Source: European Medicines Agency (EU) Revision Year: 2024 Publisher: Blueprint Medicines (Netherlands) B.V., Gustav Mahlerplein 2, 1082 MA Amsterdam, Netherlands
Pharmacotherapeutic group: antineoplastic agents, protein kinase inhibitor
ATC code: L01EX18
Avapritinib is a Type 1 kinase inhibitor that has demonstrated biochemical in vitro activity on the PDGFRA D842V and KIT D816V mutants associated with resistance to imatinib, sunitinib and regorafenib with half maximal inhibitory concentrations (IC50) of 0.24 nM and 0.27 nM, respectively, and greater potency against clinically relevant KIT exon 11, KIT exon 11/17 and KIT exon 17 mutants than against the KIT wild-type enzyme.
In cellular assays, avapritinib inhibited the autophosphorylation of KIT D816V and PDGFRA D842V with IC50 of 4 nM and 30 nM, respectively. In cellular assays, avapritinib inhibited the proliferation in KIT mutant cell lines, including a murine mastocytoma cell line and a human mast cell leukaemia cell line. Avapritinib also showed growth inhibitory activity in a xenograft model of murine mastocytoma with KIT exon 17 mutation.
The ability of avapritinib to prolong the QT interval was assessed in 27 patients administered avapritinib at doses of 300/400 mg (1.33 times the 300 mg dose recommended for GIST patients, 12 to 16 times the 25 mg dose recommended for ISM patients) once daily in an open-label, single-arm study in patients with GIST. The estimated mean change from baseline in QTcF was 6.55 ms (90% confidence interval [CI]: 1.80 to 11.29) at the observed steady state geometric mean Cmax of 899 ng/mL (12.8-fold higher than the steady state geometric mean Cmax of avapritinib at 25 mg dose once daily in patients with ISM). No effect on heart rate or cardiac conduction (PR, QRS, and RR intervals) was observed.
The efficacy and safety of avapritinib was assessed in a multi-centre, single-arm, open-label clinical study (BLU-285-1101; NAVIGATOR). Patients with a confirmed diagnosis of GIST and an Eastern Clinical Oncology Group (ECOG) performance status (PS) of 0 to 2 (58% and 3% of patients had ECOG status 1 and 2, respectively) were included in the study. A total of 217 patients received a starting dose of either 300 mg or 400 mg once daily.
Efficacy was assessed on the basis of overall response rate (ORR) according to Response Evaluation Criteria In Solid Tumours (RECIST) v1.1 modified for patients with unresectable or metastatic GIST (mRECIST v1.1) and duration of response (DOR), as evaluated by a Blinded Independent Central Review (BICR).
In addition, a total of 239 patients have received treatment with avapritinib at the relevant starting dose in an ongoing open-label, randomised phase 3 study (BLU-285-1303; VOYAGER) in which PFS is the primary endpoint. Ninety six additional patients received avapritinib in this study after disease progression on the regorafenib control treatment (crossover). As of the last data cut-off date, 9th March 2020, the median treatment duration was 8.9 months in patients with GIST harbouring the PDGFRA D842V mutation included in this study, which provides some preliminary comparative safety data.
A total of 38 patients with unresectable or metastatic GIST harbouring the PDGFRA D842V mutation were enrolled and treated with avapritinib at a starting dose of either 300 mg or 400 mg once daily. In the NAVIGATOR study 71% of patients with unresectable or metastatic GIST harbouring the PDGFRA D842V mutation had dose reductions to 200 mg or 100 mg once daily during the course of therapy. Median time to dose reduction was 12 weeks. The GIST patients were required to have unresectable or metastatic disease and have a documented PDGFRA D842V mutation determined by a locally available diagnostic test. At 12 months, 27 patients were still on avapritinib with 22% receiving 300 mg once daily, 37% receiving 200 mg once daily and 41% receiving 100 mg once daily.
Baseline demographics and disease characteristics were median age of 64 years (range: 29 to 90 years), 66% male, 66% white, ECOG PS of 0-2 (61% and 5% of patients had ECOG status 1 and 2, respectively), 97% had metastatic disease, largest target lesion was >5 cm for 58%, 90% had prior surgical resection, and median number of prior lines of tyrosine kinase inhibitors of 1 (range: 0 to 5).
