Materia Medica

Gemtesa® (vibegron)

haBiBuR Rahman, PhaRmD COuRtney simPkins, PhaRmD Intro

Gemtesa® (vibegron) is a novel β3-adrenergic receptor (β3-AR) agonist that is FDA approved for treatment of overactive bladder (OAB) with symptoms of urge incontinence, urgency, and urinary frequency.1 It is the first selective β3-AR agonist to achieve FDA approval since introduction of mirabegron in 2012, the only other β3-AR agonist on the market. Gemtesa® is highly selective, with a greater than 9000-fold selectivity for the β3-AR compared to β1 or β2 receptors. The selectivity of this agent is a point of emphasis as broad β receptor agonism can lead to greater adverse drug reactions. Other OAB medications target muscarinic receptors and have significant anticholinergic effects.2

Safety

In a 2018 phase 3 trial conducted in patients of Japanese descent with OAB, the incidence of drug-related adverse events associated with Gemtesa® was similar to placebo and less than the comparator anticholinergic, imidafenacin.3 In this four-arm, parallel-group, 12-week active treatment, placebo-controlled trial, patients with OAB symptoms for greater than or equal to 6 months were randomized to receive Gemtesa® 50mg daily (n=370), Gemtesa® 100mg daily (n=369), placebo (n=369), or imidafenacin 0.1mg twice daily (n=117) in a 3.3:3.3:3.3:1 ratio respectively. Safety was assessed based on rates of adverse events, clinical testing, postvoid residuals, vitals, and 12-lead electrocardiogram (ECG). Clinical tests included hematological markers, biochemical markers, and urinalysis. Treatment-emergent adverse events (TEAE) were all adverse events recorded after the start of each treatment that may or may not be attributed to each treatment arm. From a safety standpoint, the most common TEAE was nasopharyngitis (8.6%, 9.5%, 7.3%, 3.4%), cystitis (2.4%, 2.2%, 0.8%, 0.9%), and blood alkaline phosphatase increases (0%, 0.3%, 0.3%, 2.6%) for the 50mg, 100mg, placebo, and imidafenacin treatment arms respectively. Drug-related TEAE were adverse events that occurring during treatment that investigators attributed to each treatment arm. The most common drug related TEAE were blood alkaline phosphatase increase (0%, 0.3%, 0.3%, 1.7%) and hypertension (0%, 0%, 0%, 1.7%). Serious TEAE included back pain, pyelonephritis, colon cancer, acute myeloid leukemia, dizziness, and breast cancer. These occurred in 1 patient in each active drug treatment arm and in 3 patients in the placebo arm, none of which were thought to be related to the intervention. TEAEs that led to discontinuation were in 3 patients in the 50mg Gemtesa® group (edema, eczema, and neutrophil count decrease), and 3 patients in the 100mg Gemtesa® group (supraventricular tachycardia, blood creatinine increase, and abdominal pain). There were no other notable changes in clinical laboratory values and vital signs than the ones mentioned. There were similar rates of ECG changes among all groups as well as no substantial changes in postvoid residuals. This study demonstrated the relative safety of Gemtesa® with low incidences of key safety parameters.

In a phase 3 trial, patients with OAB were treated with Gemtesa® 50mg (n=116) or 100mg (n=51), and the long-term safety profile of the medication was evaluated.4 In patients that did not respond appropriately within 8 weeks to 50mg, they were increased to 100mg and continued this treatment for 44 weeks. The primary safety outcome was evaluated in overall percentages of TEAE which were 55.1% and 16.2% for 50mg and 100mg respectively. Three cases of cystitis and 5 cases of postvoid residual increase were discovered, all in the 50mg group and none in the 100mg group. Severe TEAE, which were angina pectoris (n=1), falls (n=1),

and cerebral infarction (n=1), occurred only in the 50mg group. Besides cerebral infarction, all other severe TEAEs were not considered to be caused by Gemtesa® because there was no correlation between adverse event onset and dose administration. A third of all TEAE were reported within the first 12 weeks of treatment and decreased in a time dependent manner. No clinically significant changes were found in clinical labs, vitals, or ECG changes after 1 year of treatment.

There is little concern for toxicities related to drug metabolism and clearance with Gemtesa®. The drug has not shown to be a significant inhibitor or inducer of major cytochrome P450 enzymes.5 With concomitant administration of ketoconazole, diltiazem, rifampin, or tolterodine, no significant differences were observed in Gemtesa® pharmacokinetics.1 The coadministration with digoxin increased digoxin area under the curve by 21%. Renal dose adjustments are not required for mild to severe renal impairment. Patients with an eGFR less than 15mL/min/1.73 m2 with or without hemodialysis, use is not recommended as it has not been studied in this patient population. No hepatic dose adjustments are required in patients with a Child-Pugh score of A or B but in patients with a score of C, use is not recommended as it has also not been studied.

