Summary Basis of Decision for Ayvakyt

Refer to the What steps led to the approval of Ayvakyt? section for more information about the review process for this submission.

Clinical Pharmacology

Avapritinib, the medicinal ingredient in Ayvakyt, is a tyrosine kinase inhibitor that targets KIT D816V, platelet-derived growth factor receptor α (PDGFRA), and PDGFRA D842 mutants as well as multiple KIT exon 11, KIT exon 11/17, and KIT exon 17 mutants with half maximal inhibitory concentrations (IC50) below 28 nM in biochemical assays. The constitutive activation of KIT and PDGFRA receptor tyrosine kinases have been implicated in the pathogenesis of a number of oncology malignancies and rare hematologic diseases. In cellular assays, avapritinib inhibited the autophosphorylation of KIT D816V and PDGFRA D842V with IC50 of 4 nM and 30 nM, respectively, and was less potent against wild-type KIT. Further, avapritinib inhibited the proliferation in KIT mutant cell lines, including a murine mastocytoma cell line and a human mast cell leukemia cell line. Avapritinib also showed growth inhibitory activity in a xenograft model of murine mastocytoma with a KIT exon 17 mutation.

The clinical pharmacology of avapritinib with single and multiple dosing has been studied in healthy subjects and in patients with gastrointestinal stromal tumours (GIST) and advanced systemic mastocytosis (AdvSM).

Conclusions derived from data collected in clinical trials conducted with the use of avapritinib capsules may be considered applicable to the tablet formulation currently proposed for the Canadian market given the comparable exposure (area under the plasma concentration-time curve [AUC] and maximum concentration [C_max]) demonstrated between the two formulations in a bridging study. Dose proportionality of exposure between the 400 mg and 100 mg tablets and for the dose range of 30 g to 400 mg demonstrated in the pharmacokinetic studies shows that the pharmacokinetic results from the studies conducted using the 25 mg and 100 mg strengths can be extrapolated to the other proposed strengths of Ayvakyt which were not used in the pivotal safety and efficacy studies.

Steady state concentrations of avapritinib were reached by Day 15 following once daily dosing at the recommended dose of 200 mg where the geometric mean C_max was 377 ng/mL (percentage of coefficient of variation [CV%]: 62%), the AUC over 24 hours (AUC_0-24) was 6,600 h*ng/mL (CV%: 54%), and the ratio of clearance to bioavailability (CL/F) was 29.7 L/h (CV%: 104% ). The median time to peak concentration (T_max) was 4.03 h and the half life (t_1/2) was 39.4 h. The apparent volume of distribution (Vz/F) of avapritinib of 1,780 L (CV%: 36%) indicates extensive distribution into tissues from plasma.

When avapritinib was taken with a meal, C_max and AUC increased by 59% and 29%, respectively, compared to the fasted state. Therefore, it is recommended that Ayvakyt be taken on an empty stomach. Patients are advised not to eat for at least 2 hours before and at least 1 hour after taking Ayvakyt.

Unchanged avapritinib (49%) and its metabolites, M690 (35%) and M499 (14%), were the major circulating compounds following an oral dose. M499 is pharmacologically active but, compared to avapritinib, its enantiomers are 10.5- and 3.1-fold less potent against KIT D816V in vitro; therefore it is not likely to contribute to efficacy at the recommended dose.

Fecal excretion is the major elimination pathway for avapritinib as 70% of the radioactive dose was recovered in feces and 18% was excreted in urine in a mass balance study.

Following a single 100 mg oral dose of avapritinib, subjects with severe hepatic impairment had a mean 61% increase in AUC from time zero to infinity (AUC_0-inf) for unbound avapritinib, compared to healthy subjects. Based on the population pharmacokinetic analysis, avapritinib exposures were unchanged for patients with mild or moderate hepatic impairment and no dose adjustment is recommended. The starting dose is recommended to be reduced from 200 mg to 100 mg once daily for patients with severe hepatic impairment.

No dose adjustment is recommended for patients with mild or moderate renal impairment as their avapritinib clearance was unchanged based on population pharmacokinetics. Patients with severe renal impairment or end-stage renal disease have not been studied.

