Lixivaptan (VPA-985) is an orally-active, non-peptide, selective vasopressin V₂ receptor

antagonist An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain.autosomal dominant polycystic kidney disease Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common, life-threatening Genetic disorder, inherited human disorders and the most common hereditary kidney disease. It is associated with large interfamilial and intrafamilia ...

(ADPKD), the most common form of

polycystic kidney disease Polycystic kidney disease (PKD or PCKD, also known as polycystic kidney syndrome) is a genetic disorder in which the renal tubules become structurally abnormal, resulting in the development and growth of multiple cysts within the kidney. These ...

. The U.S.

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...

(FDA) has granted

orphan drug An orphan drug is a medication, pharmaceutical agent that is developed to treat certain rare medical conditions. An orphan drug would not be profitable to produce without government assistance, due to the small population of patients affected by th ...

designation to lixivaptan for the treatment of ADPKD.

Mechanism of action

Lixivaptan is a potent,

non-peptide In molecular biology and pharmacology, a small molecule or micromolecule is a low molecular weight (≤ 1000 daltons) organic compound that may regulate a biological process, with a size on the order of 1 nm. Many drugs are small molecules; t ...

, selective

vasopressin receptor antagonist A vasopressin receptor antagonist (VRA) is an agent that interferes with action at the vasopressin receptors. Most commonly VRAs are used in the treatment of hyponatremia, especially in patients with congestive heart failure, liver cirrhosis or ...

. It is a member of the vaptan class of drugs.

Hyponatremia

V₂ receptor antagonists inhibit the binding of

arginine vasopressin Mammalian vasopressin, also called antidiuretic hormone (ADH), arginine vasopressin (AVP) or argipressin, is a hormone synthesized from the ''AVP'' gene as a peptide prohormone in neurons in the hypothalamus, and is converted to AVP. It ...

vasopressin receptor 2 Vasopressin receptor 2 (V2R), or arginine vasopressin receptor 2 (officially called AVPR2), is a protein that acts as receptor for vasopressin. AVPR2 belongs to the subfamily of G-protein-coupled receptors. Its activity is mediated by the Gs t ...

(V₂R) in kidney tubular epithelial cells, thereby having a net effect of

aquaresis An aquaretic is a novel class of drug that is used to promote aquaresis, the excretion of water without electrolyte loss. Strictly speaking, aquaretics are not diuretics but are sometimes classified as such. Aquaresis is preferable to diuresis ...

, or electrolyte free water excretion. This property of vaptans explains their use as therapies to treat euvolemic and

hypervolemic Hypervolemia, also known as fluid overload, is the medical condition where there is too much fluid in the blood. The opposite condition is hypovolemia, which is too little fluid volume in the blood. Fluid volume excess in the intravascular compa ...

hyponatremia.

ADPKD

V₂ receptor antagonists may have utility as therapies for ADPKD. Genetic mutations associated with ADPKD cause an increase in intracellular levels of

cyclic adenosine monophosphate Cyclic adenosine monophosphate (cAMP, cyclic AMP, or 3',5'-cyclic adenosine monophosphate) is a second messenger, or cellular signal occurring within cells, that is important in many biological processes. cAMP is a derivative of adenosine tri ...

(cAMP), which results in increased cellular proliferation and

cyst A cyst is a closed sac, having a distinct envelope and division compared with the nearby tissue. Hence, it is a cluster of cells that have grouped together to form a sac (like the manner in which water molecules group together to form a bubb ...

formation and expansion in the kidney. Cyst growth displaces and destroys normal kidney tissue, leading to a decreased number and function of

nephrons The nephron is the minute or microscopic structural and functional unit of the kidney. It is composed of a renal corpuscle and a Nephron#Renal tubule, renal tubule. The renal corpuscle consists of a tuft of capillary, capillaries called a glomer ...

. Because intracellular cAMP is a secondary messenger for vasopressin acting at V₂R (

), V₂ receptor antagonists can restore normal levels of intracellular cAMP, thereby delaying cyst growth. Treatment with specific V₂ receptor antagonists have shown a reduction in kidney size and cyst volume in animal models of PKD. In particular, lixivaptan has demonstrated beneficial effects on cystic disease progression in rat and mouse models of ADPKD.

Research

V₂ Receptor Antagonists in ADPKD

Proof of efficacy for V₂ receptor antagonists to treat

ADPKD Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common, life-threatening inherited human disorders and the most common hereditary kidney disease. It is associated with large interfamilial and intrafamilial variability, wh ...

has been demonstrated by clinical trials with tolvaptan, a vasopressin antagonist in the same drug class as lixivaptan. In clinical studies, tolvaptan showed a significant decrease in the rate of disease progression in patients with ADPKD, which led to regulatory approvals for tolvaptan as a treatment of ADPKD in many countries, including the U.S., the EU, Japan, Canada, Australia, and Korea, among others. However, tolvaptan therapy is associated with potentially life-threatening

liver toxicity Hepatotoxicity (from ''hepatic toxicity'') implies chemical-driven liver damage. Drug-induced liver injury (DILI) is a cause of acute and chronic liver disease caused specifically by medications and the most common reason for a drug to be withdr ...

in patients with ADPKD. Because of the risk of liver toxicity, in the US, tolvaptan is only available for ADPKD under a restricted distribution program (a

Risk Evaluation and Mitigation Strategies Risk Evaluation and Mitigation Strategies (REMS) is a program of the US Food and Drug Administration for the monitoring of medications with a high potential for serious adverse effects. REMS applies only to specific prescription drugs, but can app ...