Efficacy results from study BLU-285-1101 (NAVIGATOR) for GIST patients harbouring the PDGFRA D842V mutation are summarised in Table 6. The data represent a median duration of follow-up of 26 months across all patients with PDGFRA D842V mutations who were alive, the median OS had not been reached with 74% of patients alive. The median progression free survival was 24 months. Radiographic tumour reductions were observed in 98% of patients.
Table 6. Efficacy results for PDGFRA D842V-Mutation in GIST patients (NAVIGATOR study):
| Efficacy Parameter | N=38 |
|---|---|
| mRECIST 1.1 ORR1, (%) (95% CI) CR PR | 95 (82.3, 99.4) 13 82 |
| DOR (months), median (CI) | 22.1 (14.1, NE) |
Abbreviations: CI=confidence interval; CR=complete response; DOR=duration of response; mRECIST 1.1=Response Evaluation Criteria In Solid Tumours v1.1 modified for patients with unresectable or metastatic GIST; N=number of patients; NE=not estimable; ORR=overall response rate; PR=partial response
1 ORR is defined as patients who achieved a CR or PR (CR + PR)
In patients with PDGFRA D842V-mutant GIST treated at starting doses of 300 or 400 mg once daily the ORR based on central radiology review by mRECIST v1.1 criteria was 95%.
Based on preliminary results from the ongoing phase 3 study BLU-285-1303 (VOYAGER) in a subset of 13 patients with PDGFRA D842V mutations, partial response was reported in 3 out of 7 patients in the avapritinib group (43% ORR) and none of the 6 patients in the regorafenib group (0% ORR). The median PFS there was not estimable in patients with PDGFRA D842V mutations randomized to avapritinib (95% CI: 9.7, NE) compared to 4.5 months in patients receiving regorafenib (95% CI: 1.7, NE).
The efficacy and safety of avapritinib was assessed in a multi-center, single-arm, open-label Phase 2 study BLU-285-2202 (PATHFINDER). Eligible patients were required to have an ECOG PS of 0 to 3. Patients with high and very high risk AHNs such as AML or high risk MDS, and Philadelphia chromosome-positive malignancies were excluded. Palliative and supportive care medications were allowed. The response-evaluable population according to modified IWG-MRT-ECNM criteria as adjudicated by a central committee includes patients with a diagnosis of AdvSM, who had received at least 1 dose of avapritinib, had at least 2 post-baseline bone marrow assessments and had been on study for at least 24 weeks, or had an end of study visit. The primary efficacy outcome measure was ORR per modified IWG-MRT-ECNM criteria as adjudicated by the central committee. Of 107 patients enrolled in the study, 67 patients had at least one prior systemic therapy and were treated at a starting dose of 200 mg orally once daily.
The assessment of the primary efficacy endpoint was based on a total of 47 AdvSM patients, evaluable according to the modified IWG-MRT-ECNM response criteria, enrolled in the study, who received at least one prior systemic therapy and a starting dose of 200 mg avapritinib once daily with 78.7% of patients having received prior midostaurin, 17.0% prior cladribine, 14.9 % prior interferon alpha, 10.6% prior hydroxycarbamide and 6.4% prior azacytidine. Thirty seven (79%) out of the 47 patients with AdvSM who received at least one prior systemic therapy and a starting dose of 200 mg avapritinib had one or more dose reductions during the course of therapy with a median time to dose reduction of 6 weeks. The study population characteristics were: median age of 69 years (range: 31 to 86 years), 70% male, 92% white, ECOG PS of 0-3 (66% and 34% of patients had an ECOG PS of 0-1 and 2-3, respectively), and 89% had a detectable KIT D816V mutation. Before initiation of avapritinib treatment, the median bone marrow mast cell infiltrate was 70%, the median serum tryptase level was 325 ng/mL, and the median KIT D816V mutant allele fraction (MAF) was 26.2%.
Efficacy results in patients with AdvSM enrolled in the study, who received at least one prior systemic therapy and a starting dose of 200 mg avapritinib once daily, with a median duration of follow-up of 12 months are summarized in Table 7.
