Fostamatinib Disodium Hexahydrate: A Novel Treatment for Adult Immune Thrombocytopenia

Immune thrombocytopenia (ITP) is an autoimmune disease associated with substantial heterogeneity and varying outcomes. Significant bleeding, including intracranial hemorrhage, is a persistent risk for patients with ITP, along with cardiovascular disease. ITP has also been associated with decreased patient functionality and quality of life. The primary goal of ITP therapy is to lower the risk of bleeding and associated complications by raising platelet counts to levels that provide adequate hemostasis with minimal treatment-related toxicity. Current first-line treatments include corticosteroids, as well as intravenous and anti-D immunoglobulin. Despite the availability of several second-line options, the need for additional treatment options that can provide a stable, long-term response with few adverse effects is critical and ongoing. Fostamatinib disodium hexahydrate is an oral spleen tyrosine kinase inhibitor that produces a rapid, durable response in patients who have failed one or other treatments. Additionally, fostamatinib is well tolerated, and adverse effects can be actively mitigated through dose reduction, dose interruption, or standard therapeutic approaches.

Am J Manag Care. 2019;25:-S0

In 1951 at the Barnes-Jewish Hospital in St. Louis, Missouri, Dr William J. Harrington injected himself with approximately 1 pint of blood from a woman with a persistently low blood platelet count, in an effort to prove that her symptoms were associated with a factor in her blood that was causing platelet destruction. After experiencing a generalized seizure, Harrington’s platelet count decreased from 250 × 10⁹/L to 10 × 10⁹/L. Further, he experienced gingival, nasal, and rectal bleeding, along with petechiae (tiny bruises). Harrington spent 3 days sleeping upright supported by pillows, to reduce intracerebral pressure and avoid experiencing an intracranial hemorrhage, before making a full recovery. Incredibly, after this ordeal, 7 individuals from his staff volunteered to undergo the same procedure to confirm the physician’s findings.¹

Why is a low platelet count, known as thrombocytopenia, of such medical importance that volunteers were willing to risk their health to uncover its underlying causes? The signs and symptoms of thrombocytopenia vary in scope and severity, ranging from petechiae/bruising and oral cavity blood blisters, through prolonged mucocutaneous bleeding (eg, epistaxis or menorrhagia), to intracranial hemorrhage that can lead to death in severe cases. The risk for bleeding is a constant source of concern for patients, leading to restriction of activities, impaired functionality, and decreased quality of life.² The petechiae and bruising can be visually disturbing, leading to social isolation. Patients with immune thrombocytopenia (ITP) often suffer from depression and fatigue, which can be debilitating.^3,4

Thrombocytopenia can be caused by many different factors. The factor that was transferred to Harrington from his patient’s blood was later discovered to be anti-platelet antibodies.⁵ Autoimmune platelet destruction, or ITP, is one of the most common forms of thrombocytopenia.

ITP is a heterogeneous disease that varies widely with respect to the degree and duration of response to treatment. Both approved and off-label treatment options are available, but there is no reliable method for predicting patient response, rendering the choice of therapy largely empiric and based on individual clinician experience.^6,7 In fact, neither the treatment guidelines from the American Society of Hematology (ASH)⁶ nor an international consensus document⁷ provide prescriptive recommendations regarding hierarchy, priority, or treatment order among second-line or later treatment options after patients have failed first-line corticosteroid therapy.^6,7 The absence of clinical consensus around the treatment sequence is clearly reflected among the fragmented practice patterns observed in the United States.⁸ ITP may last for decades, and there is no single treatment option that universally provides a response or is well tolerated in all patients. Consequently, many clinicians resort to cycling their patients through various agents over time due to lack of efficacy, loss of response, or intolerability.⁷

Fostamatinib is an oral treatment for chronic ITP in adults and is the first treatment to target spleen tyrosine kinase (SYK), which plays a key role in a known pathway of platelet destruction in ITP. Fostamatinib was evaluated in two phase 3, randomized, double-blind, placebo-controlled, 24-week trials, which led to approval of fostamatinib for the treatment of adults with chronic ITP in April 2018 by the FDA.⁹ These studies included patients who had previously had an insufficient response to at least 1 ITP treatment. Patients who responded to fostamatinib showed rapid, durable increases in functional platelet levels that led to improved clinical outcomes such as reduced bleeding events and a reduced need for rescue medication.⁹ Fostamatinib has been shown to have a manageable safety and tolerability profile.^9-11

