Estradiol vaginal inserts (4 µg and 10 µg) for treating moderate to severe vulvar and vaginal atrophy: a review of phase 3 safety, efficacy and pharmacokinetic data

Abstract

Objective: To review safety, efficacy and pharmacokinetic (PK) data from the phase 3 REJOICE trial, which evaluated a 17β-estradiol (E2) softgel vaginal insert approved in 2018 for moderate to severe dyspareunia associated with menopausal vulvar and vaginal atrophy (VVA).

Methods: REJOICE (Clinicaltrials.gov: NCT02253173) was a randomized, double-blind, placebo-controlled trial in which women with moderate to severe dyspareunia due to menopausal VVA received 4 µg, 10 µg or 25 µg of an E2 vaginal insert or placebo for 12 weeks. The published data for the recently approved 4 µg and 10 µg doses of the E2 vaginal insert, including four co-primary efficacy endpoints (change from baseline to week 12 in percentages of superficial and parabasal cells, vaginal pH and severity of dyspareunia), safety and PK (which included serum E2 levels measured by gas chromatography and tandem mass spectrometry), are summarized here.

Results: Women were randomized to receive the E2 vaginal insert (4 µg [n = 186] or 10 µg [n = 188]; Imvexxy^a) or placebo (n = 187) in the modified intention-to-treat population. The E2 vaginal insert (4 µg and 10 µg) significantly improved the percentages of superficial and parabasal cells (p < .0001), vaginal pH (p < .0001), and the severity score for dyspareunia (p < .05) from baseline to week 12 compared with placebo. The recently approved E2 vaginal insert was well tolerated, with no clinically significant differences in treatment-emergent or serious adverse events versus placebo. Systemic absorption of E2 with both doses was minimal.

Conclusions: The recently FDA-approved E2 softgel vaginal insert (4 µg and 10 µg) was safe and effective over 12 weeks for treating moderate to severe dyspareunia due to menopausal VVA with minimal systemic E2 levels.

Keywords:

• Dyspareunia
• estradiol
• menopause
• VVA
• vaginal atrophy

Introduction

Vulvar and vaginal atrophy (VVA) involves the thinning, drying and loss of elasticity of the vaginal epithelium due to a reduction in circulating estrogens after menopause¹. Nearly 70% of all postmenopausal women report clinical symptoms associated with VVA, such as vaginal dryness, irritation, itching, dysuria and pain or bleeding with sexual activity^2–5. Surveys of postmenopausal women found that VVA symptoms had negative consequences on their relationships, sex life, enjoyment of sex and self-esteem, and reduced their overall quality of life^4,6. The negative impact of VVA symptoms emphasizes the need for initiating treatment. The Women’s EMPOWER survey found that three-quarters of current or former prescription VVA therapy users, and almost two-thirds of never users or over-the-counter/lubricant users would consider a product to alleviate VVA symptoms to improve sexual activity⁵.

For symptomatic women with moderate to severe VVA who do not respond adequately to nonhormonal moisturizers and lubricants, the North American Menopause Society (NAMS), the International Menopause Society (IMS) and the American College of Obstetricians and Gynecologists (ACOG) recommend the use of low-dose vaginal, transdermal or systemic estrogens, and if VVA is the only menopausal symptom, vaginal estrogen is preferred^7–9. Although a recent study showed no difference in vaginal symptoms with vaginal estradiol, vaginal moisturizer and placebo gel¹⁰, several flaws limit the conclusions of the study¹¹. Other prospective clinical VVA studies have demonstrated superiority of vaginal estrogens compared with placebo¹². Despite treatment availability, multiple surveys have found that many respondents are not aware of or are unfamiliar with available vaginal estrogen treatment options^{4–6,13–15}. Surveys have also shown that, even when women are aware of therapy, they still have concerns regarding the safety and/or side effects of systemic hormone exposure^5,6,14. Perceived risk of systemic absorption and concern over the risk for side effects were given in the 2016 EMPOWER survey as the least favored attributes of currently available products by current or former users, and never users, respectively⁵.

