“Living with FSGS [focal segmental glomerulosclerosis] impacts every aspect of my life…physically, mentally, financially. It’s hard to keep hope sometimes. It’s not just the medical bills…it’s the travel [to see a specialist out of state]; it’s the time spent talking to insurance companies and pharmacies. There is physical fatigue and emotional exhaustion that impact the day to day. My body has changed so many times because of the disease and treatments that I’ve had to buy a whole new wardrobe multiple times…. Every aspect of your life is totally flipped around,” shared Becky Bunker, a person living with FSGS for 2.5 years.
In recent years, there has been an increasing interest in developing new therapies for people with FSGS. This rare glomerular disease affects children and adults and has a high likelihood of progression to kidney failure. There are no approved treatments, and the available options are far from perfect, with limited efficacy and significant side effects. Although we now have a much better understanding of the cause(s) of FSGS and its natural history, much more work remains to be done to understand the disease pathobiology and accelerate the development of effective treatments for various causes of FSGS.
Although we now have a much better understanding of the cause(s) of FSGS and its natural history, much more work remains to be done to understand the disease pathobiology and accelerate the development of effective treatments.
Over the past 5 years, the kidney community has done important work to identify endpoints and outline regulatory pathways for new therapies with the patient experience at the center. The Kidney Health Initiative (KHI) convened a group of experts—including patients, clinicians, representatives from the US Food and Drug Administration (FDA), industry, and trialists—to identify potential clinical trial endpoints for FSGS. Under the leadership of Keisha L. Gibson, MD, FASN, MPH (University of North Carolina, Chapel Hill), and Laura H. Mariani, MD, MS, FASN (University of Michigan), three manuscripts, outlining strengthens and limitations of proteinuria and estimated glomerular filtration rate (eGFR) as trial endpoints and novel biomarkers as drug development tools, are in the final stages of development for publication. “What we learned through the KHI project is that there must be strong evidence to support a surrogate endpoint for clinical trials. The KHI project highlighted the urgent need to come together as a community and share existing patient-level data, in a manner that adequately protects patient privacy and that honors informed consent, to address the current gaps in the evidence,” said Mariani. “We hope that with the continued work through a new data-sharing effort, we will provide the needed guidance for [the] FDA, industry, clinicians, and patients,” she continued.
Although the FDA currently accepts a complete remission or near normalization of proteinuria as a surrogate endpoint and basis for traditional approval of new treatments for FSGS, further work is needed to support the use of lesser changes in proteinuria as a basis for accelerated or traditional approval. Proteinuria and GFR as Clinical Trial Endpoints in Focal Segmental Glomerulosclerosis (PARASOL) is a collaborative, international effort that aims to define the quantitative relationships between short-term changes in biomarkers (e.g., proteinuria and GFR) and long-term outcomes to support the use of alternative proteinuria-based endpoints as a basis for accelerated or traditional approval (1). The project is sponsored by NephCure (lead), the International Society of Glomerular Disease (ISGD), the KHI, and the National Kidney Foundation (NKF). The project is led by primary investigators Matthias Kretzler, MD, and Mariani; biostatistical support by Margaret Helmuth, MS; Abigail Smith, PhD; and Alex Mercer, PhD; and project management support by Howard Trachtman, MD, FASN, and ISGD staff including Executive Director Laurel Damashek, MA. (See Table 1 for a complete listing of the Organizing Committee.)
PARASOL Organizing Committee
Critical to the success of this effort will be data sharing from various registries and other data sources (Table 2). The community’s efforts to develop these registries are a tribute to the many primary investigators and also to the patients who graciously agree to enroll in the registry and share their data. The data sets are unique and will require harmonization to use their different strengths. “With every call or invitation to join us, we have received a warm welcome and agreement to participate. We all recognize that the investment in FSGS clinical trials is important to our clinical care and appreciate the interest in this effort, which will use data to definitively answer the relationship between short-term changes in biomarkers and long-term outcomes,” said Kretzler.
Pending registries and data sets to support PARASOL
PARASOL has defined an aggressive timeline with a milestone to submit the results for presentation at Kidney Week 2024 in San Diego, CA. The project deliverables include:
A series of internationally supported cross-stakeholder workshops with community discussion and review of the analyses, including the FDA and European Medicines Agency, as well as professional and patient non-profit advocacy organizations, culminating in a public scientific consensus workshop
Suggested endpoint models derived from analysis of data sets, to inform feasible trial designs and future regulatory pathways for FSGS
Relevant peer-reviewed published paper(s) and communications
Over 60 people are participating in the collaborative effort led by the team at the University of Michigan and partnering organizations. The drive and passion to prioritize this work come from interacting with people living with FSGS who are willing to contribute their data or participate in a clinical trial. “Data sharing can transform a drug development landscape. I’m very excited about this effort to bring together the available data to identify alternative proteinuria-based endpoints that could potentially be used to establish the efficacy of new therapies for FSGS,” said Aliza Thompson, MD, MS, deputy director of the Division of Cardiology and Nephrology at the Center for Drug Evaluation and Research at the FDA. Josh Tarnoff, NephCure chief executive officer, reflected, “Being in the room, I was struck by the sense of community, with all the world’s key FSGS databases coming together for the first time to address this critical issue. The collaboration among and between the various organizations—patient and professional—is unprecedented. We are thrilled and enthusiastically anticipate a positive outcome by year end.”
“Industry has shown a strong commitment to developing new therapies for patients with FSGS,” said Uptal Patel, MD, chair of the KHI. “KHI is pleased to join NephCure, ISGD, and NKF and greatly appreciates the willingness of the community to share data. The community has had some recent successes in defining clinical trial endpoints that [have] transformed therapeutic options for patients with some kidney diseases. Similarly, we hope to advance pathways to develop therapies in collaboration with all the FSGS stakeholders involved in clinical trials including primary investigators, clinicians, [the] FDA, patients, and researchers,” Patel added. Kerry Willis, PhD, chief scientific officer at the NKF, shared: “The NKF is pleased to participate in this effort and plans to offer our knowledge and experience from NKF’s previous clinical trial endpoint-related work throughout the process. We look forward with anticipation to seeing where these analyses can take us making better use of biomarkers and designing successful trials.”