Disease Overview, Epidemiology, and Burden of Illness

Heterogeneity of Immune Thrombocytopenia

ITP is an autoimmune disease that can arise apparently spontaneously (primary ITP) or develop in response to an underlying condition, such as infection with Helicobacter pylori, hepatitis C, or HIV (secondary ITP).¹² A principle of managing secondary ITP is to focus on treating the underlying condition, as this will usually resolve the thrombocytopenia.¹²

Primary ITP is characterized clinically by a low platelet count (<100 x 10⁹/L) in the absence of other causes or disorders that may be associated with thrombocytopenia, and it is therefore considered a diagnosis of exclusion, with no currently available specific clinical or laboratory parameters.⁶ The ITP International Consensus Report characterizes ITP into 3 distinct phases based on disease duration: newly diagnosed ITP (<3 months following diagnosis); persistent ITP (3-12 months from diagnosis); and chronic ITP (>12 months’ duration).⁷ Patients with chronic ITP account for the majority of the total population with ITP.¹³ Most adults with ITP will progress to chronic ITP, and it has been estimated that only a minority of patients experience a durable remission within 1 year of disease onset.¹⁴

ITP is associated with increased rates of morbidity and mortality; the disease symptoms can range from mild bruising to life-threatening bleeds.¹⁵ Consequently, ITP increases healthcare resource utilization due to emergency treatment, hospital admissions, primary care visits, and specialist visits.^16-18 Treatment decisions cannot be based on platelet levels alone and should take into consideration patient risk factors such as advanced age, activity level, associated comorbidities, and concurrent medications.⁷ This means that treatment must be individualized because a safe platelet threshold for maintaining adequate hemostasis in one patient may not be appropriate for another. In practice, however, 30-50 x 10⁹/L is often used as a general treatment or safety threshold that is applicable to the majority of patients.⁷

Pathophysiology of Immune Thrombocytopenia

The classic understanding of ITP pathophysiology involves platelets being coated by immunoglobulin G (IgG) antiplatelet auto-antibodies. This leads to the clearing of platelets from the bloodstream by macrophages, which are located primarily in the spleen and also in the liver.^13,19 However, there are other mechanisms of platelet destruction, as shown by the treatment failure of splenectomy in 30% to 50% of adult patients with chronic ITP.^7,20,21 Alternative mechanisms include complement-dependent platelet lysis^22,23 and direct T-cell—mediated cytotoxicity of platelets.^24-26 See Figure 1 for a visualization of the pathophysiology of ITP.^27-31

In addition to increased platelet destruction, impaired platelet production may also contribute to the pathogenesis of ITP.³² Auto-antibodies in blood plasma can have inhibitory effects on megakaryocyte production and maturation.^33,34 There may be a subset of patients with chronic ITP with fewer megakaryocytes than healthy controls, who have a lower platelet count because of defects in megakaryocyte production and/or maturation³⁵ (Figure 1).^27-31

The relative importance of these different mechanisms of platelet destruction and impaired production can vary from patient to patient, which may explain both the clinical heterogeneity of the disease³⁶ and the differential responses to various treatments.^20,37

Burden of Chronic ITP

The main concern in patients with ITP is the risk of significant bleeding, such as intracranial hemorrhage,³⁸ which can be fatal.³⁹ The frequency of fatal hemorrhage varies in the literature, with some studies reporting a rate of about 1.6%.⁴⁰ Since few patients experience complete remission, this risk of bleeding can persist for decades.

