Fostamatinib: First Global Approval
Abstract
Rigel Pharmaceuticals is actively engaged in the development of fostamatinib (marketed as TAVALISSE), a targeted inhibitor of spleen tyrosine kinase (SYK). This drug is being investigated as a potential therapeutic agent for a range of autoimmune and inflammatory conditions, including immune thrombocytopenia (ITP), autoimmune haemolytic anaemia, and IgA nephropathy. The development program for fostamatinib reached a significant milestone following the successful completion of the Phase III FIT clinical trial program, which yielded positive results. Consequently, fostamatinib recently received its initial regulatory approval in the United States. This landmark approval authorizes its use for the treatment of thrombocytopenia (low platelet counts) in adult patients who suffer from chronic ITP and have previously demonstrated an insufficient response to other available treatments. This article aims to provide a concise summary of the key developmental milestones that led to this pivotal first approval of fostamatinib, highlighting its journey from early research to clinical application.
Introduction
Fostamatinib, commercially known as TAVALISSE, is a meticulously engineered small molecule that functions as a spleen tyrosine kinase (SYK) inhibitor. This compound is under active development by Rigel Pharmaceuticals (Rigel) with the strategic aim of providing a novel treatment option for several challenging autoimmune conditions, specifically immune thrombocytopenia (ITP), autoimmune haemolytic anaemia, and IgA nephropathy. Fostamatinib achieved its initial regulatory approval in the United States, specifically for the management of thrombocytopenia in adult patients who have chronic ITP and have previously experienced an inadequate response to other therapeutic interventions. While there was earlier exploration into the drug’s potential in various other indications, including rheumatoid arthritis (RA), chronic lymphocytic leukaemia, diffuse large B cell lymphoma, solid tumors, and T cell lymphoma, development in these areas appears to have been either suspended or discontinued.
Immune thrombocytopenia (ITP) is a distinct bleeding disorder characterized by the autoimmune destruction of platelets. This pathological process begins when anti-platelet IgG antibodies bind to specific surface antigens on platelets, rendering them susceptible to SYK-dependent Fcy receptor (FcyR)-mediated phagocytosis by macrophages. By inhibiting SYK, fostamatinib effectively disrupts this destructive process, leading to an improved platelet count in patients with ITP. The recommended initial dosage of fostamatinib is 100 mg administered twice daily. This dosage can be increased to 150 mg twice daily if the patient’s platelet count has not risen to at least 50 × 10^9/L after one month of treatment.
It is important to note that treatment with fostamatinib may lead to an increase in blood pressure. Therefore, blood pressure should be regularly monitored in all patients receiving fostamatinib therapy. Antihypertensive therapy should be adjusted or initiated as necessary to ensure effective blood pressure control. In instances where blood pressure control cannot be adequately attained, interruption, complete cessation, or downward dosage titration of fostamatinib may be necessary. Furthermore, patients receiving fostamatinib should undergo monthly liver function testing. Treatment should be interrupted or titrated downward in patients who develop signs of hepatotoxicity. Interruption of fostamatinib therapy is also recommended for patients who develop severe (grade ≥ 3) diarrhea or neutropenia (an absolute neutrophil count < 1.0 × 10^9/L for more than 72 hours). This comprehensive safety profile has been meticulously extracted and modified from the AdisInsight database, which systematically tracks drug development worldwide across its entire lifecycle, from initial discovery through pre-clinical and clinical studies to market launch and beyond. Company Agreements In February 2010, Rigel Pharmaceuticals entered into a significant exclusive worldwide license agreement with AstraZeneca. This agreement granted AstraZeneca comprehensive rights for the global development and commercialization of fostamatinib. Under the terms of this partnership, AstraZeneca acquired the rights to fostamatinib for various indications, most notably including rheumatoid arthritis (RA). Furthermore, AstraZeneca assumed full responsibility for all aspects of the drug's development, regulatory filings, manufacturing, and global commercialization efforts. However, in June 2013, AstraZeneca made a strategic decision not to proceed