Eculizumab Therapy for Dense Deposit Disease and C3 Nephropathy
Eculizumab Therapy for Dense Deposit Disease and C3 Nephropathy
This open label, non-blinded, proof of concept efficacy and safety study of eculizumab in
 patients with biopsy proven DDD or C3 nephropathy. The trial will consist of adult patients
 with these diseases who have > 1 gram of proteinuria or a decreased glomerular filtration
 rate (GFR), both predictors of a poor long-term outcome in many glomerular diseases. The
 patients will be treated with eculizumab for one year.

 The goals will be to determine whether treatment leads to an improvement in kidney function,
 defined by remissions of proteinuria and improvements in estimated GFR (measured by serum
 creatinine), and to improvement in histologic parameters, including percentage of
 non-affected glomeruli, interstitial fibrosis, intensity of C3 staining of
 immunofluorescence, and amount of electron dense deposits by electron microscopy.
Dense deposit disease (DDD), also called membranoproliferative glomerulonephritis (MPGN) type
 II, is a rare form of glomerulonephritis named because of the characteristic appearance of
 electron-dense material in the glomerular basement membrane observed on kidney biopsy. The
 principle immune defect in DDD is excessive activation of the alternative complement pathway,
 with deposition of complement components in the glomerular basement membrane. Hence, by
 immunofluorescence microscopy, there is heavy C3 deposited along the basement membrane. Some
 patients have been found to have deficiencies of Factor H or Factor I, inhibitors of C3
 activation. Others have a C3 nephritic factor, an antibody that activates the alternative
 complement cascade. It has recently been recognized that C3 nephropathy, a rare glomerular
 disease with mesangial cell proliferation and C3 deposition by immunofluorescence microscopy,
 is associated with similar over-activation of the alternative complete cascade.

 While DDD affects mostly children and young adults, in the series of 32 patients from
 Columbia with DDD whose biopsies were read from 1977-2007, 18 patients (56%) were older than
 16 years of age at the time of diagnosis, and about 40% of patients were over 30 years old.
 The age division is important for two reasons. First, in the Columbia series, children
 appeared to have better clinical outcomes than adults. While 25.9% of all patients had a
 complete remission, there was a significant distinction between adults, of whom only 7.1%
 achieved complete remission, and children, of whom 46.1% achieved complete remission. Of the
 remaining patients who did not achieve remission, 42.9% of adults, compared to only 7.7% of
 children, progressed to end stage renal disease (ESRD) over a mean follow-up of over 5 years.
 Second, as there are no large clinical trials to guide specific interventions for DDD and the
 role of immunomodulatory therapies still remains controversial, many nephrologists advocate
 using immunomodulatory therapy only in selected adult patients.

 Immunomodulatory therapies not specifically targeted to DDD, such as corticosteroids,
 cyclophosphamide, and calcineurin inhibitors, have either been unsuccessful or not studied in
 a meaningful number of patients to warrant routine use. However, as the principal defect
 underlying DDD is excessive activation of the alternative complement pathway, with deposition
 of complement components in the glomerular basement membrane, a therapy that directly targets
 the alternative complement pathway may prove particularly beneficial for this disease.

 Eculizumab is a humanized monoclonal antibody that binds with high affinity to C5. The drug
 is FDA-approved for the treatment of paroxysmal nocturnal hemoglobinuria (in which mutations
 of complement regulatory proteins on hematopoietic cells lead to alternative complement
 pathway-mediated hemolysis). It is currently being studied for use in atypical hemolytic
 uremic syndrome, a rare disease marked by diffuse micro-thromboses related to activation of
 the alternative complement system. Eculizumab prevents cleavage of C5, thereby precluding
 formation of C5a, which has been implicated in glomerular inflammation in animal models of
 DDD. Moreover, by inhibiting the activation of C5, it prevents the formation of the membrane
 attack complex C5-9. Speculatively, this drug could provide effective, targeted therapy for
 patients with DDD.
Inclusion Criteria:

 -  Adult patients with biopsy proven DDD or C3 nephropathy, at least 18 years of age

 -  24-hour urine protein > 1000 mg/day, urine protein:creatinine ratio > 1.0, or acute
 renal failure (defined as > 50% increase in serum creatinine from baseline)

 -  Willing and able to sign informed consent

 -  Patients of childbearing age must agree to use birth control

 -  Patients must be willing to be vaccinated against meningococcal disease or have
 documentation of previous vaccination against meningococcal disease

 Exclusion Criteria:

 -  Patients under 18 years of age

 -  Patients unable to sign informed consent

 -  Patients having received rituximab or another monoclonal antibody within 6 months of
 the trial

 -  Patients currently taking and unable to discontinue other immunomodulatory therapies
 (e.g. cyclosporine, high-dose steroids, mycophenolate mofetil) unless these other
 therapies are indicated for prophylaxis of transplant rejection (e.g. stable doses of
 mycophenolate mofetil and/or calcineurin inhibitor). Patients on chronic steroid
 therapy who are unable to taper down to <10 mg/day will be excluded.

 -  Patients of childbearing age who refuse to use birth control

 -  Patients with a baseline estimated GFR less than 30 ml/min/1.73m2

 -  Patients with other renal diseases (e.g. diabetic nephropathy, renal vascular disease)
 that would interfere with interpretation of the study.

 -  Patients with comorbid conditions that would interfere with completion of the trial
 (malignancies, congestive heart failure (CHF), recent myocardial infarction).

 -  Patients with known contraindications to the use of eculizumab, including refusal to
 receive N. meningitides vaccine prior to therapy