A systematic literature search in the year 2000 on the natural course of the disease in 1817 patients with ITP found that untreated ITP could be associated with a marked reduction in life expectancy. For example, a 30-year-old patient with ongoing ITP was estimated to have a loss of 20.4 years of life expectancy, while a 70-year-old was estimated to have a loss of 9.4 years.¹⁴ More recent studies show an increase in mortality risk of 22% to 50% in patients hospitalized with ITP.^16,41 ITP is also associated with increased cardiovascular risk, and patients with ITP have a 38% greater likelihood of developing cardiovascular disease (ie, ischemic heart disease, stroke, transient ischemic attack, and heart failure) compared with matched controls.⁴²

ITP can substantially affect patients’ functionality and health-related quality of life (QoL). For example, a fear of bleeding associated with low platelet counts leads to patients limiting their daily activities, including decreased or no participation in outdoor activities and exercise. Patients may also tend to avoid air travel and crowds, in order to limit jostling and resultant bruising, which can be extensive and emotionally damaging. Social stigma associated with bruising, due to suspicions about spousal or parental abuse, means that patients may feel embarrassed and seek social isolation, both of which can lead to depression when the disease is of longer duration.³ Work absenteeism or tardiness due to bleeding episodes (eg, extended nosebleeds, hospitalizations) can also contribute to significant anxiety among individuals with ITP. Fatigue is another significant component of morbidity that is often overlooked, despite being the most commonly reported symptom. Fatigue has a considerable effect on patients’ lives, hindering their ability to carry out normal daily activities.^3,4

Formal measurement of the impact of ITP on patients’ QoL has been performed using general instruments, including the 36-Item Short Form Health Survey, EuroQoL-5D , and a validated disease-specific questionnaire called the ITP Patient Assessment Questionnaire, all of which have shown the significant and broadranging effects of ITP on patients’ lives.^43,44

Epidemiology of Immune Thrombocytopenia

The incidence of ITP in adults is estimated to be 1.6 to 3.9 cases per 100,000/year and increases with age, reaching 4.6 cases per 100,000/year for people over 60 years of age.^45-47 Approximately 9% of patients achieve remission within 1 year of disease onset,⁶ meaning that most patients with newly diagnosed ITP go on to develop chronic ITP. The prevalence of adult ITP increases with age, with estimates ranging from 4 to 20 cases per 100,000 in the United States.^46,48

Current Treatment Options and Unmet Needs

Treatment Goals

The primary goal of ITP therapy is to lower the risk of bleeding and associated complications by raising platelet counts to levels that provide adequate hemostasis with minimal treatment-related toxicity.^6,7,49 Individual treatment targets for platelet counts vary depending on the individual patient and the treatment. However, 30 x 10⁹/L to 50 x 10⁹/L is often used as a target to guide treatment in patients who cannot achieve normal platelet counts.⁷

Treatment Choices

Physicians who treat patients with ITP have a variety of therapeutic options available with guidance on disease management accessible from 2 major clinical guidelines: the Evidence-Based Practice Guideline for ITP published by ASH⁶ in 2011 and an International Consensus Report published by an international working group of experts in 2010.⁷ Both guidelines recommend using corticosteroids as the standard initial therapy for ITP but caution against their long-term use. They suggest intravenous immunoglobulin (IVIg) and intravenous anti-D (IV anti-D) as alternative or complementary first-line treatments.^6,7 However, there is no defined treatment order among second-line therapies, which include rituximab (not FDA-approved for ITP), thrombopoietin receptor agonists (TPO-RAs), and splenectomy.^6,7 These guidelines were written prior to the approval of fostamatinib and are currently being updated.

A key difficulty in the management of ITP is that the durability of response to both first- and second-line therapies is not sustained in a high proportion of patients, and these treatment-refractory patients often go on to receive additional lines of therapy.^8,13

In order to better understand the sequencing of therapies for ITP, we analyzed prescription claims data from a large clearing house (Symphony Health PatientSource^®, Phoenix, AZ), which collects data from pharmacies and providers about insurance claims for prescription payments across the United States.⁸ The ITP prescription claims data for 7 years from 2009 to 2016 were included and represent approximately 40,000 patients with 2,500,000 claims associated with an ITP diagnosis code (Symphony Health, PatientSource^®, 7 years ending November 2016). Figure 2 shows the pattern of medications prescribed for ITP for each line of therapy.⁸ During the first line of therapy for ITP, 93% of patients in the analysis received steroids alone, and other treatments were used by 1% to 2% of patients.⁸ During subsequent lines of therapy, the use of steroids as a monotherapy declined substantially, and the use of other medications or splenectomy increased. Steroids continued to be used in combination with other treatments, and 57% to 73% of patients continued to receive steroids in subsequent lines of therapy. Overall, the sequencing of therapy was highly variable, with an assortment of different treatments being used and discontinued, with little discernible pattern.

