Perspectives on Drug Development in Autosomal Recessive Polycystic Kidney Disease

Introduction

Autosomal recessive polycystic kidney disease (ARPKD) is a rare hepatorenal fibrocystic disease that often presents prenatally or in the first year of life and remains a major cause of morbidity and mortality in pediatric nephrology. Here, we summarize key aspects discussed in a session on drug development in ARPKD that took place during the 2021 PKD Regulatory Summit. Multiple obstacles remain, but the initiation of the first phase 3 trials documents progress in the field. Lessons learned from autosomal dominant polycystic kidney disease (ADPKD) will strongly influence ARPKD drug development.

ARPKD is mainly caused by variants in PKHD1 encoding the protein fibrocystin, although exceptional cases with other genetic variants (e.g., in DZIP1L) have been described (1). Typical clinical symptoms include bilateral cystic kidney disease presenting with organ enlargement and a variable degree of functional CKD. Prenatal kidney disease may result in oligo-/anhydramnios with subsequent pulmonary hypoplasia and severe perinatal respiratory disease. The clinical liver phenotype usually presents as congenital hepatic fibrosis or Caroli syndrome with portal hypertension and a higher risk of cholangitis (1,2).

Clinical symptoms and courses can be highly variable, and current genotype-phenotype correlations can only partly explain this variability (1,3). Patients with ARPKD and biallelic PKHD1 variants predicted to result in complete loss of function of fibrocystin are associated with severe kidney and liver phenotypes. Recent data revealed the relevance of the localization of the variant in patients with missense variants for progression of kidney or liver disease (3).

Although ARPKD and ADPKD are distinct disorders, preclinical and clinical data suggest genetic and pathophysiologic overlap, including dysregulation of similar intracellular signaling cascades. In addition, ARPKD and ADPKD have some similar clinical features, including kidney enlargement, hypertension, and reduced GFR. Therefore, drug development in ADPKD has the potential to inform some aspects of clinical trials in ARPKD, such as selection of candidate therapies and end points (1).

Current Autosomal Recessive Polycystic Kidney Disease Treatment

Drug development for ARPKD has been hampered by the rareness of the disease (with an estimated incidence of one in 26,500 live births in America), limited preclinical models, knowledge gaps on longitudinal disease courses and prognostic markers of this variable disease, and a lack of clearly defined applicable primary end points for clinical trials (1,4). Treatment in ARPKD therefore currently remains largely symptomatic and on the basis of expert opinions and personal experiences (2). General therapeutic principles for pediatric CKD apply, including BP targets ≤50th percentile. There are no approved therapies for ARPKD. Predictions of a disease course for an individual patient are currently very challenging.

The “Autosomal Recessive Polycystic Kidney Disease Three-Disease” Framework and Considerations for Trial Design

Although ARPKD is a clearly defined disorder, three subaspects were highlighted at the PKD Regulatory Summit during the discussion on envisioning treatment approaches and study designs. These are neonatal respiratory disease, kidney disease after the neonatal period, and liver disease. The different disease manifestations may clinically develop partly independently and become symptomatic at different ages, with potential implications for a time point of therapeutic interventions (1–3). Whether a single treatment could positively influence all three disease aspects currently remains unknown. It appears likely that the underlying pathobiologic mechanisms in the different organs are overlapping but not identical. Yet, it is clear that any interventional trial for a primary end point evaluating kidney or liver disease in ARPKD would need to closely monitor courses of both organs for safety aspects.

Pulmonary hypoplasia is considered to result from prenatal kidney disease, although the exact mechanisms underlying pulmonary hypoplasia in ARPKD are not fully understood. Courses of neonatal respiratory disease are variable. Treatment is mainly focused on stabilizing the acute respiratory status in severe disease and on avoiding secondary sequelae (2). The rarity, acuity, and variability of neonatal ARPKD will be a major challenge for achieving the preferable goal of randomized controlled trials in this specific population. Use of observational natural history or historical control data is generally limited to situations in which the course of the disease is highly predictable and the treatment effect is large.

Kidney disease may progress rapidly after birth but can show progression over months and years. Kidney disease was the focus of discussion at the PKD Regulatory Summit. Given the high likelihood that small numbers of patients will be included even for kidney-related end points, it will be of utmost importance to ensure comparable risk stratification among participants in ARPKD trials. Genetic and clinical risk markers for early dialysis dependency have been identified and can now serve for enrichment of high-risk cohorts in randomized controlled trials (5,6). This includes biallelic truncating variants in PKHD1 and prenatal findings of oligo-/anhydramnios, kidney cysts, and enlarged kidneys. Indeed, the clinical criteria have been applied in the design of the first phase 3 trials of tolvaptan in children with ARPKD (NCT04782258 and NCT04786574). Future work may extend these risk stratification criteria, potentially combining them with blood, urine, or imaging biomarkers. Established fluid biomarkers for ADPKD will be tempting candidates to study in ARPKD.

Obvious end points for trials on kidney disease in ARPKD include kidney survival or loss of kidney function, although the clinical course is heterogenous and published reference data for the latter remain scarce (7). Reasonably likely surrogate end points that predict or correlate with kidney disease progression akin to height-adjusted total kidney volume in ADPKD have not yet been established for ARPKD, but other potential magnetic resonance imaging biomarkers of kidney disease progression are being studied (8). To establish such surrogate end points, more real-life data from existing internationally harmonized observational registry studies in Europe and the United States will be required to characterize longitudinal progression of kidney disease in ARPKD (4,9).

