Sildenafil (Page 4 of 6)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Sildenafil was not carcinogenic when administered to rats for up to 24 months at 60 mg/kg/day, a dose resulting in total systemic exposure (AUC) to unbound sildenafil and its major metabolite 33- and 37-times, for male and female rats respectively, the human exposure at the RHD of 20 mg three times a day. Sildenafil was not carcinogenic when administered to male and female mice for up to 21 and 18 months, respectively, at doses up to a maximally tolerated level of 10 mg/kg/day, a dose equivalent to the RHD on a mg/m 2 basis.

Sildenafil was negative in in vitro bacterial and Chinese hamster ovary cell assays to detect mutagenicity, and in vitro human lymphocytes and in vivo mouse micronucleus assays to detect clastogenicity.

There was no impairment of fertility in male or female rats given up to 60 mg sildenafil/kg/day, a dose producing a total systemic exposure (AUC) to unbound sildenafil and its major metabolite of 19- and 38-times for males and females, respectively, the human exposure at the RHD of 20 mg three times a day.

14 CLINICAL STUDIES

SUPER-1 (NCT00644605) -Sildenafil monotherapy [20 mg, 40 mg, and 80 mg three times a day] A randomized, double-blind, placebo-controlled study of sildenafil (SUPER-1) was conducted in 277 patients with PAH (defined as a mean pulmonary artery pressure ≥ 25 mmHg at rest with a pulmonary capillary wedge pressure < 15 mmHg). Patients were predominantly WHO Functional Classes II-III. Allowed background therapy included a combination of anticoagulants, digoxin, calcium channel blockers, diuretics, and oxygen. The use of prostacyclin analogues, endothelin receptor antagonists, and arginine supplementation were not permitted. Patients who had failed to respond to bosentan were also excluded. Patients with left ventricular ejection fraction less than 45% or left ventricular shortening fraction less than 0.2 also were not studied.

Patients were randomized to receive placebo (n=70) or sildenafil 20 mg (n = 69), 40 mg (n = 67) or 80 mg (n = 71) three times a day for a period of 12 weeks. They had either primary pulmonary hypertension (PPH) (63%), PAH associated with CTD (30%), or PAH following surgical repair of left-to-right congenital heart lesions (7%). The study population consisted of 25% men and 75% women with a mean age of 49 years (range: 18 to 81 years) and baseline 6-minute walk distance between 100 and 450 meters (mean 343).

The primary efficacy endpoint was the change from baseline at Week 12 (at least 4 hours after the last dose) in the 6 minute walk distance. Placebo-corrected mean increases in walk distance of 45-50 meters were observed with all doses of sildenafil. These increases were significantly different from placebo, but the sildenafil dose groups were not different from each other (see Figure 3), indicating no additional clinical benefit from doses higher than 20 mg three times a day. The improvement in walk distance was apparent after 4 weeks of treatment and was maintained at Week 8 and Week 12.

Figure 3. Change from Baseline in 6-Minute Walk Distance (meters) at Weeks 4, 8, and 12 in SUPER-1: Mean (95% Confidence Interval)

Figure 9. Change from Baseline in 6-Minute Walk Distance (meters) at Weeks 4, 8, and 12 in Study 1: Mean (95% Confidence Interval)
(click image for full-size original)

Figure 4 displays subgroup efficacy analyses in SUPER-1 for the change from baseline in 6-Minute Walk Distance at Week 12 including baseline walk distance, disease etiology, functional class, gender, age, and hemodynamic parameters.

Figure 4. Placebo-Corrected Change From Baseline in 6-Minute Walk Distance (meters) at Week 12 by study subpopulation in SUPER-1: Mean (95% Confidence Interval)

Figure 10. Placebo-Corrected Change From Baseline in 6-Minute Walk Distance (meters) at Week 12 by study subpopulation in Study 1: Mean (95% Confidence Interval)
(click image for full-size original)

Key: PAH = pulmonary arterial hypertension; CTD = connective tissue disease; PH = pulmonary hypertension; PAP = pulmonary arterial pressure; PVRI = pulmonary vascular resistance index; TID = three times daily.

