The need for more efficient and diverse choices of therapy for patients with ITP has led to the development of several novel treatments over the years. One such therapy in clinical trial includes Rilzabrutinib, a Bruton tyrosine kinase (BTK) inhibitor formerly known as PRN1008. Rilzabrutinib is an oral covalent inhibitor of Bruton tyrosine kinase targeting the role of BTK in the underlying pathophysiology of platelet destruction. Phase 1/2 dose-escalation results suggest that taking 400 mg twice a day is the best dose for combining clinical activity and safety.
Congenital deficiency of BTK, called “Bruton’s X-linked Agammaglobulinemia” results in the absence of B cells (the ones leading to production of antibodies of all kinds) as well as absence of antibodies. However inhibiting BTK does not deplete B cells but rather blocks them from working to produce autoantibodies. Unlike rituximab which depletes B cells but has a very small effect on their more developed cells (plasma cells), BTK inhibitors have major effects in both of these cell types. Syk (spleen tyrosine kinase) is the target of fostamatinib (brand name is TAVALISSE®) which does a part of its signalling inside the cell via BTK. However, blocking BTK vs blocking Syk clinically seem to have different effects (see discussion of fostamatinib below).
The Rilzabrutinib, a BTK inhibitor, works by blocking inflammatory immune cells and destructive signaling associated with autoantibodies in many different types of white blood cells in addition to preventing new autoantibodies from being produced. Developed by Principia BioPharma (recently acquired by Sanofi), Rilzabrutinib has already revealed successful results with adult ITP patients who have a baseline platelet count less than 30,000/ µL and who have tried multiple ITP treatments in the past.
To date, Rilzabrutinib has been well-tolerated when used exclusively as a monotherapy or when used in combination with other ITP therapies, such as TPO-RA’s or corticosteroids. There have not been any reported treatment related bleeding or thrombotic events. Adverse effects reported were generally minimal. The primary goal was also met in the initial phase 1/2 trial which including participants achieving two or more consecutive platelet counts greater than 50,000/ µL at least five days apart, and an increase of at least 20,000/ µL from baseline with no need for rescue therapy.
Overall, in phase 1/2 of the clinical trial, Rilzabrutinib has shown to have durable clinical activity and a well-tolerated safety profile making this an attractive option for ITP patients who have not had optimal responses with other available therapies, and who prefer an oral medication over infusions that often require a hospital visit. Phase three of the clinical trial is now in process.
In this study, post hoc data from the two phase three randomized clinical trials for the drug, Fostamatinib (brand name TAVALISSE®) were analyzed to determine if use of the drug in earlier phases of ITP would be beneficial. Currently, Fostamatinib is used more like a third-line therapy following corticosteroids, IVIG, rituximab, and TPO-RA’s. Fostamatinib is a spleen tyrosine kinase (SYK) inhibitor approved by the FDA for chronic immune thrombocytopenia (cITP) treatment. Developed by Rigel pharmaceuticals, fostamatinib comes in tablet form and is taken twice daily with or without food. The drug works by targeting the SYK enzyme in the body to inhibit it from destroying platelets in patients with ITP. Syk has an important role in macrophages (cells phagocytosing antibody-coated platelets) and has been demonstrated in studies in mice to block destruction of platelets with antibody on them. However, Syk is also important in lymphocytes and could have an effect over time to reduce production of anti-platelet antibodies.
Adult ITP patient data from FIT 1 and FIT 2 and the open-label FIT 3 extension trial were used for the analysis, up until December (2019). Results revealed that when Fostamatinib was used as a second-line therapy following previous treatment with corticosteroids, or danazol with or without IVIG the platelet response was greater compared to when it was used as a third-line therapy (or later) following treatment with splenectomy, rituximab, TPO-RA’s, cyclosporin, azathioprine, mycophenolate mofetil, vincristine, and/or dapsone. Over 90% of participants achieved a platelet count over 30,000 µL when Fostamatinib was used as a second-line therapy, versus 63% when used as a third-line or later therapy. Response rates decreased with additional lines of therapy. Response to Fostamatinib was greatest in participants who were in the persistent ITP phase (90%) compared to those who had chronic ITP for over two years (51%). Most responders did so within 4 weeks of initiating treatment. Durability was defined as a percentage of the number of days participants maintained a response after achieving a count of at least 50,000 µL and not falling below 30,000 µL on two consecutive blood draws – apart, and not requiring rescue therapy. Durability was longer when Fostamatinib was used as a second-line therapy rather than a third-line or later therapy. There was less reporting of participants requiring rescue therapy when Fostamatinib was used as a second-line therapy compared to a third-line or later therapy. Adverse effects reported were generally mild and were reported less when Fostamatinib was used as a second-line therapy rather than a third-line or later therapy.
Overall, post-hoc analysis revealed that Fostamatinib is effective and safe to use as a second-line therapy, and early use in treatment of ITP is supported by data collected so far.
Rigel pharmaceuticals and Medison Pharma (Medison) have recently announced that TAVALISSE, also known as fostamatinib, is now approved by Health Canada for use in Canadian adult patients with ITP who have had an insufficient response, or no response, to other approved ITP therapies. Developed by Rigel pharmaceuticals, fostamatinib has already received approval for use in the US since April (2018). Last October, Rigel partnered with Medison to commercialize the drug in Canada and Israel. TAVALISSE comes in tablet form and is taken twice daily with or without food. The drug works by targeting the SYK enzyme in the body to inhibit it from destroying platelets in patients with ITP. Syk has an important role in macrophages (cells phagocytosing antibody-coated platelets) and has been demonstrated in studies in mice to block destruction of platelets with antibody on them. However, Syk is also important in lymphocytes and could have an effect over time to reduce production of anti-platelet antibodies. Canadian adults with ITP are encouraged to talk to their health care provider if they are interested in seeing if TAVALISSE is suitable for them.