Novel Therapies for Resistant FSGS (FONT II): Phase II Clinical Trial

SPECIFIC AIMS A significant percentage of patients with primary FSGS are resistant to
corticosteroids and other immunosuppressive medications. In view of the rising incidence of
this disease and the grim prognosis for patients with resistant disease, it is imperative
that new therapeutic approaches be evaluated in an efficient and systematic manner. This
will enable accurate assessment of the risk-benefit ratio of novel therapies and guide the
design of future Phase III randomized clinical trials.

Specific Aim #1: To evaluate two novel therapies for resistant FSGS -- anti-TNF-α antibody
and galactose -- against standard therapy

Specific Aim #2: To identify one or more novel agents as candidates for future study in a
Phase III randomized clinical trial

OVERALL STUDY DESIGN Screening/Run-In: There is no formal run-in period in the phase II
trial because patients with resistant FSGS who will be eligible for this study often have
unstable kidney function and are prone to sudden decline in GFR. An effort will be made to
achieve randomization within 2 weeks of the screening visit.

In order to achieve a comparable baseline assessment prior to initiation of one of the novel
therapies, the patients must be off all immunosuppressive medications for 30 days. In
addition, patients will be placed on the maximal tolerated doses of an ACEI, an ARB, and a
lipid-lowering drug defined above based upon measurements of blood pressure, serum K+,
creatinine, and cholesterol concentrations. Patients will have to be on stable doses of the
ACEI/ARB treatment for a minimum of 2 weeks prior to randomization into the FONT Phase II
study to insure that the initiation of novel therapy does not coincide with a
hemodynamically induced change in proteinuria. In order to implement this part of
conservative medical therapy, a 2-12 week Screening/Run-In period will precede
randomization. Rescreening will be necessary if patients are not randomized to one of the
three treatment arms within 12 weeks of the initial screening assessment.

Duration of novel therapy: Novel therapies will be administered for 6 months before
assessing efficacy, i.e., >50% reduction in proteinuria. Although the novel therapies target
renal fibrosis, it is anticipated that this period of treatment will be sufficient to
document a beneficial effect on proteinuria.

Screening/Run-In: There is no formal run-in period in the phase II trial because patients
with resistant FSGS who will be eligible for this study often have unstable kidney function
and are prone to sudden decline in GFR. An effort will be made to achieve randomization
within 2 weeks of the screening visit.

In order to achieve a comparable baseline assessment prior to initiation of one of the novel
therapies, the patients must be off all immunosuppressive medications for 30 days. In
addition, patients will be placed on the maximal tolerated doses of an ACEI, an ARB, and a
lipid-lowering drug defined above based upon measurements of blood pressure, serum K+,
creatinine, and cholesterol concentrations. Patients will have to be on stable doses of the
ACEI/ARB treatment for a minimum of 2 weeks prior to randomization into the FONT Phase II
study to insure that the initiation of novel therapy does not coincide with a
hemodynamically induced change in proteinuria. In order to implement this part of
conservative medical therapy, a 2-12 week Screening/Run-In period will precede
randomization. Rescreening will be necessary if patients are not randomized to one of the
three treatment arms within 12 weeks of the initial screening assessment.

Duration of novel therapy: Novel therapies will be administered for 6 months before
assessing efficacy, i.e., >50% reduction in proteinuria. Although the novel therapies target
renal fibrosis, it is anticipated that this period of treatment will be sufficient to
document a beneficial effect on proteinuria.

Frequency of visits: Patients will be evaluated after 0, 2, 8, 16, and 26 weeks of treatment
with the novel therapy or conservative medical therapy alone. Thus, there will be a total of
6 visits during the treatment period. A follow-up evaluation will be performed at 1 month, 3
months, and 6 months after discontinuation of the novel therapy, and then every 6 months
until the end of the funding period.

Baseline studies

1. Interval History and physical examination

2. Urine protein and creatinine excretion Proteinuria (Up/c) will be expressed as the
protein: creatinine ratio (mg: mg) in an early morning specimen.

3. Serum creatinine and calculated GFR, glucose, albumin, pregnancy test

4. A urine, plasma, serum and DNA sample will be collected for storage in the NIDDK
FSGS-CT Biorepository. A request will be made to store any residual renal tissue
collected for clinical indications during the FONT trial in the NIDDK Biorepository.

Follow-up assessment: Week 2, 8, and 16 Visits

1. Interval history, physical examination, assessment of adverse events

2. First morning urine protein excretion

3. Laboratory analysis as charted below. Urine pregnancy test at 8 and 16 week visit

Final Outcome Visit (Week 26)

1. History and physical examination

2. Morning urine protein and creatinine excretion x 2 (The value will represent the
average of two samples collected during the week before the visit.)

3. Serum creatinine and calculated GFR, Serum Na+, K+, HCO3, Cl-, glucose, CPK

4. BUN, albumin, cholesterol, AST, ALT, alkaline phosphatase, CBC, ANA, C3 levels,
pregnancy test

5. Urine, serum and plasma for biorepository

6. TSQM patient questionnaire

Preliminary safety, patient tolerance, and PK data for the two novel therapies,
rosiglitazone and adalimumab, that will be used in the Phase II trial were generated through
the successful performance of a Phase I study.

