Drug repurposing in autosomal dominant polycystic kidney disease

Abstract

Autosomal dominant polycystic kidney disease is characterized by progressive kidney cyst formation that leads to kidney failure. Tolvaptan, a vasopressin 2 receptor antagonist, is the only drug approved to treat patients with autosomal dominant polycystic kidney disease who have rapid disease progression. The use of tolvaptan is limited by reduced tolerability from aquaretic effects and potential hepatotoxicity. Thus, the search for more effective drugs to slow down the progression of autosomal dominant polycystic kidney disease is urgent and challenging. Drug repurposing is a strategy for identifying new clinical indications for approved or investigational medications. Drug repurposing is increasingly becoming an attractive proposition because of its cost-efficiency and time-efficiency and known pharmacokinetic and safety profiles. In this review, we focus on the repurposing approaches to identify suitable drug candidates to treat autosomal dominant polycystic kidney disease and prioritization and implementation of candidates with high probability of success. Identification of drug candidates through understanding of disease pathogenesis and signaling pathways is highlighted. Autosomal dominant polycystic kidney disease is characterized by progressive kidney cyst formation that leads to kidney failure. Tolvaptan, a vasopressin 2 receptor antagonist, is the only drug approved to treat patients with autosomal dominant polycystic kidney disease who have rapid disease progression. The use of tolvaptan is limited by reduced tolerability from aquaretic effects and potential hepatotoxicity. Thus, the search for more effective drugs to slow down the progression of autosomal dominant polycystic kidney disease is urgent and challenging. Drug repurposing is a strategy for identifying new clinical indications for approved or investigational medications. Drug repurposing is increasingly becoming an attractive proposition because of its cost-efficiency and time-efficiency and known pharmacokinetic and safety profiles. In this review, we focus on the repurposing approaches to identify suitable drug candidates to treat autosomal dominant polycystic kidney disease and prioritization and implementation of candidates with high probability of success. Identification of drug candidates through understanding of disease pathogenesis and signaling pathways is highlighted. Drug repurposing aims to identify new indications for approved or investigational drugs that have undergone extensive safety and efficacy investigation. Advantages over de novo drug development are lower risk of failure, reduced time to market, and cost saving.1Nosengo N. Can you teach old drugs new tricks?.Nature. 2016; 534: 314-316Crossref PubMed Scopus (366) Google Scholar Historically, drug candidates have been identified through serendipitous observation of off-target or newly recognized on-target effects.2Pushpakom S. Iorio F. Eyers P.A. et al.Drug repurposing: progress, challenges and recommendations.Nat Rev Drug Discov. 2019; 18: 41-58Crossref PubMed Scopus (1821) Google Scholar Currently, systematic approaches, computational and experimental, are used to identify candidates. These are then assessed in animal models, followed by phase 2 clinical trials.Editor’s NoteIn their review, Zhou and Torres provide a perspective of drug repurposing in autosomal dominant polycystic kidney disease (ADPKD), the most common form of monogenic disorder affecting the kidney. The choice of ADPKD to illustrate the potential of drug repurposing is particularly relevant, considering the positive results obtained with tolvaptan—an orally active, selective vasopressin V2 receptor antagonist (OPC-41061) developed by Otsuka Pharmaceuticals in Japan, that was initially approved for the treatment of hyponatremia or volume overload in heart failure. From there, the authors review the methods used to identify candidates for repurposing, the potential pathways relevant for cystogenesis and cyst progression in ADPKD, the insights provided by genetic studies, and the way to prioritize potential drug candidates for rapid translation to address a critical unmet need in nephrology. In their review, Zhou and Torres provide a perspective of drug repurposing in autosomal dominant polycystic kidney disease (ADPKD), the most common form of monogenic disorder affecting the kidney. The choice of ADPKD to illustrate the potential of drug repurposing is particularly relevant, considering the positive results obtained with tolvaptan—an orally active, selective vasopressin V2 receptor antagonist (OPC-41061) developed by Otsuka Pharmaceuticals in Japan, that was initially approved for the treatment of hyponatremia or volume overload in heart failure. From there, the authors review the methods used to identify candidates for repurposing, the potential pathways relevant for cystogenesis and cyst progression in ADPKD, the insights provided by genetic studies, and the way to prioritize potential drug candidates for rapid translation to address a critical unmet need in nephrology. Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic disorder leading to kidney failure. Disruption of polycystin 1 or polycystin 2, caused by mutations in PKD1 or PKD2, accounts for most of ADPKD. Dysfunction of polycystin 1 or polycystin 2 results in dysregulation of G protein and intracellular calcium signaling and multiple downstream signaling pathways. Pathophysiological processes involved include aberrant cell proliferation, fluid secretion, inflammation, and fibrosis. Cyclic adenosine monophosphate (cAMP) signaling plays a central role by stimulating cystic epithelial cell proliferation and fluid secretion (Figure 1). Vasopressin acting on V2 receptor on the basolateral membrane is the main hormonal regulator of cAMP production in collecting duct and distal nephron cells. Genetic deletion of vasopressin inhibited cyst development in Pkhd1 gene–mutated polycystic kidney (PCK) rats.3Wang X. Wu Y. Ward C.J. et al.Vasopressin directly regulates cyst growth in polycystic kidney disease.J Am Soc Nephrol. 