PACES-1 (NCT00159861) — Sildenafil Co-administered with Epoprostenol A randomized, double-blind, placebo controlled study (PACES-1) was conducted in 267 patients with PAH who were taking stable doses of intravenous epoprostenol. Patients had to have a mean pulmonary artery pressure (mPAP) greater than or equal to 25 mmHg and a pulmonary capillary wedge pressure (PCWP) less than or equal to 15 mmHg at rest via right heart catheterization within 21 days before randomization, and a baseline 6-minute walk test distance greater than or equal to 100 meters and less than or equal to 450 meters (mean 349 meters). Patients were randomized to placebo or sildenafil (in a fixed titration starting from 20 mg, to 40 mg and then 80 mg, three times a day) and all patients continued intravenous epoprostenol therapy.

At baseline patients had PPH (80%) or PAH secondary to CTD (20%); WHO functional class I (1%), II (26%), III (67%), or IV (6%); and the mean age was 48 years, 80% were female, and 79% were Caucasian.

There was a statistically significant greater increase from baseline in 6-minute walk distance at Week 16 (primary endpoint) for the sildenafil group compared with the placebo group. The mean change from baseline at Week 16 (last observation carried forward) was 30 meters for the sildenafil group compared with 4 meters for the placebo group giving an adjusted treatment difference of 26 meters (95% CI: 10.8, 41.2) (p = 0.0009).

Patients on sildenafil achieved a statistically significant reduction in mPAP compared to those on placebo. A mean placebo-corrected treatment effect of -3.9 mmHg was observed in favor of sildenafil (95% CI: -5.7, -2.1) (p = 0.00003).

Time to clinical worsening of PAH was defined as the time from randomization to the first occurrence of a clinical worsening event (death, lung transplantation, initiation of bosentan therapy, or clinical deterioration requiring a change in epoprostenol therapy). Table 4 displays the number of patients with clinical worsening events in PACES-1. Kaplan-Meier estimates and a stratified log-rank test demonstrated that placebo-treated patients were 3 times more likely to experience a clinical worsening event than sildenafil-treated patients and that sildenafil-treated patients experienced a significant delay in time to clinical worsening versus placebo-treated patients (p = 0.0074). Kaplan-Meier plot of time to clinical worsening is presented in Figure 5.

Table 4. Clinical Worsening Events in PACES-1

Placebo

(N = 131)

Sildenafil Tablets

(N = 134)

Number of subjects with clinical worsening first event

23

8

First Event

All Events

First Event

All Events

Death, n

3

4

0

0

Lung Transplantation, n

1

1

0

0

Hospitalization due to PAH, n

9

11

8

8

Clinical deterioration resulting in:

 Change of Epoprostenol Dose, n

9

16

0

2

 Initiation of Bosentan, n

1

1

0

0

Proportion Worsened  95% Confidence Interval

0.187

(0.12 – 0.26)

0.062

(0.02 – 0.10)

Figure 5. Kaplan-Meier Plot of Time (in Days) to Clinical Worsening of PAH in PACES-1

Figure 11. Kaplan-Meier Plot of Time (in Days) to Clinical Worsening of PAH in Study 2
(click image for full-size original)

Improvements in WHO Functional Class for PAH were also demonstrated in patients on sildenafil compared to placebo. More than twice as many sildenafil-treated patients (36%) as placebo-treated patients (14%) showed an improvement in at least one functional New York Heart Association (NYHA) class for PAH.

Study A1481243 (NCT00323297) — Sildenafil Added to Bosentan Therapy – Lack of Effect on Exercise Capacity
A randomized, double-blind, placebo controlled study was conducted in 103 patients with PAH who were on bosentan therapy for a minimum of three months. The PAH patients included those with primary PAH, and PAH associated with CTD. Patients were randomized to placebo or sildenafil (20 mg three times a day) in combination with bosentan (62.5 to 125 mg twice a day). The primary efficacy endpoint was the change from baseline at Week 12 in 6-minute walk distance (6MWD). The results indicate that there is no significant difference in mean change from baseline on 6MWD observed between sildenafil 20 mg plus bosentan and bosentan alone.

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