Summary Basis of Decision for Doptelet

Clinical Pharmacology

Avatrombopag, the medicinal ingredient in Doptelet, is an orally bioavailable, small-molecule thrombopoietin receptor agonist that stimulates proliferation and differentiation of megakaryocytes from bone marrow progenitor cells, thereby leading to an increased production of platelets.

The clinical pharmacology studies evaluated the pharmacokinetics of single and repeat oral doses of avatrombopag in healthy adults, the pharmacokinetic and pharmacodynamic relationship between avatrombopag plasma concentrations and platelet counts, the effect of intrinsic and extrinsic factors on the pharmacokinetics of avatrombopag, the potential for drug-drug interactions, and the potential for prolongation of the QT interval and QT interval corrected for heart rate (QTc). Population pharmacokinetic models and population pharmacokinetic and pharmacodynamic models were developed for each of the intended patient populations: adult patients with chronic liver disease and adult patients with chronic immune thrombocytopenia.

Oral administration of avatrombopag resulted in dose- and exposure-dependent elevations in platelet counts. The onset of the platelet count increase occurred within 3 to 5 days of the start of treatment and the peak platelet response was observed 10 to 13 days after treatment initiation. Platelet counts decreased gradually after the end of treatment, returning to near baseline values.

A double-blind, placebo- and positive-controlled, crossover thorough QT/QTc study in 47 healthy subjects assessed the effect of a single dose of 100 mg avatrombopag on electrocardiogram parameters. Neither the maximum therapeutic exposures corresponding to the 5-day therapeutic regimen of 60 mg avatrombopag once daily nor supratherapeutic exposures were reached in the study. The measured exposures were similar to those produced by the 5-day therapeutic regimen of 40 mg avatrombopag once daily. At this exposure level, avatrombopag did not prolong the QTc interval to any clinically relevant extent. Information on the limited drug exposures evaluated in the thorough QT/QTc study was included in the Doptelet Product Monograph. An analysis of data pooled from the clinical studies in patients with chronic liver disease suggests that a mean QTc interval prolongation by more than 20 ms is not anticipated with the highest recommended therapeutic dosing regimen for Doptelet.

Avatrombopag exhibited dose-proportional pharmacokinetics after single doses from 10 mg (0.5 times the lowest approved dosage) to 80 mg (1.3 times the highest recommended dosage). The pharmacokinetic properties of avatrombopag were similar in healthy subjects and patients with chronic liver disease.

After administration of a single 40 mg dose of avatrombopag to healthy volunteers under fed conditions, the intrasubject and intersubject variability of avatrombopag exposure was reduced when compared to administration under fasting conditions. Based on these findings, the Doptelet Product Monograph recommends that avatrombopag should be administered with food.

Avatrombopag is primarily metabolized by cytochrome P450 (CYP) enzymes CYP3A4 and CYP2C9. Effects of coadministered moderate or strong dual CYP3A4 and CYP2C9 modulators on the pharmacokinetics of avatrombopag and relevant recommendations for adjusting the starting dose of Doptelet are included in the Doptelet Product Monograph.

Overall, the clinical pharmacology data support the use of Doptelet for the specified indications.

For further details, please refer to the Doptelet Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The submitted clinical data provided evidence of efficacy of Doptelet for the two target patient populations: adult patients with severe thrombocytopenia and chronic liver disease, and adult patients with chronic immune thrombocytopenia.

Patients with severe thrombocytopenia and chronic liver disease

The efficacy of Doptelet in the treatment of severe thrombocytopenia in patients with chronic liver disease scheduled to undergo an invasive procedure was evaluated in two pivotal, randomized, double-blind, placebo-controlled studies of identical design (ADAPT-1 and ADAPT-2). In both studies, patients were assigned to one of two cohorts based on their platelet count at baseline: low baseline platelet count (less than 40 × 10⁹/L) cohort or high baseline platelet count (from 40 × 10⁹/L to less than 50 × 10⁹/L) cohort. Within each cohort, patients were stratified by the risk of bleeding associated with their scheduled procedure (low, moderate, or high) and by the hepatocellular carcinoma status (yes or no). Patients were randomized in a ratio of 2:1 to receive Doptelet or matching placebo once daily with a meal for 5 days. Patients in the low baseline platelet count cohort received 60 mg of Doptelet, whereas those in the high baseline platelet count cohort received 40 mg of Doptelet. Procedures were scheduled 5 to 8 days after the last dose of study drug.