Table 7. Efficacy results for patients with advanced systemic mastocytosis who received at least one prior systemic therapy in PATHFINDER:
| Efficacy parameter | Overall | ASM | SM-AHN | MCL |
|---|---|---|---|---|
| ORR1 per modified IWG- MRT-ECNM, n (%) (95% confidence interval) Response per modified IWG- MRT-ECNM category, n (%) CR CRh PR CI | N=47 28 (60) (44.3, 73.6) 1 (2) 4 (9) 19 (40) 4 (9) | N=8 5 (63) (24.5, 91.5) 0 2 (25) 3 (38) 0 | N=29 19 (66) (45.7, 82.1) 1 (3) 2 (7) 13 (45) 3 (10) | N=10 4 (40) (12.2, 73.8) 0 0 3 (30) 1 (10) |
| DOR2 (months), median (95% confidence interval) DOR rate at 12 months, % DOR rate at 24 months, % | N=28 NR (NE, NE) 100.0 85.6 | N=5 NR (NE, NE) 100.0 NE | N=19 NR (NE, NE) 100.0 83.3 | N=4 NR (NE, NE) 100.0 NE |
| Time to response (months), median (min, max) | N=28 1.9 (0.5, 12.2) | N=5 2.3 (1.8, 5.5) | N=19 1.9 (0.5, 5.5) | N=4 3.6 (1.7, 12.2) |
| Time to CR/CRh (months), median (min, max) | N=5 3.7 (1.8, 14.8) | N=2 2.8 (1.8, 3.7) | N=3 5.6 (1.8, 14.8) | N=0 NE |
Abbreviations: CI=clinical improvement; CR=complete remission; CRh=complete remission with partial recovery of peripheral blood counts; DOR=duration of response; NE=not estimable; NR=not reached; ORR=overall response rate; PR=partial remission
1 ORR per modified IWG-MRT-ECNM is defined as patients who achieved a CR, CRh, PR or CI (CR + CRh + PR+CI)
2 Estimated from Kaplan-Meier analysis
Among patients treated with avapritinib at a starting dose of 200 mg once daily following at least one prior systemic therapy, 83.1% of patients had ≥50% decrease of bone marrow mast cells with 58.5% patients having complete elimination of bone marrow mast cell aggregates; 88.1% of patients had ≥50% reduction in serum tryptase with 49.3% reducing serum tryptase <20 ng/mL; 68.7% of patients had a ≥50% decrease in KIT D816V MAF in blood and 60.0% of patients had ≥35% spleen volume reduction from baseline.
In a supportive multi-center, single-arm, open-label Phase 1 study BLU-285-2101 (EXPLORER), the ORR according to the mIWG-MRT-ECNM criteria was 73% (95% confidence interval: 39.0, 94.0) for 11 AdvSM patients who received at least one prior systemic therapy and a starting dose of 200 mg avapritinib once daily.
The efficacy and safety of avapritinib was assessed in study BLU-285-2203 (PIONEER), a randomised, double-blind, placebo-controlled, 3-part study conducted in adult patients with ISM with moderate-to-severe symptoms not adequately controlled by best supportive care. In Part 2 (pivotal part), patients were randomised to receive avapritinib at the recommended dose of 25 mg orally once daily with best supportive care (141 patients) versus placebo with best supportive care (71 patients). The randomized portion of the study consisted of a 24-week period. Part 3 of study BLU-285-2203 is ongoing.
The primary endpoint in Part 2 was mean change from baseline to Week 24 in total symptom score (TSS) as measured by the ISM Symptom Assessment Form (ISM-SAF). The ISM-SAF is a patient-reported outcome tool made up of a 12-item questionnaire developed specifically to assess symptoms in patients with ISM. Patient-reported severity scores for 11 ISM symptoms (bone pain, abdominal pain, nausea, spots, itching, flushing, fatigue, dizziness, brain fog, headache, diarrhoea; 0=none; 10=worst imaginable) are summed to calculate the TSS (range 0-110), with higher scores representing greater symptom burden. The 12th item of the questionnaire assesses the number of diarrhoea episodes.
For the purpose of the study, enrolled patients needed a total symptom score (TSS) of 28 or greater at screening. Patients were required to have failed to achieve adequate symptom control for 1 or more baseline symptoms with at least 2 symptomatic therapies, including but not limited to: H1 antihistamines, H2 antihistamines, proton pump inhibitors, leukotriene inhibitors, cromolyn sodium, corticosteroids, or omalizumab.
