Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2021 Publisher: Instituto Grifols, S.A., Can Guasc, 2 Parets del Vallès, 08150 Barcelona Spain
Pharmacotherapeutic group: Antihemorrhagics, other systemic haemostatics
ATC code: B02BX09
Fostamatinib mediates its activity effectively through its major metabolite, R406, which is a tyrosine kinase inhibitor with demonstrated activity against spleen tyrosine kinase (SYK). R406 inhibits signal transduction of B-cell receptors and Fc-activating receptors, which play a key role in antibody-mediated cellular responses. The fostamatinib metabolite R406 reduces antibody-mediated destruction of platelets.
The efficacy and safety of fostamatinib has been demonstrated in two Phase III, randomised, double-blind, placebo-controlled studies (C788-047 and C788-048) in adult patients with previously treated persistent (3-12 months since diagnosis) or chronic (greater than 12 months since diagnosis) ITP.
A total of 150 patients with persistent or chronic ITP, who had an insufficient response to previous treatment (which included corticosteroids, immunoglobulins, splenectomy, and/or a thrombopoietin receptor agonists) were enrolled in two identical, double-blind, placebo-controlled studies that were conducted in different countries.
For each study, patients were randomised 2:1 to fostamatinib or placebo for 24 weeks; randomisation was stratified with respect to prior splenectomy and severity of thrombocytopenia. Stable concurrent ITP therapy (glucocorticoids [less than 20 mg prednisone equivalent per day], azathioprine, or danazol) was allowed, and rescue therapy was permitted, if needed. All patients initially received study drug at 100 mg twice daily (or matching placebo). Based on platelet count and tolerability, dose escalation to 150 mg twice daily (or matching placebo) was undertaken in 86% of patients at Week 4 or later.
Patients enrolled in the placebo-controlled studies had a median age of 54 years old (range: 20 to 88 years; median age in C788-047 was 57.0 and in C788-048 was 49.5 years), and the majority were female (61%) and were white (93%). Prior ITP treatments were varied (median of 3, range of 1-14), with the most common including corticosteroids (94%), immunoglobulins (53%), and thrombopoietin receptor agonists (TPO-RA) (48%). Most patients had chronic ITP (93%), with a median time since ITP diagnosis of 8.5 years, and 35% had undergone splenectomy. At baseline, the median platelet count was 16,000/µL (with almost half [45%] less than 15,000/µL) and 47% were on stable ITP therapy. Of the 102 patients with ITP who received fostamatinib, 28 (27%) were 65 years of age and older while 11 (11%) were 75 years of age and older.
In Study C788-047, 76 patients were randomised; 51 to the fostamatinib group and 25 to the placebo group. In Study C788-048, 74 patients were randomised; 50 to the fostamatinib group and 24 to the placebo group. The efficacy of fostamatinib was based on the primary endpoint of stable platelet response (at least 50,000/µL on at least 4 of the 6 visits between Weeks 14 to 24). Study outcomes for C788-047 and C788-048 are shown in table 4.
Table 4. Study outcomes from placebo-controlled clinical studies:
| Study Outcomes | Statistical Parameters | Study C788-047 | Study C788-048 | Pooled studies | Refractory population6 | ||||
|---|---|---|---|---|---|---|---|---|---|
| Fosta (N=51) | PBO (N=25) | Fosta (N=50) | PBO (N=24) | Fosta (N=101) | PBO (N=49) | Fosta (N=72) | PBO (N=33) | ||
| Stable platelet response1,2 | n (%) | 8 (16) | 0 (0) | 9 (18) | 1 (4) | 17 (17) | 1 (2) | 10 (14) | 0 (0) |
| CI 95% | (5.7, 25.7) | (0, 0) | (7.4, 28.7) | (0, 12.2) | (9.5, 24.1) | (0, 6.0) | (5.9, 21.9) | (0.0, 0.0) | |
| p-value | p3 = 0.0471 | NS | p3 = 0.0071 | P3 = 0.0287 | |||||
| Eligible for C788-0494 at Week 125 | n (%) | 28 (55) | 22 (88) | 33 (66) | 19 (79) | 61 (60) | 41 (84) | 43 (60) | 29 (88) |
| Completed study (Week 24) | n (%) | 12 (24) | 1 (4) | 13 (26) | 2 (8) | 25 (25) | 3 (6) | 16 (22) | 1 (3) |
1 Includes all patients with platelet counts and excludes patients whose platelet counts were measured following rescue therapy after Week 10.
2 Stable platelet response was prospectively defined as a platelet count of at least 50,000/µL on at least 4 of the 6 visits between Weeks 14 and 24.
