Eculizumab Therapy for Dense Deposit Disease and C3 Nephropathy

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