Inherited cystic diseases include a spectrum of disorders, such as autosomal dominant polycystic kidney disease (ADPKD), autosomal recessive polycystic kidney disease (ARPKD), autosomal dominant polycystic liver disease, and an expanding group of recessively inherited diseases collectively termed hepatorenal fibrocystic disorders. ADPKD is the most common monogenic disorder that can lead to kidney failure, with a prevalence of 600,000 people in the United States (1). ARPKD is associated with significant kidney- and liver-related morbidity and mortality in children, with >50% of affected individuals progressing to kidney failure within the first decade of life (2).

Although one therapy (tolvaptan) has been approved in the United States and other regions for the treatment of ADPKD, the development of clear regulatory pathways and viable end points would be critical for further development in the area of polycystic kidney and liver disorders.

On May 19–20, 2021, representatives from academia, industry, regulatory agencies (US Food and Drug Administration and European Medicines Agency), and the patient community came together to discuss the unmet needs in ADPKD and ARPKD drug and regulatory development as part of the 2021 PKD Regulatory Summit. The conference was organized by the PKD Outcomes Consortium from Critical Path Institute in partnership with the PKD Foundation. The issues discussed covered a broad range of topics, including obstacles to drug development for early ADPKD and ARPKD, clinical trial design in ADPKD, development of novel biomarkers for disease progression, development of clinical outcome assessment tools, and disease progression modeling.

The following series of Perspective articles summarize the salient points from the three sessions of the Summit, including drug development for ARPKD, early ADPKD, and clinical trial design for ADPKD. The conclusions drawn from these Perspective articles emphasize:

(1) The importance of international collaborations and large observational studies, which are critical for shedding light on the different risk patterns in ARPKD (given its multiple temporal disease manifestations), thus paving the way for future interventional trials. The criticality of stringent patient selection, clinical descriptions, and biosampling as part of the trial process will be essential for progress (3).

(2) The need to define the best timing for interventions and identifying novel targets that are relevant in the early ADPKD disease stage. Challenges to this include the identification and validation of indicators, both measuring and predicting disease progression from childhood, and distinguishing slow from rapid progressors in the early-stage ADPKD population (4).

(3) The importance of standardization of the key elements of an ADPKD pivotal trial template that can serve to derisk and potentially accelerate the development of therapies. As well as the importance of designing trials that are accessible to patients to enter and remain across the ≥2 year study duration that ADPKD trials would require (5).

Much unmet need remains in polycystic kidney disease, both on the regulatory and therapeutic sides. Continued collaboration and data-sharing efforts in the field among relevant stakeholders are needed to achieve enhanced prognostic and therapeutic biomarkers, end points, and a feasible regulatory pathway (for all forms of PKD including ARPKD), which will hopefully lead to more therapies becoming available for affected individuals.

S. Fedeles reports being employed by the Critical Path Institute and is an author on the WO2015057894A1 patent (published in April 2015) “Methods for treating polycystic kidney disease and polycystic liver disease.” R.D. Perrone reports having consultancy agreements with Caraway, Navitor, Otsuka, Palladiobio, Reata, and Sanofi-Genzyme; having other interests in, or relationships with, Critical Path Institute, PKD Foundation, and UpToDate; serving on a speakers bureau for Haymarket Media; receiving research funding from Kadmon, Palladiobio, Reata, and Sanofi; serving in an advisory or leadership role for Otsuka, PalladioBio, and Sanofi-Genzyme; and receiving honoraria from Otsuka, Reata, and Sanofi-Genzyme.

The content of this article reflects the personal experience and views of the authors and should not be considered medical advice or recommendation. The content does not reflect the views or opinions of the American Society of Nephrology (ASN) or CJASN. Responsibility for the information and views expressed herein lies entirely with the authors.

S. Fedeles wrote the original draft, and S. Fedeles and R.D. Perrone reviewed and edited the manuscript.

Published online ahead of print. Publication date available at www.cjasn.org.

See related Perspectives, “Perspectives on Drug Development in Autosomal Recessive Polycystic Kidney Disease,” on pages 1551–1554; “Perspectives on Drug Development in Early ADPKD,” on pages 1555–1558; and “Current Challenges and Perspectives on Developing a Clinical Trial Design for ADPKD,” on pages 1559–1562.