3 p-value from Fisher Exact test
4 C788-049: open label extension study
5 Patients who did not respond to treatment after 12 weeks were eligible to enrol in open-label extension study.
6 Refractory patient population defined as the subgroup of patients who had received three or more prior other ITP therapies
Fosta = fostamatinib; PBO = placebo; NS = Did not demonstrate a statistically significant difference between treatment arms
An initial therapeutic response (platelet count ≥50,000/μL) was observed within 6 weeks for most responders (11 of 17 responders) and within 12 weeks for all stable responders.
Among patients who were stable responders, the median platelet count increased to 95,000/µL across post-baseline visits with a maximum of 150,000/µL. Rescue medication was required by 30% and 45% of patients receiving fostamatinib or placebo, respectively.
During the placebo-controlled studies, the incidence of bleeding occurred in 29% and 37% of patients in the fostamatinib and placebo arms, respectively. The incidence of moderate or severe bleeding-related adverse events (AEs) (16.3% vs. 9.9%) and serious adverse events (SAEs) (10.2% vs 5.0%) was about twice as high in the placebo group compared with the fostamatinib group. Only one subject treated with fostamatinib experienced a severe bleeding-related event (contusion), while three subjects treated with placebo experienced severe events (gastrointestinal haemorrhage, menorrhagia and petechiae). In sum, there were trends for reduced bleeding-related AEs with fostamatinib compared to placebo; differences between the groups were not statistically significant.
Platelet count responses for patients treated with TAVLESSE were further analysed as shown in table 5. Results are shown for both the pooled population (from Studies C788-047 and C788-048) and a refractory patient population defined as the subgroup of patients who had received three or more prior other ITP therapies. For all platelet count parameters, the results for the pooled population are comparable to the refractory patient population.
Table 5. Summary of platelet count parameters by subgroup – pooled patient population (C788-047 and C788-048) and refractory patient population:
| Parameters | Pooled Population Fostamatinib N=101 | Refractory Patient Population Fostamatinib N=72 |
|---|---|---|
| Subject With Platelet Response (≥50000/µL) at Week 12, n (%) | ||
| Yes | 23 (22.8%) | 14 (19.4%) |
| No | 78 (77.2%) | 58 (80.6%) |
| Change From Baseline in Platelet Count (/µL) at Week 12 | ||
| Median | 4000 | 3000 |
| Range | (-15000, 220000) | (-5000, 159000) |
| Median Platelet Count (/µL) Over Time | ||
| Median | 22000 | 16750 |
| Range | (1000, 254500) | (1000, 105500) |
The C788-049 trial is an open label extension study. Patients from C788-047 and C788-048 who completed 24 weeks of treatment, or who did not respond to treatment after 12 weeks, were eligible to enrol in this study. Patients remained blinded to their treatment assignment from the previous study (fostamatinib or placebo), so their starting dose in this study was based on their final platelet count.
For the C788-049 trial, 123 patients were enrolled, 44 patients previously randomised to placebo and 79 patients previously randomised to fostamatinib.
In a prospectively defined analysis, the 44 subjects treated with placebo in the prior study were evaluated for stable response for fostamatinib (from the first 24 weeks of the study) with their placebo data as the comparator for this objective measure. Ten of these subjects (22.7%) (including a single subject who was classified as a placebo responder in the prior study) met the criteria for stable response. Thus, the difference in response from fostamatinib compared with placebo was 20.5% (95% CI = 8.5-32.4).
Among the patients who achieved stable response in C788-047, C788-048 and C788-049 trials, 18 subjects maintained the platelet count of at least 50,000/µL for 12 months or longer.
The European Medicines Agency has waived the obligation to submit the results of studies with fostamatinib in all subsets of the paediatric population for the treatment of thrombocytopenia for patients with chronic immune thrombocytopenia (ITP), who have had an insufficient response to a previous treatment (e.g., corticosteroids), (see section 4.2 for information on paediatric use).
Following oral administration, the prodrug fostamatinib is rapidly converted to its active metabolite R406, presumably via enzymes in the gut.
After oral administration of fostamatinib, the mean absolute bioavailability of R406 was 55% with high variability (range 30–85%). The median Tmax of R406 is approximately 1.5 hours (range: 1 to 4 hours). Negligible levels of fostamatinib were found in plasma.
After a single 150 mg oral dose of fostamatinib, mean (± standard deviation [SD]) exposure estimates of R406 are 550 (± 270) ng/mL for Cmax and 7080 (± 2670) ng/mL for AUC. R406 exposure is approximately dose proportional up to 200 mg twice daily (1.3 times the 150 mg dose). R406 accumulates approximately 2- to 3-fold upon twice daily dosing at 100–160 mg (0.67 to 1.06 times the 150 mg dose).
Fostamatinib is highly bound to plasma proteins (98.3% in human plasma) and distributes reversibly into blood cells. The mean (± SD) volume of distribution at steady-state of R406 is 256 (± 92) L.
