First patient enrolled in Phase 1 trial testing fostamatinib for SCD
NHLBI study will evaluate safety, tolerability of repurposed therapy
The first patient has been enrolled in a Phase 1 clinical trial evaluating the safety and tolerability of Rigel Pharmaceuticals’ fostamatinib — a medication approved in the U.S. for treating an autoimmune condition — in people with sickle cell disease (SCD).
The Phase 1 study (NCT05904093) is sponsored by the National Heart, Lung, and Blood Institute (NHLBI), part of the National Institutes of Health (NIH), and will be conducted at a single site in Bethesda, Maryland. It expects to enroll up to 25 SCD patients, ages 18 to 65, by invitation.
Fostamatinib is the active ingredient in Tavalisse, which is approved in the U.S. for adults with treatment-resistant chronic immune thrombocytopenia, an autoimmune disease marked by low platelet counts. In SCD, fostamatinib is being investigated for its potential to reduce blood clotting complications without increasing bleeding risk and to help mitigate red blood cell sickling.
“Our Phase 1 study evaluating fostamatinib in patients with sickle cell disease is an opportunity to explore a potential new treatment option for a disease that is associated with a high degree of recurrent acute pain events and other acute and chronic potentially life-threatening complications,” Richard Childs, MD, scientific director of the NHLBI, said in a Rigel press release.
Enrollment in fostamatinib trial by invitation
A genetic disease, SCD is caused by the production of abnormal hemoglobin, the protein that carries oxygen in red blood cells. As a result, these cells become rigid and sickle-shaped, making it difficult for them to pass through small blood vessels. This, in turn, may restrict blood flow, causing damage and inflammation to different tissues and organs, and increasing the risk of painful vaso-occlusive crises.
People with SCD are also at a higher risk of developing inflammation-driven blood clots, or thrombo-inflammation, which can lead to a series of complications. However, standard treatments used to prevent these clots may also increase the risk of bleeding, posing a challenge for both clinicians and patients in managing these complications.
Fostamatinib blocks the activity of an enzyme called spleen tyrosine kinase, or SYK, suppressing the antibody-mediated destruction of platelets — the cell fragments involved in blood clotting. The therapy is also thought to prevent thrombo-inflammation and enhance the stability of the red blood cell membrane, thereby reducing sickling.
In preclinical studies, R406, the active metabolite of fostamatinib, suppressed the production of neutrophil extracellular traps, a fibrous mesh of DNA and proteins released by these immune cells, that can promote blood clotting. In a humanized SCD mouse model, R406 significantly decreased platelet aggregation, essenting clumping, without affecting bleeding time.
“Preclinical research conducted by NIH/NHLBI investigators lead us to believe that SYK inhibition may have the potential to reduce complications related to red cell sickling and thrombo-inflammation in this patient population,” Childs said.
The study focuses on an area of critical unmet need [in sickle cell disease].
The open-label Phase 1 study will be led by principal investigator Swee Lay Thein, MD, senior investigator and chief of the sickle cell branch at the NHLBI, with study materials provided by Rigel.
The study is enrolling by invitation. To be eligible, patients must not have had a blood transfusion in the preceding two months and must have adequate organ function. Additionally, if on hydroxyurea, participants must have been on a stable dose for at least three months.
Participants will receive a 100 mg dose of oral fostamatinib twice daily for 14 days, or two weeks. If well tolerated, the dose will be increased to 150 mg, twice daily for 28 days, or nearly one month.
The study’s primary goal is to assess the safety and tolerability of fostamatinib. Secondary objectives are evaluating the impact of SYK inhibition on red blood cell membrane integrity and deformability, rate of sickling, platelet activation and aggregation, neutrophil activation, and neutrophil extracellular trap formation.
Raul Rodriguez, Rigel’s president and CEO, said the company is “excited to support another important study conducted by the NIH/NHLBI for fostamatinib, as they investigate SYK inhibition and its potential to benefit patients with sickle cell disease.”
According to Rodriguez, “the study focuses on an area of critical unmet need and contributes to Rigel’s mission to improve the lives of patients with hematologic disorders and cancer.”
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