PROMACTA (Page 7 of 9)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Eltrombopag does not stimulate platelet production in rats, mice, or dogs because of unique TPO receptor specificity. Data from these animals do not fully model effects in humans.

Eltrombopag was not carcinogenic in mice at doses up to 75 mg/kg/day or in rats at doses up to 40 mg/kg/day (exposures up to 4 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 2 times the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day).

Eltrombopag was not mutagenic or clastogenic in a bacterial mutation assay or in two in vivo assays in rats (micronucleus and unscheduled DNA synthesis, 10 times the human clinical exposure based on Cmax in patients with ITP at 75 mg/day and 7 times the human clinical exposure based on Cmax in patients with chronic hepatitis C at 100 mg/day). In the in vitro mouse lymphoma assay, eltrombopag was marginally positive (less than 3-fold increase in mutation frequency).

Eltrombopag did not affect female fertility in rats at doses up to 20 mg/kg/day (2 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and similar to the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). Eltrombopag did not affect male fertility in rats at doses up to 40 mg/kg/day, the highest dose tested (3 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 2 times the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day).

13.2 Animal Pharmacology and/or Toxicology

Treatment-related cataracts were detected in rodents in a dose- and time-dependent manner. At greater than or equal to 6 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 3 times the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day, cataracts were observed in mice after 6 weeks and in rats after 28 weeks of dosing. At greater than or equal to 4 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 2 times the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day, cataracts were observed in mice after 13 weeks and in rats after 39 weeks of dosing [see Warnings and Precautions (5.5)].

Renal tubular toxicity was observed in studies up to 14 days in duration in mice and rats at exposures that were generally associated with morbidity and mortality. Tubular toxicity was also observed in a 2-year oral carcinogenicity study in mice at doses of 25, 75, and 150 mg/kg/day. The exposure at the lowest dose was 1.2 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 0.6 times the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day. No similar effects were observed in mice after 13 weeks at exposures greater than those associated with renal changes in the 2-year study, suggesting that this effect is both dose- and time-dependent.

14 CLINICAL STUDIES

14.1 Persistent or Chronic ITP

Adults: The efficacy and safety of PROMACTA in adult patients with persistent or chronic ITP were evaluated in three randomized, double-blind, placebo-controlled trials and in an open-label extension trial.

In Study TRA100773B and Study TRA100773A (referred to as Study 773B and Study 773A, respectively [NCT00102739]), patients who had completed at least one prior ITP therapy and who had a platelet count less than 30 x 109 /L were randomized to receive either PROMACTA or placebo daily for up to 6 weeks, followed by 6 weeks off therapy. During the trials, PROMACTA or placebo was discontinued if the platelet count exceeded 200 x 109 /L.

The median age of the patients was 50 years and 60% were female. Approximately 70% of the patients had received at least 2 prior ITP therapies (predominantly corticosteroids, immunoglobulins, rituximab, cytotoxic therapies, danazol, and azathioprine) and 40% of the patients had undergone splenectomy. The median baseline platelet counts (approximately 18 x 109 /L) were similar among all treatment groups.

Study 773B randomized 114 patients (2:1) to PROMACTA 50 mg or placebo. Of 60 patients with documented time since diagnosis, approximately 17% met the definition of persistent ITP with time since diagnosis of 3-12 months. Study 773A randomized 117 patients (1:1:1:1) among placebo or 1 of 3 dose regimens of PROMACTA, 30 mg, 50 mg, or 75 mg each administered daily. Of 51 patients with documented time since diagnosis, approximately 14% met the definition of persistent ITP.

The efficacy of PROMACTA in this trial was evaluated by response rate, defined as a shift from a baseline platelet count of less than 30 x 109 /L to greater than or equal to 50 x 109 /L at any time during the treatment period (Table 16).

Table 16. Studies 773B and 773A: Platelet Count Response (≥ 50 x 109 /L) Rates in Adults With Persistent or Chronic Immune Thrombocytopenia
a p- value < 0.001 for PROMACTA versus placebo.

Study

PROMACTA

50 mg Daily

Placebo

773B

43/73 (59%)a

6/37 (16%)

773A

19/27 (70%)a

3/27 (11%)

The platelet count response to PROMACTA was similar among patients who had or had not undergone splenectomy. In general, increases in platelet counts were detected 1 week following initiation of PROMACTA and the maximum response was observed after 2 weeks of therapy. In the placebo and 50-mg–dose groups of PROMACTA, the trial drug was discontinued due to an increase in platelet counts to greater than 200 x 109 /L in 3% and 27% of the patients, respectively. The median duration of treatment with the 50-mg dose of PROMACTA was 43 days in Study 773B and 42 days in Study 773A.

Of 7 patients who underwent hemostatic challenges, additional ITP medications were required in 3 of 3 placebo group patients and 0 of 4 patients treated with PROMACTA. Surgical procedures accounted for most of the hemostatic challenges. Hemorrhage requiring transfusion occurred in one placebo group patient and no patients treated with PROMACTA.