While ASH has recommended consideration of splenectomy before TPO-RA agonists, the International Consensus Report does not indicate a preference for second-line treatment options for ITP, leaving the decision in the hands of the medical practitioner. The treatment of ITP continues to evolve with more options available to prevent or delay the use of splenectomy.⁵⁰ One retrospective analysis of treatment options by year demonstrated that in the past decade, there was a trend toward a reduction in the use of splenectomy as second-line treatment, reflecting the availability and efficacy of new ITP therapies as second-line treatment options in the management of ITP.⁵⁰

Corticosteroids

Corticosteroids are the established first-line treatment for most patients with ITP^6-8 and typically include oral prednisone, IV methylprednisolone, or high-dose (40 mg/day) dexamethasone. Corticosteroids have been shown to generate a rapid response in approximately two-thirds of patients.⁵¹

The detrimental effects of corticosteroids often outweigh their benefits if they are used for prolonged periods,⁷ and their efficacy often wanes over time. For example, only 10% to 20% of patients achieve long-term remission after 1 year of treatment with prednisone.⁵¹ For these reasons, guidelines recommend rapidly tapering the dose of corticosteroids after 4 weeks in both responders and nonresponders.⁷

Adverse effects associated with prolonged corticosteroid use include diabetes, osteoporosis, and hypertension.^7,51,52 Moreover, short-term use of corticosteroids in patients with ITP is associated with an increased risk of serious infections.⁵³

Intravenous Immunoglobulin

IVIg may be used as a first-line treatment for patients in whom corticosteroids are contraindicated. Alternatively, IVIg can be used alongside corticosteroids as there appear to be some synergistic effects.⁷ IVIg is also used as a rescue therapy.⁷ The mechanism of action of IVIg is not completely understood and may include inhibition of Fc-receptor—mediated platelet phagocytosis, suppression of antiplatelet antibody production, anti-idiotypic inhibition of antiplatelet antibodies, or accelerated elimination of antiplatelet antibodies.⁵⁴

Response rates with IVIg are similar to those with corticosteroids; however, responses with IVIg are short-lived, with most patients reverting to pretreatment platelet levels after 3 to 4 weeks.⁵¹ IVIg infusions take several hours, and adverse effects may include headaches and, rarely, renal failure and thrombosis.⁷ Therefore, IVIg is typically utilized as an adjunctive therapy in the management of ITP and not as a monotherapy.

Anti-D Immunoglobulin

IV anti-D can be used as a first-line treatment in rhesus(D)-positive, nonsplenectomized patients with ITP.^6,7 IV anti-D can be infused in a shorter time and patients may experience a longer treatment response than with IVIg, with some individuals still responding at 26 months.⁵⁵ Additional tests are required before IV anti-D can be used, including blood group, direct antiglobulin test, and reticulocyte count.⁷

Adverse effects associated with the use of IV anti-D include hemoglobinuria, hemolytic anemia, disseminated intravascular coagulation, and renal failure.⁵⁵

Treatment Choices: Second-Line and Third-Line

Rituximab

Rituximab (Rituxan; Biogen/Genentech) is a monoclonal antibody that targets the CD20 antigen expressed on the surface of B cells. It is used for the treatment of lymphoma at a dose of 100 mg/m² or 375 mg/m² IV weekly for 4 weeks.⁵⁶ Although rituximab has not been approved for the treatment of chronic ITP, it has become an off-label treatment option that uses the same dosing schedule as that used for lymphoma treatment. Rituximab depletes B lymphocytes, which are responsible for antiplatelet antibody production. Overall responses were seen in 40% to 63% of patients,^57-60 although a recent small, randomized controlled trial failed to demonstrate a statistically significant difference in response to rituximab versus placebo in patients treated with concurrent corticosteroids.⁶¹ Fewer than 40% of patients who responded to rituximab maintain a durable response at 1 year.^59,60,62,63

