Rituximab Treatment of Focal Segmental Glomerulosclerosis

Focal segmental glomerulosclerosis (FSGS) remains an enigmatic disease despite many years of
study. There has been a recent increased incidence of FSGS particularly in African Americans
in whom the outcome tends to be worse. In about 30% of patients transplanted for FSGS, the
disease recurs and often results in severe nephrotic syndrome and accelerated graft loss.
FSGS is a common cause of nephrotic disease accounting for 10-20% of cases of idiopathic
nephrotic syndrome in children and 35% of cases in adults. Most cases are refractory to
current therapy resulting in the ultimate progression to end stage renal disease. Overall,
FSGS accounts for about 15% of pediatric and 5% of adult cases of end stage renal disease.
With the frequent post transplant recurrence, the morbidity and mortality of FSGS is
increased. Thus, FSGS is a disease that is associated with a large cost to society and
long-term morbidity to the individual patient. A treatment that could induce permanent
remission and reverse organ damage would make a major contribution to society by reduction of
these expenses. A circulating Permeability Factor (PF, Savin Factor) has been suspected as
central to the pathogenesis of recurrent disease but its identity has been difficult to
discern. The molecular weight has reported to be between 30 and 100 kDa. Although, PF has
been reported to adhere to protein A columns and such columns can be part of the treatment of
FSGS, this molecular weight would exclude PF being an intact antibody. Immunosuppressive
agents have been the only therapy demonstrating efficacy, albeit partial, suggesting that at
least some cases of FSGS are immune mediated. While high dose steroids are the first line of
treatment for FSGS, cyclosporine has been efficacious in randomized trials and has been used
for steroid resistant FSGS but is associated with substantial toxicity. If cyclosporine
fails, cyclophosphamide, plasmapheresis, protein A immunoabsorption, and most recently
mycophenolate mofetil (MMF) have been used with variable efficacy.

Rituximab, primarily indicated for treatment of lymphoma, has become a first line agent in
the treatment of post transplant lymphoma. However, it has been used with increased frequency
to treat various autoimmune diseases including those such as rheumatoid arthritis that have
been thought to be primarily T-cell mediated and others such as immune thrombocytopenia
purpura that have been thought to be primarily B-cell mediated. In a trial being conducted by
the Immune Tolerance Network, ANCA positive vasculitis is being treated with rituximab and it
appears that a short course of rituximab leads to tolerance in this autoimmune disease.
Rituximab's mechanism of action in the various autoimmune diseases for which has efficacy has
been variously suggested to result from elimination of either circulating autoantibody, by
elimination of B-cell produced cytokines, or by interference with the antigen presentation
provide by B cells.

We have recently had a case of immediate post transplant recurrence of FSGS in a child that
failed to respond to MMF, steroids, long-term plasmapheresis and conversion from tacrolimus
to cyclosporine. The FSGS associated proteinuria however completely resolved at about 6
months after treatment of post transplant lymphoma with 6 doses of rituximab. A similar case
that also resolved after treatment of PTLD with rituximab was recently reported. While the
mechanism of action of both cyclosporine and MMF is unknown in FSGS, both drugs have been
shown to have activity against B cells. The response seen in these two recent cases following
treatment with a B cell specific agent leads to the hypothesis that at least some cases of
FSGS have an autoimmune mechanism in which B cells play a central role. We propose to test
this hypothesis by the treatment of patients with recurrent or primary persistent FSGS with
rituximab.

This study will be a single center, single-arm, pilot trial. As the study will be registered
at clintrials.gov, subjects may be referred from outside physicians. However, all treatment
will be done at IU in the GCRC. After meeting inclusion/exclusion criteria and signing the
consent, serum for PF levels, and blood for B cell flow cytometry will be obtained. Rituximab
(375 mg/m2) will be administered intravenously as per current package label in a facility
capable of handling infusion reactions. Subjects would be pre dosed with diphenhydramine and
acetaminophen. Solu-Medrol, 1.5 mg/kg would be dosed 1 hour prior to the first dose of
rituximab. Three subsequent doses of rituximab will be given at weekly intervals. Study
visits will then be conducted monthly thereafter for the 6 months and then every 3 months, at
which time, assessments of safety will be made. Efficacy will be determined by monitoring
first AM Uprotein/C ratio. Flow cytometry, PF factor, urine proteomics and general blood work
including CBC, Chemistry, electrolytes, serum immunoglobulin will also be done. During the
second year, subjects would be followed every three months. The primary endpoint will be
resolution of proteinuria defined as a Up/C ratio of <0.2. Secondary endpoints will be the
number of subjects who achieve partial remission defined at a fall of 50% or more in the Up/C
ratio from the pre-treatment baseline; the number of patients who develop a recurrence or
increase of proteinuria on samples obtained at least 4 weeks apart; effect of treatment on PF
levels; safety as measured by infections and drug infusion reactions. Consideration will be
given to a plan of redosing in subjects who relapse after initial response.

Inclusion Criteria:

1. Primary FSGS involving either native kidneys or primary FSGS recurring after renal
transplantation. Age 5-60 years at onset of signs or symptoms of FSGS

2. Estimated GFR ≥ 40 ml/min/1.73 m2

3. Up/c > 1.0 g protein/g creatinine on first am void

4. Biopsy confirmed as primary FSGS (including all subtypes). At least 1 glomerulus
demonstrating segmental sclerosis or minimal change FSGS or idiopathic mesangial
proliferation with negative immunostains by light microscopy and no dense deposits on
electron microscopy. Biopsy required but can be normal for those subjects with rapid
recurrence of post transplant FSGS.

5. Steroid resistance as defined by primary physician

6. If participant is female with reproductive potential, she must be willing to avoid
pregnancy and have a negative pregnancy test

7. At least one month from last immunization received

Exclusion Criteria:

1. Are immunodeficient or have clinically significant chronic lymphopenia

2. Have an active infection or positive PPD test result

3. Be currently pregnant or lactating, or anticipate getting pregnant

4. Have serologic evidence of current or past HIV, Hepatitis B, or Hepatitis C infection

5. Have any complicating medical issues that interfere with study conduct or cause
increased risk

6. Have a history of malignancies within the last five years except for adequately
treated skin cancer

7. Have severe cardiac problems such as angina or medically treated arrythmia