There is an urgent need to systematically develop and evaluate novel therapies for patients with resistant primary FSGS because the disease is becoming more prevalent and the risk of progressive loss of kidney function is especially high in those who do not achieve a reduction in proteinuria in response to standard immunosuppressive therapy. The rationale for the FONT trial is that absent a consistent immunolopathological target of treatment, interventions designed to reduce renal fibrosis offer the best hope of stabilizing kidney function and preventing or attenuating the steady decline in kidney function and the need for renal replacement therapy. This approach is feasible in patients with primary FSGS, irrespective of whether it is linked to genetic mutations in podocyte proteins or if there is no demonstrable molecular basis for the glomerular disease .
The results of FONT Phase I study indicate that adalimumab and rosiglitazone are safe and generally well tolerated in patients with primary FSGS. In addition, pharmacokinetic analyses indicate that because of a reduced area under the curve and enhanced clearance, the dosage of both agents needs to be modified upward in order to achieve drug levels that are comparable to those observed when the drugs are used for FDA approved indications in patients with normal kidney function and without nephrotic-range proteinuria [11, 12]. The outcomes of the two Phase I trials justify moving forward with the assessment of these two agents. Clarification of any benefit of rosiglitazone and/or adalimumab therapy requires the performance of a randomized clinical trial in which the efficacy of these antifibrotic agents is compared to a parallel group given conservative medical therapy alone - an angiotensin converting enzyme inhibitor, an angiotensin receptor blocker, and a statin. This question hopefully will be answered in the ongoing FONT Phase II trial.
Determination of the efficacy of adalimumab and rosiglitazone as antifibrotic agents in resistant primary FSGS will require performance of Phase II and III randomized controlled studies that enroll a sufficient number of patients and have statistical power to demonstrate a clinically significant effect on hard endpoints such as change in GFRe or on surrogate markers like proteinuria. However, therapeutic treatment period and follow-up interval in clinical trials are often not long enough to adequately demonstrate differences in clinically relevant hard renal outcomes such as doubling of serum creatinine and need to initiate renal replacement therapy . Therefore, an important consideration in evaluating novel therapies for renal disease is to ascertain whether the impact of the experimental intervention is prolonged and is manifest even after discontinuation of the study drug. This accounts for our focus in this report on GFRe rather than surrogate markers like proteinuria and blood pressure that are detailed in the primary reports of the FONT Phase I trials [11, 12]. The FDA has strongly recommended that this type of assessment be incorporated into the analysis of efficacy novel therapies for glomerular disorders . The 'legacy" effect has been examined in studies that tested interventions to lower serum glucose concentration and blood pressure in patients with diabetes [16–18]. However, this type of analysis has not become a standard element in the design of clinical trials in nephrology, especially those involving pediatric patients.
This report represents an initial step in this direction by comparing the slope of the GFRe versus time curve prior to and after treatment with adalimumab or rosiglitazone in the FONT Phase I study. To the best of our knowledge, this is first time such an assessment has been conducted in patients with primary FSGS. The results indicate that approximately 30% of 21 patients had a clinically measurable slowing of the rate of deterioration in kidney function for up to a year after the 16-week treatment with either adalimumab or rosiglitazone. We acknowledge that the number of patients in each group is small, consistent with a Phase I study. Therefore, it is premature to draw any conclusion about the efficacy of the test therapies without studies involving a larger cohort given the antifibrotic agents for an extended period or to make any meaningful comparison between the two treatments.
There are several limitations to this study. The use of formulas to estimate GFR in children and adults is the subject of ongoing controversy. Newer formulas have been proposed that may predict the level of kidney function more accurately [19, 20]. The age-appropriate Schwartz and Cockcroft-Gault formulas were used consistently for the entire study period and, therefore, changes in GFRe should not be effected by shortcomings in the formulas, per se. We did not rely on the MDRD formula which is inaccurate in patients with GFRe greater than 60 ml/min/1.73 m2 . In addition, the serum creatinine measurements used to calculate GFRe during follow-up were not performed in a central laboratory or standardized. Nonetheless, they were consistent for each patient and should reflect disease progression in individual cases.
We acknowledge that it would be premature to speculate on the frequency and magnitude of long-term benefit of antifibrotic therapy based on this small relatively heterogeneous cohort. The clinical ramifications of the change in the slope of the GFRe versus time line needs clarification in larger series of patients. However, one cannot gainsay the value of studies like the FONT trial in which there are well defined criteria for enrollment and patient management is controlled. Finally, because the follow-up was conducted after completion of the formal protocol, the treatments that the patients in each group received were uncontrolled. Therefore, we cannot attribute any beneficial long-term effect on GFRe to a delayed effect of the FONT antifibrotic interventions or to the uncontrolled therapies prescribed during the post-FONT treatment period.