Demographic and baseline characteristics of the study population were similar between the pooled low and high baseline platelet count cohorts. The median age of the patients was 58 years (range:19 to 86 years), 66% of patients were male, 61% were White, 34% were Asian, and 3% were Black. The model for end-stage liver disease (MELD) scores were lower than 10 in 37.5% of patients, from 10 to 14 in 46.3% of patients, and higher than 14 and lower than 24 in 16.2% of patients. According to Child-Turcotte-Pugh classification scores, 56.4% of patients were categorized within Child-Turcotte-Pugh Class A, 38.1% were within Class B, and 5.6% were within Class C. The MELD and Child-Turcotte-Pugh classifications assess the liver disease severity and overall prognosis based on different parameters.

Overall, the majority of patients (60.8% [248/408]) in all treatment groups underwent procedures associated with low bleeding risk (such as gastrointestinal endoscopy and colonoscopy), 17.2% (70/408) of patients underwent procedures associated with moderate bleeding risk (such as liver biopsy and chemoembolization for hepatocellular carcinoma), and 22.1% (90/408) of patients underwent procedures associated with high bleeding risk (such as dental procedures, radiofrequency ablation, and vascular catheterization). The proportions of patients undergoing procedures in each of the bleeding risk categories were similar between the Doptelet and placebo groups.

In ADAPT-1 study, 149 patients were treated with Doptelet and 82 patients received placebo. In ADAPT-2 study, there were 128 patients who received Doptelet and 76 patients who received placebo.

The primary efficacy endpoint in both studies was the proportion of patients who did not require a platelet transfusion or rescue procedure for bleeding after randomization and up to 7 days after a scheduled procedure. Secondary efficacy endpoints included the proportion of patients who achieved platelet counts of greater than or equal to 50 × 10⁹/L on the day of procedure (prior to receiving a platelet transfusion or undergoing the scheduled procedure), and the change from baseline in platelet count to the day of procedure (prior to receiving a platelet transfusion or undergoing the scheduled procedure).

In both studies, the Doptelet treatment groups had statistically significantly greater proportions of responders, i.e., patients who did not require a platelet transfusion or any rescue procedure for bleeding after randomization and up to 7 days after a scheduled procedure than the corresponding placebo treatment groups.

In the low baseline platelet count cohort of ADAPT-1, 66% of Doptelet-treated patients and 23% of placebo-treated patients did not require a platelet transfusion or rescue procedure for bleeding (p<0.0001). Similarly, there were 69% of Doptelet-treated patients and 35% of placebo-treated patients in the low baseline platelet count cohort of ADAPT-2 who did not require a platelet transfusion or rescue procedure for bleeding (p = 0.0006).

In the high platelet count cohort of ADAPT-1, the proportion of responders was 88% in the Doptelet-treated group compared to 38% in the placebo-treated group (p<0.0001). In ADAPT-2, the proportion of responders in the high platelet count cohort was also found to be significantly greater in the Doptelet-treated group compared to the placebo-treated group (88% versus 33%, p<0.0001).

Data for the secondary efficacy points supported the primary efficacy point results in both studies. In the Doptelet-treated groups, there were higher proportions of patients who achieved the target platelet count of greater than or equal to 50 × 10⁹/L on the procedure day compared to the placebo-treated groups. The mean change in platelet counts from baseline to the day of procedure was higher in the Doptelet-treated patients relative to that observed in the placebo-treated patients.

In both studies, the mean platelet count in the Doptelet-treated patients started to increase on Day 4 of the 5-day treatment, peaked on Day 10 to Day 13 (5 to 8 days from the last Doptelet dose), and then started to decrease by 7 days post procedure, returning to baseline values by Day 35.

The positive treatment effect of Doptelet was consistent across all major subgroups evaluated, i.e., those defined by age, sex, race, geographic region, bleeding risk, MELD score, Child-Turcotte-Pugh classes, and etiology of liver disease.

