Linzagolix with and without hormonal add-back therapy for the treatment of symptomatic uterine fibroids: two randomised, placebo-controlled, phase 3 trials.

BACKGROUND: Uterine fibroids are common non-cancerous neoplasm that cause heavy menstrual bleeding and other signs. Linzagolix is an oral gonadotropin-releasing hormone receptor antagonist taken once per day that dose-dependently suppresses gonadal steroids and might reduce uterine-fibroid-associated signs. Two phase 3 trials were conducted to confirm the efficacy and safety of linzagolix at full-suppression (200 mg) and partial-suppression (100 mg) doses with or without hormonal add-back therapy (1 mg oestradiol and 0·5 mg norethisterone acetate) compared with placebo for the treatment of symptomatic uterine fibroids. METHODS: PRIMROSE 1 and PRIMROSE 2 were identical 52-week, randomised, parallel, double-blind, placebo-controlled, phase 3 trials conducted at clinics in the USA (PRIMROSE 1) and Europe and the USA (PRIMROSE 2). Eligible women with uterine fibroid-associated heavy menstrual bleeding (menstrual blood loss >80 mL per cycle) were randomly assigned in a 1:1:1:1:1 ratio to one of five masked treatments: (1) placebo, (2) 100 mg linzagolix per day alone, (3) 100 mg linzagolix per day with once-per-day hormonal add-back therapy (1 mg oestradiol and 0·5 mg norethisterone acetate), (4) 200 mg linzagolix per day alone, or (5) 200 mg linzagolix per day with once-per-day hormonal add-back therapy (1 mg oestradiol and 0·5 mg norethisterone acetate). The primary endpoint was a response (menstrual blood loss ≤80 mL and ≥50% reduction from baseline) at 24 weeks in women who received at least one dose of treatment and did not meet any exclusion criteria based on predosing assessments. These trials are registered with ClinicalTrials.gov (NCT03070899 and NCT03070951). The trials have been completed. FINDINGS: Between May, 2017, and October, 2020, in PRIMROSE 1, 574 women were enrolled, of which 48 discontinued and 15 were excluded; therefore, 511 women were included in the full analysis set; and in PRIMROSE 2, 535 women were enrolled, of which 24 did not receive the study drug and ten women were excluded from the study, resulting in 501 women being included in the full analysis set. In both trials, a significantly higher proportion of women had a reduction in heavy menstrual bleeding in all linzagolix (with or without add-back therapy) treatment groups compared with the placebo group (p≤0·003). In PRIMROSE 1, the response rates were 56·4% (95% CI 45·8-66·6%) in the 100 mg group, 66·4% (56·6-75·2%) in the 100 mg plus add-back therapy group, 71·4% (61·8-79·8%) in the 200 mg group, and 75·5% (66·0-83·5%) in the 200 mg plus add-back therapy group, compared with 35·0% (25·8-45·0%) in the placebo group. In PRIMROSE 2, the response rates were 56·7% (46·3-66·7%) in the 100 mg group, 77·2% (67·8-85·0%) in the 100 mg plus add-back therapy group, 77·7% (68·4-85·3%) in the 200 mg group, and 93·9% (87·1-97·7%) in the 200 mg plus add-back therapy group, compared with 29·4% (20·8-39·3%) with placebo. The most common adverse events up to 24 weeks were hot flushes (35% of participants in PRIMROSE 1 and 32% in PRIMROSE 2 with linzagolix [200 mg] alone and 3-14% in all other groups). INTERPRETATION: Linzagolix (100 mg or 200 mg) with or without add-back therapy significantly reduced heavy menstrual bleeding. Partial suppression with once-per-day linzagolix (100 mg) without add-back therapy potentially provides a unique option for the chronic treatment of symptomatic uterine fibroids in women who cannot or do not want to take concomitant hormonal add-back therapy. FUNDING: ObsEva.

Treatment of symptomatic uterine adenomyosis with linzagolix, an oral gonadotrophin-releasing hormone antagonist: a pilot study.

