Vibegron, sold under the brand name Gemtesa, is a medication for the treatment of

overactive bladder Overactive bladder (OAB) is a condition where there is a frequent feeling of needing to urinate to a degree that it negatively affects a person's life. The frequent need to urinate may occur during the day, at night, or both. If there is loss ...

. Vibegron (other names: RVT-901; MK4618; KRP114V; URO-901) is a selective

beta-3 adrenergic receptor The beta-3 adrenergic receptor (β3-adrenoceptor), also known as ADRB3, is a beta-adrenergic receptor, and also denotes the human gene encoding it. Function Actions of the β3 receptor include *Enhancement of lipolysis in adipose tissue. *Ther ...

agonist An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ago ...

. The most common side effects include headache,

urinary tract infection A urinary tract infection (UTI) is an infection that affects part of the urinary tract. When it affects the lower urinary tract it is known as a bladder infection (cystitis) and when it affects the upper urinary tract it is known as a kidney ...

common cold The common cold or the cold is a viral infectious disease of the upper respiratory tract that primarily affects the respiratory mucosa of the nose, throat, sinuses, and larynx. Signs and symptoms may appear fewer than two days after exposu ...

, diarrhea, nausea, and

upper respiratory tract infection An upper respiratory tract infection (URTI) is an illness caused by an acute infection, which involves the upper respiratory tract, including the nose, sinuses, pharynx, larynx or trachea. This commonly includes nasal obstruction, sore throat, t ...

. It was approved for medical use in the United States in December 2020.

Medical uses

Vibegron is

indicated In medicine, an indication is a valid reason to use a certain test, medication, procedure, or surgery. There can be multiple indications to use a procedure or medication. An indication can commonly be confused with the term diagnosis. A diagnosis ...

for the treatment of

with symptoms of urge urinary incontinence, urgency, and urinary frequency in adults.

History and discovery

The

(beta3AR) was discovered in the late 1980s and initially, beta3AR

s were investigated as treatment for obesity and diabetes. A number of compounds were tested in clinical trials but didn't show sufficient benefits in these areas. Since the 2000s, there is evidence that there are beta3AR on the

detrusor muscle The detrusor muscle, also detrusor urinae muscle, muscularis propria of the urinary bladder and (less precise) muscularis propria, is smooth muscle found in the wall of the bladder. The detrusor muscle remains relaxed to allow the bladder to stor ...

of the bladder. The detrusor muscle contracts during urination and remains relaxed to allow the bladder to store urine. Vibegron is a selective beta3AR agonist that is developed in Japan by Kyorin Pharmaceutical Co., Ltd,

Kissei Kissei Pharmaceutical is a pharmaceutical company based in Matsumoto, Nagano, Japan. Products discovered or developed by Kissei include: * Difelikefalin * Fostamatinib (trade name Tavalisse) * Linzagolix * Mitiglinide (Glufast) * Remogliflozin etab ...

Pharmaceutical Co., Ltd, and Urovant Sciences to treat overactive bladders and pain caused by

irritable bowel syndrome Irritable bowel syndrome (IBS) is a "disorder of gut-brain interaction" characterized by a group of symptoms that commonly include abdominal pain and or abdominal bloating and changes in the consistency of bowel movements. These symptoms may ...

. It was globally approved on September 21, 2018, in Japan for OAB. Vibegron has been proven effective in five key

clinical trials 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 ...

. A

phase IIb 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 phases ...

global trial completed in 2013 of 1395 patients, of which 89.7% were women and 63.3% had not been treated previously, demonstrated a significant decrease in daily

micturition Urination, also known as micturition, is the release of urine from the urinary bladder through the urethra to the outside of the body. It is the urinary system's form of excretion. It is also known medically as micturition, voiding, uresis, ...

s and urgent urinary incontinence episodes upon administration of vibegron. An international phase III trial of 506 participants completed in 2019 found statistically significant efficacy of vibegron after 2 weeks of daily administration. The adverse effect rates in patients treated with vibegron were comparable to those in patients who received a placebo. GEMTESA, a drug using vibegron as an active ingredient, was approved by the FDA on December 23, 2020, after an additional phase III international trial of 1085 patients.

Society and culture

Legal status

Vibegron was approved for medical use in the United States in December 2020.

Names

Vibegron is the international nonproprietary name.

Mechanism of action

Vibegron is a selective agonist for the beta-3 adrenergic receptor. The receptors are located in the kidneys, urinary tract and bladder tissue. Upon binding, the β3 receptor undergoes a conformational change. This induces the activation of adenylate cyclases via

G proteins G proteins, also known as guanine nucleotide-binding proteins, are a family of proteins that act as molecular switches inside cells, and are involved in transmitting signals from a variety of stimuli outside a cell to its interior. Their act ...

and thereby promotes the formation of

cyclic adenosine monophosphate Cyclic adenosine monophosphate (cAMP, cyclic AMP, or 3',5'-cyclic adenosine monophosphate) is a second messenger important in many biological processes. cAMP is a derivative of adenosine triphosphate (ATP) and used for intracellular signal transd ...