Use of a vaginal delivery system is thought in part to minimize increases in circulating estrogen levels with lower, locally applied doses of estrogens^7,16, possibly resulting in a lower systemic risk profile⁷. Ultra-low-dose vaginal estrogens (≤10 µg estradiol [E2]) have been developed in an attempt to achieve these outcomes. A 17β-E2 softgel vaginal insert (Imvexxy^a, formerly called TX-004HR) was approved by the US Food and Drug Administration (FDA) in 2018 for the treatment of moderate to severe dyspareunia, a symptom of VVA, due to menopause¹⁷. The objective of this review was to summarize the phase 3 safety, efficacy and pharmacokinetic (PK) data of this ultra-low-dose E2 (4 µg and 10 µg) vaginal therapy.

Methods

Reviewed here are safety, efficacy and PK data of this ultra-low-dose, E2, softgel vaginal insert, which have been previously reported in separate publications^18,19. One publication reported the primary safety and efficacy data¹⁸, while the second reported data from a PK substudy¹⁹. While three doses of the E2 vaginal insert were evaluated (4 µg, 10 µg and 25 µg), the two lower doses are clinically available, largely due to the favorable results with the two lower doses and the recommendation for using the lowest effective dose. Therefore, this review will focus on the 4 µg and 10 µg E2 vaginal inserts, discussing the primary efficacy and safety data of the E2 vaginal insert in the context of its PK profile.

The study design of the REJOICE trial (NCT02253173) has been previously described^18,19; the protocol was approved by an institutional review board and written consent was obtained from the women prior to their participation. A PK substudy was also conducted in a subset of women enrolled in the REJOICE trial.

Briefly, postmenopausal women (40–75 years of age) who reported moderate to severe dyspareunia as their most bothersome symptom (MBS), and had ≤5% superficial cells on vaginal cytological smear and vaginal pH >5.0, were enrolled at 89 sites located in the US and Canada. Postmenopausal status was defined in this study as 12 months of spontaneous amenorrhea, 6 months of spontaneous amenorrhea with FSH levels >40 mIU/mL, or at least 6 weeks after bilateral oophorectomy. Women (n = 764) were randomized to one of three doses of E2 softgel vaginal inserts (4 µg, 10 µg or 25 µg) or matching placebo and were instructed to digitally self-administer one E2 vaginal insert into the vagina (about 2 inches), at approximately the same time of day, daily for 2 weeks and then twice weekly (approximately 3 to 4 days apart) for 10 weeks. The E2 vaginal insert is a small, light pink, tear-shaped capsule (Figure 1) that releases E2 when it comes in contact with the vaginal mucosa¹⁷. Women could not have used any hormone therapy, selective estrogen receptor modulators, or vaginal lubricants or moisturizers during the study or within the required washout period prior to the study.

Figure 1. Image of the E2 softgel vaginal insert with dimensions.

Consistent with the FDA’s recommendations on clinical studies of estrogen products for treating symptoms of VVA²⁰, four co-primary efficacy endpoints were evaluated in the REJOICE trial and included changes from baseline to week 12 compared with placebo for: (1) percentage of vaginal superficial cells; (2) percentage of vaginal parabasal cells; (3) vaginal pH; and (4) severity of the MBS of moderate to severe dyspareunia associated with VVA¹⁸. Dyspareunia was defined as vaginal pain associated with sexual activity. Improvements in the objective physiological parameters would be demonstrated by increases in the percentages of superficial cells and decreases in the percentages of parabasal cells and vaginal pH. Prespecified secondary endpoints included these co-primary endpoint measures at weeks 2, 6 and 8¹⁸. Adverse events reported throughout the 12-week study period were summarized to describe overall safety and tolerability in the safety population (all randomized women who had at least one dose of study medication)¹⁸. Endometrial safety was evaluated based on endometrial biopsies taken by board-certified gynecologists at baseline and at week 12 or end of treatment in the safety population¹⁸. Diagnoses were based on the agreement of three independent pathologists; if no agreement, the most severe pathologic diagnosis was used²⁰.

A separate randomization protocol was performed for the women who were included in the PK substudy¹⁹. Briefly, the PK substudy assessed serum hormone concentrations of E2 and estrone (E1) using gas chromatography/tandem mass spectrometry (GC/MS/MS)¹⁹. Serum samples were obtained at screening, and at day 1 and day 14 before dosing, and then at five post-dose time points (2, 4, 6, 10, and 24 h) on days 1 and 14, and one final sample at day 84, approximately 4 days after the last dose¹⁹. PK parameters analyzed included area under the serum concentration–time curve (AUC_0–24), average concentration (C_avg) and peak concentration (C_max) for each E2 vaginal insert on days 1 and 14¹⁹.

