Analysis of Durability of Response to Avatrombopag (AVA) from a Phase 3b Multicenter, Randomized, Double-Blind, Placebo (PBO)-Controlled, Parallel-Group Trial to Evaluate the Efficacy and Safety of AVA for the Treatment of Pediatric Patients with Immune Thrombocytopenia
Authors: Grace Rachael F. , Leblebisatan Goksel , Aydinok Yesim , Unal Sule , Grainger John D. , Zhang Jessica , Jamieson Brian , Kolodny Scott 
Published: December 2024

Background: After failure of first-line therapies (e.g. corticosteroids or immunoglobulin) in pediatric immune thrombocytopenia (ITP), treatment options for children include immunosuppressants and thrombopoietin receptor agonists (TPO-RAs).
The oral TPO-RA AVA could be a desirable option for pediatric patients as it does not require an injection in a physician's office and can be taken with meals and does not carry food-type or timing restrictions.
Top-line results of the Phase 3b, multicenter, randomized, double-blind, placebo-controlled, parallel-group trial to evaluate the efficacy and safety of AVA for the treatment of pediatric patients with immune thrombocytopenia were recently reported (Grace R, et al HemaSphere, 2024;8:(S1):469-470). The primary efficacy endpoint of this study was the durable platelet response measured by the proportion of patients achieving at least 6 out of 8 weekly platelet counts ≥50 × 109/L during the last 8 weeks of the 12-week core-phase treatment period in the absence of rescue therapy. Results were 27.8% for AVA versus 0% for PBO (p=0.0077) in a population where 20/75 (26.7%) had failed to respond to a previous TPO-RA.
The aim of the current analyses is to expand the evaluation of platelet response durability with AVA treatment in pediatric ITP as well as to evaluate the durability of the clinically meaningful response (CMR).
Methods: The Phase 3b, multicenter, randomized, double-blind, placebo-controlled, parallel-group trial evaluated the efficacy and safety of AVA for the treatment of pediatric patients with ITP for ≥6 months (NCT04516967).
Eligible participants were children with ITP of ≥6 months duration aged 1 year to 17 years with mean platelet counts 30×109/L or less (mean of two measurements during the screening period) with no single count greater than 35×109/L.
Patients were randomly assigned (3:1) to receive AVA or PBO for 12 weeks stratified by age group (1 to &lt;6 years, 6 to &lt;12 years, 12 to &lt;18 years); the dose of study drug was adjusted to achieve a target PC of 50 to 150×109/L.
These post-hoc analyses evaluate the durability of platelet response (R) [PC ≥50 × 109/L ] as well as the durability of the CMR [PC ≥30 × 109/L] utilizing the following measures: 1) proportion of time with a R or CMR during the 6 month core phase and 2) proportion of patients with a R or CMR for 3, 4, 5, 6, 7 or 8 of the last 8 weeks of the core phase. All response criteria require an absence of rescue therapy.
Results: Overall, 75 patients aged 1 to 17 years were enrolled; 54 were randomized to AVA and 21 to PBO.
50/54 (92.6%) of AVA patients and 4/21 (19.1%) of PBO patients achieved a CMR with 48/54 (88.9%) of AVA patients versus 2/21 (9.5%) of PBO patients achieving a R at any point during the core phase.
Utilizing the CMR definition, a response was seen in 83.3% (p&lt;0.0001), 75.9% (p&lt;0.0001), 59.3% (p&lt;0.0001) , 48.1% (p&lt;0.0001) , 31.5% (p=0.0019) , and 13.0% (p=0.1802) of AVA patients during the final 3/8, 4/8, 5/8, 6/8, 7/8, and 8/8 weeks of the core phase, respectively, versus 0% of placebo (PBO) patients at each time point.
The mean (SD) and median (Min,Max) percentage of time with a CMR was 62.5% (21.04) and 66.7% (1.4, 92.2) for AVA and 16.7% (10.70) and 19.0% (2.0, 26.8) for PBO, respectively.
Of the patients achieving a CMR, 47/50 (94.0%) of AVA patients achieved a CMR greater than 25% of time during the core phase; 36/50 (72.0%) of AVA patients achieved a CMR greater than 50% of the core phase; and 18/50 (36%) greater than 75% of the core phase.
Utilizing the R definition, a response was seen in 75.9% (p&lt;0.0001), 57.4% (p&lt;0.0001), 40.7% (p=0.0002) , 27.8% (p=0.0077) , 13.0% (p=0.1802) , and 1.9% (p=1.0) of AVA patients during the final 3/8, 4/8, 5/8, 6/8, 7/8, and 8/8 weeks of the core phase, respectively, versus 0% of placebo (PBO) patients at each of the time points.
The mean (SD) and median (Min,Max) percentage of time with a R was 51.0% (17.13) and 51.2% (9.4, 92.2) for AVA and 8.1% (8.72) and 8.1% (2.0, 14.3) for PBO, respectively.
Of the patients achieving an R, 46/48 (95.8%) of AVA patients achieved a R greater than 25% of the core phase; 26/48 (54.2%) of AVA patients achieved a durable R greater than 50% of the core phase; and 4/48 (8.3%) achieved a durable R greater than 75% of the core phase.
Summary/Conclusion: Pediatric ITP patients demonstrated a significant and consistent durable response to AVA during the core phase of this Phase 3b study of a refractory ITP population, regardless of how the response was measured.