(cAMP). The consequence of this cascade is an increased intracellular cAMP concentration, which triggers activation of cAMP-dependent

protein kinase A In cell biology, protein kinase A (PKA) is a family of enzymes whose activity is dependent on cellular levels of cyclic AMP (cAMP). PKA is also known as cAMP-dependent protein kinase (). PKA has several functions in the cell, including regulatio ...

and causes a reduction of Ca2+ concentration in the

cytoplasm In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. The ...

. The kinase then

phosphorylates In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, whi ...

myosin Myosins () are a superfamily of motor proteins best known for their roles in muscle contraction and in a wide range of other motility processes in eukaryotes. They are ATP-dependent and responsible for actin-based motility. The first myosin ...

chains and thereby inhibits muscle contraction. The final effect of vibegron is muscle relaxation in the bladder. Due to this muscle relaxation, bladder capacity increases and symptoms of overactive bladder are relieved.

Metabolism

The two main metabolic pathways are the

oxidation Redox (reduction–oxidation, , ) is a type of chemical reaction in which the oxidation states of substrate change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is the gain of electrons or a d ...

and

glucuronidation Glucuronidation is often involved in drug metabolism of substances such as drugs, pollutants, bilirubin, androgens, estrogens, mineralocorticoids, glucocorticoids, fatty acid derivatives, retinoids, and bile acids. These linkages involve glycosid ...

of vibegron. Two oxidative metabolites and three glucuronide metabolites can be formed. The exact structure of these metabolites have not been studied yet. In vitro,

CYP3A4 Cytochrome P450 3A4 (abbreviated CYP3A4) () is an important enzyme in the body, mainly found in the liver and in the intestine. It oxidizes small foreign organic molecules (xenobiotics), such as toxins or drugs, so that they can be removed from t ...

is the enzyme responsible for the metabolism of vibegron, facilitating oxidative metabolism. Eventually, still a large part of the unmodified drug is excreted through feces and urine.

Indications

Vibegron is indicated for people with OAB. Urgency

urinary incontinence Urinary incontinence (UI), also known as involuntary urination, is any uncontrolled leakage of urine. It is a common and distressing problem, which may have a large impact on quality of life. It has been identified as an important issue in geria ...

(UUI), urgency and urinary frequency in adults are the most common symptoms for this condition. The drug is

contraindicated In medicine, a contraindication is a condition that serves as a reason not to take a certain medical treatment due to the harm that it would cause the patient. Contraindication is the opposite of indication, which is a reason to use a certain tre ...

in patients with known hypersensitivity to vibegron itself or single components of the drug. The inactive components of the drug for which allergic reactions can occur are sodium croscarmellose,

hydroxypropyl cellulose Hydroxypropyl cellulose (HPC) is a derivative of cellulose with both water solubility and organic solubility. It is used as an excipient, and topical ophthalmic protectant and lubricant. Chemistry HPC is an ether of cellulose in which some of t ...

magnesium stearate Magnesium stearate is the chemical compound with the formula . It is a soap, consisting of salt containing two equivalents of stearate (the anion of stearic acid) and one magnesium cation (Mg2+). Magnesium stearate is a white, water-insoluble pow ...

mannitol Mannitol is a type of sugar alcohol used as a sweetener and medication. It is used as a low calorie sweetener as it is poorly absorbed by the intestines. As a medication, it is used to decrease pressure in the eyes, as in glaucoma, and to lower ...

and

microcrystalline cellulose Microcrystalline cellulose (MCC) is a term for refined wood pulp and is used as a texturizer, an anti-caking agent, a fat substitute, an emulsifier, an extender, and a bulking agent in food production. The most common form is used in vitamin sup ...

. The thin coating of the drug with green color contains FD&C Blue No. 2. Vibegron treatment should be discontinued if

urinary retention Urinary retention is an inability to completely empty the bladder. Onset can be sudden or gradual. When of sudden onset, symptoms include an inability to urinate and lower abdominal pain. When of gradual onset, symptoms may include loss of bladd ...

occurs. Use with nonselective muscarinic antagonists may increase the risk of urinary retention. The manufacturer suggests discontinuing vibegron if an elevated

digoxin Digoxin (better known as Digitalis), sold under the brand name Lanoxin among others, is a medication used to treat various heart conditions. Most frequently it is used for atrial fibrillation, atrial flutter, and heart failure. Digoxin is on ...

concentration occurs.

Efficacy and side effects

Efficacy

Vibegron was evaluated in patients with OAB in several clinical studies. A large active-controlled study, called Empower, showed the beneficial effects of the drug to treat the condition and UUI. Primary outcomes of different clinical trials showed there was an overall increase in efficacy. These outcomes concluded that there was a reduction in urgency to urinate, a decrease in micturitions and a decrease in average volume voided per micturition. There is also an improvement observed of the symptoms when vibegron is administered over a longer period (52 weeks) concluding that it is effective and safe for longer use. In severe patients, increasing the dose was accompanied by similar beneficial effects when there was first a lack of these.

