Tavalisse (Fostamatinib Disodium Hexahydrate) First Spleen Tyrosine Kinase Inhibitor Approved for Chronic Immune Thrombocytopenia

Chronic immune thrombocytopenia (ITP), also referred to as idiopathic thrombocytopenic purpura or immune thrombocytopenic purpura, is an autoimmune disorder that is caused by inadequate platelet production and increased platelet destruction.^1,2 Although information on the epidemiology of ITP is not well-established, ITP may affect approximately 53,000 individuals in the United States. ITP is 2 to 3 times more prevalent in women than in men, and its prevalence increases with age.^1,2

ITP can cause mucosal or skin bleeding, or in more severe cases, gastrointestinal, genitourinary, or intra­cranial bleeding.^1,3 From 2006 to 2012, the number of ITP-related hospitalizations increased steadily by 30%, and the average length of stay was 6 days.⁴ Overall, patients with ITP incurred higher costs, longer hospital stays, and greater mortality risks than the general US hospital-discharge population.⁴

Treatment approaches for ITP may include medications to increase the platelet count, and in some cases, surgical removal of the spleen (splenectomy). Pharmacologic treatments generally include corticosteroids, with or without intravenous immunoglobulin; thrombopoietin receptor agonists; or other immune-suppressing drugs.^3,5 Patients whose ITP does not respond to treatment or who cannot tolerate it may cycle through many treatments.³

Tavalisse, First-in-Class SYK Inhibitor, FDA Approved for Chronic ITP

On April 17, 2018, the US Food and Drug Administration (FDA) approved fostamatinib disodium hexa­hydrate (Tavalisse; Rigel Pharmaceuticals), an oral spleen tyrosine kinase (SYK) inhibitor, for the treatment of adults with chronic ITP who had an insufficient response to previous treatment.^6-8

Fostamatinib disodium hexahydrate is the first SYK inhibitor approved by the FDA for the treatment of patients with chronic ITP.⁷ The FDA approval of fostamatinib disodium hexahydrate was based on data from the FIT clinical trial program.^6-8

“Chronic ITP is challenging to treat because the heterogeneity of the disease makes it difficult to predict how an individual patient will respond to available treatments and not all patients can find a treatment that works well for them,” said James Bussel, MD, Professor Emeritus of Pediatrics, Weill Cornell Medicine. “The FDA approval of fostamatinib arms physicians with a new treatment option, which works via a novel mechanism.”⁷

Mechanism of Action

SYK signaling is a key process in platelet destruction associated with ITP. Fostamatinib disodium hexahydrate is a tyrosine kinase inhibitor that has exhibited activity against SYK. Fostamatinib is a prodrug that is converted in the gut to R406, the major active metabolite of fostamatinib. R406 inhibits signal transduction of Fc-activating receptors and B-cell receptor and reduces the antibody-mediated destruction of platelets.⁸

Dosing and Administration

Fostamatinib disodium hexahydrate is available as 100-mg and 150-mg tablets.⁸

The recommended dose of fostamatinib is 100 mg orally twice daily, with or without food; after 4 weeks, the dose is increased to 150 mg twice daily, if required, to achieve platelet counts of ≥50 × 109/L (as needed) to reduce the risk for bleeding. Adverse reactions should be managed using dose reduction, treatment interruption, or treatment discontinuation. If after 12 weeks of treatment the patient’s platelet count does not increase to a level sufficient to avoid clinically significant bleeding, fostamatinib should be discontinued.⁸

The 3 FIT Clinical Trials

The efficacy and safety of fostamatinib disodium hexahydrate were evaluated in 2 double-blind, placebo-­controlled studies, FIT-1 and FIT-2, and in an open-­label extension study, FIT-3.^3,8

FIT-1 and FIT-2 were identically designed studies that included 150 patients (median age, 54 years) with persistent or chronic ITP who had an insufficient response to previous therapy (corticosteroids, immunoglobulins, splenectomy, and/or a thrombopoietin receptor agonist).^3,8 The majority (93%) of the patients had chronic ITP, with an 8.45-year median duration of disease; 35% had undergone splenectomy.8 Patients were randomized in a 2:1 ratio to fostamatinib or to placebo for 24 weeks and were stratified based on previous splenectomy and the severity of thrombocytopenia. The initial dose of fostamatinib was 100 mg twice daily and was escalated to 150 mg twice daily, based on platelet count and tolerability; 88% of patients received a dose escalation to 150 mg twice daily at week 4 or later.⁸

Overall, a greater proportion of patients who received fostamatinib than those who received placebo achieved a stable platelet response, without rescue at 4 of 6 visits between weeks 14 to 24 (Table 1).3,8 Furthermore, 43% versus 14% of patients, respectively (P = .0006), achieved an overall response, defined as ≥1 platelet counts ≥50 × 109/L within the first 12 weeks of treatment.3 In addition, bleeding was reported in 29% and in 37% of patients in the fostamatinib and placebo groups, respectively; the incidences of moderate, severe, and serious bleeding events are shown in Table 2.⁸

In the open-label FIT-3 extension study, ¹⁰ (23%) patients who were newly exposed to fostamatinib had a stable platelet response.⁸

Of the patients who achieved a stable response in the 3 FIT clinical trials, 18 patients maintained a stable platelet count of at least 50 × 109/L for ≥12 months.⁸

