Further Characterization of Thromboembolic Events and Association with Platelet Count Occurring during the Avatrombopag Immune Thrombocytopenia (ITP) Clinical Development Program

Background: ITP management often requires subsequent therapy beyond current first line treatments (corticosteroids or intravenous immunoglobulin). The use of thrombopoietin receptor agonists (TPO-RAs) as second-line treatment, in lieu of splenectomy or rituximab, has become more common and is supported by recent American Society of Hematology (ASH) guidelines (Neunert, 2019).

The TPO-RAs eltrombopag (ELT) and romiplostim (ROMI) have been utilized in patients with ITP for over a decade, whereas avatrombopag (AVA) was more recently approved in June 2019.

Thromboembolic events (TEEs) are not uncommon in ITP, with studies showing that up to 8% of patients experience an arterial or venous event (Sarpatwari, 2010; Vianelli, 2013). As agents that potentiate endogenous platelet production, TPO-RAs as a class may increase the risk of thromboembolism, with such events occurring in a variety of TPO-RA ITP studies. However, it is not well-understood what increased risk, over and above the inherent risk associated with ITP, TPO-RAs pose in regard to thromboembolic events (Catala-Lopez, 2015).

We previously reported on the general characterization of thromboembolic events occurring during the avatrombopag ITP clinical development program (ASH 2020). Currently, we evaluate platelet counts both prior to and following the specific TEE event and report on any dosage change of avatrombopag in proximity to the TEE event.

Aims: To further characterize TEEs occurring across the AVA ITP clinical development program and expand the understanding of any possible role of change in platelet count (PC) as a predictor of TEEs with AVA.

Methods: 4 studies were conducted evaluating AVA in patients with ITP (two Phase 2 and two Phase 3 trials). In total, 128 patients received AVA treatment, with an average duration of exposure of ≥180 days. Occurrence of TEEs was an adverse event of special interest that was monitored closely in these studies. At the time of each TEE, the following information was collected: platelet count, AVA dose, study day of event and other medical history and lifestyle factors potentially increasing the risk for thromboembolism. PCs were also collected at each study visit as well as unplanned visits per protocol. Patients with history of arterial or venous thrombosis and more than 2 significant risk factors were excluded from the Phase 3 studies.

Results: As previously reported, a total of 11 TEEs occurred in 9/128 (7%) of AVA treated patients, with one patient experiencing 3 events. No clustering of events was noted, with cerebrovascular accident being the only specific event occurring in more than one patient (occurring in 2/11 patients).

In the current analysis, variability was observed in the platelet count at the time of TEE, ranging from 19,000 - 571,000/µL. Two patients experienced events at a platelet count >400,000/µL, whereas five events occurred at a PC <50,000/µL. The mean value of three PCs prior to the event in each individual patient were low (PC<130,00/µL) in 7/11 (64%), normal (PC between 130,000/µL-450,000/µL) in 4/11 (36%), and high (PC>450,000/ µL ) in 0/11 (0%) of patients. The mean value of three PCs following the event in each individual patient were low in 6/11 (55%), normal in 4/11 (36%), and high in 1/11 (9%) of patients. The change in mean PC status from prior to the event to following the event was no change in 7/11 (64%), low to normal in 2/11 (18%), low to high in 0/11 (0%), normal to low in 1/11 (9%), and normal to high in 1/11 (9%) of patients.

There were no changes in AVA dose within three weeks of any TEE event.

The onset of thromboembolic events ranged from study day 8 to 335, with no clear pattern materializing regarding duration of drug exposure and the onset of the TEE. Thromboembolic events were noted at daily doses of AVA ranging from 10 - 40 mg. No deaths were noted in the ITP development program.

Conclusions: The TEEs noted with AVA treatment typically occurred at PCs below the upper bound of normal (450,000/µL), without relationship to drug dose and at varying number of days on study drug. No clear patterns regarding the occurrence of thromboembolic events with AVA treatment or platelet count could be determined. Clinicians should carefully monitor PC and assess the risk for thromboembolism in each individual patient treated with a TPO-RA.

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