In the RAISE study (NCT00370331), 197 patients were randomized (2:1) to receive either PROMACTA 50 mg once daily (n = 135) or placebo (n = 62) for 6 months, during which time the dose of PROMACTA could be adjusted based on individual platelet counts. Of 145 patients with documented time since diagnosis, 19% met the definition of persistent ITP. Patients were allowed to taper or discontinue concomitant ITP medications after being treated with PROMACTA for 6 weeks. Patients were permitted to receive rescue treatments at any time during the trial as clinically indicated.

The median ages of the patients treated with PROMACTA and placebo were 47 years and 52.5 years, respectively. Approximately half of the patients treated with PROMACTA and placebo (47% and 50%, respectively) were receiving concomitant ITP medication (predominantly corticosteroids) at randomization and had baseline platelet counts less than or equal to 15 x 109 /L (50% and 48%, respectively). A similar percentage of patients treated with PROMACTA and placebo (37% and 34%, respectively) had a prior splenectomy.

The efficacy of PROMACTA in this trial was evaluated by the odds of achieving a platelet count greater than or equal to 50 x 109 /L and less than or equal to 400 x 109 /L for patients receiving PROMACTA relative to placebo and was based on patient response profiles throughout the 6-month treatment period. In 134 patients who completed 26 weeks of treatment, a sustained platelet response (platelet count greater than or equal to 50 x 109 /L and less than or equal to 400 x 109 /L for 6 out of the last 8 weeks of the 26-week treatment period in the absence of rescue medication at any time) was achieved by 60% of patients treated with PROMACTA, compared with 10% of patients treated with placebo (splenectomized patients: PROMACTA 51%, placebo 8%; non-splenectomized patients: PROMACTA 66%, placebo 11%). The proportion of responders in the group of patients treated with PROMACTA was between 37% and 56% compared with 7% and 19% in the placebo treatment group for all on-therapy visits. Patients treated with PROMACTA were significantly more likely to achieve a platelet count between 50 x 109 /L and 400 x 109 /L during the entire 6-month treatment period compared with those patients treated with placebo.

Outcomes of treatment are presented in Table 17 for all patients enrolled in the trial.

Table 17. RAISE: Outcomes of Treatment in Adults With Persistent or Chronic Immune Thrombocytopenia

Outcome

PROMACTA

n = 135

Placebo

n = 62

Mean number of weeks with platelet counts ≥ 50 x 109 /L

11.3

2.4

Requiring rescue therapy, n (%)

24 (18)

25 (40)

Among 94 patients receiving other ITP therapy at baseline, 37 (59%) of 63 patients treated with PROMACTA and 10 (32%) of 31 patients in the placebo group discontinued concomitant therapy at some time during the trial.

In the EXTEND study (NCT00351468), patients who completed any prior clinical trial with PROMACTA were enrolled in an open-label, single-arm trial in which attempts were made to decrease the dose or eliminate the need for any concomitant ITP medications. PROMACTA was administered to 302 patients in EXTEND; 218 patients completed 1 year, 180 patients completed 2 years, 107 patients completed 3 years, 75 patients completed 4 years, 34 patients completed 5 years, and 18 patients completed 6 years of therapy. The median baseline platelet count was 19 x 109 /L prior to administration of PROMACTA. Median platelet counts at 1, 2, 3, 4, 5, 6, and 7 years on study were 85 x 109 /L, 85 x 109 /L, 105 x 109 /L, 64 x 109 /L, 75 x 109 /L, 119 x 109 /L, and 76 x 109 /L, respectively.

Pediatric Patients: The efficacy and safety of PROMACTA in pediatric patients 1 year and older with persistent or chronic ITP were evaluated in two double-blind, placebo-controlled trials. The trials differed in time since ITP diagnosis: at least 6 months versus at least 12 months. During the trials, doses could be increased every 2 weeks to a maximum of 75 mg once daily. The dose of PROMACTA was reduced if the platelet count exceeded 200 x 109 /L and interrupted and reduced if it exceeded 400 x 109 /L.

In the PETIT2 study (NCT01520909), patients refractory or relapsed to at least one prior ITP therapy with a platelet count less than 30 x 109 /L (n = 92) were stratified by age and randomized (2:1) to PROMACTA (n = 63) or placebo (n = 29). The starting dose for patients aged 6 to 17 years was 50 mg once daily for those at least 27 kg and 37.5 mg once daily for those less than 27 kg, administered as oral tablets. A reduced dose of 25 mg once daily was used for East Asian patients aged 6 to 17 years regardless of weight. The starting dose for patients aged 1 to 5 years was 1.2 mg/kg once daily (0.8 mg/kg once daily for East Asian patients) administered as oral suspension.

The 13-week, randomized, double-blind period was followed by a 24-week, open-label period where patients from both arms were eligible to receive PROMACTA.

