vibegron

Vibegron, once daily 75 mg provided significant reduction in micturition, urgency episodes and urge incontinence, and increased the volume per micturition.{{cite journal | vauthors = Staskin D, Frankel J, Varano S, Shortino D, Jankowich R, Mudd PN | title = International Phase III, Randomized, Double-Blind, Placebo and Active Controlled Study to Evaluate the Safety and Efficacy of Vibegron in Patients with Symptoms of Overactive Bladder: EMPOWUR | journal = The Journal of Urology | volume = 204 | issue = 2 | pages = 316–324 | date = August 2020 | pmid = 32068484 | doi = 10.1097/ju.0000000000000807 | s2cid = 211161769 }}

Vibegron is indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and urinary frequency in adults.

Generally, the introduction of β3 adrenergic receptors agonists such as vibegron has improved overactive bladder (OAB) management by minimizing anticholinergic-related adverse effects.{{cite journal | vauthors = Kelleher C, Hakimi Z, Zur R, Siddiqui E, Maman K, Aballéa S, Nazir J, Chapple C | display-authors = 6 | title = Efficacy and Tolerability of Mirabegron Compared with Antimuscarinic Monotherapy or Combination Therapies for Overactive Bladder: A Systematic Review and Network Meta-analysis | journal = European Urology | volume = 74 | issue = 3 | pages = 324–333 | date = September 2018 | pmid = 29699858 | doi = 10.1016/j.eururo.2018.03.020 | doi-access = free }} Monotherapy with a β3 adrenergic agonist may be preferred in older patients, those with high anticholinergic burden, and older adults with multiple comorbidities.{{cite journal | vauthors = Kennelly MJ, Rhodes T, Girman CJ, Thomas E, Shortino D, Mudd PN | title = Efficacy of Vibegron and Mirabegron for Overactive Bladder: A Systematic Literature Review and Indirect Treatment Comparison | journal = Advances in Therapy | volume = 38 | issue = 11 | pages = 5452–5464 | date = November 2021 | pmid = 34537953 | doi = 10.1007/s12325-021-01902-8 | pmc = 8520873 }} An ambulatory blood pressure monitoring study showed that treatment with vibegron was not associated with clinically meaningful effects on blood pressure or heart rate. Treatment with vibegron was also associated with improvements in patient-reported measures of quality of life. Vibegron was generally effective, safe and well tolerated, thus represents a valuable treatment option for patients with OAB.{{cite journal | vauthors = Frankel J, Staskin D, Varano S, Kennelly MJ, Jankowich RA, Haag-Molkenteller C | title = An Evaluation of the Efficacy and Safety of Vibegron in the Treatment of Overactive Bladder | journal = Therapeutics and Clinical Risk Management | volume = 18 | pages = 171–182 | date = March 2022 | pmid = 35264853 | doi = 10.2147/tcrm.s310371 | pmc = 8901416 | doi-access = free }}

The most common side effects of vibegron are dry mouth, constipation, headache, nasopharyngitis, diarrhea, nausea, bronchitis, urinary tract infection and upper respiratory tract infection. In case of urinary retention, the patient should stop using the drug. Risk assessment for the drug in pregnant people has yet to be evaluated.

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 or inducing CYP3A4, CYP2D6 and CYP2C9 in the liver.{{Cite web|vauthors=Stambakio H|date=2019|title=AUA 2019: Once-Daily Vibegron, a Novel Oral β3 Agonist Does Not Inhibit CYP2D6, a Common Pathway For Drug Metabolism in Patients on OAB Medications|url=https://www.urotoday.com/conference-highlights/aua-2019-annual-meeting/aua-2019-lower-urinary-tract-conditions/112099-aua-2019-once-daily-vibegron-a-novel-oral-3-agonist-does-not-inhibit-cyp2d6-a-common-pathway-for-drug-metabolism-in-patients-on-oab-medications.html|access-date=2 March 2021|archive-date=19 July 2021|archive-url=https://web.archive.org/web/20210719211121/https://www.urotoday.com/conference-highlights/aua-2019-annual-meeting/aua-2019-lower-urinary-tract-conditions/112099-aua-2019-once-daily-vibegron-a-novel-oral-3-agonist-does-not-inhibit-cyp2d6-a-common-pathway-for-drug-metabolism-in-patients-on-oab-medications.html|url-status=live}}{{cite journal | vauthors = Bragg R, Hebel D, Vouri SM, Pitlick JM | title = Mirabegron: a Beta-3 agonist for overactive bladder | journal = The Consultant Pharmacist | volume = 29 | issue = 12 | pages = 823–37 | date = December 2014 | pmid = 25521658 | pmc = 4605389 | doi = 10.4140/TCP.n.2014.823 }}{{cite journal | vauthors = Araklitis G, Baines G, da Silva AS, Robinson D, Cardozo L | title = Recent advances in managing overactive bladder | journal = F1000Research | volume = 9 | pages = 1125 | date = 11 September 2020 | pmid = 32968482 | pmc = 7489273 | doi = 10.12688/f1000research.26607.1 | doi-access = free }}