Quality of life Quality of life (QOL) is defined by the World Health Organization as "an individual's perception of their position in life in the context of the culture and value systems in which they live and in relation to their goals, expectations, standards ...

of the patients is improved, including a reduction of

nocturia Nocturia is defined by the International Continence Society (ICS) as “the complaint that the individual has to wake at night one or more times for voiding (''i.e. to urinate'').” The term is derived from Latin ''nox, night'', and Greek '' �αο ...

Adverse effects

The most common side effects of vibegron are a dry mouth, constipation, headache,

nasopharyngitis The common cold or the cold is a viral infectious disease of the upper respiratory tract that primarily affects the respiratory mucosa of the nose, throat, sinuses, and larynx. Signs and symptoms may appear fewer than two days after exposu ...

, diarrhea, nausea,

bronchitis Bronchitis is inflammation of the bronchi (large and medium-sized airways) in the lungs that causes coughing. Bronchitis usually begins as an infection in the nose, ears, throat, or sinuses. The infection then makes its way down to the bronchi. ...

and

. An indication is made that upon urinary retention development, the patient should stop using the drug. Risk assessment for the drug in pregnant people has yet to be evaluated.

Interactions

Vibegron is, in contrast to other OAB drugs, very selective and leads to a lesser degree of unwanted side effects. Vibegron is found to be a substrate for CYP3A4 in vivo, but does not actually induce or inhibit any of the cytochrome P450 enzymes and is thus less likely to take part in drug–drug interactions (DDI). Here vibegron differs from the previous overactive bladder drug mirabegron, which was known to be associated in various drug–drug interactions by inhibiting

CYP2D6 Cytochrome P450 2D6 (CYP2D6) is an enzyme that in humans is encoded by the ''CYP2D6'' gene. ''CYP2D6'' is primarily expressed in the liver. It is also highly expressed in areas of the central nervous system, including the substantia nigra. CYP2D ...

or inducing CYP3A4, CYP2D6 and

CYP2C9 Cytochrome P450 family 2 subfamily C member 9 (abbreviated CYP2C9) is an enzyme protein. The enzyme is involved in metabolism, by oxidation, of both xenobiotics, including drugs, and endogenous compounds, including fatty acids. In humans, the prote ...

in the liver. Using vibegron only (monotherapy) has positive effects on OAB and UUI, but a combination with other drugs can have additional effects. In a study with

antimuscarinic A muscarinic receptor antagonist (MRA) is a type of anticholinergic agent that blocks the activity of the muscarinic acetylcholine receptor. The muscarinic receptor is a protein involved in the transmission of signals through certain parts of the ...

drugs, more DDIs were investigated using a model of rhesus monkeys. Dose combinations of vibegron and

tolterodine Tolterodine, sold under the brand name Detrol among others, is a medication used to treat frequent urination, urinary incontinence, or urinary urgency. Effects are seen within an hour. It is taken by mouth. Common side effects include heada ...

showed increased bladder capacity, the effects of both drugs at low doses strengthened each other, known as synergism. The addition of

darifenacin Darifenacin (trade name Enablex in United States and Canada, Emselex in the European Union) is a medication used to treat urinary incontinence due to an overactive bladder. It was discovered by scientists at the Pfizer research site in Sandwich, ...

to vibegron created greater bladder relaxation only when used at high doses. Additionally, co-administration with imidafenacin shows an increase in bladder capacity and voided volume in comparison to monotherapy. Possibly, a widely adapted treatment will be the combination of beta-3-adrenergic agonist with a nonselective M2/ M3 antagonist as the most prevalent option. Clinical studies show no significant drug–drug interaction, aside from a serum concentration increase of digoxin when taken with vibegron. Maximal concentrations and systemic exposure (Cmax and area under the curve (AUC)) of digoxin are both increased as a result of DDI. Apart from the no to little DDIs, vibegron has an additional safety quality in that it does not cross the blood-brain barrier and therefore does not induce cognitive impairment. Furthermore, vibegron can be taken with or without food, this does not have an effect on vibegron plasma concentrations.

Toxicity

Effects on animals

Pregnant rats were given very high daily oral doses of vibegron during the period of

organogenesis Organogenesis is the phase of embryonic development that starts at the end of gastrulation and continues until birth. During organogenesis, the three germ layers formed from gastrulation (the ectoderm, endoderm, and mesoderm) form the internal orga ...

and showed no embryo-fetal developmental toxicity up to 300 mg/kg/day. Similar data was found in rabbits. Maternal toxicity was observed when doses exceeded 100 mg/kg/day in lactating rats. Clinical studies show that vibegron is not toxic, safe and well-tolerated in patients.

References

External links

* * {{Portal bar , Medicine Beta3-adrenergic agonists Phenylethanolamines