Additional patient-reported key secondary efficacy endpoints were the proportion of avapritinib- treated patients achieving ≥50% and ≥30% reduction from baseline through Week 24 in TSS compared to placebo. Objective measures of mast cell burden were also reported as key secondary efficacy endpoints and included the proportion of patients with a ≥50% reduction from baseline through Week 24 in serum tryptase, peripheral blood KIT D816V allele fraction and in bone marrow mast cells.
The study population characteristics were: median age of 51 years (range: 18 to 79 years), 73% were female, 80% were white, and 94% had a KIT D816V mutation. At baseline, the mean TSS was 50.93 (range: 12.1 to 104.4), the median serum tryptase level was 39.20 ng/mL (range: 3.6 to 501.6 ng/mL), the median KIT D816V mutant allele fraction was 0.32% by digital-droplet polymerase chain reaction (ddPCR) and the median bone marrow mast cell infiltrate was 7%.
The majority of patients (99.5%) received concomitant best supportive care at baseline (median of 3 therapies). The most common therapies were H1 antihistamines (98.1%), H2 antihistamines (66%), leukotriene inhibitors (34.9%) and cromolyn sodium (32.1%).
Avapritinib treatment demonstrated statistically significant improvements for all primary and key secondary efficacy endpoints compared to placebo, as summarized in Table 8.
Table 8. Reduction in ISM-SAF TSS and measures of mast cell burden in patients with indolent systemic mastocytosis in PIONEER at Week 24:
| Efficacy Parameter | AYVAKYT (25 mg once daily) + BSC N=141 | Placebo + BSC N=71 | One-sided p-value |
|---|---|---|---|
| ISM-SAF TSS | |||
| Mean change in TSS | |||
| Change from baseline (95% CI) | -15.58 (-18.61, -12.55) | -9.15 (-13.12, -5.18) | 0.003 |
| Difference from placebo (95% CI) | -6.43* (-10.90, -1.96) | ||
| % of patients achieving ≥50% reduction in TSS (95% CI) | 25 (17.9, 32.8) | 10 (4.1, 19.3) | 0.005 |
| % of patients achieving ≥30% reduction in TSS (95% CI) | 45 (37.0, 54.0) | 30 (19.3, 41.6) | 0.009 |
| Measures of mast cell burden | |||
| % of patients with a ≥50% reduction in serum tryptase (95% CI) | N=141 54 (45.3, 62.3) | N=71 0 (0.0, 5.1) | <0.0001 |
| % of patients with a ≥50% reduction in peripheral blood KIT D816V allele fraction or undetectable (95% CI) | N=118 68 (58.6, 76.1) | N=63 6 (1.8, 15.5) | <0.0001 |
| % of patients with a ≥50% reduction in bone marrow mast cells or no aggregates (95% CI) | N=106 53 (42.9, 62.6) | N=57 23 (12.7, 35.8) | <0.0001 |
Abbreviations: BSC=best supportive care, CI=confidence interval, ISM-SAF=indolent systemic mastocytosis symptom assessment form, TSS=total symptom score
* Reduction in TSS is a result of a mean decrease in all individual symptoms that make up the ISM-SAF.
The long-term efficacy of avapritinib is assessed in an open-label extension of PIONEER in patients receiving 25 mg of avapritinib (Part 3). Overall, 201 patients rolled over from Part 2 into Part 3 of PIONEER. Avapritinib-treated patients from Part 2 continued to report improvements in TSS over time out to approximately 48 weeks (Part 3 C7D1) of treatment with a mean change from baseline in TSS of -18.05 points (95% CI -21.55, -14.56). Placebo-treated patients from Part 2 who received avapritinib in Part 3 reported substantial additional reductions in their TSS scores within the first 24 weeks of treatment (Part 3 C7D1) with a total mean change from baseline in TSS of -19.71 points (95% CI -24.32, -15.11), which included a further 10.78 point reduction from Part 3 baseline just prior to rolling over to avapritinib.
Forty-two percent of the patients who received AYVAKYT at a starting dose of 300 mg and 400 mg once daily in NAVIGATOR were 65 years or older. No overall differences in efficacy were observed in comparison with younger patients. Only limited data are available from the use of avapritinib in patients aged 75 years or older (8% (3 out of 38)).