RESEARCH QUESTION: Does a once-daily regimen of linzagolix, a new oral gonadotrophin-releasing hormone (GnRH) antagonist, given at a fully suppressive dose (200 mg) for 12 weeks, followed by a partially suppressive dose (100 mg) for a further 12 weeks, reduce adenomyotic uterine size and associated symptoms? DESIGN: Eight women (aged 37-45 years) with adenomyosis confirmed by magnetic resonance imaging (MRI) were enrolled in a single-centre, open-label pilot study. The primary efficacy end-point was the change in uterine volume on MRI at 24 weeks. Secondary efficacy end-points included serum oestradiol, overall pelvic pain, dysmenorrhoea, non-menstrual pelvic pain, dyspareunia, dyschezia and quality of life (QoL). Bone mineral density (BMD) was assessed at baseline and 24 weeks. RESULTS: At baseline, uterine volume (mean ± SD) was 333 ± 250 cm3. After 24 weeks, it was 204 ± 126 cm3, a reduction of 32% from baseline (P = 0.0057). After 12 weeks, it was 159 ± 95 cm3, a reduction of 55% (P < 0.0001). Median serum oestradiol was suppressed below 20 pg/ml during the 12 weeks on 200 mg linzagolix, and maintained below 60 pg/ml on 100 mg linzagolix. Improvements in overall pelvic pain, dysmenorrhoea, non-menstrual pelvic pain, dyspareunia, dyschezia and QoL were observed. Mean percentage change in BMD loss at 24 weeks was -2.4%, -1.3% and -4.1% for the spine, femoral neck and total hip, respectively. The most common adverse events were hot flushes. CONCLUSIONS: A once-daily regimen of 200 mg linzagolix for 12 weeks and then 100 mg for another 12 weeks decreased adenomyotic uterine volume and improved associated symptoms.

Uterine Adenomyosis Treated by Linzagolix, an Oral Gonadotropin-Releasing Hormone Receptor Antagonist: A Pilot Study with a New 'Hit Hard First and then Maintain' Regimen of Administration.

(1) Background: The aim of the present pilot study was to study the effect of a new oral gonadotropin-releasing hormone antagonist on adenomyosis. (2) Methods: Eight premenopausal women, aged between 37 and 45 years, presenting with heavy menstrual bleeding, pelvic pain, and dysmenorrhea due to diffuse and disseminated uterine adenomyosis, confirmed by magnetic resonance imaging (MRI), received 200 mg linzagolix once daily for a period of 12 weeks, after which they were switched to 100 mg linzagolix once daily for another 12 weeks. The primary efficacy endpoint was the change in volume of the adenomyotic uterus from baseline to 24 weeks, evaluated by MRI. Secondary efficacy endpoints included the change in uterine volume from baseline to 12 and 36 weeks by MRI, and also weeks 12, 24, and 36 assessed by transvaginal ultrasound (TVUS). Other endpoints were overall pelvic pain, dysmenorrhea, non-menstrual pelvic pain, dyspareunia, amenorrhea, quality of life measures, bone mineral density (BMD), junctional zone thickness, and serum estradiol values. (3) Results: Median serum estradiol was suppressed below 20 pg/mL during the 12 weeks on linzagolix 200 mg, and maintained below 60 pg/mL during the second 12 weeks on linzagolix 100 mg. At baseline, the mean ± SD uterine volume was 333 ± 250 cm3. After 24 weeks of treatment, it was 204 ± 126 cm3, a reduction of 32% (p = 0.0057). After 12 weeks, the mean uterine volume was 159 ± 95 cm3, a reduction of 55% from baseline (p = 0.0001). A similar pattern was observed when uterine volume was assessed by TVUS. Improvements in overall pelvic pain, dysmenorrhea, non-menstrual pelvic pain, dyspareunia, and dyschezia, as well as quality of life measured using the EHP-30 were also observed. Mean percentage BMD loss at 24 weeks was, respectively, -2.4%, -1.3%, and -4.1% for the spine, femoral neck, and total hip. The most common adverse events were hot flushes, which occurred in 6/8 women during the first 12 weeks, and 1/8 women between 12 and 24 weeks. (4) Conclusions: Linzagolix at a dose of 200 mg/day reduced uterine volume, and improved clinically relevant symptoms. Treatment with 100 mg thereafter retains the therapeutic benefits of the starting dose while minimizing side effects. This 'hit hard first and then maintain' approach may be the optimal way to treat women with symptomatic adenomyosis.