Rituximab causes infusion reactions in approximately 18% of patients with ITP, which can be fatal in a small minority of patients.⁵⁹ Other potentially fatal adverse reactions include severe mucocutaneous reactions, hepatitis B virus reactivation, and progressive multifocal leukoencephalopathy.⁵⁶ Non-fatal adverse effects associated with rituximab for the treatment of ITP include first-infusion fever/chills, rash or scratchiness in the throat, serum sickness, and (very rarely) bronchospasm, retinal artery thrombosis, and infection.⁷

Thrombopoietin Receptor Agonists

TPO-RAs mimic the action of thrombopoietin by stimulating platelet production through binding and activating the TPO receptor.⁶⁴ Two TPO-RAs have been approved by the FDA for use in patients with chronic ITP who have had an insufficient response to a prior treatment: romiplostim (Nplate, Amgen), an Fc-peptide fusion protein administered weekly as a subcutaneous injection,⁶⁵ and eltrombopag (Promacta, Novartis), a small nonpeptide molecule administered orally on a daily basis.⁶⁶

Overall response rates (a single platelet response of 50 x 10⁹/L) at any time during treatment ranged from 79% to 88% for romiplostim and 59% to 79% for eltrombopag.^65-69 Durable response rates ranged from 38% to 61% for romiplostim and 37% to 56% for eltrombopag.^65,66 The mean duration of response was reported to be 30 months with romiplostim and 15 months with eltrombopag.^65-69 Most patients take treatment breaks, and the average duration of continuous therapy (defined as no treatment gap of >30 days) is 108 days with romiplostim and 110 to 131 days with eltrombopag.^70,71 The most common reported adverse events are pain (arthralgia, myalgia, extremity pain, abdominal pain, shoulder pain), dizziness, insomnia, dyspepsia, and paresthesia for romiplostim⁶⁵ and gastrointestinal disturbances (nausea, diarrhea, vomiting), upper respiratory tract infection, urinary tract infection, increased alanine aminotransferase, and myalgia for eltrombopag.⁶⁶

TPO-RAs may cause fluctuations in platelet counts,⁷² and the increased platelet counts could potentially cause thrombotic/thromboembolic complications, particularly portal vein thrombosis.^65,66 Thromboembolic events have been reported in approximately 6% of patients in clinical trials with TPO-RAs^67,68 although frequencies as high as 15% to 26% were reported in some cohorts.⁶⁷ TPO-RAs are also associated with an increased risk of progression of myelodysplastic syndromes to acute myeloid leukemia.^65,66 The eltrombopag prescribing information also has a boxed warning about the risk of severe and potentially life-threatening hepatotoxicity.⁶⁶

Splenectomy

Splenectomy is the surgical removal of the spleen, which is the primary site of platelet destruction and also a site of auto-antibody production. Approximately 80% of patients with ITP respond to splenectomy, and 50% to 70% of patients maintain a long-term response of more than 5 years.^7,21 However, approximately one-third of adult patients will relapse after splenectomy, often within 2 years post surgery, which may be related to the different mechanisms of platelet destruction and impaired platelet production underpinning the disease.^22,25,32

Splenectomy may be associated with surgical complications that require prolonged hospitalization,⁷³ as well as the long-term risks for thrombosis and serious infections, which can be fatal.^74-79 Furthermore, the presence of comorbidities in older patients can contribute to increased surgery-related complications.²¹ The use of splenectomy has decreased over the years, with the emergence of new pharmacological treatments for ITP.⁵⁰

Other Immunosuppressant Therapies

Off-label use of other immunosuppressant agents in patients with chronic ITP (eg, alemtuzumab, azathioprine, cyclophosphamide, cyclosporine, danazol, dapsone, and mycophenolate mofetil) is sometimes considered, particularly as salvage therapy or in addition to second-line agents.⁷ The safety and efficacy of these agents in patients with chronic ITP have not been evaluated in well-designed prospective clinical trials. They have shown some clinical activity in small, uncontrolled studies in ITP, albeit often with a short duration of response and/or less favorable safety profile.^7,80-84 For this reason, the use of these agents, either as monotherapy or in combination therapy, is usually reserved for patients who do not respond to standard-of-care treatments.