The co-administration of a strong cytochrome P450 (CYP) 3A inhibitor with a single 200 mg dose of avapritinib increased avapritinib C_max by 38% and AUC_0-inf by 321%. Physiologically based pharmacokinetic modelling shows an increase of 600% for AUC over the dosing interval (AUC_tau) for a 300 mg once daily dose at steady state, and an increase of 205% when avapritinib is co-administered with a moderate CYP3A inhibitor. The co-administration of avapritinib with strong or moderate CYP3A inhibitors should be avoided. If concomitant use with a moderate CYP3A inhibitor cannot be avoided, the starting dose of avapritinib should be reduced from 200 mg to 50 mg once daily.

The co-administration of a strong CYP3A inducer with a single 400 mg dose of avapritinib decreased avapritinib C_max by 74% and AUC_0-inf by 92%. Physiologically based pharmacokinetic modeling shows a decrease of 62% for AUC_tau for a 300 mg once daily dose at steady state with the concomitant use of a moderate CYP3A inducer. The co-administration of avapritinib with strong or moderate CYP3A inducers should be avoided.

Large mean increases from baseline in the corrected QT (QTc) interval (>20 ms) were not predicted by the exposure-response analysis for the mean steady state C_max (899 ng/mL) in patients with GIST given avapritinib at 300 mg or 400 mg once daily.

Population pharmacokinetic analyses indicate that age, body weight, race, and gender have no clinically meaningful effect on the pharmacokinetics of avapritinib.

Significant exposure-safety relationships were observed for some safety endpoints where increased exposure is predicted to have higher risk of the several adverse events (Grade ≥3 adverse events, cognitive effect, and edema) while significant exposure-efficacy relationships were also observed for some efficacy endpoints (time to response and time to complete remission).

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

Clinical Efficacy

The efficacy of Ayvakyt was evaluated in studies BLU-285-2101 and BLU-285-2202, two multicentre, single-arm clinical studies evaluating the efficacy, safety, and clinical pharmacology of avapritinib in adult patients with AdvSM, including aggressive systemic mastocytosis (ASM), systemic mastocytosis with an associated hematological neoplasm (pSM-AHN), or mast cell leukemia (MCL).

The primary efficacy outcome of studies BLU-285-2101 and BLU-285-2202 was the overall response rate (ORR) based on the modified International Working Group-Myeloproliferative Neoplasms Research and Treatment-European Competence Network on Mastocytosis (mIWG-MRT-ECNM) response criteria determined by the central response assessment committee. The primary efficacy analysis population consisted of 88 patients who had a centrally confirmed diagnosis of AdvSM as per the World Health Organization systemic mastocytosis classification and diagnosis criteria. Thirteen of these patients had ASM, 57 had SM-AHN, and 18 had MCL. In these 88 patients, the median age was 68 years (range: 31 to 88 years), 63% were male, 90% were White, 67% had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1, and 33% had an ECOG performance status of 2 to 3. Additionally, these patients received the recommended 200 mg daily dose of Ayvakyt, were evaluable per the mIWG-MRT-ECNM criteria, and had an adequate follow-up in both studies.

In the primary efficacy analysis population, the ORR was 68.2% (95% confidence interval: 57.4, 77.7), with 4.5% of patients experiencing complete remission, 13.6% experiencing complete remission with partial hematologic recovery, 44.3% experiencing partial remission, and 5.7% experiencing Clinical Improvement. Responses were observed for all disease types, with an ORR of 69.2% for patients with ASM, 73.7% for patients with SM-AHN, and 50% for patients with MCL. The high ORRs indicate that Ayvakyt therapy meaningfully reduced mast cell burden and improved symptoms of systemic mastocytosis-related organ damage.

Sensitivity and subgroup analyses were conducted for the ORR. The results were generally consistent with and supportive of the primary analysis. The changes in mast cell burden measured by bone marrow mast cells, serum tryptase, and KIT D816V mutation allele fraction were also supportive of the primary analysis.

With a median follow-up of 15.4 months, the median duration of response was not estimable. The Kaplan-Meier estimate of the probability of an ongoing response was 97% at 12 months in all responders, and 100%, 95.8%, and 100% in responders with ASM, SM-AHM, and MCL, respectively. This response is considered durable.

Ayvakyt has not been directly compared with other available therapies for AdvSM. The survival and quality-of-life benefits of Ayvakyt have not been established.

