Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder that occurs when the immune system does not generate adequate platelets and produces antibodies that attack and destroy platelets.1,2 The estimated prevalence of ITP in US adults is 9.5 per 100,000 people, and the incidence of ITP increases with age.3,4 ITP that persists for ≥12 months is considered to be chronic ITP.4 Chronic ITP occurs 2 to 3 times more frequently in women than in men.2
ITP is characterized by abnormally low platelet counts, which can manifest as bleeding under the skin (ie, petechiae, purpura, or larger spots called ecchymoses) and can lead to other bleeding episodes, including epistaxis (nosebleeds) and bleeding of the gums or oral mucosa.1,4 In more severe cases, ITP can lead to gastrointestinal bleeding, genitourinary bleeding, or anemia.1,4 In rare cases, life-threatening intracranial bleeding can occur.1 As the patient’s platelet count drops, the risk for bleeding symptoms increases.4
Overall, hospitalized patients with ITP incur higher costs, have longer inpatient stays, and have greater mortality risks than the general US hospital-discharge population.5 From 2006 to 2012, the number of ITP-related hospitalizations increased by nearly 30%, and the average length of hospital stay was approximately 6 days.5
The diagnosis of ITP is based on excluding other causes of thrombocytopenia, including acute leukemia, aplastic anemia, and the use of certain medications.4 The first-line treatment of ITP includes corticosteroids, anti-RHo(D), intravenous gamma globulin, and immunosuppressant agents.4,6 Patients with severe bleeding may require a platelet transfusion and hospitalization.2
Patients who are intolerant of or whose disease relapses while receiving initial therapy may require a splenectomy.4 The second-line therapies for ITP include the thrombopoietin receptor agonists eltrombopag (Promacta) and romiplostim (Nplate), the spleen tyrosine kinase inhibitor fostamatinib (Tavalisse), and other agents.3,4,6
Avatrombopag a New Oral Treatment for Chronic ITP
On June 27, 2019, avatrombopag (Doptelet; Dova Pharmaceuticals) was approved by the US Food and Drug Administration (FDA) for the treatment of thrombocytopenia in adults with chronic ITP who have had an insufficient response to a previous treatment.7
Avatrombopag was initially approved by the FDA in May 2018 for the treatment of thrombocytopenia in adults with chronic liver disease who are scheduled to undergo a medical or dental procedure, becoming the first drug to receive FDA approval for this indication.8 Avatrombopag, an oral thrombopoietin receptor agonist, was granted a priority review by the FDA for this indication.8
Remarking on the recent expanded indication of avatrombopag for chronic ITP, Caroline Kruse, President and CEO, Platelet Disorder Support Association, a patient advocacy organization for patients with ITP, stated, “ITP patients should work with their clinician to choose a therapy that supports their lifestyle and aims to achieve the best possible result to treat their ITP. That’s why having additional treatment options is so important.”7
Ms Kruse added, “We are thrilled to have a new, oral TPO-RA [thrombopoietin receptor agonist] available for adult patients with ITP. Every new treatment provides more choices and new hope to our community.”7
Mechanism of Action
Avatrombopag is an orally bioavailable, small-molecule thrombopoietin receptor agonist that mimics the action of thrombopoietin and stimulates the proliferation and differentiation of megakaryocytes, thereby increasing the production of circulating platelets.6,9
Dosing and Administration
Avatrombopag is available as a 20-mg tablet administered orally. Avatrombopag should be taken with food.9
For the treatment of chronic ITP, the initial dose of avatrombopag is 20 mg (1 tablet) once daily. The dose or frequency of dosing should be adjusted to maintain a platelet count of ≥50 × 109/L as necessary to reduce the risk for bleeding. The dose of avatrombopag should not exceed 40 mg per day.9 The dosing for chronic liver disease is detailed in the prescribing information for avatrombopag.9
For patients with chronic liver disease, no dosage adjustments are needed.9
Pivotal Clinical Trial for Chronic ITP
The efficacy of avatrombopag for chronic ITP was evaluated in a randomized, double-blind, placebo-controlled, phase 3 clinical trial that included 49 patients (median age, 44 years) with chronic ITP.
The primary efficacy end point was cumulative number of weeks of platelet response (platelet count ≥50 × 109/L) during the 6-month treatment duration in the absence of rescue therapy.6,9 For patients who received treatment with avatrombopag, the median duration of exposure was 26 weeks; for patients who received placebo, the median duration of exposure was 6 weeks.