Patients with chronic immune thrombocytopenia

One Phase III, multicentre, randomized, double-blind, placebo-controlled study provided the pivotal evidence of efficacy of Doptelet in adult patients with chronic immune thrombocytopenia who have had an insufficient response to a previous treatment. The study included patients who had previously received one or more therapies for immune thrombocytopenia (including but not limited to corticosteroids, immunoglobulins, azathioprine, danazol, cyclophosphamide, and/or rituximab) and had an average of screening and baseline platelet counts of less than 30 × 10⁹/L. Forty-nine patients were centrally stratified by splenectomy status, baseline platelet count (less than or equal to 15 × 10⁹/L or from greater than 15 × 10⁹/L to less than 30 × 10⁹/L), and use of concomitant medication for immune thrombocytopenia. The patients were randomized in a ratio of 2:1 to receive Doptelet (32 patients) or placebo (17 patients) for 6 months. Doptelet was administered at a starting dose of 20 mg once daily, and the doses were subsequently titrated depending on platelet count (down-titrated to a minimum of 5 mg once daily or up-titrated to a maximum of 40 mg once daily).

The demographic and baseline characteristics were similar between the treatment groups. The median age of the patients was 44 years (range: 18 to 69 years). Sixty-three percent of patients were female, 94% were White, 4% were Asian, and 2% were Black. The median duration of treatment was 26 weeks in the Doptelet group and 6 weeks in the placebo group.

The primary efficacy endpoint of the study was the cumulative number of weeks of platelet response, defined as the cumulative number of weeks with platelet count of greater than or equal to 50 × 10⁹/L during 6 months of treatment in the absence of rescue therapy.

Doptelet-treated patients had a greater cumulative number of weeks with platelet counts greater than or equal to 50 × 10⁹/L in the absence of rescue therapy than those who received placebo (a median duration of 12.4 [range 0 to 25] versus 0 [range 0 to 2] weeks, p<0.0001). Similarly, the proportion of patients who had platelet count of greater than or equal to 50 × 10⁹/L on Day 8, a secondary efficacy endpoint, was larger (p<0.0001) in the Doptelet group (66% [21/32]) compared to the placebo group (0% [0/17]).

Indication

The New Drug Submission for Doptelet was filed by the sponsor with the following proposed indications:

Doptelet (avatrombopag) is indicated for:

• the treatment of thrombocytopenia in adult patients with chronic liver disease who are scheduled to undergo a procedure.

• the treatment of thrombocytopenia in adult patients with chronic immune thrombocytopenia who have had an insufficient response to a previous treatment.

Health Canada revised the indications to include the degree of severity of thrombocytopenia in adult patients with chronic liver disease who are scheduled to undergo an invasive procedure, thereby reflecting the populations studied in the pivotal trials, ADAPT-1 and ADAPT-2. Accordingly, Health Canada approved the following indications:

Doptelet (avatrombopag) is indicated for:

• the treatment of severe thrombocytopenia in adult patients with chronic liver disease who are scheduled to undergo an invasive procedure.

• the treatment of thrombocytopenia in adult patients with chronic immune thrombocytopenia who have had an insufficient response to a previous treatment.

For more information, refer to the Doptelet Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The safety profile of Doptelet was characterized in adult patients with severe thrombocytopenia and chronic liver disease and in adult patients with chronic immune thrombocytopenia.

Patients with severe thrombocytopenia and chronic liver disease

The safety of Doptelet in patients with severe thrombocytopenia and chronic liver disease was evaluated in the pivotal studies ADAPT-1 and ADAPT-2 (described in the Clinical Efficacy section). The population pooled from the two studies included 430 randomized patients who received at least one dose of study drug and had undergone at least one post-dose safety assessment. There were 274 patients in the combined Doptelet group (patients treated with the 40 mg or 60 mg dose) and 156 patients in the combined placebo group across the two baseline platelet count cohorts.