Results

Participant disposition and baseline demographics

Of the 764 postmenopausal women who were randomized to treatment in the REJOICE trial, 186 were randomized to the 4 µg E2 vaginal insert, 188 to the 10 µg insert and 187 to placebo¹⁸, contributing 561 women to the modified intent-to-treat population (MITT)¹⁸. The MITT population had a mean age of 59 years and a mean BMI of 27 kg/m². The majority (87%) of women were white and 12% were African American. No differences in demographic and baseline characteristics were noted among the treatment groups¹⁸. Over 90% of the women also reported moderate to severe dryness as part of their menopausal VVA¹⁸.

Efficacy

Significant improvements from baseline in the percentage of superficial cells (increases) and parabasal cells (decreases) were observed as early as week 2 and sustained up to week 12 with both vaginal E2 doses compared with placebo (p < .0001 at weeks 2, 6, 8 [secondary endpoints] and 12)¹⁸. The mean percentage increases from baseline to week 12 in the superficial cell percentages were 18% with the 4 µg vaginal E2 insert and 17% with the 10 µg insert versus 6% with placebo (p < .0001; Figure 2(A))¹⁸. Mean percentage decreases from baseline to week 12 in parabasal cell percentages were −41% and −44% with the 4 µg and 10 µg doses, respectively, versus −7% with placebo (p < .0001; Figure 2(B))¹⁸. Significant decreases in vaginal pH with the 4 µg (-1.3 points) and 10 µg (-1.4 points) E2 vaginal inserts were also observed up to week 12 (Figure 2(C)) compared with placebo (-0.3 points) and were seen as early as week 2 (p < .0001 at weeks 2, 6, 8 [secondary endpoints] and 12)¹⁸.

Figure 2. Changes from baseline over 12 weeks in: (A) percentage of superficial cells; (B) percentage of parabasal cells; (C) vaginal pH; and (D) dyspareunia severity scores in the REJOICE trial for the 4 µg (n = 186) and 10 µg (n = 188) E2 vaginal inserts versus placebo (n = 187). *p < .05; †p < .01; ‡p < .0001 vs. placebo.

A significant reduction in the mean severity score for dyspareunia was reported with the 4 µg and 10 µg E2 vaginal inserts versus placebo as early as week 2 (secondary endpoint) and sustained up to week 12 (p < .05)¹⁸. The mean decrease in the dyspareunia score from baseline to week 12 was −1.5 for the 4 µg dose (p < .05) and −1.7 for the 10 µg dose (p < .0001) compared with −1.3 for placebo (Figure 2(D))¹⁸.

Safety and tolerability

Overall, the ultra-low-dose E2 softgel vaginal insert was found to be safe and well tolerated (Table 1)¹⁸. Headache was the most common treatment-emergent adverse event (TEAE) observed in all treatment groups (4 µg E2 [6.3%] and 10 µg E2 [7.3%]; placebo [7.8%])¹⁸. Other TEAEs reported in ≥3% of women included vaginal discharge, nasopharyngitis, vulvovaginal pruritus, back pain, urinary tract infection, upper respiratory tract infection and oropharyngeal pain in descending order, and were reported at an incidence of  < 5% (Table 1)¹⁸. Headache was the only treatment-related TEAE occurring in ≥3% and was reported numerically more in women who received the E2 vaginal insert (3.7% with 4 µg; 2.6% with 10 µg) than in women who received placebo (3.1%)¹⁸. The treatment-related TEAE of vaginal discharge was reported by numerically fewer women with the E2 vaginal insert (2.6% with 4 µg; 3.1% with 10 µg) than with placebo (6.3%)¹⁸. Most TEAEs were mild to moderate in severity, and few study discontinuations due to adverse events (1.0% [4 µg]; 1.6% [10 µg]; 2.6% [placebo]) were reported¹⁸.

Table 1. Treatment-emergent adverse events reported for ≥3% in any treatment arm (safety population).