2008; 19: 102-108Crossref PubMed Scopus (220) Google Scholar Vasopressin 2 receptor antagonists (mozavaptan, tolvaptan, lixivaptan, and mambaquaretin-1) ameliorated cyst growth in multiple polycystic kidney disease (PKD) animal models.4Zhou X. Torres V.E. Emerging therapies for autosomal dominant polycystic kidney disease with a focus on cAMP signaling.Front Mol Biosci. 2022; 9981963Crossref Scopus (1) Google Scholar The promising preclinical findings supported the candidacy of tolvaptan, a US Food and Drug Administration (FDA)–approved drug for the treatment of euvolemic and hypervolemic hyponatremia, for repurposing in ADPKD. Tolvaptan treatment over 3 years in the Tolvaptan Efficacy and Safety in Management of ADPKD and Its Outcomes (TEMPO) 3:4 trial decreased total kidney growth by 49% and rate of glomerular filtration rate (GFR) decline by 26% in patients with ADPKD with estimated GFR (eGFR) ≥60 ml/min per 1.73 m2 at high risk of rapid disease progression.5Torres V.E. Chapman A.B. Devuyst O. et al.Tolvaptan in patients with autosomal dominant polycystic kidney disease.N Engl J Med. 2012; 367: 2407-2418Crossref PubMed Scopus (1033) Google Scholar Tolvaptan treatment over 1 year in the Replicating Evidence of Preserved Renal Function: An Investigation of Tolvaptan Safety and Efficacy (REPRISE) trial slowed the rate of eGFR decline in patients with ADPKD with late-stage disease.6Torres V.E. Chapman A.B. Devuyst O. et al.Tolvaptan in later-stage autosomal dominant polycystic kidney disease.N Engl J Med. 2017; 377: 1930-1942Crossref PubMed Scopus (316) Google Scholar These 2 landmark clinical trials led to approval of tolvaptan for rapidly progressive ADPKD.5Torres V.E. Chapman A.B. Devuyst O. et al.Tolvaptan in patients with autosomal dominant polycystic kidney disease.N Engl J Med. 2012; 367: 2407-2418Crossref PubMed Scopus (1033) Google Scholar,6Torres V.E. Chapman A.B. Devuyst O. et al.Tolvaptan in later-stage autosomal dominant polycystic kidney disease.N Engl J Med. 2017; 377: 1930-1942Crossref PubMed Scopus (316) Google Scholar Tolvaptan is not tolerated by 15% of patients because of aquaretic effects and requires a Risk Evaluation and Mitigation Strategy for potential hepatotoxicity. Therefore, there is an urgent need for better tolerated and more effective treatments. In this review, we discuss repurposing approaches (Figure 2) to identify potential candidates (Table 1).Figure 2Approaches to identify candidates in drug repurposing for autosomal dominant polycystic kidney disease. Serendipitous observations, experimental approaches (understanding of disease pathogenesis and signaling pathways and high-throughput screening), and computational approaches (analysis of clinical database, genome-wide association studies [GWASs], transcriptional gene profiling, and target protein expression) can be used to identify repurposing opportunities. Isolated observations in patients can be extended to analysis of clinical databases. Experimental and computational approaches can be used individually or in combination.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Table 1Potential drug candidates for repurposing in ADPKDDrugTargetIndications (approved or clinical trial)Safety profilePreclinical studiesMetforminaAlready ongoing clinical trial for ADPKD.AMPKFDA approved for type 2 DMNausea, bloating, diarrhea; lactic acidosis GFR ml/min per 1.73 results in and approved for with of and in for to heart approved for drug patients in ongoing clinical trial for for cystic and for in and and from US kidney for for and in ongoing clinical trial for approved for type 2 fluid for and ongoing clinical trial for for type 2 heart failure, and in results in and for in and in ongoing clinical trial for for ADPKD, and for in for for of heart in in of and at approved for ongoing clinical trial for approved for and autosomal dominant polycystic kidney kidney adenosine protein adenosine cystic kidney in 2 US Food and Drug glomerular filtration polycystic PubMed for of in with ongoing clinical trial for ADPKD. in a new ADPKD, autosomal dominant polycystic kidney kidney adenosine protein adenosine cystic kidney in 2 US Food and Drug glomerular filtration polycystic PubMed for of in with potential of on of kidney cyst growth was in a with ADPKD and with the to growth et and efficacy of treatment in polycystic kidney PubMed Scopus Google Scholar cAMP production through acting on G to and ameliorated and polycystic disease in Torres V.E. et cystogenesis in a of polycystic disease by adenosine PubMed Scopus (220) Google et is more effective in cystogenesis in with polycystic kidney and PubMed Scopus Google Scholar and slowed the growth of polycystic and on the rate of eGFR decline in phase 3 clinical N. et in later-stage autosomal dominant polycystic kidney disease a Med. 2019; PubMed Scopus Google N. et of on kidney and cyst growth in autosomal dominant polycystic kidney disease a PubMed Scopus Google et of on kidney in patients with autosomal dominant polycystic kidney the 1 clinical PubMed Scopus Google Scholar progression to kidney in 1 the efficacy and reduced the aquaretic of tolvaptan in C.J. 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