Adverse Events

The most common (≥5% and more than placebo) adverse reactions reported with fostamatinib disodium hexahydrate were diarrhea (31%), hypertension (28%), nausea (19%), respiratory infection (11%), dizziness (11%), increased alanine aminotransferase levels (11%), increased aspartate aminotransferase levels (9%), rash (9%), abdominal pain (6%), fatigue (6%), chest pain (6%), and neutropenia (6%). In the ITP double-blind studies, serious adverse reactions that occurred in 1% of patients were febrile neutropenia, diarrhea, pneumonia, and hypertensive crisis. Severe adverse reactions included dyspnea and hypertension (both 2%); and arthralgia, neutropenia, chest pain, diarrhea, dizziness, nephrolithiasis, pain in extremity, toothache, syncope, and hypoxia (all 1%).⁸

Fostamatinib disodium hexahydrate has no contra­indications.⁸

Drug Interactions

Patients who receive fostamatinib disodium hexahydrate should be monitored for toxicities and may require a dose reduction when given concurrently with a strong cytochrome (CY) P3A4 inhibitor, because concomitant use with strong CYP3A4 inhibitors increases exposure to R406 (its major active metabolite), which may increase the risk for adverse reactions.⁸

The concomitant use of fostamatinib with strong CYP3A4 inducers is not recommended, because strong CYP3A4 inducers reduce exposure to R406.⁸

CYP3A4 substrate drugs, breast cancer resistance protein substrate drugs (eg, rosuvastatin), and P-glycoprotein substrate drugs (eg, digoxin) should be monitored for toxicities and may require dose reduction when used concomitantly with fostamatinib, because this may increase the concentrations of these substrate drugs.⁸

Use in Specific Populations

Lactating women should be advised not to breastfeed during treatment with fostamatinib and for at least 1 month after the last dose, because of the potential for serious adverse reactions in a breastfed child.⁸

No overall differences in the efficacy of fostamatinib were observed between patients aged ≥65 years and younger patients.⁸

Warnings and Precautions

Patients who receive fostamatinib disodium hexahydrate should have their blood pressure monitored every 2 weeks until stable, and then monthly. Hypertension should be managed with standard antihypertensive treatment; if necessary, treatment with fostamatinib should be reduced, interrupted, or discontinued. The absolute neutrophil count should be monitored monthly, and patients should be monitored for infection. If the patient’s neutrophil count drops below 1.0 × 109/L, treatment with fostamatinib should be interrupted, reduced, or discontinued.⁸

Hepatotoxicity can occur with fostamatinib treatment; patients should be monitored with liver function tests monthly during treatment.⁸

Patients who have diarrhea should be managed with supportive measures, and if diarrhea becomes severe, treatment with fostamatinib should be interrupted, reduced, or discontinued.⁸

Fostamatinib can cause fetal harm when administered to a pregnant woman; women of reproductive potential should be advised to use effective contraception during treatment and for at least 1 month after the last dose.⁸

Conclusion

The FDA approval of oral fostamatinib disodium hexahydrate provides a first-in-class treatment option for patients with chronic ITP that did not respond sufficiently to previous treatment. Fostamatinib disodium hexahydrate is the first SYK inhibitor approved by the FDA. In 3 pivotal clinical trials, it was shown to reduce antibody-mediated platelet destruction, demonstrating durable platelet responses in patients with chronic ITP.

References

1. National Institutes of Health. Immune thrombocytopenia. www.nhlbi.nih.gov/health-topics/immune-thrombocytopenia. Accessed December 10, 2018.
2. Feudjo-Tepie MA, Robinson NJ, Bennett D. Prevalence estimates of adult chronic idiopathic thrombocytopenic purpura (ITP) in the United States. Blood. 2007;110:3202.
3. Bussel J, Arnold DM, Grossbard E, et al. Fostamatinib for the treatment of adult persistent and chronic immune thrombocytopenia: results of two phase 3, randomized, placebo-controlled trials. Am J Hematol. 2018;93:921-930.
4. An R, Wang PP. Length of stay, hospitalization cost, and in-hospital mortality in US adult inpatients with immune thrombocytopenic purpura, 2006–2012. Vasc Health Risk Manag. 2017;13:15-21.
5. Mayo Clinic. Idiopathic thrombocytopenic purpura (ITP). August 9, 2017. www.mayoclinic.org/diseases-conditions/idiopathic-thrombocytopenic-purpura/diagnosis-treatment/drc-20352330. Accessed December 10, 2018.
6. US Food and Drug Administration. FDA approves fostamatinib tablets for ITP. April 17, 2018. www.fda.gov/drugs/informationondrugs/approveddrugs/ucm604956.htm. Accessed December 6, 2018.
7. Rigel Pharmaceuticals. Rigel announces FDA approval of Tavalisse (fosta­matinib disodium hexahydrate) for chronic immune thrombocytopenia (ITP) in adult patients. April 17, 2018. www.prnewswire.com/news-releases/rigel-announces-fda-approval-of-tavalisse-fostamatinib-disodium-hexahydrate-for-­chronic-immune-thrombocytopenia-itp-in-adult-patients-300631702.html. Accessed December 11, 2018.
8. Tavalisse (fostamatinib disodium hexahydrate) tablets, for oral use [prescribing information]. South San Francisco, CA: Rigel Pharmaceuticals; April 2018.