Unmet Needs

The heterogeneous nature of ITP means that individual patient responses to therapy vary both in magnitude and in duration. A substantial proportion of patients have disease that either fails to respond to therapy or shows an attenuated response over time. In addition, serious adverse effects may limit the use of some therapies in a proportion of patients. Consequently, many patients cycle through a number of different therapies with no clear guidance on which treatment to use after corticosteroids (Figure 2⁸).^7,51 Rather, clinical judgment about the relative safety risks for each patient, often taking patient preference and expected compliance into consideration, frequently forms the basis of the decision as to which treatment is selected. Thus, a need exists for a treatment that generates a durable response and has manageable and moderate adverse effects.

Cost of Disease

ITP can cause increased healthcare resource utilization from emergency treatment, hospital admissions, primary care visits, and specialist visits.^16-18 Bleeding-related episodes are the most clearly defined cost; the average cost of a bleeding episode was estimated to be $4703 in 2012⁸⁵ and $6022 in 2017.⁸⁶ The average annual costs for bleeding-related episodes alone are $8465 for patients with platelet counts ≥50 × 10⁹/L but rise to $34,473 for patients with platelet counts <50 × 10⁹/L.⁸⁵

In examining the costs associated with ITP overall, patients with the disease have longer average hospital stays (6.02 days for patients with ITP vs 4.7 days for all conditions) than do those with other disorders (according to data from the 2006-2012 time period). Consequently, hospital stays associated with ITP are more costly ($16,594 for patients with ITP vs $11,200 for all conditions).¹⁶ One study estimated that 45% of the costs associated with ITP are attributable to emergency department services, and 46% are related to hospital admissions.¹⁷ Another study showed that patients with ITP have more visits with primary care physicians and specialists; in the month prior to completing the survey, 20% of 1002 patients with ITP had primary care visits compared with 11% of 1031 age- and gender-matched controls, and 28% had specialist visits compared with 11% in controls.¹⁸

Cost of Current Treatment Pathway

The treatment of ITP is limited by the variable durability of treatment response; more than half of all patients experience bleeding-related episodes or require rescue medication.⁸⁷ These bleeding episodes are associated with expensive hospitalizations⁸⁶ and rescue medications such as IVIg, which incur administration costs in addition to the cost of drug acquisition.^88,89

The adverse effects of treatments for ITP are also burdensome. Corticosteroids are associated with multiple adverse effects, including hypertension, bone fractures, metabolic syndrome, and peptic ulcers,⁵² which, in turn, are associated with additional costs.⁹⁰ IVIg and IV anti-D are associated with rare but very costly adverse effects, such as thrombosis and renal failure.^7,55 Rituximab can cause fatal infusion reactions, severe mucocutaneous reactions, and progressive multifocal leukoencephalopathy.⁵⁶ TPO-RAs are associated with progression of myelodysplastic syndromes to acute myeloid leukemia, thrombotic/thromboembolic complications, and, with eltrombopag, hepatotoxicity.^65,66

Fostamatinib for Chronic Immune Thrombocytopenia

Fostamatinib disodium hexahydrate (Tavalisse®, Rigel) is the first-in-class and only oral inhibitor of SYK that is indicated for the treatment of thrombocytopenia in adult patients with chronic ITP who have had an insufficient response to a previous treatment.⁹¹ In ITP, Fcg receptors on macrophages bind to auto-antibodies on platelets, activating a signaling cascade involving SYK that culminates in macrophage-mediated platelet phagocytosis.^29,92 The inhibition of SYK signaling prevents platelet destruction by activated macrophages (Figure 1 ^27-31).^13,29 Fostamatinib is the first treatment to target a specific pathway in the pathophysiology of ITP.

