DOPTELET Film-coated tablet

Active ingredients: Avatrombopag

12.1. Mechanism of Action

Avatrombopag is an orally bioavailable, small molecule TPO receptor agonist that stimulates proliferation and differentiation of megakaryocytes from bone marrow progenitor cells, resulting in an increased production of platelets. Avatrombopag does not compete with TPO for binding to the TPO receptor and has an additive effect with TPO on platelet production.

12.2. Pharmacodynamics

Platelet Response

DOPTELET administered to adult patients resulted in dose- and exposure-dependent elevations in platelet counts. The onset of the platelet count increase was observed within 3 to 5 days of the start of treatment, with peak effect after 10 to 13 days. Post treatment, platelet counts decreased gradually, returning to near baseline values.

Cardiac Electrophysiology

At exposures similar to that achieved at the 40 mg and 60 mg dose, DOPTELET did not prolong the QT interval to any clinically relevant extent. Mean QTc prolongation effects >20 ms are not anticipated with the highest recommended therapeutic dosing regimen based on analysis of data from the pooled clinical trials in patients with chronic liver disease.

12.3. Pharmacokinetics

Avatrombopag demonstrated dose-proportional pharmacokinetics after single doses from 10 mg (0.25 times the lowest approved dosage) to 80 mg (1.3 times the highest recommended dosage). Healthy subjects administered 40 mg of avatrombopag had a geometric mean (CV) maximal concentration (Cmax) of 166 (84) ng/mL and area under the time-concentration curve extrapolated to infinity (AUC0-inf) of 4198 (83%) ng.hr/mL. The pharmacokinetics of avatrombopag were similar in both healthy subjects and the chronic liver disease population.

Absorption

The median time to maximal concentration (Tmax) occurred at 5 to 6 hours post-dose.

Effect of Food

Avatrombopag AUC0-inf and Cmax were not affected when DOPTELET was co-administered with a low fat meal (500 calories, 3 g fat, 15 g protein, and 108 g carbohydrates) or a high fat meal (918 calories, 59 g fat, 39 g protein, and 59 g carbohydrates). The variability of avatrombopag exposure was reduced by 40% to 60% with food. The Tmax of avatrombopag was delayed by 0 to 2 hours when DOPTELET was administered with a low-fat or high-fat meal (median Tmax range 5 to 8 hours) compared to the fasted state.

Distribution

Avatrombopag has an estimated mean volume of distribution (CV) of 180 L (25). Avatrombopag is greater than 96% bound to human plasma proteins.

Elimination

The mean plasma elimination half-life (CV) of avatrombopag is approximately 19 hours (19). The mean (CV) of the clearance of avatrombopag is estimated to be 6.9 L/hr (29).

Metabolism

Avatrombopag is primarily metabolized by cytochrome P450 CYP2C9 and CYP3A4.

Excretion

Fecal excretion accounted for 88% of the administered dose, with 34% of the dose excreted as unchanged avatrombopag. Only 6% of the administered dose was found in urine.

Specific Populations

Age (18-86 years), body weight (39-175 kg), sex, race [Whites, African-Americans, and East Asians (i.e., Japanese, Chinese and Koreans)], and any hepatic impairment (Child-Turcotte-Pugh (CTP) grade A, B, and C, or Model for End-Stage Liver Disease (MELD) score 4-23) and mild to moderate renal impairment (CLcr ≥30 mL/min) did not have clinically meaningful effects on the pharmacokinetics of avatrombopag.

The effect of age (<18 years) and severe renal impairment (CLcr <30 mL/min, Cockcroft-Gault) including patients requiring hemodialysis on avatrombopag pharmacokinetics is unknown.

Drug Interactions

Clinical Studies

Table 7 summarizes the effect of other drugs on the pharmacokinetics of avatrombopag.