Preferred Term	4 µg E2 (n = 191)	10 µg E2 (n = 191)	Placebo (n = 192)
Any subject with reported TEAE	97 (50.8)	94 (49.2)	111 (57.8)
Headache	12 (6.3)	14 (7.3)	15 (7.8)
Vaginal discharge	5 (2.6)	6 (3.1)	13 (6.8)
Nasopharyngitis	5 (2.6)	6 (3.1)	10 (5.2)
Vulvovaginal pruritus	4 (2.1)	3 (1.6)	10 (5.2)
Back pain	9 (4.7)	1 (0.5)	8 (4.2)
Urinary tract infection	5 (2.6)	5 (2.6)	4 (2.1)
Upper respiratory tract infection	5 (2.6)	6 (3.1)	5 (2.6)
Oropharyngeal pain	1 (0.5)	0 (0)	1 (0.5)

Data reported as n (%).

Abbreviation. TEAE, treatment-emergent adverse event.

No serious TEAEs were reported in the 4 µg E2 group, 3 women reported 4 serious TEAEs (1 woman had sinus node dysfunction and an ankle fracture, 1 had arthralgia and 1 had malignant melanoma) in the 10 µg E2 group, and 1 woman reported cervical myelopathy in the placebo group¹⁸. No serious TEAEs were considered related to treatment, and no deaths occurred¹⁸.

No diagnoses of endometrial hyperplasia or malignancy were made at week 12 in the safety population (n = 574 [placebo, 4 µg and 10 µg groups])¹⁸.

Pharmacokinetics

A total of 72 postmenopausal women were randomized in the PK substudy¹⁹. Of these, 54 were randomized with allocation to the 4 µg E2 vaginal insert (n = 18), 10 µg insert (n = 19) and placebo (n = 17)¹⁹. Mean serum baseline levels of estradiol (E2) ranged from 3.9 to 4.9 pg/mL and estrone (E1) from 15.3 to 20.3 pg/mL in the 4 µg, 10 µg dose and placebo groups. Figure 3 illustrates the mean serum E2 concentrations over time for each dose versus placebo on days 1 and 14. Mean serum E2 levels were ≤5.0 pg/mL for each treatment group at baseline and remained low over the 24 hours on measurement days 1 and 14, except for slightly higher levels at 2 hours on day 1 that were not observed on day 14¹⁹. Day 84 mean serum E2 concentrations with the E2 vaginal inserts were similar to those observed at baseline and with placebo¹⁹.

Figure 3. Unadjusted mean serum E2 concentrations with E2 softgel vaginal inserts: (A) 4 µg E2 (n = 18) and (B) 10 µg E2 (n = 19) compared with placebo (n = 17) on days 1 and 14. Reprinted with permission from Wolters Kluwer from Archer DF, Constantine GD, Simon J, et al. TX-004HR vaginal estradiol has negligible to very low systemic absorption of estradiol. Menopause 2017;24:510-16.

No significant differences in unadjusted E2 measures for AUC, C_max or C_avg were noted between the 4 µg E2 dose and placebo on days 1 or 14 (Table 2)¹⁹. The only significant difference between the 10 µg E2 dose and placebo was C_max on day 1 (mean 10.9 pg/mL vs. 6.6 pg/mL; p < .05)¹⁹. Unadjusted estrone AUC, C_max and C_avg values were all significantly lower (p < .05) than or similar to placebo with the 4 µg and 10 µg E2 dose on days 1 and 14 (Table 2)¹⁹, and hourly data does not show a similar pattern to that of E2 at 2 hours on day 1.

Table 2. Unadjusted pharmacokinetic parameters.

	4 µg E2 (n = 18)	10 µg E2 (n = 19)	Placebo (n = 17)
Estradiol
Day 1
AUC, pg*h/mL	91.7 ± 37.9	138.2 ± 75.2	116.6 ± 77.3
Cmax, pg/mL	6.5 ± 2.1	10.9 ± 5.0^a	6.6 ± 4.9
Cavg, pg/mL	3.9 ± 1.5	5.8 ± 3.1	4.9 ± 3.2
Day 14
AUC, pg*h/mL	87.2 ± 42.8	110.1 ± 54.6	104.2 ± 66.4
Cmax, pg/mL	4.8 ± 2.3	7.3 ± 2.4	5.5 ± 3.4
Cavg, pg/mL	3.6 ± 1.8	4.6 ± 2.3	4.3 ± 2.8
Estrone
Day 1
AUC, pg*h/mL	290.2 ± 123.7^a	462.7 ± 195.6	467.9 ± 278.8
Cmax, pg/mL	15.8 ± 6.1^a	23.5 ± 9.9	25.7 ± 18.4
Cavg, pg/mL	13.0 ± 4.7^a	19.3 ± 8.2	19.5 ± 11.6
Day 14
AUC, pg*h/mL	326.6 ± 114.1	464.1 ± 243.9	426.8 ± 180.7
Cmax, pg/mL	16.0 ± 5.5^a	23.9 ± 13.5	22.8 ± 10.9
Cavg, pg/mL	13.6 ± 4.8	19.3 ± 10.2	17.8 ± 7.5