Clinical Benefits

The safety and efficacy of fostamatinib were evaluated in 2 double-blind, randomized, placebo-controlled, phase 3 studies (FIT1 and FIT2; NCT02076399 and NCT02076412, respectively) and an open-label, extension (OLE) study (FIT3; NCT02077192). The FIT1 and FIT2 studies were conducted in 150 adults with chronic ITP over 24 weeks, and the FIT3 study is ongoing.^9,93

These were the first phase 3 studies that included ITP patients with prior exposure to TPO-RAs. All patients had received at least 1 prior treatment: 93% had received corticosteroids, 47% had received TPO-RAs, 34% had received rituximab, and 34% had undergone splenectomy. At baseline, the median duration of disease was 8.5 years, and all patients had at least 3 platelet counts of less than 30 × 10⁹/L including 2 measurements within the preceding 3 months.^9,93

Fostamatinib was administered orally at a starting dose of 100 mg bid that could be increased to 150 mg bid (depending on platelet counts and tolerability) after week 4. By the end of the study period, 88% of patients had been titrated up to 150 mg bid. As an oral treatment, fostamatinib is easy to administer and requires minimal titration, reducing both the expenditure of clinical time and the utilization of healthcare resources.⁹³

Platelet Response

The primary endpoint of stable response was stringently defined as a platelet count of ≥50 x 10⁹/L on at least 4 of 6 visits during weeks 14 through 24. Overall response was defined as a platelet count of ≥50 x 10⁹/L during weeks 1 to 12 and was a post hoc analysis. Combined results from the FIT1 and FIT2 studies showed a stable response rate of 18% with fostamatinib versus 2% with placebo (P = .0003; sensitivity analysis showed 17% versus 2%, P = .007), and an overall response rate of 43% with fostamatinib versus 14% with placebo (P = .0006) (Figure 3).⁹ Median postbaseline platelet counts over 24 weeks were 95 x 10⁹/L in stable responders, 49 x 10⁹/L in overall responders, 14 x 10⁹/L in nonresponders, and 17.5 x 10⁹/L with placebo. Platelet responses to fostamatinib among responders were generally rapid; responders achieved an initial platelet threshold of ≥50 x 10⁹/L at a median of 15 days.⁹ However, some patients had a slower but steady increase in platelet counts that exceeded 50 x 10⁹/L during weeks 2 to 12 or after the initial 12-week treatment period.⁹³ The phase 3 results led to the approval of fostamatinib for the treatment of adults with chronic ITP by the US FDA in April 2018.

Across the phase 3 studies and the open-label extension (OLE) study, 146 patients were treated with fostamatinib, and 64 of 146 (44%) patients achieved an overall response, which included 43 of 101 (43%) patients from the fostamatinib arm and 21 of 44 (48%) patients who were transitioned to fostamatinib from the placebo arm of the phase 3 studies.⁹³ The overall response to fostamatinib was maintained over the course of treatment; median platelet counts remained ≥50 x 10⁹/L at all visits, with a median post-baseline platelet count of 63 x 10⁹/L (Figure 4).⁹³ The majority of overall responders maintained their response for the duration of time on fostamatinib, including those patients who had failed prior therapy with a TPO-RA (Figure 5).⁹³ The median duration of the first overall response to fostamatinib was not reached and is estimated to be greater than 28 months, based on the Kaplan-Meier curve (Figure 6).⁹³

While 17 patients achieved a stable response to fostamatinib in the randomized studies,10 of 44 (23%) placebo patients from the randomized studies achieved a stable response to fostamatinib in the OLE study; thus, the total number of stable responders was 27 of 146 (18%) patients in the fostamatinib exposure population. Fostamatinib stable responders generally had a durable long-term response, and 18 of 27 (67%) patients maintained a stable response for at least 1 year.⁹³ Moreover, an additional 7 stable responders (26%) remained on fostamatinib for more than 1 year because of persistent clinical benefit, despite having 1 or more platelet counts drop below 50 x 10⁹/L, and 5 of these patients regained their response. The other 2 patients with a stable response had not reached 12 months of therapy as of the data cutoff date (April 2017). Overall, 93% of patients who achieved a stable response continued to respond and/or derive clinical benefit after 12 months of treatment, and the median duration of first stable response was not reached and estimated to be greater than 28 months.⁹³