Indication

The New Drug Submission for Ayvakyt was filed by the sponsor with the following proposed indication, which Health Canada subsequently approved:

Ayvakyt (avapritinib tablets) is indicated for the treatment of adult patients with advanced systemic mastocytosis (AdvSM). Advanced systemic mastocytosis includes patients with aggressive systemic mastocytosis (ASM), systemic mastocytosis with an associated hematological neoplasm (SM-AHN), and mast cell leukemia (MCL).

Ayvakyt is not recommended for the treatment of patients with platelet counts of less than 50 x 10⁹/L.

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

Clinical Safety

The clinical safety of Ayvakyt was evaluated in studies BLU-285-2101 and BLU-285-2202 (see Clinical Efficacy section above). In these studies, the safety population consisted of 126 patients with AdvSM who were treated with the recommended 200 mg daily dose of Ayvakyt. The median duration of treatment was 41 weeks.

The most common adverse reactions (reported in ≥20% of patients) were peripheral edema, anemia, periorbital edema, thrombocytopenia, diarrhea, and nausea. The most common Grade ≥3 adverse reactions (in ≥5% of patients) were anemia, thrombocytopenia, neutropenia, decreased neutrophil count, and decreased platelet count. The most common serious adverse reactions (in ≥1% of patients) were subdural hematoma, anemia, ascites, pleural effusion, acute kidney injury, gastrointestinal hemorrhage, intra-abdominal hemorrhage, and hemorrhage. Fatal adverse reactions occurred in 2.4% of patients. Adverse events leading to treatment interruption, dose modification, and treatment discontinuation occurred in 66.7%, 72.2%, and 18.3% of patients, respectively.

Cognitive effects were reported in 19% of patients, including cognitive disorders, memory impairment, and confusional state. Intracranial hemorrhage occurred in 3.2% of patients. Severe thrombocytopenia was identified as a primary risk factor for intracranial hemorrhage. Ayvakyt is not recommended for patients with severe thrombocytopenia. Avapritinib was teratogenic and embryotoxic in non-clinical studies and can cause fetal harm when administered to pregnant women.

Overall, the adverse reactions were generally manageable in most patients with close monitoring, dosage modifications, and supportive care. Appropriate warnings and precautions are in place in the approved Ayvakyt Product Monograph to address the identified safety concerns, including a caveat regarding the limitation of use in the Indication section that states avapritinib is not recommended for patients with severe thrombocytopenia.

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

The non-clinical package included key non-clinical findings from proof-of-concept primary pharmacodynamic studies. These studies demonstrated that avapritinib is an inhibitor of disease-relevant KIT and platelet-derived growth factor receptor α (PDGFRA) mutant kinases in the low nanomolar range, as well as having anti-tumour activity in human and murine-derived tumour xenografts. Additionally, various binding assays did not reveal overt off-target effects of avapritinib on a panel of kinases, transporters, and channels. Moreover, the half-maximal inhibitory concentration (IC50) values for most targets were above the estimated unbound avapritinib fraction in patients with advanced systemic mastocytosis (AdvSM) at the recommended dose; as such, these were not considered pharmacologically relevant.

There were no significant avapritinib-related effects on human Ether-à-go-go-related gene (hERG) potassium channels in vitro or on cardiovascular and respiratory parameters using a dog model. These results are consistent with a Phase I clinical study conducted in patients with gastrointestinal stromal tumours (GIST), where there were no clinically relevant effects on QT parameters after the administration of avapritinib.

Non-clinical absorption, distribution, metabolism, and excretion mass balance studies revealed that avapritinib was highly bound to plasma proteins, relatively stable in plasma samples, and crossed the blood-brain barrier in rats. A number of metabolites were identified, mainly through metabolism by cytochrome P450 3A4. Importantly, there were no unique human metabolites. These studies provide a maximum tolerated dose in mice, rats, and dogs, for subsequent toxicology studies. Overall, single-dose administration of avapritinib showed high bioavailability, a half-life of approximately 10 to 18 hours, and elimination mainly through the feces via biliary and active intestinal excretion.

Consistent with International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines, the toxicology development for Ayvakyt consisted of repeat-dose studies in rats and dogs, in vivo and in vitro genotoxicity studies, fertility and embryofetal development studies in rats, and a carcinogenicity study in mice. Most toxicologic effects were mechanism based and were similar between rat and dogs, with some exceptions.

