Highlights
- Avatrombopag achieved a durable platelet response in 28% of pediatric patients with persistent or chronic immune thrombocytopenia (ITP), compared to 0% with placebo.
- 81% of avatrombopag-treated patients showed at least two consecutive platelet responses versus none in the placebo group.
- The safety profile was reassuring, with no deaths, thromboembolic events, or severe bleeding episodes.
- Avatrombopag offers a convenient oral option with flexible administration and no dietary restrictions for children and adolescents with ITP.
Study Background and Disease Burden
Immune thrombocytopenia (ITP) is an acquired, immune-mediated disorder characterized by reduced platelet counts and increased bleeding risk. In children, ITP may present acutely, but a significant subset develops persistent (≥3 months) or chronic (≥12 months) disease, often requiring repeated or long-term therapy. Traditional treatment modalities—including corticosteroids, intravenous immunoglobulin (IVIg), and splenectomy—are associated with variable efficacy and notable adverse effects. With the advent of thrombopoietin receptor agonists (TPO-RAs), targeting the underlying deficit in platelet production, management has shifted towards safer, more targeted therapies. However, until recently, oral TPO-RAs with proven efficacy and safety profiles in the pediatric population have been limited, representing a significant unmet medical need.
Study Design
The AVA-PED-301 study (ClinicalTrials.gov: NCT04516967) was a global, multicenter, randomized, double-blind, placebo-controlled, phase 3b trial designed to evaluate avatrombopag—a second-generation oral TPO-RA—in children and adolescents aged 1 to less than 18 years with primary ITP of at least 6 months’ duration and insufficient response to prior therapy. Patients were randomized in a 3:1 ratio to receive avatrombopag (20 mg oral tablet daily for ages ≥6 years; 10 mg oral suspension daily for ages 1 to <6 years) or matching placebo, with dose titration to maintain platelet counts between 50 and 150 × 109/L. The core phase spanned 12 weeks, with efficacy analysis based on the full analysis set and safety evaluated in all treated patients.
The primary efficacy endpoint was a durable platelet response, defined as achieving at least six out of eight weekly platelet counts ≥50 × 109/L during the last 8 weeks of the 12-week treatment period, in the absence of rescue therapy. A key alternative endpoint was the proportion of patients achieving at least two consecutive platelet assessments ≥50 × 109/L, also without rescue therapy.
Key Findings
A total of 75 patients were randomized (54 to avatrombopag, 21 to placebo), with balanced demographic characteristics across groups. The majority were White, and nearly half of the avatrombopag group were female.
Durable Platelet Response: 28% (15/54) of avatrombopag recipients achieved the primary endpoint versus 0% (0/21) in the placebo group (difference 28%, 95% CI 16-40; p=0.0077). This demonstrates a clinically and statistically significant benefit of avatrombopag over placebo in achieving sustained platelet elevation.
Alternative Platelet Response: 81% (44/54) of patients on avatrombopag achieved at least two consecutive platelet responses compared to 0% in the placebo group (difference 81%, 95% CI 71-92; p<0.0001), highlighting the rapid and robust response profile of the drug.
Safety: The most frequently reported adverse events (AEs) included petechiae (n=20), epistaxis (n=16), and headache (n=14), consistent with the underlying disease. Serious adverse events occurred in 5 (9%) avatrombopag-treated patients versus 1 (5%) in the placebo group. Importantly, there were no deaths, thromboembolic events, or grade 3 or higher bleeding events, and no new safety signals were identified. The tolerability profile supports avatrombopag’s use in pediatric patients, with adverse events generally mild to moderate and manageable.
Pharmacokinetics/Pharmacodynamics: While detailed pharmacokinetic and pharmacodynamic data were not elaborated in the summary, the dosing regimen and response rates suggest effective and predictable drug exposure across the pediatric age spectrum.
Expert Commentary
The AVA-PED-301 trial provides high-level evidence supporting avatrombopag as an effective option for children and adolescents with ITP unresponsive to standard therapy. The oral administration, lack of dietary restrictions, and favorable safety profile address important practical and clinical barriers associated with other TPO-RAs, such as eltrombopag’s interactions with food and need for fasting, or romiplostim’s injectable route.
Guidelines from the American Society of Hematology and international pediatric hematology societies have increasingly endorsed TPO-RAs for chronic ITP in children, but choice of agent has often been influenced by safety, route, and patient preference. The findings from AVA-PED-301 are likely to shift practice towards avatrombopag, especially for patients and families favoring oral therapy with fewer administration constraints.
Study limitations include modest sample size and relatively short duration of controlled observation, which may not capture rare or long-term adverse events. The majority White cohort also raises questions about generalizability to more diverse populations. Nonetheless, the trial’s rigorous design and clear separation between groups lend weight to its conclusions.
Mechanistically, avatrombopag’s selective agonism of the TPO receptor on megakaryocytes enhances platelet production without the hepatotoxicity concerns seen with some other agents, further supporting its favorable risk-benefit profile in pediatrics.
Conclusion
The AVA-PED-301 phase 3b study establishes avatrombopag as a safe, effective, and convenient oral TPO-RA for children and adolescents with persistent or chronic ITP who have failed previous therapies. Its durable platelet response, rapid onset, and manageable safety profile make it a promising addition to the therapeutic arsenal for pediatric ITP. Longer-term follow-up and real-world studies will be important to confirm durability of effect, safety, and optimal positioning within treatment algorithms.
References
1. Grace RF, Leblebisatan G, Aydinok Y, Ünal Ş, Grainger JD, Zhang J, Smallwood L, de León E, Jamieson BD; AVA-PED-301 Study Group. Avatrombopag for the treatment of children and adolescents with immune thrombocytopenia (AVA-PED-301): a multicentre, randomised, double-blind, placebo-controlled, phase 3b study. Lancet Haematol. 2025 Jul;12(7):e494-e504. doi: 10.1016/S2352-3026(25)00107-3.
2. Neunert C, Terrell DR, Arnold DM, et al. American Society of Hematology 2019 guidelines for immune thrombocytopenia. Blood Adv. 2019;3(23):3829-3866.