Responses to fostamatinib were observed among patients with long-standing ITP (average time from diagnosis of 8.5 years), who were heavily pre-treated (splenectomy, rituximab, and/or TPO-RAs) and are considered difficult to treat. Lower rates of response have been observed in studies of rituximab and other agents among heavily pretreated patients with a longer ITP duration compared with earlier stage patients.^94,95 Fostamatinib was also effective in 75% of patients with persistent ITP (<12 months).⁹³ Subgroup analyses illustrate overall responses across subgroups categorized by duration of ITP, prior TPO-RA therapy, prior splenectomy, and baseline platelet count (Figure 7), demonstrating that fostamatinib can produce a platelet response among diverse types of patients, including those with and without multiple exposures to prior ITP treatments and those with longer and shorter durations of ITP.⁹

Control of Bleeding and Use of Rescue Medication

Patients who responded to fostamatinib demonstrated good control of hemostasis. Moderate/severe bleeding-related adverse events were seen in 9% of overall responders and 10% of nonresponders on fostamatinib compared with 16% of those on placebo (Table 1).⁹ Bleeding-related serious adverse events did not occur in any overall responders compared with 7% among nonresponders and 10% in placebo-treated patients.⁹ Rescue medication was used by 16% of overall responders and 34% of nonresponders to fostamatinib, compared with 45% of patients receiving placebo (Figure 8).⁹ In stable responders, 17% used rescue medication only in the first week, prior to achieving a response. In contrast, nonresponders and placebo patients used rescue medication throughout the study (up to week 24).⁹ Types of rescue medication included IVIg, corticosteroids, and platelet transfusion, as recommended by clinical guidelines.⁹

Safety

Fostamatinib was generally well tolerated, with 10% of patients discontinuing treatment with fostamatinib compared with 8% receiving placebo in the phase 3 studies.⁹³ The most common adverse events reported with fostamatinib are consistent with known kinase inhibitor class effects,⁹⁶ including gastrointestinal disorders, hypertension, and transaminase elevation (Table 2).⁹ No single “preferred term” adverse event led to discontinuation of more than 1 patient in either treatment group.

Most adverse events were mild to moderate in severity and were manageable with appropriate monitoring and standard therapeutic approaches, including dose reductions or treatment interruptions.⁹³ Overall, 31% of patients receiving fostamatinib compared to 17% receiving placebo had a treatment modification: interruption (18% vs 10%), reduction (9% vs 2%), or withdrawal (10% vs 8%). Serious adverse events were reported in 13% of patients receiving fostamatinib and 21% of patients receiving placebo; severe adverse events were reported in 16% of patients receiving fostamatinib and 15% of patients receiving placebo. In the OLE study, adverse events led to dose interruptions in 23% of patients and discontinuation due to adverse events occurred in 16% of patients including 2 stable responders. No new adverse events were detected with long-term use of fostamatinib in the OLE study.⁹³ The safety profile of fostamatinib in ITP clinical trials is consistent with the overall safety profile observed in 3240 patients with rheumatoid arthritis.^10,11,97

Summary

ITP is a rare disease with significant symptoms that can lead to serious medical complications or death. It is a heterogeneous disease in terms of the clinical symptoms, underlying pathophysiology, and patient responses to treatment, which makes management challenging.

There is no consensus on the optimal treatment strategy for ITP. The therapeutic landscape for second-line treatments is fragmented, with little guidance on which treatments to use or the order in which treatments should be used. Current treatment options have shown unpredictable responses, uncertain durability, poor tolerability, and/or safety concerns. Therefore, the need for additional treatment options that can provide a stable, long-term response with few adverse effects is critical and ongoing.

Fostamatinib disodium hexahydrate is a novel agent that represents a novel class of treatment for ITP and produces a rapid, durable response and efficacy in patients who have experienced failure with a prior treatment. Fostamatinib is well tolerated, and adverse effects can be actively mitigated through dose reduction, interruption, or discontinuation. Fostamatinib is a convenient oral medication that can be taken with or without food and is associated with fewer bleeding events and a reduced need for rescue medication. Patients typically respond in 15 days to fostamatinib and continue responding to treatment for a median duration of response exceeding 28 months.

Acknowledgments

Editorial and medical writing support under the guidance of the authors was provided by James Williams, PhD (Apothecom, UK), and was funded by Rigel in accordance with Good Publication Practice (GPP3) guidelines (Ann Intern Med. 2015;163:461-464).

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