Application site affects the pharmacokinetics of topical testosterone applied to the axilla compared with the inner arm.

PURPOSE: This study compared the pharmacokinetics of a single dose of 1% testosterone solution after application to the inner arm or the axilla as application sites for transdermal testosterone therapy. METHODS: Healthy, not pregnant, premenopausal women, 18 to 45 years of age with a body mass index of 20 to 28 kg/m(2) were enrolled into a single-center, open-label, randomized, 2-way crossover study. Serum total testosterone (TT), free testosterone (fT), and sex hormone binding globulin concentrations were measured. Pharmacokinetic parameters determined from serum TT and fT included area under the serum concentration versus time curve from time zero (pre-dose) until 72 hours post-dose (AUC0-72), Cmax, and Tmax. Descriptive statistics were performed on serum concentrations of TT and fT for each site. ANOVA was performed on AUC0-72 and Cmax. FINDINGS: A single-dose application of 1% testosterone solution to the inner arm and the axilla produced clear increases in TT and fT. Slower and lower increases in TT and fT were observed after treatment to the inner arm. Based on baseline-corrected AUC versus time curves, the bioavailability of 1% testosterone solution was increased 2-fold for the axilla compared with the inner arm. IMPLICATIONS: The absorption of a 1% testosterone solution was significantly greater after application to the axilla than to the inner arm. Study number DDS16; Australian Therapeutic Goods Administration, CTN 2005/158.

Assessing the utility of an anti-malarial pharmacokinetic-pharmacodynamic model for aiding drug clinical development.

BACKGROUND: Mechanistic within-host models relating blood anti-malarial drug concentrations with the parasite-time profile help in assessing dosing schedules and partner drugs for new anti-malarial treatments. A comprehensive simulation study to assess the utility of a stage-specific pharmacokinetic-pharmacodynamic (PK-PD) model for predicting within-host parasite response was performed. METHODS: Three anti-malarial combination therapies were selected: artesunate-mefloquine, dihydroartemisinin-piperaquine, and artemether-lumefantrine. The PK-PD model included parameters to represent the concentration-time profiles of both drugs, the initial parasite burden and distribution across the parasite life cycle, and the parasite multiplication factor due to asexual reproduction. The model also included the maximal killing rate of each drug, and the blood drug concentration associated with half of that killing effect (in vivo EC50), derived from the in vitro IC50, the extent of binding to 0.5% Albumax present in the in vitro testing media, and the drugs plasma protein binding and whole blood to plasma partitioning ratio. All stochastic simulations were performed using a Latin-Hypercube-Sampling approach. RESULTS: The simulations demonstrated that the proportion of patients cured was highly sensitive to the in vivo EC50 and the maximal killing rate of the partner drug co-administered with the artemisinin derivative. The in vivo EC50 values that corresponded to on average 95% of patients cured were much higher than the adjusted values derived from the in vitro IC50. The proportion clinically cured was not strongly influenced by changes in the parameters defining the age distribution of the initial parasite burden (mean age of 4 to 16 hours) and the parasite multiplication factor every life cycle (ranging from 8 to 12 fold/cycle). The median parasite clearance times, however, lengthened as the standard deviation of the initial parasite burden increased (i.e. the infection became more asynchronous). CONCLUSIONS: This simulation study demonstrates that the PD effect predicted from in vitro growth inhibition assays does not accord well with the PD effect of the anti-malarials observed within the patient. This simulation-based PK-PD modelling approach should not be considered as a replacement to conducting clinical trials but instead as a decision tool to improve the design of a clinical trial during drug development.

SPL7013 Gel (VivaGel®) retains potent HIV-1 and HSV-2 inhibitory activity following vaginal administration in humans.