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 drugs, more DDIs were investigated using a model of rhesus monkeys. Dose combinations of vibegron and tolterodine showed increased bladder capacity, the effects of both drugs at low doses strengthened each other, known as synergism. The addition of darifenacin to vibegron created greater bladder relaxation only when used at high doses.{{cite journal | vauthors = Di Salvo J, Nagabukuro H, Wickham LA, Abbadie C, DeMartino JA, Fitzmaurice A, Gichuru L, Kulick A, Donnelly MJ, Jochnowitz N, Hurley AL, Pereira A, Sanfiz A, Veronin G, Villa K, Woods J, Zamlynny B, Zycband E, Salituro GM, Frenkl T, Weber AE, Edmondson SD, Struthers M | display-authors = 6 | title = Pharmacological Characterization of a Novel Beta 3 Adrenergic Agonist, Vibegron: Evaluation of Antimuscarinic Receptor Selectivity for Combination Therapy for Overactive Bladder | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 360 | issue = 2 | pages = 346–355 | date = February 2017 | pmid = 27965369 | doi = 10.1124/jpet.116.237313 | doi-access = free | title-link = doi }} 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.{{Cite web|work=Medscape|title=Vibegron (Rx)|url=https://reference.medscape.com/drug/gemtesa-vibegron-4000077|access-date=2 March 2021|archive-date=22 May 2022|archive-url=https://web.archive.org/web/20220522071258/https://reference.medscape.com/drug/gemtesa-vibegron-4000077|url-status=live}} 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.

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 and thereby promotes the formation of cyclic adenosine monophosphate (cAMP). The consequence of this cascade is an increased intracellular cAMP concentration, which triggers activation of cAMP-dependent protein kinase A and causes a reduction of Ca2+ concentration in the cytoplasm. The kinase then phosphorylates myosin chains and thereby inhibits muscle contraction.{{cite journal | vauthors = Rechberger T, Wróbel A | title = Evaluating vibegron for the treatment of overactive bladder | journal = Expert Opinion on Pharmacotherapy | volume = 22 | issue = 1 | pages = 9–17 | date = January 2021 | pmid = 32993398 | doi = 10.1080/14656566.2020.1809652 | s2cid = 222166213 }}

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.{{cite journal | vauthors = Yoshida M, Takeda M, Gotoh M, Yokoyama O, Kakizaki H, Takahashi S, Masumori N, Nagai S, Hashimoto K, Minemura K | display-authors = 6 | title = Efficacy of novel β₃ -adrenoreceptor agonist vibegron on nocturia in patients with overactive bladder: A post-hoc analysis of a randomized, double-blind, placebo-controlled phase 3 study | journal = International Journal of Urology | volume = 26 | issue = 3 | pages = 369–375 | date = March 2019 | pmid = 30557916 | pmc = 6912249 | doi = 10.1111/iju.13877 }}

The two main metabolic pathways are the oxidation and glucuronidation 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 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.

The beta-3 adrenergic receptor (beta3AR) was discovered in the late 1980s{{cite journal | vauthors = Schena G, Caplan MJ | title = Everything You Always Wanted to Know about β₃-AR * (* But Were Afraid to Ask) | journal = Cells | volume = 8 | issue = 4 | pages = 357 | date = April 2019 | pmid = 30995798 | pmc = 6523418 | doi = 10.3390/cells8040357 | doi-access = free | title-link = doi }} and initially, beta3AR agonists were investigated as treatment for obesity and diabetes.{{cite journal | vauthors = Edmondson SD, Zhu C, Kar NF, Di Salvo J, Nagabukuro H, Sacre-Salem B, Dingley K, Berger R, Goble SD, Morriello G, Harper B, Moyes CR, Shen DM, Wang L, Ball R, Fitzmaurice A, Frenkl T, Gichuru LN, Ha S, Hurley AL, Jochnowitz N, Levorse D, Mistry S, Miller RR, Ormes J, Salituro GM, Sanfiz A, Stevenson AS, Villa K, Zamlynny B, Green S, Struthers M, Weber AE | display-authors = 6 | title = Discovery of Vibegron: A Potent and Selective β3 Adrenergic Receptor Agonist for the Treatment of Overactive Bladder | journal = Journal of Medicinal Chemistry | volume = 59 | issue = 2 | pages = 609–23 | date = January 2016 | pmid = 26709102 | doi = 10.1021/acs.jmedchem.5b01372 }} A number of compounds were tested in clinical trials but didn't show sufficient benefits in these areas.