The median duration of platelet response (≥50 × 109/L) during 6 months of treatment, and without rescue therapy, was 12.4 weeks in the avatrombopag arm versus 0 weeks in the placebo group (Table). Moreover, at day 8, 66% of the patients who received avatrombopag maintained the target platelet count of ≥50 × 109/L compared with 0% of the patients who received placebo (P <.0001).6,9
In patients with chronic ITP, the most common (≥10%) adverse reactions reported in clinical trials with avatrombopag were headache (31%), fatigue (28%), contusion (26%), epistaxis (19%), upper respiratory tract infection (15%), arthralgia (13%), gingival bleeding (13%), petechiae (11%), and nasopharyngitis (10%).9
The discontinuation of avatrombopag as a result of adverse reactions (ie, headache) among patients with chronic ITP was reported in 2 (1.6%) of 128 patients.9
Avatrombopag has no contraindications.9
The concomitant use of avatrombopag with a moderate or a strong dual inhibitor of cytochrome (CY) P2C9 and CYP3A4 increases the exposure of avatrombopag, which may increase the risk for avatrombopag-associated adverse events.9
The concomitant use of avatrombopag with a moderate or a strong dual inducer of CYP2C9 and CYP3A4 decreases the exposure of avatrombopag, which may reduce the drug’s efficacy.9
Use in Specific Populations
Avatrombopag may cause fetal harm when administered to a pregnant woman. The data on avatrombopag in pregnant women are not sufficient to determine any associated risk for adverse developmental outcomes.9
No data are available on the presence of avatrombopag in human milk or its effect on the breastfed child or on milk production. Because of the potential for serious adverse reactions from avatrombopag in a breastfed child, women should not breastfeed during treatment with avatrombopag and for at least 2 weeks after the last dose.9
The clinical studies of avatrombopag did not include enough older patients aged ≥65 years to establish whether they respond to avatrombopag different from younger patients.9
Warnings and Precautions
Thrombopoietin receptor agonists, including avatrombopag, are associated with thrombotic and thromboembolic complications in patients with chronic ITP and chronic liver disease. The patient’s platelet counts should be monitored for thromboembolic events; if a thromboembolic event occurs, treatment should be started immediately.9
When avatrombopag is administered to patients with known risk factors for thromboembolism, including prothrombotic conditions, the potential for increased thrombotic risk should be considered carefully.9
Avatrombopag should not be used in patients with chronic ITP or chronic liver disease for the purpose of normalizing platelet counts; dosing guidelines should be followed to achieve target platelet counts, and patients should be monitored closely for the signs and symptoms of thromboembolic events.9
The recently approved new indication for avatrombopag provides a new oral treatment option that may improve outcomes for appropriate patients with chronic ITP who have not responded to previous treatment. In clinical trials, avatrombopag demonstrated superior efficacy compared with placebo in the median cumulative number of weeks of platelet response (≥50 × 109/L), and the majority of patients who received avatrombopag achieved the target platelet counts at day 8 of treatment. Moreover, avatrombopag was superior to placebo in maintaining the target platelet-count range during the 6-month treatment period.
- National Institutes of Health. Immune thrombocytopenia. Genetics Home Reference. July 16, 2019. https://ghr.nlm.nih.gov/condition/immune-thrombocytopenia. Accessed July 10, 2019.
- National Institutes of Health. Immune thrombocytopenia. www.nhlbi.nih.gov/health-topics/immune-thrombocytopenia. Accessed July 10, 2019.
- Lambert MP, Gernsheimer TB. Clinical updates in adult immune thrombocytopenia. Blood. 2017;129:2829-2835.
- National Organization for Rare Disorders. Immune thrombocytopenia. Updated 2015. https://rarediseases.org/rare-diseases/immune-thrombocytopenia/. Accessed July 10, 2019.
- 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.
- Jurczak W, Chojnowski K, Mayer J, et al. Phase 3 randomised study of avatrombopag, a novel thrombopoietin receptor agonist for the treatment of chronic immune thrombocytopenia. Br J Haematol. 2018;183:479-490.
- Dova Pharmaceuticals. Dova Pharmaceuticals announces FDA approval of supplemental new drug application for Doptelet (avatrombopag) for treatment of chronic immune thrombocytopenia (ITP). June 27, 2019. https://dova.com/wp-content/uploads/2019/06/doptelet-itp-approval-press-release-6-26-19.pdf. Accessed July 3, 2019.
- US Food and Drug Administration. FDA approves new drug for patients with chronic liver disease who have low blood platelets and are undergoing a medical procedure. May 21, 2018. www.fda.gov/news-events/press-announcements/fda-approves-new-drug-patients-chronic-liver-disease-who-have-low-blood-platelets-and-are-undergoing. Accessed July 3, 2019.
- Doptelet (avatrombopag) tablets, for oral use [prescribing information]. Durham, NC: Dova Pharmaceuticals; June 2019.