Table 7. Drug Interactions: Changes in Pharmacokinetics of Avatrombopag in the Presence of Co-Administered Drug:

Co-administered Drug* Geometric Mean Ratio [90% CI] of Avatrombopag PK with/without Co-administered Drug (No Effect=1.00)
AUC0-inf Cmax
Strong CYP3A Inhibitor
Itraconazole 1.37 (1.10, 1.72) 1.07 (0.86, 1.35)
Moderate CYP3A and CYP2C9 Inhibitor
Fluconazole 2.16 (1.71, 2.72) 1.17 (0.96, 1.42)
Moderate CYP2C9 and Strong CYP3A Inducer
Rifampin 0.57 (0.47, 0.62) 1.04 (0.88, 1.23)
P-gp Inhibitor
Cyclosporine 0.83 (0.65, 1.04) 0.66 (0.54, 0.82)
P-gp and Moderate CYP3A Inhibitor
Verapamil 1.61 (1.21, 2.15) 1.26 (0.96, 1.66)

* at steady-state, except for cyclosporine which was administered as a single dose.

In Vitro Studies Where Drug Interaction Potential Was Not Further Evaluated Clinically

CYP enzymes: Avatrombopag does not inhibit CYP1A, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A, does not induce CYP1A, CYP2B6, CYP2C, or CYP3A, and weakly induces CYP2C8 and CYP2C9.

Transporter systems: Avatrombopag inhibits organic anion transporter (OAT) 3 and breast cancer resistance protein (BCRP), but not organic anion transporter polypeptide (OATP) 1B1 and 1B3, organic cation transporter (OCT) 2, or OAT1.

Avatrombopag is not a substrate for OATP1B1, OATP1B3, OCT2, OAT1, or OAT3.

12.5. Pharmacogenomics

The CYP2C9*2 and CYP2C9*3 loss-of-function polymorphisms result in reduced CYP2C9 enzymatic activity. In a pooled pharmacogenomic analysis of avatrombopag studies, subjects heterozygous for CYP2C9 loss-of-function polymorphisms (intermediate metabolizers [n=24]) had approximately 1.4-fold higher exposure and subjects homozygous for CYP2C9 loss-of-function polymorphisms (poor metabolizers [n=2]) had approximately 2-fold higher exposure compared to subjects wild-type for CYP2C9 (normal metabolizers [n=94]).

13.1. Carcinogenesis, Mutagenesis, Impairment of Fertility

In two-year carcinogenicity studies, avatrombopag was administered orally at doses of 20, 60, and 160 mg/kg/day in mice and doses of 20, 50, and 160 mg/kg/day in rats. Avatrombopag induced a statistically significant increase in neuroendocrine cell (enterochromaffin-like cell, ECL cell) gastric tumors (carcinoids) in the stomach at 160 mg/kg in female rats. The 160 mg/kg/day dose resulted in exposures 117 times the AUC observed in patients at the maximum recommended dose of 60 mg once daily. The gastric carcinoids were considered likely due to prolonged hypergastrinemia observed in toxicity studies. Hypergastrinemia-related gastric carcinoids in rodents are generally considered to be of low risk or relevance to humans.

Avatrombopag was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay or clastogenic in an in vitro human lymphocyte chromosomal aberrations assay or in an in vivo rat bone marrow micronucleus assay.

Avatrombopag did not affect fertility or early embryonic development in male rats at exposures 22 times, or in female rats at exposures 114 times, the AUC observed in patients at the maximum recommended dose of 60 mg once daily.

14. Clinical Studies

14.1 Patients with Chronic Liver Disease

The efficacy of DOPTELET for the treatment of thrombocytopenia in patients with chronic liver disease who are scheduled to undergo a procedure was established in 2 identically-designed multicenter, randomized, double-blind, placebo-controlled trials (ADAPT-1 [NCT01972529] and ADAPT-2 [NCT01976104]). In each trial, patients were assigned to the Low Baseline Platelet Count Cohort (<40 × 109/L) or the High Baseline Platelet Count Cohort (≥40 to <50 × 109/L) based on their platelet count at baseline. Patients were then randomized in a 2:1 ratio to either DOPTELET or placebo. Patients were stratified according to hepatocellular cancer (HCC) status and risk of bleeding associated with the elective procedure (low, moderate, or high). Patients undergoing neurosurgical interventions, thoracotomy, laparotomy or organ resection were not eligible for enrollment.

Patients in the Low Baseline Platelet Count Cohort received 60 mg DOPTELET or matching placebo once daily for 5 days, and patients in the High Baseline Platelet Count Cohort received 40 mg DOPTELET or matching placebo once daily for 5 days. Eligible patients were scheduled to undergo their procedure (low, moderate, or high bleeding risk) 5 to 8 days after their last dose of treatment. Patient populations were similar between the pooled Low and High Baseline Platelet Count Cohorts and consisted of 66% male and 35% female; median age 58 years and 61% White, 34% Asian, and 3% Black.