Of the 47 patients who received AYVAKYT at a starting dose of 200 mg and who received at least one prior systemic therapy in PATHFINDER, 64% were 65 years or older, while 21% were 75 years and older. No overall differences in efficacy were observed between patients ≥65 years and those <65 years.
Of the 141 patients with ISM who received AYVAKYT in Part 2 (pivotal part) of PIONEER, 9 (6%) patients were 65 years or older, while 1 (<1%) patient was 75 years and older. No patients over the age of 84 were included. Overall, no meaningful differences in efficacy were observed between patients ≥65 years and those <65 years.
The European Medicines Agency has deferred the obligation to submit the results of studies with AYVAKYT in one or more subsets of the paediatric population with a relapsed/refractory solid tumour harbouring mutations in either KIT or PDGFRA (see section 4.2 for information on paediatric use).
The European Medicines Agency has waived the obligation to submit the results of studies with AYVAKYT in all subsets of the paediatric population with mastocytosis (see section 4.2 for information on paediatric use).
This medicinal product has been authorised under a so-called 'conditional approval' scheme.
This means that further evidence on this medicinal product is awaited.
The European Medicines Agency will review new information on this medicinal product at least every year and this SmPC will be updated as necessary.
Following administration of avapritinib once daily, steady state was reached by 15 days.
After a single dose and repeat dosing of avapritinib, systemic exposure of avapritinib was dose- proportional over the dose range of 30 to 400 mg once daily in patients with unresectable or metastatic GIST. The steady state geometric mean (CV%) maximum concentration (Cmax) and area under the concentration-time curve (AUC0-tau) of avapritinib at 300 mg once daily was 813 ng/mL (52%) and 15400 h•ng/mL (48%), respectively. The geometric mean accumulation ratio after repeat dosing was 3.1 to 4.6.
Steady-state Cmax and AUC of avapritinib increased proportionally over the dose range of 30 mg to 400 mg once daily in patients with AdvSM. The steady state geometric mean (CV%) Cmax and AUC0-24 of avapritinib at 200 mg once daily was 377 ng/mL (62%) and 6600 h•ng/mL (54%), respectively. The geometric mean accumulation ratio after repeat dosing (30-400 mg) was 2.6 to 5.8.
The Cmax and AUC of avapritinib increased proportionally over the dose range of 25 mg to 100 mg once daily in patients with ISM. The steady state geometric mean (CV%) Cmax and AUC0-24 of avapritinib at 25 mg once daily was 70.2 ng/mL (47.8%) and 1330 h•ng/mL (49.5%), respectively. The geometric mean accumulation ratio after repeat dosing was 3.59.
Following administration of single oral doses of avapritinib of 25 to 400 mg, the median time to peak concentration (Tmax) ranged from 2 to 4 hours postdose. The absolute bioavailability has not been determined. The population estimated mean oral bioavailability of avapritinib in patients with GIST and AdvSM is 16% and 47% lower, respectively, compared to that in patients with ISM.
Avapritinib Cmax and AUCinf were increased by 59% and 29%, respectively, in healthy subjects administered avapritinib after a high fat meal (approximately 909 calories, 58 grams carbohydrate, 56 grams fat and 43 grams protein) compared to the Cmax and AUCinf after overnight fasting.
Avapritinib is 98.8% bound to human plasma proteins in vitro and the binding is not concentration-dependent. The blood-to-plasma ratio is 0.95. Population estimated apparent central volume of distribution of avapritinib (Vc/F) is 971 L at median lean body weight of 54 kg. The inter-individual variability of Vc/F is 50.1%.
In vitro studies demonstrated that oxidative metabolism of avapritinib is predominantly mediated by CYP3A4, CYP3A5 and to a minor extent by CYP2C9. The relative contributions of CYP2C9 and CYP3A to the in vitro metabolism of avapritinib were 15.1% and 84.9%, respectively. The formation of the glucuronide M690 is catalysed mainly by UGT1A3.
