Diana earned her PhD and PharmD with distinction in the field of Medicinal and Pharmaceutical Chemistry at the Universidade do Porto. She is an accomplished oncology scientist with 10+ years of experience in developing and managing R&D projects and research staff directed to the development of small proteins fit for medical use.
Immune thrombocytopenia (ITP) is an autoimmune disease that leads to a low platelet count and an increased risk of bleeding. The first-line treatment of ITP aims to reduce bleeding and increase the number of platelets, which is often achieved with the administration of corticosteroids. Second- and third-line treatments include thrombopoietin receptor agonists (TPO-RAs), Rituxan® (rituximab), fostamatinib, splenectomy, and immunomodulatory agents such as mycophenolate mofetil and cyclosporin A.1
There are currently several therapies in development that aim to fill in different gaps identified in ITP management, such as the need for improved treatment efficacy and increased response to first-line treatments.1
Thrombopoietin Receptor Agonists
Thrombopoietin receptor agonists act by increasing megakaryocytes and subsequent platelet production. Hetrombopag olamine is a small nonpeptide TPO-RA of the same class as Promacta® (eltrombopag) that is currently in development. A phase 3 clinical trial and extension study have shown good platelet response rates of about 85% with the administration of the investigational therapy, which is higher than that following the administration of placebo. Hetrombopag does not influence platelet aggregation, is well tolerated, and has a manageable safety profile. The approval of this experimental treatment is currently limited to China as a second-line treatment for ITP.1
Read more about ITP treatment
There is currently 1 Syk inhibitor approved by the US Food and Drug Administration (FDA): Tavalisse® (fostamatinib). However, 2 other oral, selective, and reversible inhibitors have been studied: HMPL-523 and SKI-O-703 (cevidoplenib). These molecules promote the inhibition of macrophage phagocytosis and the subsequent decrease in platelet destruction.1 The efficacy of HMPL-523 will be evaluated in a phase 3 clinical trial (NCT05029635),2 and the safety, pharmacokinetics, and pharmacodynamics of SKI-O-703 have been studied in single and multiple ascending doses.1
Bruton Tyrosine Kinase Inhibitors
Bruton tyrosine kinases (BTK) are cytoplasmic proteins required for B-cell development, B-cell functioning, and antibody production.1,3 BTKs contribute to the release of inflammatory mediators in autoimmune disorders, the enhancement of phagocytosis, and antigen presentation in myeloid cells.1 Several BTK inhibitors (BTKIs) aimed at treating diseases such as some cancers have been already developed. The inhibition of platelet aggregation, however, has been reported with BTKIs such as ibrutinib but not with rilzabrutinib (PRN1008).3 Rilzabrutinib has shown a good safety profile at doses up to 400 mg twice a day as well as rapid and sustained activity that improves over time.1 This experimental treatment received Orphan Drug designation from the FDA and has shown an overall response rate of 33% in a phase 1/2 clinical trial.4 A phase 3 clinical trial — LUNA3 (NCT04562766) — is currently ongoing.1,5
Read more about ITP clinical trials
Inhibitors of the Neonatal Fc Receptor
The neonatal Fc receptor (FcRn) is responsible for the modulation of the half-lives of immunoglobulin G (IgG) and albumin.3 It is important for preventing IgG degradation during transcytosis of circulating IgG.1 In addition to recycling physiological IgG, it also recycles pathologic IgG. The blockage of FcRn leads to the breakdown of IgG in endosomes and a reduction in IgG recycling, therefore reducing the number of circulating autoantibodies.1,3
Two anti-FcRn molecules are currently being developed, rozanolixizumab and efgartigimod. Rozanolixizumab is a monoclonal antibody directed against FcRn that is administered subcutaneously in patients with persistent or chronic ITP.4 This investigational therapy is currently being studied in a phase 3 clinical trial (NCT04596995).6
Efgartigimod is a human IgG1-derived Fc fragment that acts as an FcRn blocker. A phase 2 clinical trial showed that efgartigimod was well tolerated, that it reduced total IgG levels by nearly 64% compared to baseline values, and that a relevant increase in platelet count could be observed. Different phase 3 clinical trials are currently ongoing.1
Read more about ITP pathophysiology
CD38 is a cell surface molecule that is expressed on antibody-producing plasmablasts, short-lived and long-lived plasma cells, natural killer (NK) cells, and antigen-induced activated T and B cells. This molecule is involved in cell adhesion and signal transduction pathways. The blockage of CD38 may lead to the depletion of plasma cells and plasmablasts as well as a decrease in autoantibody production.1
Daratumumab is an anti-CD38 monoclonal antibody with a long plasma half-life that induces apoptosis in CD38-expressing cells. Recent data indicate that this drug may reach an acceptable response despite the refractoriness of the cohort studied. Its administration through prolonged dose intervals may improve patients’ quality of life. TAK-079 (mezagitamab), a different anti-CD38 monoclonal antibody, is also currently being investigated.1
Read more about ITP therapies
The complement system may be involved in the pathogenesis of ITP. Although it may represent a potential therapeutic target, more studies are needed to establish this association.3 Studies have been performed on Enjaymo™ (sutimlimab), a monoclonal antibody that inhibits the classical complement pathway that supports the immune-mediated destruction of platelets. However, treatment with Enjaymo led to the recurrence of thrombocytopenia, despite showing a rapid and durable response in patients with severe chronic ITP who failed to respond to at least 2 prior therapies.1,4
Read more about ITP prognosis
Other Experimental Therapies
Other experimental therapies in development include bortezomib, a proteasome inhibitor that induces apoptosis of long-lived plasma cells and leads to the reduction of antiplatelet antibodies in patients with steroid-resistant or relapsed ITP.4 PRTX-100, a purified staphylococcal protein A, has also been studied and shown efficacy in murine models of ITP. This molecule is able to modulate the immune system by binding B cells and monocytes.4 A clinical trial with 6 adult patients has revealed an acceptable safety profile for the experimental therapy, but only 1 patient showed a platelet response when receiving the lowest dose of PRTX-100.1
1. Mingot-Castellano ME, Bastida JM, Caballero-Navarro G, et al; Grupo español de PTI. Novel therapies to address unmet needs in ITP. Pharmaceuticals (Basel). 2022;15(7):779. doi:10.3390/ph15070779
2. Phase III study on HMPL-523 for treatment of ITP. ClinicalTrials.gov. August 31, 2021. Accessed October 25, 2022.
3. Provan D, Semple JW. Recent advances in the mechanisms and treatment of immune thrombocytopenia. EBioMedicine. 2022;76:103820. doi:10.1016/j.ebiom.2022.103820
4. Khadka S, Kasireddy V, Dhakal PK, Dadiboyina C. Evolving treatment modalities for immune thrombocytopenia in adults. J Community Hosp Intern Med Perspect. 2021;11(1):115-119. doi:10.1080/20009666.2020.1843237
5. Study to evaluate rilzabrutinib in adults and adolescents with persistent or chronic immune thrombocytopenia (ITP) (LUNA 3). ClinicalTrials.gov. September 24, 2020. Updated September 29, 2022. Accessed October 25, 2022.
6. A study to investigate the long-term safety, tolerability, and efficacy of rozanolixizumab in study participants with persistent or chronic primary immune thrombocytopenia (ITP) (myOpportunITy3). ClinicalTrials.gov. October 22, 2020. Updated October 24, 2022. Accessed October 25, 2022.
Reviewed by Kyle Habet, MD, on 10/27/2022.