(REMS program). The FDA-approved prescribing information for tolvaptan for ADPKD includes a

boxed warning In the United States, a boxed warning (sometimes "black box warning", colloquially) is a type of warning that appears near the beginning of the package insert for certain prescription drugs, so called because the U.S. Food and Drug Administratio ...

for the risk of serious liver toxicity.

Clinical studies

Hyponatremia

Lixivaptan was previously administered to more than 1600 subjects across 36

clinical studies Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, dietar ...

as part of a prior clinical development program for the treatment of

hyponatremia Hyponatremia or hyponatraemia is a low concentration of sodium in the Serum (blood), blood. It is generally defined as a sodium concentration of less than 135 mmol/L (135 mEq/L), with severe hyponatremia being below 120 mEq/L. Symp ...

sponsored by Cardiokine, Inc. Across these studies, lixivaptan showed prolonged inhibition of the vasopressin V2 receptor, as measured by changes in

pharmacodynamic Pharmacodynamics (PD) is the study of the biochemistry, biochemical and physiology, physiologic effects of drugs (especially pharmaceutical drugs). The effects can include those manifested within animals (including humans), microorganisms, or comb ...

markers such as urine osmolality, plasma copeptin, and

estimated glomerular filtration rate Renal functions include maintaining an acid–base balance; regulating fluid balance; regulating sodium, potassium, and other electrolytes; clearance (medicine), clearing toxins; absorption of glucose, amino acids, and other small molecules; reg ...

(eGFR). Development of lixivaptan for hyponatremia indications is no longer ongoing.

ADPKD

Palladio conducted the ELiSA Phase II study with lixivaptan in 31 ADPKD patients. In this study, the proportion of study subjects who showed a urine osmolality response consistent with full vasopressin V₂ receptor inhibition was qualitatively and quantitatively similar to the published effect seen in clinical studies conducted with tolvaptan. A Phase III study by Palladio to investigate whether it is safe and effective for the treatment of ADPKD was commenced in October 2021. The Phase III program with lixivaptan consists of two ongoing clinical trials: the ACTION and ALERT studies.

The ACTION study

The ACTION study is a pivotal registration-enabling

Phase III clinical trial The phases of clinical research are the stages in which scientists conduct experiments with a health intervention to obtain sufficient evidence for a process considered effective as a medical treatment. For drug development, the clinical phase ...

of lixivaptan in patients with ADPKD. It is projected to enroll 1350 patients in more than 20 countries worldwide. If the ACTION study is successful, it will provide the main clinical evidence supporting the potential safety and efficacy of lixivaptan for the treatment of ADPKD. The ACTION trial consists of two main parts. In Part 1 of the study, after completing the screening, run-in and titration periods, study subjects will enter a two-arm,

double-blind In a blind or blinded experiment, information which may influence the participants of the experiment is withheld until after the experiment is complete. Good blinding can reduce or eliminate experimental biases that arise from a participants' expec ...

, placebo-controlled, randomized period during which they will receive lixivaptan or placebo for 12 months. This part of the trial will compare the change in estimated glomerular filtration rate (eGFR) measurements between the two groups to investigate the efficacy of lixivaptan in slowing the decline in kidney function. This is followed by Part 2 of the study, during which all study participants who complete Part 1 will receive lixivaptan in a single-arm, open-label phase for an additional 12 months. Part 2 will investigate whether lixivaptan's effect on kidney function continues to accrue over time. Altogether, including the titration periods, participants in the ACTION study will be taking study drug for more than two years, including lixivaptan for at least one year. It is expected that Part 1 will be ; Part 2 is projected to

The ALERT study

The second Phase III study with lixivaptan is the ALERT study. The goal of this study is to investigate whether lixivaptan can be safely used in patients with

who were previously treated with tolvaptan, but who had to permanently discontinue tolvaptan therapy due to

. In the study, following

titration Titration (also known as titrimetry and volumetric analysis) is a common laboratory method of Quantitative research, quantitative Analytical chemistry, chemical analysis to determine the concentration of an identified analyte (a substance to be ...

to an optimal dose, up to 50 patients with ADPKD will be enrolled and treated with lixivaptan for 52 weeks. They will be monitored frequently for signs of liver toxicity for as long as they are taking lixivaptan. At the completion of the 52 weeks maintenance period, patients will be eligible to continue to receive lixivaptan in an open label extension study.

DILIsym simulations

Tolvaptan was studied in DILIsym®, a state of the art, multiscale

computational model A computational model uses computer programs to simulate and study complex systems using an algorithmic or mechanistic approach and is widely used in a diverse range of fields spanning from physics, engineering, chemistry and biology to economics ...

that uses non-clinical and clinical drug data to predict whether a drug could cause idiosyncratic liver toxicity. DILIsym® replicated accurately the liver toxicity observed with tolvaptan in clinical studies. Conversely, results from the DILIsym® study with lixivaptan suggest that lixivaptan may be less likely to cause idiosyncratic liver toxicity within this modeling system. Whether this result reliably predicts a lower risk of liver injury for lixivaptan will require more clinical safety data, which will be collected as part of the two ongoing Phase III clinical studies.

References

{{Oxytocin and vasopressin receptor modulators Drugs acting on the cardiovascular system Vasopressin receptor antagonists

Mechanism of action

Hyponatremia

ADPKD

Research

V2 Receptor Antagonists in ADPKD

Clinical studies

Hyponatremia

ADPKD

The ACTION study

The ALERT study

DILIsym simulations

References

V₂ Receptor Antagonists in ADPKD