Immune thrombocytopenia - Emerging treatments

Rilzabrutinib

Rilzabrutinib is an investigational oral Bruton kinase inhibitor, designed to treat immune-mediated diseases. It has a dual mechanism of action, inhibiting B-cell activation and interrupting antibody-coated cell phagocytosis by Fc gamma receptors in the spleen and liver. It is currently being evaluated in a phase 3 trial comparing rilzabrutinib with placebo in adults and adolescents with persistent or chronic immune thrombocytopenia (ITP).[88][89] A phase 1 and 2 trial including 60 patients with ITP (median baseline platelet count 15 × 10⁹/L [15 × 10³/microlitre]) who had failed previous treatments (median 4 therapies) showed that 40% of participants achieved a response (platelet count ≥50 × 10⁹/L [≥50 × 10³/microlitre]) with rilzabrutinib. Median time to response was 11.5 days. No treatment-related bleeding or thrombotic events higher than grade 2 were reported. Common treatment-related adverse events included diarrhoea (32% of patients), nausea (30%), and fatigue (10%).[90] The Food and Drug Administration (FDA) has granted fast track designation to this drug for the treatment of ITP.

Efgartigimod alfa

Efgartigimod alfa is a human IgG1-derived Fc fragment, developed to target neonatal Fc receptors to accelerate pathological IgG degradation in autoimmune disorders. It is currently being evaluated in phase 3 trials for the management of persistent or chronic ITP.[91] In a phase 3 trial of efgartigimod alfa, including 131 patients with chronic ITP, a sustained platelet count response (≥50 × 10⁹/L [≥50 × 10³/microlitre] for at least 4 of the last 6 weeks) was achieved in 22% of patients compared with 5% receiving a placebo.[92] Efgartigimod alfa was well tolerated, with only mild-to-moderate adverse events. Efgartigimod alfa is currently licensed for the treatment of myasthenia gravis, but not ITP.

Sutimlimab

Sutimlimab is a humanised monoclonal antibody that targets C1s in the classical complement pathway. In a phase 1 trial including 12 patients with chronic or refractory ITP, 5 patients (42%) achieved durable platelet count responses (≥50 × 10⁹/L [≥50 × 10³/microlitre] in ≥50% of follow-up visits) and 4 achieved complete response (platelet count ≥100 × 10⁹/L [≥100 × 10³/microlitre]). A response could be maintained in every CR patient by prolonged sutimlimab administration. The median time to response was 2 days. Sutimlimab was generally well tolerated and no patients discontinued treatment due to drug-related adverse events.[93] A phase 2 trial is ongoing.[94] Sutimlimab is currently licensed for the treatment of cold agglutinin disease-associated haemolysis, but not ITP.

Thrombopoietin receptor agonists in pregnancy

Thrombopoietin receptor agonists are not currently recommended in pregnancy, because they are likely to cross the placenta and their safety is not established. However, there is some evidence suggesting that they may have a role in treating severe ITP in pregnant women prior to delivery. A retrospective, observational study including 15 women (17 pregnancies) in women with ITP treated with eltrombopag or romiplostim during pregnancy reported no significant adverse events in the mother or neonate. Initial response to treatment was achieved in 77% of patients.[95] A retrospective review of data from 186 pregnancies in women exposed to romiplostim did not report any specific safety concerns.[96] Multiple case reports support safety (except for the increased risk of neonatal thrombocytosis) and efficacy of thrombopoietin receptor agonists given in the third trimester. Emerging evidence suggests romiplostim may have a role in increasing platelet count to prepare for delivery.[15][97]

Avatrombopag in children

Avatrombopag (a second-generation oral thrombopoietin receptor agonist) is approved for the treatment of adults with chronic ITP who have had an insufficient response to a previous treatment. The safety and efficacy of avatrombopag in children with ITP who have had an insufficient response to a previous treatment is being evaluated in a phase 3b randomised, placebo-controlled trial.[43][98]