with regulatory filings for fostamatinib, a decision based on the results obtained from the Phase III OSKIRA program in patients with RA. Consequently, AstraZeneca returned all rights pertaining to fostamatinib back to Rigel. Patent Information Fostamatinib, as a chemical composition of matter, is comprehensively covered by multiple United States patents. The latest of these composition of matter patents is set to expire in September 2026. This patent may be eligible for an extension under the patent term extension rules, which can be granted in relation to the time spent conducting clinical trials. Furthermore, numerous additional US patents, with expiry dates ranging between April 2023 and December 2034, cover various aspects of fostamatinib. These include methods of using fostamatinib to treat a variety of indications, specific methods of its manufacture, various formulations, and compositions of matter pertaining to certain intermediates employed in its synthesis. Corresponding patent applications have been diligently filed outside the US under the Patent Cooperation Treaty (PCT), aiming for broad international protection. Moreover, a significant patent specifically covering the drug as a composition of matter and in compositions for use in treating various diseases has been formally granted by the European Patent Office, further solidifying its intellectual property protection. R406, which is recognized as the active metabolite of fostamatinib, is also covered as a composition of matter by a dedicated US patent scheduled to expire in February 2025. Additionally, R406 is protected by two broader composition of matter US patents, set to expire in February 2023 and July 2024, respectively. Corresponding applications for R406 have similarly been filed outside the US under the Patent Cooperation Treaty (PCT), ensuring its international intellectual property safeguarding. Scientific Summary Pharmacodynamics Fostamatinib functions as a prodrug, meaning it is administered in an inactive form and subsequently converted within the body to its pharmacologically active metabolite, R406, a process that primarily occurs in the gut. R406 has demonstrated potent inhibitory activity against spleen tyrosine kinase (SYK) *in vitro*, with an impressive IC50 (half maximal inhibitory concentration) of 41 nM. Mechanistically, R406 exerts its inhibitory effect by binding to the ATP (adenosine triphosphate) binding pocket of the SYK enzyme, thereby competitively inhibiting ATP binding with a Ki (inhibition constant) of 30 nM. This competitive binding mechanism prevents SYK from functioning normally. Critically, R406 exhibited a remarkable selectivity profile, demonstrating 5- to 100-fold greater potency against SYK compared to a panel of over 90 other kinases, highlighting its specificity for its intended target. In further *in vitro* investigations, R406 was confirmed to be a specific inhibitor of SYK-dependent Fcy receptor (FcyR)-mediated signaling. This critical signaling pathway is active in various immune cells, including human mast cells, macrophages, and neutrophils, underscoring R406's immunomodulatory potential. Moreover, R406 effectively blocked B-cell receptor-mediated activation of B lymphocytes, further demonstrating its broad impact on immune cell function. In a preclinical murine model designed to mimic immune thrombocytopenia (ITP), pretreatment with fostamatinib at doses of 25 or 40 mg/kg successfully protected mice against the development of thrombocytopenia after they were injected with an antibody specifically directed against integrin aIIb, a key protein involved in platelet function. Extending this protective effect, the drug also demonstrated efficacy in safeguarding mice from the development of anemia when they were injected with an anti-red cell antibody, further highlighting its potential in autoimmune conditions affecting blood cells. Pharmacokinetics R406, the active metabolite of fostamatinib, exhibits specific pharmacokinetic properties. Its mean estimated maximum concentration (Cmax) is 550 ng/mL, and its mean area under the curve (AUC) is 7080 ng·h/mL. Importantly, exposure to R406 is approximately dose-proportional across a range of fostamatinib doses, up to 200 mg administered twice daily, which is 1.3 times the maximum recommended dose of 150 mg twice daily. After repeated administration of fostamatinib at doses ranging from 100 to 160 mg twice daily, approximately a 2- to 3-fold accumulation of R406 is observed, indicating a predictable steady-state concentration. R406 reaches its median maximum concentration (tmax) at approximately 1.5 hours, and its absolute bioavailability is estimated to be 