Tolerability

Gemtesa® has been shown to be well-tolerated by patients in clinical trials. The most common drug-related TEAE were constipation (1.6%, 0.3%, 0.8%, 0.9%) and dry mouth (1.4%, 0.3%, 0.5%, 4.3%) for Gemtesa® 50mg daily (n=370), Gemtesa® 100mg daily (n=369), placebo (n=369), or imidafenacin 0.1mg twice daily (n=117) respectively.3 Data from long-term follow-up in Japanese patients also showed constipation (1.7%, 3.9%) and dry-mouth (2.6%, 3.9%) to be the most frequent adverse events for 50mg and 100mg respectivly.4 The EMPOWUR trial compared 75mg Gemtesa®, placebo, and extended release 4mg tolterodine for 12 weeks of treatment in patients with OAB.6 Similar to the short-term trial in Japanese patients, this 2020 trial found low rates of discontinuation due to adverse events with 1.7% in Gemtesa® (n=545), 1.1% in placebo (n=540), and 3.3% in tolterodine (n=430) patients. The most common adverse events were headache (4%, 2.4%, 2.6%), nasopharyngitis (2.8%, 1.7%, 2.6%), diarrhea (2.2%, 1.1%, 2.1%), nausea (2.2%, 1.1%, 1.2%) and constipation (1.7%, 1.3%, 1.4%) for the Gemtesa®, placebo, and tolterodine groups respectively. In the EMPOWUR extension trial, patients were continued on therapy for 40 weeks.7 Patients that received placebo were randomized 1:1 to get either tolterodine or Gemtesa® . Between the groups, there were no meaningful differences between the incidence and severity of adverse events. The most common adverse event reported were hypertension (8.8, 8.6%), headache (5.5%,3.9%), diarrhea (4.8%, 1.7%), constipation (3.7%, 2.6%) and nausea (3.7%, 3%) in the Gemtesa® and tolterodine groups respectively.

Efficacy

There are 2 randomized, doubleblind, phase 3 trials with both short and long-term data that show the efficacy of Gemtesa® in treatment of OAB symptoms.3 Yoshida et al had a primary outcome of change in the number of micturitions a day at 12 weeks from baseline. Their secondary outcomes included changes in baseline OAB symptom variables. They found the estimated difference in mean micturitions a day between Gemtesa® groups and placebo was -0.86 (-1.12, -0.60) for Gemtesa® 50 mg (p < 0.001) and -0.81 (-1.07, -0.55) for Gemtesa® 100mg (p < 0.001). For secondary outcomes of daily urgency episodes, urgency incontinence episodes, incontinence episodes, and nocturia episodes, both doses had significantly lower rates compared to placebo. A phase 3 trial by Yoshida et al evaluated the efficacy after 1 year of treatment in Japanese patients treated for OAB. If investigators determined patients needed further symptom management after 8 weeks of 50mg, doses were increased to 100mg. This long-term study confirmed the statistically significant OAB symptom improvements were maintained through 52 weeks and patients that initially did not have improvements with 50mg had an improved condition with dose escalation.

The international EMPOWUR trial showed that Gemtesa® 75mg dose significantly reduced micturitions per day by a mean of 1.8 compared to 1.3 in placebo, a least-square (LS) mean difference of -0.5 (95% CI -0.8, -0.2) p <0.001.6 Tolterodine had a LS mean change of 1.6, a LS mean difference of -0.3 from placebo (95% CI -0.6,

From Page 21 0.1).The study drug also reduced urge incontinence episodes by a mean of 2 episodes a day compared to 1.4 in placebo and 1.8 for tolterodine, an LS mean difference from placebo of -0.6 (95% CI -0.9, -0.3) and -0.4 (95% CI -0.7, -0.1) for Gemtesa® and tolterodine respectively. For the secondary outcomes of number of urgency episodes, volume per micturition, and proportion of incontinent patients with a 75% or greater reduction in urge incontinence episodes, Gemtesa® was statistically superior to placebo. This symptom improvement was maintained through 52 weeks as demonstrated in the EMPOWUR extension trial.7

Price

Currently the only FDA approved dose of Gemtesa® is 75mg daily, based on data from the EMPOWUR trial. The average wholesale price for a 75mg tablet is $18.34, making a month supply of Gemtesa® equal $550.20.8 A manufacturer Simple Savings Card is available if patients have a qualifying commercial insurance plan and need cost assistance.9 In comparison, the average wholesale price for a 30 day supply of mirabegron is estimated to be $500.70.10