Data unadjusted for baseline and represented as mean ± SD.

Abbreviations. AUC, area under the curve; C_avg, average concentration;C_max, peak concentration.

^a p < .05 vs. placebo using t-tests.

Discussion

Clinical safety and efficacy data reviewed here from the REJOICE trial show that the ultra-low-dose E2 softgel vaginal inserts (4 µg and 10 µg) are safe and effective for treating moderate to severe dyspareunia associated with VVA in postmenopausal women. Supporting data include significant improvements from baseline in the four measured co-primary endpoints from week 2 (secondary endpoint) to week 12, with no significant safety concerns noted with either dose. These ultra-low-dose E2 vaginal inserts provide a new option for treating women with moderate to severe dyspareunia associated with menopausal VVA, and may help alleviate concerns of women pertaining to systemic hormone absorption and associated side effects.

The early onset of action on moderate to severe dyspareunia as an MBS was demonstrated by statistically significant, patient-reported improvements with the E2 softgel vaginal insert versus placebo at week 2 as a secondary endpoint¹⁸. Dyspareunia severity reductions with this E2 vaginal insert were consistent with early significant improvements in superficial cell and parabasal cell percentages, and vaginal pH¹⁸.

The efficacy reviewed here with the 4 µg and 10 µg E2 vaginal inserts was achieved with minimal systemic absorption of E2 as measured by the highly sensitive GC/MS/MS method. Mean E2 levels with 4 µg and 10 µg vaginal E2 doses were similar to those seen at baseline and with placebo, and remained within the range of untreated, postmenopausal women ( < 10 pg/mL²¹), when given daily for 14 days¹⁹. No significant differences in the mean AUC and C_avg for E2 were observed with the 4 µg and 10 µg E2 doses versus placebo at days 1 or 14, although C_max was higher with the 10 µg E2 dose compared with placebo at day 1¹⁹. This initial increase in E2 absorption on day 1 is likely due to higher E2 absorption through untreated, thin, atrophic vaginal tissues as, after 14 days of daily treatment and E2 exposure, no significant difference in E2 levels between the 10 µg vaginal insert and placebo were found¹⁹, which is similar to what has been shown in other studies^22–24. In addition, no accumulation of E2 was supported by day 84 E2 levels. Thus, in conjunction with the efficacy data showing early symptom resolution, the PK data demonstrating minimal systemic E2 absorption are consistent with goals of local vaginal estrogen therapy for treating symptoms of menopausal VVA.

Adverse event reporting and endometrial biopsy assessments demonstrated that the 4 µg and 10 µg softgel E2 vaginal inserts were safe and well tolerated¹⁸. No clinically significant differences were noted between TEAEs reported with the E2 vaginal insert and placebo, most of the TEAEs were mild or moderate, and very few women discontinued treatment due to adverse events¹⁸. Lastly, no cases of endometrial hyperplasia or malignancy were reported with 12 weeks of the E2 vaginal insert use¹⁸. Further study would be needed to determine the risk of endometrial hyperplasia or cancer with use of low-dose vaginal estrogens unopposed by a progestogen for durations longer than 12 weeks. Approval of this E2 vaginal insert by the FDA for treating moderate to severe dyspareunia, due to menopause, does not limit duration of use¹⁷.