In the phase I study, a total of 21 patients were enrolled. 11 were assigned to receive
rosiglitazone, and 10 were assigned to receive adalimumab. The patients were evenly divided
by gender and pubertal stage. All patients had a GFR >50 mL/min/1.73 m2.

There were no serious adverse events necessitating the withdrawal of study drug.

Rosiglitazone was stopped in one child due to a questionable allergy. The patients tolerated
the experimental medications adequately based on the results of the Treatment Satisfaction
Questionnaire for Medication (TSQM) which was administered at week 16.

The PK analyses indicated that the rosiglitazone dose needs to be increased to account for
increased clearance and reduced area under the curve in patients with resistant FSGS and
nephrotic range proteinuria. For adalumimab, clearance was also enhanced especially after
receiving multiple doses. However, these results of the adalimumab PK analyses indicate that
no dose adjustment was required.

The PK data for each drug were presented in abstract form at the annual meeting of the
American Society of Nephrology and a manuscript summarizing the complete findings in
patients treated with rosiglitazone has been submitted for publication.

This Phase II will again rely on the considerable investment of time and resources on the
part of the study investigators and the NIH/NIDDK gained through the FSGS-CT (UO1-DK-63455)
and the Phase I portion of the FONT study (DK70341). Schneider Children's Hospital (SCH) and
University of North Carolina-Chapel Hill (UNC) resources including the GCRCs that were
utilized in the R21phase of them study will be available for the R33 portion of the FONT
project.

Preliminary safety, patient tolerance, and PK data for the two novel therapies,
rosiglitazone and adalimumab, that will be used in the Phase II trial were generated through
the successful performance of a Phase I study.

In the phase I study, a total of 21 patients were enrolled. 11 were assigned to receive
rosiglitazone, and 10 were assigned to receive adalimumab. The patients were evenly divided
by gender and pubertal stage. All patients had a GFR >50 mL/min/1.73 m2.

There were no serious adverse events necessitating the withdrawal of study drug.

Rosiglitazone was stopped in one child due to a questionable allergy. The patients tolerated
the experimental medications adequately based on the results of the Treatment Satisfaction
Questionnaire for Medication (TSQM) which was administered at week 16.

The PK analyses indicated that the rosiglitazone dose needs to be increased to account for
increased clearance and reduced area under the curve in patients with resistant FSGS and
nephrotic range proteinuria. For adalumimab, clearance was also enhanced especially after
receiving multiple doses. However, these results of the adalimumab PK analyses indicate that
no dose adjustment was required.

The PK data for each drug were presented in abstract form at the annual meeting of the
American Society of Nephrology and a manuscript summarizing the complete findings in
patients treated with rosiglitazone has been submitted for publication.

This Phase II will again rely on the considerable investment of time and resources on the
part of the study investigators and the NIH/NIDDK gained through the FSGS-CT (UO1-DK-63455)
and the Phase I portion of the FONT study (DK70341). Schneider Children's Hospital (SCH) and
University of North Carolina-Chapel Hill (UNC) resources including the GCRCs that were
utilized in the R21phase of them study will be available for the R33 portion of the FONT
project.

Inclusion Criteria:

- Primary FSGS confirmed by renal biopsy OR documentation of a genetic mutation in a
podocyte protein associated with the disease

- Failure to respond to prior therapy at least one of the following immunosuppressive
medications -- cyclosporine, tacrolimus, mycophenolate mofetil, sirolimus - or other
agents prescribed to lower proteinuria

- Age 1-65 years at onset of proteinuria

- Age 1-65 years at time of randomization

- Estimated GFR ≥40 mL/min/1.73 m2 using Schwartz (age <18 yr) or Cockroft-Gault (age
<18 yr) formula at screening and ≥30 mL/min/1.73 m2 at the end of the Run-In Period
and at the time of randomization

- Up/c > 1.0 g/g creatinine on first morning void

- Steroid resistance defined as failure to achieve sustained Up/c < 1.0 following a
standard course of prednisone/prednisolone/methylprednisolone prescribed for FSGS
therapy, OR contraindication/anticipated intolerance to steroid therapy defined as
severe obesity, documented decreased bone density, family history of diabetes, or a
psychiatric disorder.

- Willingness to follow the protocol, including medications, baseline and follow-up
visits, and procedures.

Exclusion Criteria:

- Lactation, pregnancy, or refusal of birth control in women of child bearing potential

- Participation in another therapeutic trial involving protocol mandated administration
of a immunosuppressive medication concurrently or 30 days prior to randomization

- Active/serious infection (including, but not limited to Hepatitis B or C, HIV)

- History of malignancy

- Abnormality in age appropriate cancer screening in accord with ACS 2003 guidelines
(appendix 17.6)

- Patients with uncontrolled blood pressure > 140/90 or > 95th percentile for
age/height at the end of the run in period

- Diabetes mellitus Type I or II

- Organ transplantation

- Congestive heart failure

- History of prior myocardial infarction

- SLE or multiple sclerosis

- Hepatic disease, defined as serum ALT/AST levels more than 2.5x the upper limit of
normal

- Hematocrit <27%

- Immunosuppressive therapy with cyclosporine, tacrolimus, mycophenolate mofetil,
azathioprine, or rapamycin in the 30 days prior or Rituximab in the 90 days prior to
randomization

- Prior treatment with the study medications, rosiglitazone or adalimumab

- Allergy to one of the study medications, i.e., rosiglitazone, adalimumab, lisinopril,
losartan or atorvastatin