55%, indicating a good proportion of the administered prodrug is converted and absorbed as the active metabolite. *In vitro* data suggest that R406 is extensively bound to proteins in human plasma, with approximately 98.3% protein binding. R406 has a mean volume of distribution of 256 L, indicating wide distribution throughout the body. Its terminal elimination half-life is approximately 15 hours, suggesting twice-daily dosing is appropriate for maintaining therapeutic concentrations. According to population pharmacokinetic analyses, the pharmacokinetic profile of fostamatinib and R406 is robust and does not appear to be significantly altered by a patient's age, gender, or ethnicity. Furthermore, the presence of renal impairment (defined as an estimated creatinine clearance between 30 and less than 50 mL/min or end-stage renal disease requiring dialysis) or hepatic impairment (classified as Child–Pugh Class A, B, or C) had no clinically relevant effect on exposure to R406 in Phase I clinical studies, indicating that dose adjustments may not be necessary for patients with these conditions. R406 undergoes metabolism primarily through two pathways: CYP450-mediated oxidation, specifically by CYP3A4, and glucuronidation, catalyzed by UDP glucuronosyltransferase 1A9. The active metabolite is predominantly (80%) excreted in faeces. Clinical studies in healthy volunteers have investigated potential drug-drug interactions. Co-administration of a single dose of fostamatinib with the potent CYP3A4 inhibitors ketoconazole (200 mg twice daily for 3.5 days, with an 80 mg fostamatinib dose) or verapamil (80 mg three times daily for 4 days, with a 150 mg fostamatinib dose) resulted in significant increases in R406 exposure by 102% and 39% respectively, compared to fostamatinib administered alone. Conversely, co-administration of a 150 mg single dose of fostamatinib with the CYP3A4 inducer rifampicin (600 mg once daily for 8 days) dramatically decreased R406 exposure by 75%, highlighting the importance of avoiding concomitant use with strong CYP3A4 inducers. Further studies revealed that co-administration of a single 40 mg dose of simvastatin (a CYP3A4 substrate) with fostamatinib 100 mg twice daily significantly increased simvastatin Cmax and AUC (by 212.5% and 164.1% respectively) and simvastatin acid Cmax and AUCt (by 182.8% and 174.2% respectively). Similarly, co-administration of a single 20 mg dose of rosuvastatin (a BCRP substrate) with fostamatinib 100 mg was associated with increases in rosuvastatin Cmax and AUC (by 188.4% and 195.6% respectively). Co-administration of fostamatinib 100 mg twice daily with digoxin (0.25 mg once daily), a P-glycoprotein substrate, in volunteers increased digoxin Cmax and AUC at steady state compared to digoxin alone (geometric mean ratios of 1.7 and 1.37 respectively). Importantly, no significant drug-drug interactions were observed when fostamatinib was co-administered with methotrexate, midazolam, ethinyl estradiol/levonorgestrel, warfarin, pioglitazone, or ranitidine. Therapeutic Trials Persistent/Chronic Immune Thrombocytopenia Phase III: Treatment with fostamatinib demonstrated clinically meaningful responses in patients with immune thrombocytopenia (ITP). This efficacy extended even to patients who had previously failed to respond to various established therapies, including splenectomy, thrombopoietic agents, and/or rituximab therapy, as evidenced in two pivotal phase III double-blind, placebo-controlled trials, FIT1 (NCT02076399) and FIT2 (NCT02076412). The enrolled patient population had a long duration of disease (with a median of 8.5 years), had received a median of 3 (up to 13) prior unique treatments, and presented with a median platelet count of 16,000/µL at baseline, indicative of severe thrombocytopenia. Patients were randomly assigned to receive either oral fostamatinib 100 mg twice daily (n = 101) or placebo (n = 49) for 24 weeks. An option to increase the fostamatinib dosage to 150 mg twice daily after 4 weeks was provided to achieve the desired response, and this dose increase occurred in a high proportion of fostamatinib recipients (89 of 101, or 88%). A significantly higher proportion of fostamatinib recipients (18%) achieved a stable response, defined as platelet counts ≥ 50,000/µL at 4 of 6 clinic visits between weeks 14 and 24, without requiring rescue therapy after week 10, compared to placebo recipients (2%) (p = 0.0003). Furthermore, 43% of fostamatinib recipients achieved an overall response, defined as at least one platelet count ≥ 50,000/µL within the first 12 weeks of treatment without rescue medication in the previous 4 weeks, compared to 14% of placebo