the biggest reasons is the lack of properly conduced randomized clinical trials for Abatacept.  Right now all we have is small case series. ACTHar Gel has its issues as well but it has been around for a long time and its use and study is starting to spread again. One of the earliest records of use of this dates to the 1950s in a historic paper from JAMA pertaining to children, as well as another report of cases from Canada in the same era. The landmark paper by Bomback et al showed that in 21 patients with nephrotic syndrome of various etiologies, ACTHar gel was capable of achieving remission. This brought the drug back to limelight in 2009 and rest is history. ACTHar gel upsets Abatecept in this match up.

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