Fostamatinib is metabolised in the gut by alkaline phosphatase to the major active metabolite, R406. R406 is extensively metabolised, primarily through pathways of CYP450-mediated oxidation (by CYP3A4) and glucuronidation (by UDP glucuronosyltransferase [UGT]1A9). R406 is the predominant moiety in the systemic circulation, and there was minimal exposure to any R406 metabolites.
In humans, the mean (± SD) terminal half-life of R406 is approximately 15 (± 4.3) hours. Approximately 20% of the administered radioactivity was recovered in the urine, primarily in the form of an N-glucuronide of R406. Renal elimination of parent drug was low. The remaining radioactivity (~80%) was recovered in the faeces, mainly represented by 2 major metabolites of R406.
R406 pharmacokinetics is linear and exposure is approximately dose-proportional up to 200 mg twice daily (1.3 times the 150 mg dose). R406 accumulates approximately 2- to 3-fold upon twice daily dosing at 100-160 mg (0.67 to 1.06 times the 150 mg dose).
Administration of fostamatinib with a high-calorie, high-fat meal (deriving approximately 150, 250, and 500–600 calories from protein, carbohydrate, and fat, respectively) increased R406 AUC by 23% and Cmax by 15%, indicating fostamatinib can be administered with or without food.
Population pharmacokinetics analyses indicate fostamatinib is not altered based on age, sex, race/ethnicity.
The pharmacokinetics of fostamatinib is not altered in subjects with renal impairment (creatinine clearance [CLcr] = 30 to <50 mL/min, estimated by Cockcroft Gault equation and end stage renal disease requiring dialysis), or hepatic impairment (Child-Pugh Class A, B and C).
In two fostamatinib 4-week rat studies (with the calcium and sodium salts), chondrodystrophy of the femoral head was observed in some animals in the highest dose groups (that were still juvenile/young during the treatment interval) and was not fully reversible by the end of the recovery period.
In a 1-month study in juvenile rabbits, fostamatinib produced growth plate dysplasia in the proximal femur and femoro-tibial joint and reduced bone marrow cellularity in the femur and sternum at 30 and 60 mg/kg/day. Increased degenerate/necrotic ovarian follicles occurred in females at all fostamatinib dose levels (including 10 mg/kg/day). The changes noted in the growth plates and ovaries are consistent with an anti-angiogenic effect.
Fostamatinib was not carcinogenic in a 2-year study in mice when administered daily by oral gavage at doses up to 500/250 mg/kg/day, and was not carcinogenic in rats when administered by oral gavage at 45 mg/kg/day. Fostamatinib and its major active metabolite (R406) were not mutagenic in an in vitro bacterial reverse mutation (Ames) assay or clastogenic in an in vitro human lymphocyte chromosomal aberration assay or an in vivo mouse bone marrow micronucleus assay.
Studies in animals have shown no adverse effect on male fertility. Given there is no evidence for mutagenic or clastogenic potential, there is no concern for male-mediated birth defects. In a fertility study with oral fostamatinib, all mating (e.g., time to mating, breeding proficiency), sperm assessments (e.g., number and motility), and organ weight (e.g., paired testis weight) parameters in male rats were unaffected by doses as high as 40 mg/kg/day. This dose yields an AUC of R406 approximately 3.8 times that of the MRHD. All mating and fertility parameters in female rats were unaffected by doses as high as 11 mg/kg/day. This dose would yield an AUC of R406 similar to that of the MRHD. A slight decrease in pregnancy rates and an increase in post-implantation loss were seen at 25 mg/kg/day. This dose would yield an AUC of R406 2.6 times that of the MRHD.
In animal reproduction studies, administration of fostamatinib to pregnant rats and rabbits during organogenesis caused adverse developmental outcomes including embryo-foetal mortality (post-implantation loss), alterations to growth (lower foetal weights), and structural abnormalities (variations and malformations) at maternal exposures (AUCs) approximately 0.3 and 10 times the human exposure at the maximum recommended human dose (MRHD) respectively.
A slight decrease in pregnancy rates and an increase in post-implantation loss in female rats was observed. Nonclinical studies have established that the administration of fostamatinib during pregnancy can increase the risk of embryonic loss, retard growth, and promote specific malformations of the kidney (including agenesis) and associated urogenital (e.g. ureter) tissues, as well as variations/malformations in major vessel and skeletal development. These effects are consistent with known targets of fostamatinib, including Syk (target), VEGFR-2 (off target) and Ret-kinase (off target). Based on nonclinical studies, any latent issues with female fertility is not expected after fostamatinib is withdrawn.
In pregnant rats and rabbits, R406 was found to cross the placenta. In general, the maternal plasma R406 concentrations were greater than the foetal plasma R406 concentrations.
In rodents, R406 was detected in maternal milk in concentrations 5- to 10-fold higher than in maternal plasma.
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