Regulatory Decision Summary for Slynd

Duchesnay Inc. filed this New Drug Submission (NDS) seeking market authorization for Slynd (drospirenone) for the prevention of pregnancy in adult and adolescent women who elect to use an oral contraceptive.

Slynd clinical programs include data from 9 Phase I, 6 Phase II, and 4 Phase III studies.

Phase I and II studies demonstrated that the non-micronized oral formulation of Slynd (drospirenone 4.0 mg tablets) has a slower rate of dissolution, but a similar exposure when compared to the micronized drospirenone 3.0 mg formulation found in the combined oral contraceptives (COC) available on the market. Inhibition of ovulation was demonstrated in 93-100% of subjects treated. Progesterone serum levels never exceeded 5 ng/mL during treatment. 90% of subjects regained ovulation post-treatment. Slynd is to be contraindicated in hepatic and renal failure.

In the Phase III Studies, two 13 cycle pivotal studies were performed. One of these studies (CF111/301) was performed in Europe and the other study (CF111/303) was performed in the United States. Two supporting studies, one comparative 9 cycle study (CF111/302) and one study in adolescents (CF111/304), were performed in Europe. Nearly 100% of subjects in studies CF111/301 and CF111/302 were Caucasian, while study CF111/303 included 22.8% of Hispanic and 35.6% African American subjects. Risk factors for venous thromboembolism were reported in 15-20% of subjects in studies CF111/301 and CF111/302, and 36% of subjects in study CF111/303. A BMI ≥30 kg/m² was observed in 5.8%, 3.5 % and 35.2 % of subjects in studies CF111/301, /302 and /303, respectively. The primary efficacy endpoint in the study CF111/303 (United States), which was the Pearl Index (PI) based on evaluable cycles in non-breastfeeding women aged ≤35 years (at the time of enrolment), was 4.0. The primary efficacy endpoint in the study CF111/301 (Europe), which was the overall PI in non-breastfeeding women aged ≤35 years, was 0.66. PI calculations for African American subjects (PI 7.0) was higher when compared to PI calculated for Caucasian subjects (PI 2.8). All PI values are acceptable.

The safety and tolerability of drospirenone (DRSP) as a progestin-only pill (POP) have been primarily evaluated in 5 Phase II and 4 Phase III studies. The frequency of treatment-emergent adverse events (TEAEs) leading to discontinuation was similar in adults (11.0%) and adolescents (10.8%). However, the frequency of discontinuation due to metrorrhagia was higher in the adolescent population (4.9% vs 1.2%). During long-term studies, 1.6% of adult subjects on DRSP and 1.8% of adult patients on desogestrel treatment reported at least one treatment-emergent serious adverse event (TESAE). In study CF111/304, two adolescents (2.0%) experienced TESAEs, one event of pharyngitis and one of joint dislocation. Most common individual TEAEs (nasopharyngitis [3.2%], headache [4.5%], acne [4.6%]) were observed in both adult and adolescent studies with very small percentage differences between studies. In adult and adolescent studies, a trend towards reduced prolonged bleeding and/or spotting days was observed with continued treatment. Scheduled and unscheduled bleeding and/or spotting also decreased during treatment in both adults and adolescents. Endometrial biopsies concluded that the mean maximal thickness with DRSP 4.0 mg treatment was 7.5 mm (-2.5 mm mean reduction). Endometrial biopsies have been performed during 13 cycles with the DRSP 4.0 mg and showed no endometrial hyperplasia. 12, 26 and 41 subjects showed high potassium levels in studies CF111/301, /302 and /303, respectively. Almost all the serum potassium levels returned to normal on subsequent testing during treatment. Three subjects in study CF111/303 were withdrawn from the study due to persistently elevated serum potassium levels. Slynd does not induce changes in the QT interval duration of treated subjects. Slynd’s safety profile is consistent with the known safety profile of drugs in the same class of POP.

In summary, Slynd is a POP (DRSP 4.0 mg; oral Tablets) that produces a significant inhibition of ovulation in adolescent and adult women. Inhibition of ovulation is maintained in spite of four scheduled 24-hour delays in pill intake. Slynd is well tolerated and the TEAE profile is consistent with the known TEAE profile of the same class of POP. The overall benefit/harm ratio of Slynd is considered positive.