UNLABELLED: SPL7013 Gel (VivaGel(®)) is a microbicide in development for prevention of HIV and HSV. This clinical study assessed retention and duration of antiviral activity following vaginal administration of 3% SPL7013 Gel in healthy women. Participants received 5 single doses of product with ≥5 days between doses. A cervicovaginal fluid (CVF) sample was collected using a SoftCup™ pre-dose, and immediately, or 1, 3, 12 or 24 h post-dose. HIV-1 and HSV-2 antiviral activities of CVF samples were determined in cell culture assays. Antiviral activity in the presence of seminal plasma was also tested. Mass and concentration of SPL7013 in CVF samples was determined. Safety was assessed by reporting of adverse events. Statistical analysis was performed using the Wilcoxon signed-rank test with Bonferroni adjustment; p≤0.003 was significant. Eleven participants completed the study. Inhibition of HIV-1 and HSV-2 by pre-dose CVF samples was negligible. CVF samples obtained immediately after dosing almost completely inhibited (median, interquartile range) HIV-1 [96% (95,97)] and HSV-2 [86% (85,94)], and activity was maintained in all women at 3 h (HIV-1 [96% (95,98), p = 0.9]; HSV-2 [94% (91,97), p = 0.005]). At 24 h, >90% of initial HIV-1 and HSV-2 inhibition was maintained in 6/11 women. SPL7013 was recovered in CVF samples obtained at baseline (46% of 105 mg dose). At 3 and 24 h, 22 mg and 4 mg SPL7013, respectively, were recovered. More than 70% inhibition of HIV-1 and HSV-2 was observed if there was >0.5 mg SPL7013 in CVF samples. High levels of antiviral activity were retained in the presence of seminal plasma. VivaGel was well tolerated with no signs or symptoms of vaginal, vulvar or cervical irritation reported. Potent antiviral activity was observed against HIV-1 and HSV-2 immediately following vaginal administration of VivaGel, with activity maintained for at least 3 h post-dose. The data provide evidence of antiviral activity in a clinical setting, and suggest VivaGel could be administered up to 3 h before coitus. TRIAL REGISTRATION: The study is registered at ClinicalTrials.gov under identifier: NCT00740584.

A pilot randomised trial of induced blood-stage Plasmodium falciparum infections in healthy volunteers for testing efficacy of new antimalarial drugs.

BACKGROUND: Critical to the development of new drugs for treatment of malaria is the capacity to safely evaluate their activity in human subjects. The approach that has been most commonly used is testing in subjects with natural malaria infection, a methodology that may expose symptomatic subjects to the risk of ineffective treatment. Here we describe the development and pilot testing of a system to undertake experimental infection using blood stage Plasmodium falciparum parasites (BSP). The objectives of the study were to assess the feasibility and safety of induced BSP infection as a method for assessment of efficacy of new drug candidates for the treatment of P. falciparum infection. METHODS AND FINDINGS: A prospective, unblinded, Phase IIa trial was undertaken in 19 healthy, malaria-naïve, male adult volunteers who were infected with BSP and followed with careful clinical and laboratory observation, including a sensitive, quantitative malaria PCR assay. Volunteers were randomly allocated to treatment with either of two licensed antimalarial drug combinations, artemether-lumefantrine (A/L) or atovaquone-proguanil (A/P). In the first cohort (n = 6) where volunteers received ∼360 BSP, none reached the target parasitemia of 1,000 before the day designated for antimalarial treatment (day 6). In the second and third cohorts, 13 volunteers received 1,800 BSP, with all reaching the target parasitemia before receiving treatment (A/L, n = 6; A/P, n = 7) The study demonstrated safety in the 19 volunteers tested, and a significant difference in the clearance kinetics of parasitemia between the drugs in the 13 evaluable subjects, with mean parasite reduction ratios of 759 for A/L and 17 for A/P (95% CI 120-4786 and 7-40 respectively; p<0.01). CONCLUSIONS: This system offers a flexible and safe approach to testing the in vivo activity of novel antimalarials. TRIAL REGISTRATION: ClinicalTrials.gov NCT01055002.

Safety and efficacy of a testosterone metered-dose transdermal spray for treating decreased sexual satisfaction in premenopausal women: a randomized trial.