In ADAPT-1, a total of 231 patients were randomized, 149 patients were treated with DOPTELET and 82 patients were treated with placebo. In the Low Baseline Platelet Count Cohort, the mean baseline platelet count for the DOPTELET-treated group was 31.1 × 109/L and for the placebo-treated patients was 30.7 × 109/L. In the High Baseline Platelet Count Cohort, the mean baseline platelet count for the DOPTELET-treated patients was 44.3 × 109/L and for placebo-treated patients was 44.9 × 109/L.

In ADAPT-2, a total of 204 patients were randomized, 128 patients were treated with DOPTELET and 76 patients were treated with placebo. In the Low Baseline Platelet Count Cohort, the mean baseline platelet count for the DOPTELET-treated group was 32.7 × 109/L and for the placebo-treated patients was 32.5 × 109/L. In the High Baseline Platelet Count Cohort, the mean baseline platelet count for the DOPTELET-treated patients was 44.3 × 109/L and for the placebo-treated patients was 44.5 × 109/L.

Across both baseline platelet count cohorts and the avatrombopag and placebo treatment groups, patients underwent a broad spectrum of types of scheduled procedures that ranged from low to high bleeding risk. Overall, the majority of patients (60.8% [248/430] subjects) in all treatment groups underwent low bleeding risk procedures, 17.2% (70/430) of patients underwent procedures associated with moderate bleeding risk, and 22.1% (90/430) of subjects underwent procedures associated with high bleeding risk. The proportions of patients undergoing low, moderate, and high-risk procedures were similar between the avatrombopag and placebo treatment groups.

The major efficacy outcome was the proportion of patients who did not require a platelet transfusion or any rescue procedure for bleeding after randomization and up to 7 days following an elective procedure. Additional secondary efficacy outcomes were the proportion of patients who achieved platelet counts of >50 × 109/L on the day of procedure, and the change in platelet count from baseline to procedure day.

Responders were defined as patients who did not require a platelet transfusion or any rescue procedure for bleeding after randomization and up to 7 days following a scheduled procedure. The following were considered rescue therapies to manage the risk of bleeding associated with a procedure: whole blood transfusion, packed red blood cell (RBC) transfusion, platelet transfusion, fresh frozen plasma (FFP) or cryoprecipitate administration, Vitamin K, desmopressin, recombinant activated factor VII, aminocaproic acid, tranexamic acid, or surgical or interventional radiology procedures performed to achieve hemostasis and control blood loss. In both baseline platelet count cohorts, patients in the DOPTELET treatment groups had a greater proportion of responders than the corresponding placebo treatment groups that was both clinically meaningful and statistically significant as detailed in Table 8.

Table 8. Proportion of Patients Not Requiring a Platelet Transfusion or Any Rescue Procedure for Bleeding by Baseline Platelet Count Cohort and Treatment Group – ADAPT-1 & ADAPT-2:

Low Baseline Platelet Count Cohort (<40 × 10 9/L)
Category ADAPT-1 ADAPT-2
DOPTELET
60 mg
(n=90)
Placebo
(n=48)
DOPTELET
60 mg
(n=70)
Placebo
(n=43)
Responders
95% CI a
66% (56, 75) 23% (11, 35) 69% (58, 79) 35% (21, 49)
Difference of Proportion vs. Placebo b
95% CI c
43% (27, 58) 34% (16, 52)
p-valued ˂0.0001 0.0006
High Baseline Platelet Count Cohort (≥40 to <50 x10 9/L)
Category ADAPT-1 ADAPT-2
DOPTELET
40 mg
(n=59)
Placebo
(n=34)
DOPTELET
40 mg
(n=58)
Placebo
(n=33)
Responders
95% CI a
88% (80, 96) 38% (22, 55) 88% (80, 96) 33% (17, 49)
Difference of Proportion vs. Placebo b
95% CI c
50% (32, 68) 55% (37, 73)
p-valued ˂0.0001 ˂0.0001

a Two-sided 95% confidence interval based on normal approximation.
b Difference of Proportion vs. placebo = Proportion of Responders for DOPTELET – Proportion of Responders for placebo.
c 95% confidence interval calculated based on normal approximation.
d By Cochran-Mantel-Haenszel Testing stratified by bleeding risk for the procedure.