The safety profile of Doptelet was generally comparable to that observed in the placebo group. The frequency, severity, and types of adverse events reported were consistent with those expected in patients with chronic liver disease. There were no unexpected safety signals. Across the pooled data from the two studies, the most common treatment-emergent adverse events (occurring in at least 3% of patients) in the combined Doptelet group versus the combined placebo group were pyrexia (10% versus 9%), abdominal pain (7% versus 6%), nausea (7% versus 7%), headache (6% versus 6%), fatigue (4% versus 3%), and peripheral edema (3% versus 2%).

In the low baseline platelet count cohort, the incidence of serious treatment-emergent adverse events was 7% in the 60 mg Doptelet group compared to 13% in the placebo group. In the high baseline platelet cohort, 8% of patients in the 40 mg Doptelet group experienced serious treatment-emergent adverse events compared to 3% of patients in the placebo group.

The most common serious adverse event in the Doptelet group was hyponatremia. There were two of the 274 Doptelet-treated patients (0.7%) who developed hyponatremia. Thromboembolic events occurred in one of the 274 Doptelet-treated patients (0.4%).

Treatment-emergent adverse events resulting in discontinuation of Doptelet occurred in two patients in the 60 mg Doptelet group. These events included anemia and myalgia reported in one of the two patients (0.4%), and pyrexia reported in the second patient (0.4%). The reported anemia and myalgia were considered treatment-related serious adverse events.

Patients with chronic immune thrombocytopenia

The safety of Doptelet in patients with chronic immune thrombocytopenia was evaluated based on pooled data from two Phase III studies (one randomized, double-blind, placebo-controlled study and one randomized, double-blind, active-controlled study) and two Phase II studies (one randomized, double-blind, placebo-controlled, dose-ranging study and one open-label extension study). The pooled data included 161 patients who received at least one dose of study drug and had a safety assessment. Of the 161 patients, 128 received 2.5 mg to 40 mg of Doptelet once daily for a median duration of exposure of 29 weeks, 22 received placebo, and 11 received eltrombopag.

In the Doptelet treatment group across the pooled safety data from the four studies, the most common treatment-emergent adverse events (occurring in at least 10% of patients and at a higher incidence than in the placebo treatment group) were headache (31% versus 14%), fatigue (28% versus 9%), contusion (26% versus 18%), epistaxis (19% versus 18%), upper respiratory tract infection (15% versus 5%), arthralgia (13% versus 0%), gingival bleeding (13% versus 0%), petechiae (11% versus 9%), and nasopharyngitis (10% versus 0%).

A higher percentage of patients experienced treatment-emergent adverse events leading to discontinuation of study drug in the Doptelet group (13.3% [17/128]) compared to placebo group (0%). The system organ classes (SOCs, as per the Medical Dictionary for Regulatory Activities, MedDRA) with the highest incidence of treatment-emergent adverse events leading to discontinuation of Doptelet were SOC Nervous System Disorders and SOC Investigations (3.9% [5/128] each), followed by SOC Blood and Lymphatic System Disorders and SOC Gastrointestinal Disorders (1.6% [2/128] each).

Serious treatment-emergent adverse events reported in more than one Doptelet-treated patient included thrombocytopenia (6.3% [8/128]), vomiting (3.1% [4/128]), decreased platelet count (2.3% [3/128]), followed by cerebrovascular accident, hemorrhagic gastritis, headache, immune thrombocytopenic purpura, and nausea (1.6% [2/128] each).

Treatment-emergent adverse events of special interest included bleeding events, recurrence of thrombocytopenia, thromboembolic events, neoplastic events, and clinically significant liver test abnormalities. Across the four studies in patients with chronic immune thrombocytopenia, bleeding events were reported in 14% of the Doptelet-treated patients compared to 4.5% of patients in the placebo groups. Recurrence of thrombocytopenia occurred in 9%, thromboembolic events in 7%, and neoplastic events in 5% of Doptelet-treated patients; none of these events was reported in the placebo groups. No treatment-emergent bone marrow pathology or gastric atrophy findings were observed in patients treated with Doptelet. In addition, there was no clinically significant signal of Doptelet-induced hepatotoxicity.

Appropriate warnings and precautions are in place in the approved Doptelet Product Monograph to address the identified safety concerns.