Simplicity

Gemtesa® once daily 75mg dose is optimal for patients that have trouble with pill burden or may forget to take a dose. The long half-life of 30.8 hours makes consequences of late dosing less severe.1 Furthermore, for patient that have trouble swallowing, tablets may be crushed and administered with applesauce. With consideration to dietary requirements, no clinically relevant pharmacokinetic differences were observed with administration of high fat meals.1 Since Gemtesa® has no renal or hepatic adjustments, no changes to therapy need to be made for patients that have a decline in renal or hepatic function, outside of eGFR less than 15 and severe hepatic impairment. In those patients, therapy would not be initiated. Although Gemtesa® is a CYP3a4 and P-gp substrate, little pharmacokinetic changes were observed with concomitant administration of strong inhibitors and inducers. This simplifies therapy as drug interaction are not of significant concern.

Bottom Line

Gemtesa® (Vibegron) is a highly selective β3-AR agonist that can be used to treat urinary symptoms of OAB. Trials have found little evidence of significant safety concerns and only mild side effects with treatment. Gemtesa® has demonstrated significant improvements in urinary symptoms in patients which is maintained at 52 weeks. Since the half-life of Gemtesa® is long, it allows for once daily 75mg dosing, making administration easy. The major drawback of Gemtesa® therapy is the cost of the medication. Although clinically it is effective and well tolerated, cost significantly limits access for patients. If cost is not a significant burden, Gemtesa® may be considered as a first-line treatment option. Dr. Habibur Rahman is a PGY1 Pharmacy resident at UPMC St. Margaret and can be reached at rahmanh@upmc.edu. Dr. Courtney Simpkins is a PGY2 Ambulatory Care Pharmacy resident at UPMC St. Margaret and can be reached at simpkinsca@upmc.edu. Dr. Heather Sakely, PharmD, BCPS, BCGP, the Director of Geriatric Pharmacotherapy and Director of the PGY2 Geriatric Pharmacy Residency served as editor and mentor for this work and can be reached at sakelyh@upmc.edu.

References

1. Gemtesa (Vibegron) [package insert].Irvine, CA: Urovant Sciences,

Inc.; 2020. 2. Scarneciu I, Lupu S, Bratu OG, et al. Overactive bladder: A review and update. Exp Ther Med. 2021;22(6):1444. doi:10.3892/

ETM.2021.10879

3. Yoshida M, Takeda M, Gotoh M,

Nagai S, Kurose T. Vibegron, a Novel Potent and Selective β(3)-Adrenoreceptor Agonist, for the Treatment of Patients with Overactive Bladder: A Randomized, Double-blind,

Placebo-controlled Phase 3 Study.

Eur Urol. 2018;73(5):783-790. doi:10.1016/j.eururo.2017.12.022 4. Yoshida M, Kakizaki H, Takahashi

S, Nagai S, Kurose T. Long-term safety and efficacy of the novel β(3) -adrenoreceptor agonist vibegron in

Japanese patients with overactive bladder: A phase III prospective study. Int J Urol Off J Japanese

Urol Assoc. 2018;25(7):668-675. doi:10.1111/iju.13596

5. Edmondson SD, Zhu C, Kar NF, et al. Discovery of Vibegron: A Potent and Selective β3 Adrenergic Receptor Agonist for the Treatment of

Overactive Bladder. J Med Chem. 2016;59(2):609-623. doi:10.1021/ acs.jmedchem.5b01372 6. Staskin D, Frankel J, Varano S,

Shortino D, Jankowich R, Mudd

PNJ. 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. J Urol. 2020;204(2):316-324. doi:10.1097/

JU.0000000000000807

7. Staskin D, Frankel J, Varano S,

Shortino D, Jankowich R, Mudd

PNJ. Once-Daily Vibegron 75 mg for Overactive Bladder: Long-Term

Safety and Efficacy from a Double-Blind Extension Study of the International Phase 3 Trial (EMPOW-

UR). J Urol. 2021;205(5):1421-1429. doi:10.1097/JU.0000000000001574 8. Lexicomp. Vibegron: Drug information. Accessed October 16, 2021. https://www.uptodate. com/contents/vibegron-drug-information?search=vibegron&source=panel_search_result&selectedTitle=1~5&usage_type=panel&kp_tab=drug_general&display_ rank=1#F55364947

9. Gemtesa (vibegron). Accessed

October 16, 2021. https://gemtesa. com/savings-program 10. Lexicomp. Mirabegron: Drug information. https://www.uptodate. com/contents/mirabegron-drug-information?search=mirabegron&source=panel_search_result&selectedTitle=1~14&usage_type=panel&kp_tab=drug_general&display_ rank=1#F14965672

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