The median age of the patients was 9 years and 48% were female. Approximately 62% of patients had a baseline platelet count less than or equal to 15 x 109 /L, a characteristic that was similar between treatment arms. The percentage of patients with at least 2 prior ITP therapies (predominantly corticosteroids and immunoglobulins) was 73% in the group treated with PROMACTA and 90% in the group treated with placebo. Four patients in the group treated with PROMACTA had undergone splenectomy.

The efficacy of PROMACTA in this trial was evaluated by the proportion of subjects on PROMACTA achieving platelet counts ≥ 50 x 109 /L (in the absence of rescue therapy) for at least 6 out of 8 weeks between Weeks 5 to 12 of the randomized, double-blind period (Table 18).

Table 18. PETIT2: Platelet Count Response (≥ 50 x 109 /L Without Rescue) for 6 out of 8 Weeks (between Weeks 5 to 12) Overall and by Age Cohort in Pediatric Patients 1 Year and Older With Chronic Immune Thrombocytopenia
a p- value = < 0.001 for PROMACTA versus placebo.

Age Cohort

PROMACTA

Placebo

Overall

26/63 (41%)a

1/29 (3%)

12 to 17 years

10/24 (42%)

1/10 (10%)

6 to 11 years

11/25 (44%)

0/13 (0%)

1 to 5 years

5/14 (36%)

0/6 (0%)

More pediatric patients treated with PROMACTA (75%) compared with placebo (21%) had at least one platelet count greater than or equal to 50 x 109 /L during the first 12 weeks of randomized treatment in absence of rescue therapy. Fewer pediatric patients treated with PROMACTA required rescue treatment during the randomized, double-blind period compared with placebo-treated patients (19% [12/63] versus 24% [7/29]). In the patients who achieved a platelet response (≥ 50 x 109 /L without rescue) for 6 out of 8 weeks (between weeks 5 to 12), 62% (16/26) had an initial response in the first 2 weeks after starting PROMACTA.

Patients were permitted to reduce or discontinue baseline ITP therapy only during the open-label phase of the trial. Among 15 patients receiving other ITP therapy at baseline, 53% (8/15) reduced (n = 1) or discontinued (n = 7) concomitant therapy, mainly corticosteroids, without needing rescue therapy.

In the PETIT study (NCT00908037), patients refractory or relapsed to at least one prior ITP therapy with a platelet count less than 30 x 109 /L (n = 67) were stratified by age and randomized (2:1) to PROMACTA (n = 45) or placebo (n = 22). Approximately 15% of patients met the definition of persistent ITP. The starting dose for patients aged 12 to 17 years was 37.5 mg once daily regardless of weight or race. The starting dose for patients aged 6 to 11 years was 50 mg once daily for those greater than or equal to 27 kg and 25 mg once daily for those less than 27 kg, administered as oral tablets. Reduced doses of 25 mg (for those greater than or equal to 27 kg) and 12.5 mg (for those less than 27 kg), each once daily, were used for East Asian patients in this age range. The starting dose for patients aged 1 to 5 years was 1.5 mg/kg once daily (0.8 mg/kg once daily for East Asian patients) administered as oral suspension.

The 7-week, randomized, double-blind period was followed by an open-label period of up to 24 weeks where patients from both arms were eligible to receive PROMACTA.

The median age of the patients was 10 years and 60% were female. Approximately 51% of patients had a baseline platelet count less than or equal to 15 x 109 /L. The percentage of patients with at least 2 prior ITP therapies (predominantly corticosteroids and immunoglobulins) was 84% in the group treated with PROMACTA and 86% in the group treated with placebo. Five patients in the group treated with PROMACTA had undergone splenectomy.

The efficacy of PROMACTA in this trial was evaluated by the proportion of patients achieving platelet counts greater than or equal to 50 x 109 /L (in absence of rescue therapy) at least once between Weeks 1 and 6 of the randomized, double-blind period (Table 19). Platelet response to PROMACTA was consistent across the age cohorts.

Table 19. PETIT: Platelet Count Response (≥ 50 x 109 /L Without Rescue) Rates in Pediatric Patients 1 Year and Older With Persistent or Chronic Immune Thrombocytopenia
a p- value = 0.011 for PROMACTA versus placebo.

PROMACTA

Placebo

Overall

28/45 (62%)a

7/22 (32%)

12 to 17 years

10/16 (62%)

0/8 (0%)

6 to 11 years

12/19 (63%)

3/9 (33%)

1 to 5 years

6/10 (60%)

4/5 (80%)

Fewer pediatric patients treated with PROMACTA required rescue treatment during the randomized, double-blind period compared with placebo-treated patients (13% [6/45] versus 50% [11/22]).

Patients were permitted to reduce or discontinue baseline ITP therapy only during the open-label phase of the trial. Among 13 patients receiving other ITP therapy at baseline, 46% (6/13) reduced (n = 3) or discontinued (n = 3) concomitant therapy, mainly corticosteroids, without needing rescue therapy.

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