Previously reported low uptake of prescription vaginal estrogens by postmenopausal women (∼7%)^4,25 may be attributed to the lack of information about available and/or effective treatments, concerns over systemic hormone absorption, or dissatisfaction with available products^4–6,26. Some of the least favored attributes of available VVA therapies were recently reported by the Women's EMPOWER survey respondents as messiness of vaginal cream and the need to use an applicator⁵. The E2 vaginal insert is expected to provide women with moderate to severe dyspareunia a novel softgel treatment choice with minimal systemic absorption of E2, which may alleviate some women’s concerns of systemic exposure. In addition, eliminating the need for an applicator or the need to measure individual doses with this E2 vaginal insert may improve user experience of a vaginal product. As part of the phase 3 REJOICE study reviewed here, 574 participants who used 4 µg of E2 (n = 191), 10 µg of E2 (n = 191) or placebo (n = 192) were surveyed at the end of the study with five questions that assessed acceptability of the softgel vaginal insert. The survey data showed that most women found the vaginal insert easy to use (85%–90%) and easy to insert (75%–82%). More women were also satisfied with the E2 vaginal insert (69%–73%) than they were with placebo (57%; p <  .001), and satisfaction with the product was correlated (r=-.551; p <  .0001) with reductions in moderate to severe dyspareunia²⁷.

Conclusions

Based on the REJOICE study, the FDA recently approved (May 2018) the E2 softgel vaginal inserts (4 µg and 10 µg doses) as safe and effective when used as labeled for treating moderate to severe dyspareunia, due to menopause, with improvements in objective vaginal markers associated with VVA, an early onset of effectiveness (2 weeks) and minimal systemic E2 absorption.

Transparency

Author contributions: All authors participated in the conception and design, or analysis and interpretation of the data for this review; drafting the paper or revising it critically for intellectual content; and final approval of the version to be published. All authors agreed to be accountable for all aspects of the work.

Declaration of financial/other relationships

G.D.C. has disclosed that she consults for multiple pharmaceutical companies, including but not limited to TherapeuticsMD, and has stock options with TherapeuticsMD. J.A.S. has disclosed that he has served (within the last year or currently) as a consultant/advisor for AbbVie, Allergan, AMAG, Amgen, Ascend Therapeutics, Azure Biotech, Bayer Healthcare, CEEK Enterprises, Covance, Millendo Therapeutics, Mitsubishi Tanage, ObsEva SA, Radius Health, Sanofi SA, Sebela, Sermonix, Shionogi, Symbiotec Pharmalab, TherapeuticsMD and Valeant; has served (within the last year or currently) on the speaker’s bureaus of Duchesnay, Novo Nordisk, Shionogi and Valeant; has received (within the past year or currently) grant/research support from AbbVie, Agile Therapeutics, Allergan, Bayer Healthcare, New England Research Institute, ObsEva SA, Palatin Technologies, Symbio Research and TherapeuticsMD; and is a stockholder (direct purchase) in Sermonix Pharmaceuticals. J.H.P. has disclosed that he has consulted for Pfizer, Shionogi and TherapeuticsMD (stock options). D.F.A. has disclosed that he serves as a consultant for Abbvie (previously Abbott Laboratories), Actavis (previously Allergan, Watson Pharmaceuticals, Warner Chilcott), Agile Therapeutics, Bayer Healthcare, Endoceutics, Exeltis (previously CHEMO), InnovaGyn, Merck (previously Schering Plough, Organon), Pfizer, Radius Health, Sermonix, Shionogi, Teva Women’s Healthcare and TherapeuticsMD; and has received research support from Actavis (previously Allergan, Watson Pharmaceuticals, Warner Chilcott), Bayer Healthcare, Endoceutics, Glenmark, Merck (previously Schering Plough, Organon), Radius Health, Shionogi and TherapeuticsMD. B.B. has disclosed that he is a Board member and an employee of TherapeuticsMD with stock/stock options. S.G. and S.M. have disclosed that they are employees of TherapeuticsMD with stock/stock options.

Acknowledgements

The authors acknowledge the medical writing assistance of Chastity Bradley PhD and Kathleen Ohleth PhD CMPP of Precise Publications LLC, which was supported by TherapeuticsMD.

Notes

Additional information

Funding

The REJOICE study was sponsored by TherapeuticsMD. The medical writing support for this manuscript provided by Chastity Bradley PhD and Kathleen Ohleth PhD CMPP of Precise Publications LLC was funded by TherapeuticsMD.

Notes

a Imvexxy is a trademark of TherapeuticsMD, Boca Raton, FL, USA