For more information, refer to the Doptelet Product Monograph, approved by Health Canada and available through the Drug Product Database.

Avatrombopag, the medicinal ingredient in Doptelet, is an orally bioavailable, small-molecule thrombopoietin receptor agonist that stimulates proliferation and differentiation of megakaryocytes from bone marrow progenitor cells, thereby leading to an increased production of platelets. Avatrombopag binds to a site of the thrombopoietin receptor different from the thrombopoietin binding site. Consequently, avatrombopag does not compete with thrombopoietin, the physiologic regulator of platelet production, for binding to the thrombopoietin receptor and has an additive effect to the effect of thrombopoietin on platelet production.

The submitted non-clinical data included a comprehensive set of pharmacodynamic, safety pharmacology, pharmacokinetic, and toxicology studies of avatrombopag. Various in vitro assays were used in conjunction with in vivo studies conducted in a wide range of species (mice, rats, dogs, guinea pigs, rabbits, and cynomolgus monkeys).

Avatrombopag was demonstrated to bind and activate the thrombopoietin receptor exclusively in humans and chimpanzees. This species specificity represented a significant limiting factor in the non-clinical program, as the safety pharmacology and toxicology studies could examine solely the off-target effects of avatrombopag.

Study designs and parameters evaluated in the safety pharmacology, pharmacokinetic, and toxicology studies of avatrombopag were consistent with relevant International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use guidelines. The majority of the non-clinical studies were conducted in accordance with good laboratory practice.

The safety pharmacology program, which evaluated the effects of avatrombopag on the cardiovascular, respiratory, and central nervous systems, did not reveal clinically relevant adverse outcomes.

The toxicology studies included single- and repeat-dose toxicity, genotoxicity, carcinogenicity, reproductive and developmental toxicity, local tolerance, antigenicity, phototoxicity, and impurity studies. Safety issues of clinical relevance were identified in the toxicology program. Notably, the mutagenic potential of several impurities in avatrombopag could not be excluded based on the data provided, which prompted a recommendation for the issuance of a Notice of Non-Compliance (NON). Subsequently, all issues of concern were resolved satisfactorily in the sponsor’s response to the NON.

In addition, the toxicology studies revealed deleterious effects of avatrombopag on embryo-fetal and postnatal development in rats and rabbits at doses producing systemic exposures corresponding to 8- to 55-fold the exposure at the maximum recommended human dose. Therefore, the Doptelet Product Monograph was revised to include more details regarding these potential risks and to state that the use of Doptelet is not recommended in pregnant women. Other adverse findings observed in the toxicity and carcinogenicity studies were considered of low relevance to humans.

The results of the non-clinical studies as well as the potential risks to humans have been included in the Doptelet Product Monograph. In view of the intended use of Doptelet, there are no pharmacological or toxicological issues within this submission to preclude authorization of the product.

For more information, refer to the Doptelet Product Monograph, approved by Health Canada and available through the Drug Product Database.

During the review of the initially submitted quality (chemistry and manufacturing) data package for Doptelet, Health Canada identified deficiencies in the sponsor’s risk assessment of the potential for formation and introduction of nitrosamine impurities in the drug product. In addition, Health Canada determined that the risk assessment of potentially mutagenic impurities was incomplete. Consequently, a Notice of Non-Compliance (NON) was issued on May 2, 2022. The review of the sponsor’s response to the NON concluded that all issues of concern were addressed satisfactorily.

Overall, the chemistry and manufacturing information submitted for Doptelet has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes. Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable. Based on the stability data submitted, the proposed shelf life of 60 months is acceptable when the drug product is stored at room temperature (15 ºC to 30 ºC).

Proposed limits of drug-related impurities are considered adequately qualified, i.e., within International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use limits.

All sites involved in production are compliant with good manufacturing practices.

None of the non-medicinal ingredients (excipients, described earlier) found in the drug product is prohibited by the Food and Drug Regulations. The excipient lactose monohydrate is derived from milk obtained from healthy animals under the same conditions as milk collected for human consumption. Satisfactory information has been provided to establish that this excipient does not pose a risk of contamination with transmissible spongiform encephalopathy agents. None of the other excipients present in the drug product is of animal or human origin.