Beyond Tolvaptan: The Next Generation of ADPKD Therapies

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disorder and the leading monogenic cause of kidney failure worldwide, affecting an estimated 12.5 million people globally. For nearly a decade, tolvaptan — a vasopressin V2 receptor antagonist — has stood alone as the only FDA-approved therapy proven to slow disease progression. It works by lowering cyclic AMP (cAMP) signaling in the kidney, one of the central drivers of cyst growth. But tolvaptan is far from a complete solution: its aquaretic side effects (excessive thirst and urination) and risk of liver toxicity limit its use and tolerability for many patients. 

The therapeutic pipeline for ADPKD now extends well beyond vasopressin blockade. This article explores the advances that are reshaping how the field thinks about treating, and potentially reversing, ADPKD both now and in the near future.  The impacts of these findings have driven an explosion in the current ADPKD therapeutic pipeline with many new drugs now moving through clinical development.  Furthermore, advancement in gene therapy and gene editing are now making single-treatment curative therapies a realistic possibility. 

The Biology: Why Cysts Form 

ADPKD is caused primarily by mutations in PKD1 or PKD2, the genes encoding polycystin-1 (PC1) and polycystin-2 (PC2). These proteins form a receptor-channel complex on the primary cilium of kidney tubule cells, where they regulate calcium signaling. When PC1 or PC2 function is reduced or lost, calcium signaling is disrupted, intracellular cAMP rises, cellular metabolism is reprogrammed, and proliferative and secretory programs are switched on — the combination that drives cysts to form and expand throughout life1. 

Ideas That Are Reshaping Drug Development

1. ADPKD is dosage-dependent, not simply “on or off.”

A crucial insight underpinning much of the new pipeline is that cyst formation is governed by a threshold of polycystin protein levels rather than a binary presence-or-absence of function. Patients — and even individual tubule cells within the same kidney — do not uniformly lack PC1 or PC2; instead, cystogenesis occurs when polycystin expression falls below a critical level in a given cell. This reframes ADPKD as a problem of insufficient dosage of a needed protein, rather than an irreversible structural defect2. 

This matters enormously for drug design. If cyst formation depends on falling below a threshold, then therapies that simply raise polycystin levels back up — even partially, and even in cells that still carry a disease-causing mutation — could be enough to prevent or slow new cyst formation, without needing to “fix” every mutant copy of the gene. This is precisely the rationale behind the gene-directed therapies discussed below, including anti-miR-17 oligonucleotides and pharmacochaperones.

2. Early ADPKD-related changes may be reversible

A second major conceptual shift is the growing preclinical evidence that some of the biological changes driving cystogenesis — abnormal cAMP signaling, metabolic reprogramming, and even early cyst expansion — are not permanently fixed once triggered. In animal models, restoring polycystin function or interrupting downstream signaling pathways can halt or reverse cystic changes, rather than merely slowing further growth3. 

Together, dosage-dependence and reversibility imply that ADPKD may be more like a chronic, modifiable metabolic disease than an inevitable structural degeneration — meaning that later-in-life interventions, not just therapies started at birth, could still meaningfully alter the disease trajectory. This has directly motivated the design of trials measuring biomarkers of mechanistic target engagement (such as urinary polycystin levels) alongside structural endpoints like total kidney volume, since a treatment that nudges polycystin dosage back above threshold should, in principle, be detectable and beneficial even in patients with established disease. 

3.  Paracrine Signaling

Pregnancy-associated plasma protein-A (PAPP-A), is an enzyme that is upregulated in ADPKD that increases local bioavailability of insulin-like growth factor-1 (IGF-1) — a signal that drives cyst-lining cell proliferation. Blocking PAPP-A’s proteolytic activity has significantly reduced cyst growth and preserved kidney function across three different preclinical mouse models of ADPKD4,5. 

4. Metabolic pathways impacting cyst growth

Cyst-lining cells display an altered, more proliferative metabolic profile (favoring glycolysis and fatty-acid synthesis over oxidative metabolism), opening the door to new and repurposed metabolic drugs6.  These include metformin, bempedoic acid, SGLT2 inhibitors, GLP-1 receptor agonists, and metabolism altering diets.

 Active Clinical Trials Involving Patients with ADPKD 

Table 1 shows a complete list of active clinical trials involving patients with ADPKD.  RN-014, JMKX003142, atorvastatin with sodium bicarbonate, and rotigotine are shown in the table for completeness but are out of scope for this summary.  

Table 1. Investigational agents and active clinical trials examining efficacy in patients with ADPKD. 

Looking Ahead: Gene and Genome Therapies 

Looking beyond the current generation of drugs in clinical development, the next generation of therapies may be dominated by single-treatment, curative gene therapies. This includes gene therapies that deliver full or partial polycystin genes as well as genome-editing approaches that correct the PKD1/PKD2 genes themselves.  Both approaches aim to raise polycystin expression durably above the threshold required to prevent cyst formation, rather than repeatedly dosing a drug. This is a direct extension of the dosage-dependence concept: if a cell’s polycystin level determines its cystic fate, then a one-time genetic correction that permanently restores adequate dosage could, in principle, provide lifelong protection from new cyst formation, complementing therapies aimed at cysts that have already formed. 

Strong pre-clinical results suggest that clinical gene therapy and gene editing studies will be initiated in the next few years.  These include: the identification of small fragments of the polycystin-1 protein whose expression reduces cyst growth in ADPKD mouse models7; the first demonstration of CRISPR base-editing to reduce liver cysts in mice8; and the first demonstration of CRISPR base-editing to reduce kidney cysts in mice9. 

Two major hurdles must still be overcome to realize efficient gene delivery to the kidney.  One hurdle is the vector capacity of common adeno-associated virus (AAV) gene therapy vectors, which is too small for the most efficient CRISPR-Cas proteins and PKD1 gene.  The second hurdle is the challenge of systemically delivering gene therapy vectors to the kidney due to the small filter size in the glomerulus.  Overcoming these obstacles would represent a genuine shift from managing ADPKD to treating its underlying genetic cause — the same trajectory that gene therapy has taken in other monogenic diseases. 

Conclusion: Toward Precision, Layered Care 

ADPKD management is moving from a single-mechanism approach (vasopressin blockade) toward a layered, mechanism-guided framework — one in which cAMP modulation, metabolic reprogramming, paracrine signaling blockade, and genotype-specific, dosage-restoring gene therapies can potentially be combined based on an individual patient’s genetic and biomarker profile. As risk-stratification tools and biomarkers (such as urinary polycystin levels and htTKV trajectories) mature, ADPKD treatment is poised to become more precise, better tolerated, and, for the first time, targeted at the disease’s root genetic cause rather than only its downstream consequences. 

Author Bio