TPO-RAs and ITP: Eltrombopag Induces High Efficacy, But Avatrombopag Offers Advantages

A pair of studies presented at the 2020 American Society of Hematology Annual Meeting analyzed the thrombopoietin receptor agonist (TPO-RA) eltrombopag in two settings: in real-world clinical practice against clinical trials experiences, and against another TPO-RA, avatrombopag.

Eltrombopag in Real-World Clinical Practice

Since 2010, eltrombopag has been available in Europe for the management of chronic primary immune thrombocytopenia (ITP), but efficacy data regarding its use has largely been limited to the confines of clinical trials.1 In a study presented by Guillaume Moulis, MD, PhD, of Toulouse University Hospital in France, real-world clinical practice data show eltrombopag is typically used early in the course of ITP in France, and overall efficacy of the therapy is comparable to that observed in clinical trials.

Dr. Moulis shared findings from the ELEXTRA study, which evaluated outcomes among 156 patients with ITP who had been exposed to eltrombopag and were enrolled in the CARMEN-France registry between 2013 and 2019. Investigators followed all patients through routine clinic visits or hospitalizations.

The median platelet count at the time of ITP diagnosis was 8×109/L, and approximately three-quarters of patients had bleeding.

The median time between ITP onset and first administration of eltrombopag was 3.3 months (range = 0.1-82.2 months). The median duration of eltrombopag exposure was 100 days (range = 1-1,427 days). At the time of starting eltrombopag, 75 patients (48.1%) had a platelet count <30×109/L and were included in the efficacy analysis. Most of these patients (n=65; 86.7%) responded to therapy, reaching platelet levels ≥30×109/L, and 53 patients (70.7%) experienced a complete response at any time during treatment exposure.

Most responders were taking concomitant therapies at the time of starting eltrombopag (n=58; 89.2%), the authors reported.

Forty-seven adverse events (AEs) were reported in the registry; the most frequently reported AEs included thrombocytosis (n=10), thrombosis (n=8), rash (n=4), hepatitis (n=3), and headache (n=3). The safety profile of eltrombopag observed in this real-world analysis was similar to that reported in the drug’s clinical trials, Dr. Moulis and coauthors observed.

Eltrombopag Versus Avatrombopag

In the second presentation, Michael D. Tarantino, MD, from the Bleeding & Clotting Disorders Institute in Peoria, Illinois, discussed eltrombopag in the context of avatrombopag, another approved TPO-RA that also has established efficacy in ITP, but carries fewer restrictions in dosing and monitoring than eltrombopag.

Dr. Tarantino discussed results from two phase II studies and two phase III studies that evaluated avatrombopag in ITP, including a head-to-head comparison trial of avatrombopag and eltrombopag that was discontinued early due to enrollment challenges.

In total, the studies included 128 patients treated with avatrombopag, 11 treated with eltrombopag, and 22 with placebo. Various efficacy analyses from these studies were performed in order to understand the consistency of avatrombopag response across different patient populations in reference to placebo and eltrombopag.

Avatrombopag appeared tolerable, as nearly all patients received the drug for at least seven days and 63.3% continued treatment for at least 180 days. The average duration of exposure for avatrombopag was 206.4 days, compared with 73.5 days for eltrombopag and 54.9 days for placebo.

In the phase II studies, the median cumulative number of weeks of platelet response (platelet counts ≥50×109/L) were 11.0 with avatrombopag versus 0 with placebo (p=0.0079). Results were similar in the placebo-controlled phase III study (12.4 weeks with avatrombopag versus 0 weeks with placebo; p<0.0001), and avatrombopag also appeared to outperform eltrombopag in the head-to-head study (5.1 weeks with avatrombopag versus 0 weeks with eltrombopag; p=0.33). Dr. Tarantino added that five eltrombopag-treated patients treated with discontinued study due to an inadequate therapeutic effect, compared with only one avatrombopag-treated patient.

Across the studies, more avatrombopag-treated patients appeared to achieve a platelet count ≥50×109/L quickly, within eight days, compared with those who received placebo or eltrombopag. Specifically, in the head-to-head study, mean and median platelet counts and changes in platelet counts from baseline began to favor avatrombopag at two weeks. Bleeding also appeared to be more common among eltrombopag-treated patients, though there were no grade ≥3 bleeds noted in either group and overall rates of AEs were similar.

“The accumulated efficacy data in the avatrombopag development program demonstrates a consistent effect across different studies conducted in a variety of countries,” Dr. Tarantino concluded, though he noted several limitations of this analysis, including a small study population and limited head-to-head data.

Study authors in Moulis et al. report relationships with Novartis, the manufacturer of eltrombopag. Study authors in Tarantino et al. report relationships with Dova Pharmaceuticals, the manufacturer of avatrombopag.

References

  1. Moulis G, Rueter M, Lafaurie M, Lapeyre-Mestre M. Eltrombopag for immune thrombocytopenia in adult patients in the real-world in France. Final results of the Elextra study. Abstract #2662. Presented at the 2020 American Society of Hematology Annual Meeting, December 7, 2020.
  2. Tarantino MD, Vredenburg M, Tian W, et al. Efficacy analyses from the immune thrombocytopenia (ITP) clinical development program for avatrombopag: comparisons with placebo and eltrombopag. Abstract #2677. Presented at the 2020 American Society of Hematology Annual Meeting, December 7, 2020.