recipients (p = 0.0006). The median time to achieve a platelet count of ≥ 50,000/µL was 15 days for overall responders and 15.5 days for stable responders. Phase II: Fostamatinib had previously shown promising efficacy as a treatment for ITP in an open-label phase II pilot study. Sixteen patients, all with platelet counts below 30 × 10^9/L for at least 3 months, received fostamatinib. The drug was initiated at a dose of 75–150 mg twice daily and incrementally increased by 25 mg twice daily biweekly, depending on the patient's response, up to a maximum dose of 175 mg twice daily. Eight patients (50%) achieved a sustained response, defined as a platelet count consistently above 50 × 10^9/L for at least 95% (median) of study visits, at a median fostamatinib dose of 125 mg twice daily. Response was not sustained in an additional four patients, and four patients were classified as non-responders. Warm Antibody Autoimmune Haemolytic Anaemia Phase II: Treatment with fostamatinib was associated with notable improvements in hemoglobin levels in patients diagnosed with warm antibody autoimmune haemolytic anaemia (AIHA). This was demonstrated in the two-stage SOAR phase II trial (NCT02612558). In Stage 1, 19 patients with either primary or secondary AIHA (defined by a hemoglobin level below 10 mg/dL) received fostamatinib 150 mg twice daily for a period of 12 weeks. Among these patients, 9 (53%) achieved a response, defined as an increase from baseline of at least 2 mg/dL to a level of at least 10 mg/dL by week 12. These responders were subsequently enrolled in an extension phase of the study. At the time of the analysis (23 February 2018), the median duration of response was more than 24 weeks, ranging from 0.1 to over 24 weeks. IgA Nephropathy Phase II: The efficacy of fostamatinib as a therapeutic agent for IgA nephropathy was evaluated in the phase II trial known as SIGN (NCT02112838). A total of 76 patients were randomized to receive either fostamatinib at doses of 100 or 150 mg twice daily, or a placebo. The overall mean reduction in proteinuria (quantified as sPCR, spot urine protein-to-creatinine ratio) after 24 weeks was not statistically significant in fostamatinib recipients compared to placebo recipients (reductions of 577 mg/g and 158 mg/g for fostamatinib 100 mg and 150 mg twice daily recipients, respectively, versus 177 mg/g with placebo). However, in a pre-specified subgroup analysis focusing on patients identified as being at an increased risk of disease progression (defined as those with baseline proteinuria exceeding 1 g/day), fostamatinib treatment was associated with a reduction in proteinuria at 24 weeks relative to placebo, although this specific finding did not achieve statistical significance. Adverse Events Adverse events (AEs) that occurred at a rate of 5% or greater in patients participating in the FIT 1 and 2 trials, and at a higher incidence in fostamatinib recipients (n = 102) compared to placebo recipients (n = 48), included: diarrhea (31% of fostamatinib vs. 15% of placebo recipients), hypertension (28% vs. 13%), nausea (19% vs. 8%), dizziness (11% vs. 8%), increased alanine aminotransferase (ALT) levels (11% vs. 0%), increased aspartate aminotransferase (AST) levels (9% vs. 0%), respiratory infection (11% vs. 6%), rash (9% vs. 2%), abdominal pain (6% vs. 2%), fatigue (6% vs. 2%), chest pain (6% vs. 2%), and neutropenia (6% vs. 0%). These data provide a comprehensive overview of the most frequently observed side effects associated with fostamatinib therapy in this patient population. Ongoing Clinical Trials Currently, there are three active clinical trials investigating fostamatinib. One of these is the extension study, FIT3, which builds upon the Phase III FIT1 and 2 trials in patients with persistent or chronic immune thrombocytopenia (NCT02077192). The second ongoing trial is the Phase II SOAR study, enrolling patients with warm antibody autoimmune haemolytic anaemia, actively recruiting participants. The third is the Phase II SIGN trial, which is evaluating fostamatinib in patients with IgA nephropathy. These ongoing trials continue to explore the therapeutic potential of fostamatinib in various autoimmune indications.
Current Status
Fostamatinib achieved its initial global regulatory approval on April 17, 2018, in the United States. This landmark approval authorizes its use for the treatment of thrombocytopenia in adult patients diagnosed with chronic immune thrombocytopenia who have previously demonstrated an insufficient response to other available treatment regimens. This marks a significant milestone in providing a new therapeutic option for a patient population with unmet medical needs.