Standard treatment for primary focal segmental glomerulosclerosis (FSGS) includes administration of corticosteroids and immunosuppressive therapy, with the goals of achieving complete remission of proteinuria and preservation of renal function. When standard treatments fail to induce remission, a number of agents are used as renoprotective therapy to delay progression of chronic kidney disease (CKD) to end stage renal disease (ESRD); however, there is a need for the development of new therapies that are safe and effective for patients with FSGS, particularly those for whom standard therapy fails. The Novel Therapies for Resistant FSGS (FONT II) trial was a randomized, multicenter Phase I/II clinical trial designed to investigate the potential efficacy of novel therapies for resistant FSGS. Two different therapies, adalimumab (a human anti-TNF-α antibody) and galactose, were evaluated against standard conservative therapy for resistant FSGS, which consists of the combination of lisinopril, losartan, and atorvastatin. Additional aims of the study included identification of one or more novel agents as candidates for evaluation in a future Phase III trial and creation of an infrastructure for the timely completion of clinical trials in patients with rare glomerular diseases such as FSGS.

Individuals with primary FSGS confirmed by renal biopsy who failed to respond to prior immunosuppressive therapy were eligible for the study. Participants were required to complete a run-in period in which they were taken off all immunosuppressive medications, including corticosteroids, for 30 days. Participants who achieved an estimated GFR ≥ 30 mL/min/1.73 m2 at the end of the run-in period were randomized to treatment with adalimumab, galactose, or standard conservative therapy. The primary outcome measure, evaluated at 6 months, was a composite of two end points, a reduction of proteinuria by 50% from the baseline value and an estimated GFR (eGFR) that was either ≥ 75% of the value at time of randomization or that was persistently ≥ 75 mL/min/1.73 m2 in those whose renal function was ≥ 75 mL/min/1.73 m2. Adverse effect profile, patient satisfaction score using the TSQM questionnaire, percent change in proteinuria (evaluated as a continuous variable) and change in or time to doubling of eGFR were also assessed as secondary outcome measures.

The study’s primary objective was to compare two different therapies, adalimumab (a human anti-TNF-α antibody) and galactose, against standard conservative therapy for resistant FSGS, which consists of the combination of lisinopril, losartan, and atorvastatin.

The primary outcome measure was a composite of two end points, a reduction of proteinuria by 50% from the baseline value and an estimated GFR that was stable compared to the value at enrollment, both measured at 6 months. Adverse effect profile, patient satisfaction score using the TSQM questionnaire, percent change in proteinuria (evaluated as a continuous variable) and change in or time to doubling of eGFR were also assessed as secondary outcome measures.

Individuals between the ages of 1-51 years who met the following criteria were eligible for enrollment:

• Primary FSGS confirmed by renal biopsy
• Failure to respond to prior therapy with at least one of the following immunosuppressive medications—cyclosporine, tacrolimus, mycophenolate mofetil, sirolimus—or other agents prescribed to lower proteinuria
• Age between 1-50 years at onset of proteinuria
• Estimated GFR ≥ 40 mL/min/1.73 m2 at screening and ≥ 30 mL/min/1.73 m2 at the end of the Run-In Period and prior to randomization
• 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.

Exclusion criteria are documented in the study protocol.

None of the adalimumab-treated subjects achieved the primary outcome, while 2 subjects in the galactose and 2 in the standard medical therapy arm had a 50 % reduction in proteinuria without a decline in eGFR. The proteinuria response did not correlate with serial changes in the serum glomerular permeability activity. Findings suggest that future studies of novel therapies for rare glomerular diseases such as FSGS may benefit from enrollment of patients earlier in the course of their disease.