Following a single dose of approximately 310 mg (~100 μCi) [14C]avapritinib to healthy subjects, oxidation, glucuronidation, oxidative deamination and N-dealkylation were the primary metabolic pathways. Unchanged avapritinib (49%) and metabolites, M690 (hydroxy glucuronide; 35%) and M499 (oxidative deamination; 14%) were the major circulating radioactive components. Following oral administration of avapritinib 300 mg once daily in patients, the steady state AUC of the constitutive enantiomers of M499, BLU111207 and BLU111208 are approximately 35% and 42% of the AUC of avapritinib. At a dose of 25 mg once daily, the metabolite to parent ratio for BLU111207 and BLU111208 was 10.3% and 17.5% respectively. Compared to avapritinib (IC50 = 4 nM), the enantiomers BLU111207 (IC50 = 41.8 nM) and BLU111208 (IC50 = 12.4 nM) are 10.5- and 3.1-fold less potent, respectively, against KIT D816V in vitro.
In vitro studies demonstrated that avapritinib is a direct inhibitor of CYP3A4 and a time-dependent inhibitor of CYP3A4, at clinically relevant concentrations (see section 4.5). In vitro, avapritinib did not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6 at clinically relevant concentrations.
In vitro, at clinically relevant concentrations, avapritinib induced CYP3A (see section 4.5). In vitro, avapritinib did not induce CYP1A2 or CYP2B6 at clinically relevant concentrations.
Following single doses of AYVAKYT in patients with GIST, AdvSM and ISM, the mean plasma elimination half-life of avapritinib was 32 to 57 hours, 20 to 39 hours and 38 to 45 hours, respectively.
Population estimated mean apparent clearance (CL/F) of avapritinib is 16.9 L/h. In AdvSM patients, time-dependent CL/F on Day 9 was reduced to 39.4% compared to GIST and ISM patients. The inter-individual variability in CL/F is 44.4%.
Following a single oral dose of approximately 310 mg (~100 μCi) [14C]avapritinib to healthy subjects, 70% of the radioactive dose was recovered in faeces and 18% excreted in urine. Unchanged avapritinib accounted for 11% and 0.23% of the administered radioactive dose excreted in faeces and urine, respectively.
In vitro, avapritinib is not a substrate of P-gp, BCRP, OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, MATE1, MATE2-K and BSEP at clinically relevant concentrations.
Avapritinib is an inhibitor of P-gp, BCRP, MATE1, MATE2-K, and BSEP in vitro (see section 4.5). In vitro, avapritinib did not inhibit OATP1B1, OATP1B3, OAT1, OAT3, OCT1, or OCT2 at clinically relevant concentrations.
No clinical drug-drug interaction studies have been conducted. Based on both population and noncompartmental pharmacokinetic analyses, the effect of gastric acid reducing agents on the bioavailability of avapritinib is not clinically relevant.
Population pharmacokinetic analyses indicate that age (18-90 years), body weight (40-156 kg), sex and albumin concentration have no effect on the exposure of avapritinib. Concomitant use of proton pump inhibitors (PPI) on bioavailability (F) and lean body weight on the apparent central volume of distribution (Vc/F) were identified as statistically significant covariates with impact on avapritinib exposure. Lean body weight (30 kg to 80 kg) showed modest impact on Cmax at steady state (+/- 5%), while concomitant use of PPIs led to ~19% reduction in AUC and Cmax. These minor effects on exposure are not clinically significant given the PK variability (>40% CV) and are not expected to impact efficacy or safety. No significant effect of race on the pharmacokinetics of avapritinib was found, although the low number of Black (N=27) and Asian (N=26) subjects limits the conclusions that can be derived based on race.
As hepatic elimination is a major route of excretion for avapritinib, hepatic impairment may result in increased plasma avapritinib concentrations. Based on a population pharmacokinetic analysis, avapritinib exposures were similar between 72 subjects with mild hepatic impairment (total bilirubin within upper limit of normal [ULN] and AST > ULN or total bilirubin >1 to 1.5 times ULN and any AST), 13 subjects with moderate hepatic impairment (total bilirubin >1.5 to 3.0 times ULN and any AST), and 402 subjects with normal hepatic function (total bilirubin and AST within ULN). In a clinical study investigating the effect of severe hepatic impairment on the pharmacokinetics of avapritinib following administration of a single oral dose of 100 mg avapritinib, the mean unbound AUC was 61% higher in subjects with severe hepatic impairment (Child-Pugh Class C) as compared to matched healthy subjects with normal hepatic function. A lower starting dose is recommended in patients with severe hepatic impairment (see section 4.2).