ARPKD liver disease is characterized by an early developmental biliary defect that in many patients results in clinical symptoms developing many years later with slow progression of biliary duct dilation, liver fibrosis, and portal hypertension. Liver manifestations generally become clinically relevant later in the disease course than kidney disease or neonatal pulmonary problems. Even though exact numbers are missing, more children with ARPKD currently survive neonatal respiratory disease and early kidney disease, and liver disease is increasingly becoming an important clinical issue (e.g., in young adults). From the point of view of study design and administration, it may be easier to set up a trial for this target group of young adults than for children. Prognostic enrichment that may be on the basis of genotype, laboratory findings, or radiologic findings, or a combination of all of these, will be essential and requires a more detailed description of disease cohorts. Finding a good end point, however, that would be reached by a substantial percentage of a study cohort in a reasonable period of time may become more of a challenge in this slowly developing and variable phenotype of a rare disease. Potential end points under consideration include ultrasound elastography with acoustic radiation force impulse and magnetic resonance–based methods, such as elastography, as quantifiable and early risk markers for portal hypertension (10). Furthermore, identification of young adult patients for a trial does not seem trivial for a rare disease that has mainly been covered by pediatricians so far.

Alternative End Points for Clinical Trials in Autosomal Recessive Polycystic Kidney Disease

Given the described issues, it seem reasonable to consider alternative end points for clinical trials on ARPKD. Patient-reported outcomes, observer (family)-reported outcomes, clinician-reported outcomes, or performance outcomes are not established for ARPKD. Most studies that reported clinical outcomes in ARPKD focused on kidney function, infections, and survival. Thus, a significant knowledge gap restrains the development of alternative end points for ARPKD. Perinatal presentation of ARPKD may result in enormous distress and anxiety in parents prenatally and in the first years of life. Involving families in discussions of potential trial designs seems to be an important and logical next step. For example, a patient-focused drug development meeting can inform drug development and regulatory decision making on the basis of information obtained from patients, families, and caregivers about aspects of the disease that matter most to them, their experiences with currently available treatments, their perspective on participation in clinical trials, and their acceptance of the potential benefits and risks of investigational products.

In addition to patient-reported outcomes, etc., novel functional imaging, fluid biomarkers, or composite clinical markers could have the potential to achieve the status of reasonably likely surrogate end points. Clearly, the research field is only at the beginning of an important journey toward improved treatment. There are, however, recent dynamic developments in the field. The establishment of the first phase 3 trials is reflecting the progress in ARPKD research.

Emerging Treatment Approaches in Autosomal Recessive Polycystic Kidney Disease

With the genetic and clinical overlap of ARPKD and ADPKD and with at least partial overlap of dysregulated signaling cascades detected in patient samples and preclinical models, drugs under assessment for ADPKD are tempting candidates for trials in ARPKD. This is exemplified by the design of the mentioned tolvaptan trials and a completed phase 1 trial of the SRC inhibitor tesevatinib for ARPKD (NCT03096080). It is obvious that special precautions are needed for children in trials, and it is also important to consider the clinical differences between typical courses of early-childhood ARPKD and the more slowly progressive ADPKD. From a pathophysiologic point of view, mechanisms of fibrosis and inflammation in the kidney and the liver in ARPKD may become important targets beyond the epithelial cell pathways mainly targeted in ADPKD. Clinical trials for drugs targeting fibrosis and inflammation may need end points specific for their mode of action rather than those focused only on cyst growth, such as total kidney volume in ADPKD.

Summary and Outlook

ARPKD clinical research is challenging because of its rarity and the heterogenous presentations of neonatal respiratory disease, postnatal kidney disease, and liver fibrosis. The development of large internationally harmonized observational studies and the identification of prognostic biomarkers will pave the way for interventional trials. Future efforts should focus on establishing and validating biomarkers of disease progression and developing specific interventions that are targeted to disease mechanisms.

Disclosures

E.A. Hartung reports serving in an advisory or leadership role for the PKD Foundation’s Scientific Advisory Committee and PKD in Children Council, serving as a member of the American Society of Pediatric Nephrology, and serving as an American Board of Pediatrics Nephrology Subboard member. M.C. Liebau serves on an advisory board of Otsuka Pharmaceuticals as a representative of the University Hospital of Cologne, reports other interests or relationships with the scientific committee of the German PKD Foundation and the scientific advisory committee of the PKD Foundation, and serves as cochair of Working Group Congenital Anomalies of the Kidney and the Urinary Tract and Ciliopathies European Reference Network on Rare Kidney Diseases and as chair of the Working Group Inherited Kidney Diseases of the European Society for Paediatric Nephrology. R.D. Perrone reports consultancy agreements with Caraway, Navitor, Otsuka, Palladiobio, Reata, and Sanofi-Genzyme; research funding from Kadmon, Palladiobio, Reata, and Sanofi; honoraria from Otsuka, Reata, and Sanofi-Genzyme; an advisory or leadership role for Otsuka, PalladioBio, and Sanofi-Genzyme; speakers bureau for Haymarket Media; and other interests or relationships with the Critical Path Institute, the PKD Foundation, and UpToDate.

Funding

ARPKD-related clinical research by M.C. Liebau is supported by Bundesministerium für Bildung und Forschung grant 01GM1903B. The 2021 PKD Regulatory Summit was funded/supported by Otsuka Pharmaceutical and the PKD Foundation.

Author Contributions

E.A. Hartung, M.C. Liebau, and R.D. Perrone conceptualized the study; M.C. Liebau wrote the original draft; and E.A. Hartung, M.C. Liebau, and R.D. Perrone reviewed and edited the manuscript.