In a 6-month study in rats at doses of 1, 3, and 10 mg/kg/day and a 9-month study in dogs at doses of 0.5, 1, and 5 mg/kg/day, target organs of toxicity included bone marrow (decreased hematopoiesis corresponding to decreased red and white blood cells and reticulocytes parameters), adrenal glands (cystic degeneration and angiectasis or hemorrhage), spleen (extramedullary hematopoiesis and increased pigmented macrophages), lymphoid organs (decreased cellularity), and reproductive organs (hemorrhagic and cystic degeneration of the corpora lutea in the ovary, vaginal mucification and mixed cell inflammation in the prostate in rats, and hypospermatogenesis in the testis in dogs). Effects observed in the spleen, ovary, and testis were only partially reversed following an 8-week recovery period. Most hematology changes and histology findings were observed in rats at doses ≥3 mg/kg/day, corresponding to 1.5 times and 3 times the human area under the concentration-time curve (AUC) at the 200 mg dose in males and females, respectively.

In studies with higher doses of avapritinib, rats manifested convulsions, which was potentially secondary to the inhibition of Nav 1.2 at systemic exposures ≥14 higher than the exposure at the clinical dose of 200 mg. Following the administration of avapritinib for 3 months in dogs, tremors were observed at 30 mg/kg/day, hemorrhage in the brain and spinal cord were observed at ≥15 mg/kg/day, and choroid plexus edema was observed in the brain at ≥7.5 mg/kg/day, corresponding to approximately 3.4 times, 1.8 times, and 1 time the human AUC at the 200 mg dose, respectively. These effects were not observed in the 9-month study at 5 mg/kg/day.

Avapritinib was not mutagenic in vitro, was positive in the in vitro chromosome aberration test in cultured human lymphocytes, and was negative in in vivo rat bone marrow micronucleus and comet tests. Therefore, avapritinib is considered to be overall non-genotoxic. Avapritinib was not carcinogenic in a 6-month transgenic mouse study up to the highest dose evaluated of 20 mg/kg/day (11 times human AUC at the 200 mg dose).

The administration of avapritinib had no direct effects on fertility in rats; however, lower sperm production and testicular weight in rats and hypospermatogenesis in dogs were observed at doses corresponding to 7.5 times and 1.2 times the 200 mg human dose, respectively. Avapritinib caused a dose-dependent increase in pre- and post-implantation loss and a lower number of viable embryos at ≥10 mg/kg/day (approximately 4.5 times the human AUC at the 200 mg dose). Avapritinib was detected in seminal fluid up to 0.5 times the concentration found in human plasma at the 200 mg dose. The administration of avapritinib to pregnant rats resulted in embryotoxic and teratogenic effects. In a dose-dependent manner, the number of viable embryos decreased, fetal body weights decreased, and the incidence of visceral malformations (hydrocephaly, interventricular septal defects, stenotic pulmonary trunk artery) and skeletal malformations (sternoschisis, fused sternebrae, misshapen sternebra) increased at doses of ≥10 mg/kg/day (roughly 6.3 times the human AUC at the 200 mg dose).

In an in vitro phototoxicity study in 3T3 mouse fibroblasts, as well as a phototoxicity study in pigmented rats, avapritinib demonstrated a slight potential for phototoxicity.

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

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

The quality (chemistry and manufacturing) information submitted for Ayvakyt has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper pharmaceutical development and supporting studies were conducted and an adequate control strategy is in place for the commercial processes. Changes to the manufacturing process and formulation (if any) made throughout the pharmaceutical development are considered acceptable upon review. Based on the stability data submitted, the proposed shelf life of 48 months is acceptable when the drug product is stored at room temperature (15 ºC to 30 ºC).

The proposed drug-related impurity limits are considered adequately qualified (e.g., within International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use limits and/or qualified from toxicological studies).

A risk assessment for the potential presence of nitrosamine impurities was conducted according to requirements outlined in Health Canada’s Guidance on Nitrosamine Impurities in Medications. The risks relating to the potential presence of nitrosamine impurities in the drug substance and/or drug product are considered negligible or have been adequately addressed (e.g., with qualified limits and a suitable control strategy.)

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

None of the non-medicinal ingredients (excipients) in the drug product are prohibited for use in drug products by the Food and Drug Regulations.

None of the excipients used in the formulation of Ayvakyt is of human or animal origin.