Based on a population pharmacokinetic analysis, avapritinib exposures were similar among 136 subjects with mild renal impairment (CLcr 60-89 mL/min), 52 subjects with moderate renal impairment (CLcr 30-59 mL/min) and 298 subjects with normal renal function (CLcr ≥90 mL/min), suggesting that no dose adjustment is necessary in patients with mild to moderate renal impairment. The pharmacokinetics of avapritinib in patients with severe renal impairment (CLcr 15-29 mL/min) or end-stage renal disease (CLcr <15 mL/min) has not been studied.
Haemorrhage in the brain and spinal cord occurred in dogs at doses greater than or equal to 15 mg/kg/day (approximately 9.0, 1.8 and 0.8 times the human exposure based on AUC at 25 mg, 200 mg and 300 mg dose once daily, respectively) and choroid plexus oedema in the brain occurred in dogs at doses greater than or equal to 7.5 mg/kg/day (approximately 4.7, 1.0 and 0.4 times the human exposure based on AUC at the clinical dose of 25 mg, 200 mg and 300 mg once daily, respectively). Rats manifested convulsions, which was potentially secondary to inhibition of Nav 1.2 at systemic exposures ≥96, 12 and ≥8-fold higher than the exposure in patients at the clinical dose of 25 mg, 200 mg and 300 mg once daily.
In a 6 month repeat dose toxicology study in rats, rats manifested haemorrhagic and cystic degeneration of the ovarian corpus lutea and vaginal mucification at dose levels greater or equal to 3 mg/kg/day with exposure margins of 15, 3 and 1.3 times the human exposure based on AUC at 25 mg, 200 mg and 300 mg, respectively. In a 9 month repeat dose toxicology study in dogs, hypospermatogenesis (¾ males) was observed at the highest dose tested, 5 mg/kg/day (5.7, 1.2 and <1 times the human exposure (AUC) at 25 mg, 200 mg and 300 mg dose, respectively).
Avapritinib was not mutagenic in vitro in the bacterial reverse mutation assay (Ames test). It was positive in the in vitro chromosome aberration test in cultured human peripheral blood lymphocytes but negative in the rats for both the bone marrow micronucleus test and for the chromosomal damage liver comet assays, and thus, overall non-genotoxic. The carcinogenic potential of avapritinib was evaluated in a 6 month transgenic mouse study where higher incidences of lower thymic cortical cellularity were noted at 10 and 20 mg/kg/day doses. A long-term carcinogenicity study with avapritinib is ongoing.
A dedicated combined male and female fertility and early embryonic development study was conducted in rats at oral avapritinib doses of 3, 10, and 30 mg/kg/day for males, and 3, 10, and 20 mg/kg/day for females. No direct effects on male or female fertility were noted at the highest dose levels tested in this study (100.8 and 62.6 times the human exposure (AUC) at 25 mg, 20.3 and 9.5 times the human exposure (AUC) at 200 mg and 8.7 and 4.1 times the human exposure (AUC) at 300 mg).
Avapritinib partitioned into seminal fluids up to 0.1 times the concentration found in human plasma at 25 mg. There was an increase in pre-implantation loss and in early resorptions with exposure margins of 15, 3 and 1.3 times the human exposure (AUC) at the clinical doses of 25 mg, 200 mg and 300 mg, respectively. Reduction in sperm production and relative testicular weight were observed in male rats administered avapritinib at exposures of 7 and 30 times, 1 and 5 times, and 0.6 and 3 times the 25 mg, 200 mg, and 300 mg human doses, respectively.
In an embryo-foetal development toxicity study in rats, avapritinib showed embryotoxic and teratogenic effects (decreases in foetal weights and viability, and increases in visceral and skeletal malformations). Oral administration of avapritinib during the period of organogenesis was teratogenic and embryotoxic in rats at exposures approximately 31.4, 6.3 and 2.7 times the human exposure (AUC) at the 25 mg, 200 mg, and 300 mg dose, respectively.
An in vitro phototoxicity study in 3T3 mouse fibroblasts as well as a phototoxicity study in pigmented rats demonstrated that avapritinib has a slight potential for phototoxicity.
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