In addition, both trials demonstrated a higher proportion of patients who achieved the target platelet count of ≥50 × 109/L on the day of procedure, a secondary efficacy endpoint, in both DOPTELET-treated groups versus the placebo-treated groups for both cohorts (Low Baseline Platelet Count Cohort – ADAPT-1: 69% vs 4%, respectively; p<0.0001, ADAPT-2: 67% vs 7%, respectively; p <0.0001; High Baseline Platelet Count Cohort – ADAPT-1: 88% vs 21%, respectively; p <0.0001: ADAPT-2: 93% vs 39%, respectively; p <0.0001). Further, both trials demonstrated a greater mean change in platelet counts from baseline to the day of the procedure, a secondary efficacy endpoint, in both DOPTELET-treated groups versus the placebo-treated groups for both cohorts (Low Baseline Platelet Count Cohort – ADAPT-1: 32 × 109/L vs 0.8 × 109/L, respectively; p<0.0001; ADAPT-2: 31.3 × 109/L vs 3.0 × 109/L, respectively; p <0.0001; High Baseline Platelet Count Cohort – ADAPT-1: 37.1 × 109/L vs 1.0 × 109/L, respectively; p <0.0001; ADAPT-2: 44.9 × 109/L vs 5.9 × 109/L, respectively; p <0.0001).

A measured increase in platelet counts was observed in both DOPTELET treatment groups over time beginning on Day 4 post-dose, that peaked on Day 10-13, decreased 7 days post-procedure, and then returned to near baseline values by Day 35.

14.2 Patients with Chronic Immune Thrombocytopenia

Randomized Phase 3 Clinical Trial

The efficacy of DOPTELET in adult patients with chronic immune thrombocytopenia was evaluated in a Phase 3, multicenter, randomized, double-blind, placebo-controlled trial (NCT01438840). Patients had previously received one or more prior chronic immune thrombocytopenia therapies and had an average of screening and baseline platelet counts <30 × 109/L. Patients were centrally stratified by splenectomy status, baseline platelet count (≤15 × 109/L or >15 × 109/L to <30 × 109/L), and use of concomitant chronic immune thrombocytopenia medication, and then randomized (2:1) to receive either DOPTELET or placebo for 6 months. Patients received a starting dose of 20 mg once daily, with doses subsequently titrated based on platelet response.

Forty-nine patients were randomized, 32 to DOPTELET and 17 to placebo, with similar mean [SD] baseline platelet counts in the 2 treatment groups (14.1 [8.6] x 109/L and 12.7 [7.8] x 109/L, respectively). The median age was 44 years, 63% were female, and 94% were Caucasian, 4% Asian and 2% Black. The median duration of exposure was 26 weeks for DOPTELET-treated patients and 6 weeks for placebo-treated patients. The major efficacy outcome in this trial was the cumulative number of weeks in which the platelet count was ≥50 × 109/L during the 6-month treatment period in the absence of rescue therapy. DOPTELET-treated patients had a longer duration of platelet counts ≥50 × 109/L in the absence of rescue therapy than those who received placebo (median 12.4 [0, 25] vs 0 [0, 2] weeks, respectively, p<0.0001) (see Table 9).

Table 9. Cumulative Number of Weeks of Platelet Response – Phase 3 Trial in Patients with Chronic Immune Thrombocytopenia:

Primary Efficacy Analysis DOPTELET (n=32) Placebo (n=17)
Cumulative Number of Weeks with a Platelet Response*
Mean (SD) 12.0 (8.75) 0.1 (0.49)
Median 12.4 0.0
Min, Max 0, 25 0, 2
p-value of Wilcoxon rank sum test <0.0001

Max=maximum, Min=minimum, SD=Standard deviation.
* Cumulative number of weeks of platelet response is defined as the total numbers of weeks in which the platelet count was ≥50 × 109/L during 6 months of treatment in the absence of rescue therapy.

In addition, a larger proportion of patients in the DOPTELET treatment group had platelet counts ≥50 × 109/L at Day 8 compared to placebo (21/32; 66% vs 0/17; 0.0%, respectively; p<0.0001).