BACKGROUND: It is not known whether premenopausal women who report low sexual satisfaction and have low circulating testosterone levels will benefit from testosterone therapy. OBJECTIVE: To evaluate the effects of exogenous testosterone in premenopausal women reporting diminished sexual function. DESIGN: Randomized, double-blind, placebo-controlled, dose-ranging trial. SETTING: 6 Australian medical centers. PATIENTS: 261 women age 35 to 46 years who reported a decrease in satisfying sexual activity relative to their younger years and had a morning serum free testosterone level less than 3.8 pmol/L (<1.1 pg/mL). INTERVENTION: 3 different doses of testosterone administered by a metered-dose transdermal spray for 16 weeks or placebo. MEASUREMENTS: The primary outcome was the mean number of self-reported satisfactory sexual events (SSEs) over 28 days at week 16. The frequency of SSEs, total number of sexual events (every 4 weeks), scores from the modified Sabbatsberg Sexual Self-Rating Scale and the Psychological General Well-Being Index, and safety variables were also measured. RESULTS: The number of SSEs increased during the treatment period in the active treatment groups and the placebo group. The mean number of SSEs over 28 days at week 16 was statistically significantly greater for women treated with the intermediate dose of testosterone therapy (one 90-microL spray) than for women treated with placebo. The least-squares mean was 2.48 versus 1.70 SSEs, respectively (event rate ratio, 1.49 [95% CI, 1.01 to 2.18]; P = 0.04). The frequency of SSEs in women treated with low and high doses of testosterone did not differ from that in women who took placebo. The rate ratios based on the least-squares mean rates of SSEs during weeks 4 to 16 for each treatment group showed statistically significant or borderline significant increases in all testosterone groups compared with the placebo group. The rate ratios for the one 56-microL spray, one 90-microL spray, and two 90-microL sprays treatment groups were 1.34 (CI, 0.97 to 1.85; P = 0.081), 1.48 (CI, 1.07 to 2.06; P = 0.018), and 1.38 (CI, 1.00 to 1.92; P = 0.052), respectively. At week 16, 95% of women treated with the one 90-microL dose had a free testosterone level less than the upper limit of the reference range for women. The most frequently reported adverse event was hypertrichosis, which was dose-related and mostly confined to the application site. No clinically relevant changes in blood test values, serum biochemical variables, or vital signs occurred. LIMITATION: The study duration was short, and the placebo effect was strong. CONCLUSION: A daily 90-microL dose of transdermal testosterone improves self-reported sexual satisfaction for premenopausal women with reduced libido and low serum-free testosterone levels by a mean of 0.8 SSE per month. The rate of SSEs with higher and lower testosterone doses did not differ from that with placebo.

An initial pharmacokinetic study with a Metered Dose Transdermal Systemfor delivery of the progestogen Nestorone as a possible future contraceptive.

BACKGROUND: Transdermal delivery of steroids is gaining popularity for contraception and hormone replacement therapy. This study aimed to test metered spray delivery of a precise dosage of Nestorone (NES) progestogen as a possible transdermal progestogen-only contraceptive. STUDY DESIGN: Six healthy postmenopausal volunteers, not recently using any hormonal therapies, comprise the sample for this study. Each subject was studied on two occasions with multiple blood sampling for assay of NES over a 24-h period: on the first occasion, after a single dosage of 3 x 90 microL NES sprays using a specially devised, precisely metered delivery device; on the second occasion, following the fifth in a series of five daily transdermal dosages of 3 x 90 microL of NES spray. Conventional pharmacokinetic parameters were calculated. NES was assayed in serum using a specific radioimmunoassay. RESULTS: Mean serum levels of NES peaked at around 20 h following dosing, and levels plateaued at 285-290 pmol/L after 4-5 days of daily spray application. All subjects achieved satisfactory serum levels, although substantial intersubject variation was noted. The apparent elimination half-life of NES after the last dose on Day 5 was 26.8 h. No unexpected adverse events were encountered. CONCLUSION: This early pharmacokinetic trial of a new transdermal steroid delivery system has demonstrated the feasibility of achieving serum levels of NES sufficient to block ovulation and potentially provide effective contraception.