Mechanism Of Action
Fostamatinib is a tyrosine kinase inhibitor with demonstrated activity against spleen tyrosine kinase (SYK). The major metabolite of fostamatinib, R406, inhibits signal transduction of Fc-activating receptors and B-cell receptor. The fostamatinib metabolite R406 reduces antibody-mediated destruction of platelets.
Mean treatment-related increases of 2.93 mmHg in systolic blood pressure and 3.53 mmHg in diastolic blood pressure over placebo were observed following TAVALISSE doses of 100 mg twice daily for 28 days. About 31% of patients in the TAVALISSE group experienced blood pressures ≥140/90 mmHg compared to 15% of patients in the placebo group. Blood pressure returned to baseline within 1 week following TAVALISSE discontinuation in 58% (11 of 19) of patients in the TAVALISSE group who had
blood pressures ≥140/90 mmHg.
At 2 times the maximum recommended dose, TAVALISSE did not prolong the QT interval to a clinically relevant extent.
TAVALISSE is a prodrug that is converted in the gut to the major active metabolite, R406. Mean (± standard deviation [SD]) exposure estimates of R406 are 550 (± 270) ng/mL for Cmax and 7080 (± 2670) ng•h/mL for AUC. R406 exposure is approximately dose proportional up to 200 mg twice daily (1.3 times the 150 mg dosage). R406 accumulates approximately 2-to 3-fold upon twice daily dosing at 100–160 mg (0.67 to 1.06 times the 150 mg dosage).
After oral administration of TAVALISSE, the absolute bioavailability of R406 was 55%. The median tmax of R406 is approximately 1.5 hours (range: 1 to 4 hours). Negligible levels of fostamatinib were found in plasma.
Effect of Food
Administration of TAVALISSE 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% [see DOSAGE AND ADMINISTRATION].
In in vitro studies, the R406 is 98.3% protein bound in human plasma. The red blood cell to plasma concentration ratio is approximately 2.6. The mean (± SD) volume of distribution at steady-state of R406 is 256 (± 92) L.
The mean (± SD) terminal half-life of R406 is approximately 15 (± 4.3) hours.
TAVALISSE is metabolized in the gut by alkaline phosphatase to the major active metabolite, R406. R406 is extensively metabolized, 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.
Following an oral dose of TAVALISSE, approximately 80% of the R406 metabolite is excreted in feces with approximately 20% excreted in the urine. The major component excreted in urine was R406 Nglucuronide. The major components excreted in feces were R406, O-desmethyl R406 and a metabolite produced by gut bacteria from the O-desmethyl metabolite of R406.
Population pharmacokinetics analyses indicate TAVALISSE is not altered based on age, sex, race/ethnicity. In addition, the pharmacokinetics of TAVALISSE is not altered in patients 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).
Drug Interaction Studies
Clinical Pharmacology Studies
No significant interactions were seen with concomitant use of TAVALISSE with the following drugs: methotrexate (OAT1/3 transporters), midazolam (CYP3A4 substrate), microgynon (ethinyl estradiol and levonorgestrel), warfarin, pioglitazone (CYP2C8 substrate) and ranitidine (H2-antagonist that increases gastric pH).
Effect Of Other Drugs On TAVALISSE
Strong CYP3A4 inhibitor:
Concomitant use of ketoconazole (200 mg twice daily for 3.5 days) with a single dose of 80 mg TAVALISSE (0.53 times the 150 mg dosage) increased R406 AUC by 102% and Cmax by 37%.
Moderate CYP3A4 Inhibitor:
Concomitant use of verapamil (80 mg three times daily for 4 days) with a single dose of 150 mg TAVALISSE increased R406 AUC by 39% and Cmax by 6% .
Concomitant use of rifampicin (600 mg once daily for 8 days) with a single dose of 150 mg TAVALISSE decreased R406 AUC by 75% and Cmax by 59% .
Effect Of TAVALISSE On Other Drugs
Concomitant use of simvastatin (single dose 40 mg) with 100 mg twice daily TAVALISSE increased simvastatin AUC by 64% and Cmax by 113% and simvastatin acid AUC by 64% and Cmax by 83%.
Concomitant use of rosuvastatin (single dose 20 mg) with 100 mg twice daily TAVALISSE increased rosuvastatin AUC by 95% and Cmax by 88%.
Concomitant use of digoxin (0.25 mg once daily) with 100 mg twice daily TAVALISSE increased digoxin AUC by 37% and Cmax by 70% .
In Vitro Studies
TAVALISSE is an inhibitor of the human P-gp efflux transporter in vitro.
CYP3A4 and UGT1A9 are involved in the metabolism of R406. R406 is a substrate of P-gp but not of other major transporters (OAT1/3, OCT2, OATP1B1/3, MRP2, and BCRP). R406 can inhibit CYP3A4 and BCRP, and can induce CYP2C8 activity.