A phase IIb 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 micturitions and urgent urinary incontinence episodes upon administration of vibegron.{{ClinicalTrialsGov|NCT01314872|A Study of the Efficacy and Safety of Vibegron (MK-4618) in Participants With Overactive Bladder (OAB) (MK-4618-008)}}{{cite journal | vauthors = Mitcheson HD, Samanta S, Muldowney K, Pinto CA, Rocha BA, Green S, Bennett N, Mudd PN, Frenkl TL | display-authors = 6 | title = Vibegron (RVT-901/MK-4618/KRP-114V) Administered Once Daily as Monotherapy or Concomitantly with Tolterodine in Patients with an Overactive Bladder: A Multicenter, Phase IIb, Randomized, Double-blind, Controlled Trial | journal = European Urology | volume = 75 | issue = 2 | pages = 274–282 | date = February 2019 | pmid = 30661513 | doi = 10.1016/j.eururo.2018.10.006 | doi-access = | title-link = doi | s2cid = 58547754 }}

An international phase III trial of 506 participants completed in 2019 found statistically significant efficacy of vibegron after two weeks of daily administration. The adverse effect rates in participants treated with vibegron were comparable to those in participants who received a placebo.{{ClinicalTrialsGov|NCT03583372|An Extension Study to Examine the Safety and Tolerability of a New Drug in Patients With Symptoms of Overactive Bladder (OAB). (Empowur) }}

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 an increase 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.{{cite journal | vauthors = Yoshida M, Takeda M, Gotoh M, Nagai S, Kurose T | title = Vibegron, a Novel Potent and Selective β₃-Adrenoreceptor Agonist, for the Treatment of Patients with Overactive Bladder: A Randomized, Double-blind, Placebo-controlled Phase 3 Study | journal = European Urology | volume = 73 | issue = 5 | pages = 783–790 | date = May 2018 | pmid = 29366513 | doi = 10.1016/j.eururo.2017.12.022 }} Quality of life of the patients is improved, including a reduction of nocturia.

Vibegron was developed in Japan by Kyorin Pharmaceutical Co., Ltd, Kissei Pharmaceutical Co., Ltd, and Urovant Sciences. It was approved for medical use in Japan in September 2018, and in the United States in December 2020.

In April 2024, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Obgemsa, intended for the symptomatic treatment of adults with overactive bladder (OAB) syndrome.{{cite press release | title=Meeting highlights from the Committee for Medicinal Products for Human Use (CHMP) 22-25 April 2024 | website=European Medicines Agency | date=26 April 2024 | url=https://www.ema.europa.eu/en/news/meeting-highlights-committee-medicinal-products-human-use-chmp-22-25-april-2024 | access-date=13 June 2024 | archive-date=5 July 2024 | archive-url=https://web.archive.org/web/20240705192841/https://www.ema.europa.eu/en/news/meeting-highlights-committee-medicinal-products-human-use-chmp-22-25-april-2024 | url-status=live }} The applicant for this medicinal product is Pierre Fabre Medicament.{{cite web | title=Obgemsa EPAR | website=European Medicines Agency | date=25 April 2024 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/obgemsa | access-date=27 April 2024 | archive-date=5 July 2024 | archive-url=https://web.archive.org/web/20240705192842/https://www.ema.europa.eu/en/medicines/human/EPAR/obgemsa | url-status=live }} Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged. Vibegron was approved for medical use in the European Union in June 2024.

Vibegron is the international nonproprietary name.{{cite journal | vauthors=((World Health Organization)) | year=2013 | title=International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 70 | journal=WHO Drug Information | volume=27 | issue=3 | page=318 | hdl=10665/331167 | hdl-access=free }}

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

{{reflist}}

• {{ClinicalTrialsGov|NCT03492281|A Study to Examine the Safety and Efficacy of a New Drug in Patients With Symptoms of Overactive Bladder (OAB) (Empowur)}}

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