R406 is an inhibitor of UGT1A1. Inhibition of UGT1A1 may result in increased unconjugated bilirubin in the absence of other LFT abnormalities.
TAVALISSE was studied in two placebo-controlled efficacy and safety studies (referred to as FIT-1 [NCT02076399] and FIT-2 [NCT02076412]), and in an open-label extension study referred to as FIT-3 (NCT 02077192).
Randomized, Placebo-Controlled Studies
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 randomized 2:1 to TAVALISSE or placebo for 24 weeks; randomization was stratified with respect to prior splenectomy and severity of thrombocytopenia. Stable concurrent ITP therapy (glucocorticoids [< 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 88% of patients at Week 4 or later. Patients who did not respond to treatment after 12 weeks, as well as patients who completed the 24-week double blind study, were eligible to enroll in open-label extension study (FIT-3).
Patients enrolled in the placebo-controlled studies had a median age of 54 years (range: 20 to 88), and the majority were female (61%) and were White (93%). Prior ITP treatments were varied, 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 8.45 years, and 35% had undergone splenectomy. At baseline, the median platelet count was 16 x 109/L (with almost half %) less than 15 x 109/L) and 47% were on stable ITP therapy.
In Study FIT-1, 76 patients were randomized; 51 to the TAVALISSE group and 25 to the placebo group. In Study FIT-2, 74 patients were randomized; 50 to the TAVALISSE group and 24 to the placebo group. The efficacy of TAVALISSE was based on stable platelet response (at least 50 x109/L on at least 4 of the 6 visits between Weeks 14 to 24). Study outcomes for FIT-1 and FIT-2 are shown in Table 5.
Table 5: Study Outcomes from Placebo-Controlled Clinical Studies
|Stable platelet response1,2
|p3 = 0.03
|Rolled-over into FIT-3 at Week 124
|Completed study (Week 24)
|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 x 109/L on at least 4 of the 6 visits between Weeks 14 and 24
3 p-value from Fisher Exact test
4 Patients who did not respond to treatment after 12 weeks were eligible to enroll in open-label extension study.
NS = Did not demonstrate a stastistically significant difference between treatment arms
In the FIT-1 and FIT-2 studies a total of 47 patients in the TAVALISSE arm had received a prior TPORA treatment; among these patients, 8 patients (17%) achieved a stable response to TAVALISSE. All 8 patients had previously discontinued TPO-RA due to loss of effect. Rescue medication was required by 30% and 45% of patients receiving TAVALISSE or placebo, respectively.
During the placebo-controlled studies, the incidence of bleeding occurred in 29% and 37% of patients in the TAVALISSE and placebo arms, respectively. Moderate, severe and serious bleeding events are described in Table 6. All severe events led to hospitalizations.
Table 6: Incidence of Moderate, Severe and Serious Bleeding-Related Events (Placebo-Controlled Efficacy Population)
||TAVALISSE Total N=101
|Placebo Total N=49
|Incidence of moderate bleeding-related adverse events
|Incidence of severe bleeding-related adverse events
|Incidence of serious bleeding-related adverse events
The FIT-3 trial is an open label extension study. Patients from FIT-1 and FIT-2 who completed 24 weeks of treatment, or who did not respond to treatment any time after 12 weeks, were eligible to enroll in this study. Patients remained blinded to their treatment assignment from the previous study (TAVALISSE or placebo), so their starting dose in this study was based on their final platelet count. Patients designated as responders (defined as achievement of platelet count of at least 50 x 109/L) at the time of roll over continued in the extension study at their current trial dose and regimen. Patients who entered the extension study as non-responders (defined as platelet count less than 50 x 109/L) received TAVALISSE 100 mg twice daily regardless of their dose and regimen in the prior study.
For the FIT-3 trial, 123 patients were enrolled, 44 patients previously randomized to placebo and 79 patients previously randomized to TAVALISSE. Stable response in this study was prospectively defined as no 2 visits, at least 4 weeks apart, with a platelet count less than 50 x 109/L, without an intervening visit with a platelet count of at least 50 x 109/L (unrelated to rescue therapy), within a period of 12 weeks following initial achievement of the target platelet count. Sixty-one of the 123 subjects (50%) have discontinued from the study early.
In a prospectively defined analysis, the 44 subjects treated with placebo in the prior study were evaluated for stable response for TAVALISSE. Ten of these subjects (23%) (including a single subject who was classified as a placebo responder in the prior study) met the criteria for stable response.
Among the subjects who achieved stable response in FIT-1, FIT-2 and FIT-3 trials, 18 subjects maintained the platelet count of at least 50 x 109/L for 12 months or longer.