Rilzabrutinib, an Oral BTK Inhibitor, in Immune Thrombocytopenia

Kuter, David J.; Efraim, Merlin; Mayer, Jiřı́; Trněný, Marek; McDonald, Vickie; Bird, Robert; Regenbogen, Thomas; Garg, Mamta; Kaplan, Zane; Tzvetkov, Nikolay; Choi, Philip Young-Ill; Jansen, A.J. Gerard; Košťál, Milan; Baker, Ross; Gumulec, Jaromír; Lee, Eun‐Ju; Cunningham, Ilona; Goncalves, Isaac; Warner, Margaret; Boccia, Ralph V.; Gernsheimer, Terry; Ghanima, Waleed; Bandman, Olga; Burns, Regan; Neale, Ann; Thomas, Dylan C.; Arora, Puneet; Zheng, Beiyao; Cooper, Nichola

doi:10.1056/nejmoa2110297

Cited by 61 publications

(51 citation statements)

References 22 publications

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“…These mechanisms explained the strong and sustained potency of rilzabrutinib in rodent arthritis and canine pemphigus models [ 54 , 107 ]. Rilzabrutinib is associated with low-level and transient AEs and displays rapid and durable clinical activity in patients with ITP [ 91 ]. However, rilzabrutinib shows limited efficacy in pemphigus patients, resulting in the termination of a phase 3 study (NCT03762265).…”

Section: An Overview Of Btk Inhibitorsmentioning

confidence: 99%

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BTK inhibitors in the treatment of hematological malignancies and inflammatory diseases: mechanisms and clinical studies

Alu

Han

et al. 2022

J Hematol Oncol

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Bruton’s tyrosine kinase (BTK) is an essential component of multiple signaling pathways that regulate B cell and myeloid cell proliferation, survival, and functions, making it a promising therapeutic target for various B cell malignancies and inflammatory diseases. Five small molecule inhibitors have shown remarkable efficacy and have been approved to treat different types of hematological cancers, including ibrutinib, acalabrutinib, zanubrutinib, tirabrutinib, and orelabrutinib. The first-in-class agent, ibrutinib, has created a new era of chemotherapy-free treatment of B cell malignancies. Ibrutinib is so popular and became the fourth top-selling cancer drug worldwide in 2021. To reduce the off-target effects and overcome the acquired resistance of ibrutinib, significant efforts have been made in developing highly selective second- and third-generation BTK inhibitors and various combination approaches. Over the past few years, BTK inhibitors have also been repurposed for the treatment of inflammatory diseases. Promising data have been obtained from preclinical and early-phase clinical studies. In this review, we summarized current progress in applying BTK inhibitors in the treatment of hematological malignancies and inflammatory disorders, highlighting available results from clinical studies.

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Section: An Overview Of Btk Inhibitorsmentioning

confidence: 99%

“…An overall response in 40% patients after a median of 167.5 days; 2. Only low-level toxicities [ 91 ] Severe COVID-19 1. Ibrutinib and zanubrutinib may interfere with viral entry and replication [ 305 ]; 2.…”

Section: Btk Inhibitors In Inflammatory Diseasesmentioning

confidence: 99%

BTK inhibitors in the treatment of hematological malignancies and inflammatory diseases: mechanisms and clinical studies

Alu

Han

et al. 2022

J Hematol Oncol

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“…The median time to achieve a platelet count of ≥50 × 10 3 /µL was 11.5 days. The authors identified the dose of 400 mg twice daily as being most suitable for further trials [ 58 , 59 ]. Likewise, the first randomized, multicenter, phase-3 study with an open-label extension phase (LUNA3, NCT04562766) is underway, with the aim of evaluating the efficacy and safety of rilzabrutinib relative to placebo in adult and adolescent patients with persistent or chronic ITP [ 60 ].…”

Section: Novel Drugs and Therapies To Treat Itpmentioning

confidence: 99%

Novel Therapies to Address Unmet Needs in ITP

et al. 2022

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Primary immune thrombocytopenia (ITP) is an autoimmune disorder that causes low platelet counts and subsequent bleeding risk. Although current corticosteroid-based ITP therapies are able to improve platelet counts, up to 70% of subjects with an ITP diagnosis do not achieve a sustained clinical response in the absence of treatment, thus requiring a second-line therapy option as well as additional care to prevent bleeding. Less than 40% of patients treated with thrombopoietin analogs, 60% of those treated with splenectomy, and 20% or fewer of those treated with rituximab or fostamatinib reach sustained remission in the absence of treatment. Therefore, optimizing therapeutic options for ITP management is mandatory. The pathophysiology of ITP is complex and involves several mechanisms that are apparently unrelated. These include the clearance of autoantibody-coated platelets by splenic macrophages or by the complement system, hepatic desialylated platelet destruction, and the inhibition of platelet production from megakaryocytes. The number of pathways involved may challenge treatment, but, at the same time, offer the possibility of unveiling a variety of new targets as the knowledge of the involved mechanisms progresses. The aim of this work, after revising the limitations of the current treatments, is to perform a thorough review of the mechanisms of action, pharmacokinetics/pharmacodynamics, efficacy, safety, and development stage of the novel ITP therapies under investigation. Hopefully, several of the options included herein may allow us to personalize ITP management according to the needs of each patient in the near future.

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“…In a clinical trial of relapsed ITP patients treated with rilzabrutinib (PRN1008) (NCT03395210), rilzabrutinib led to rapid and consistently reliable clinical activity. 40% patients reached a platelet count of 50×10 9 /L on at least two occasions and the median response time was 11.5 days ( 32 ). Treatment-emergent adverse events were mild, primarily affecting the gastrointestinal tract.…”

Section: Therapeutics Targeting Macrophagesmentioning

confidence: 99%

Current therapeutic strategies and perspectives in refractory ITP: What have we learned recently?

Shi

Liu

et al. 2022

Front. Immunol.

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Immune thrombocytopenia (ITP) is an acquired autoimmune bleeding disorder featured by increased platelet destruction and deficient megakaryocyte maturation. First-line treatments include corticosteroids, intravenous immunoglobulin and intravenous anti-D immunoglobulin. Second-line treatments consist of rituximab, thrombopoietin receptor agonists and splenectomy. Although most patients benefit from these treatments, an individualized treatment approach is warranted due to the large heterogeneity among ITP patients. In addition, ITP patients may relapse and there remains a subset of patients who become refractory to treatments. The management of these refractory patients is still a challenge. This review aims to summarize emerging therapeutic approaches for refractory ITP in several categories according to their different targets, including macrophages, platelets/megakaryocytes, T cells, B cells, and endothelial cells. Moreover, current management strategies and combination regimens of refractory ITP are also discussed.

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Rilzabrutinib, an Oral BTK Inhibitor, in Immune Thrombocytopenia

Cited by 61 publications

References 22 publications

BTK inhibitors in the treatment of hematological malignancies and inflammatory diseases: mechanisms and clinical studies

BTK inhibitors in the treatment of hematological malignancies and inflammatory diseases: mechanisms and clinical studies

Novel Therapies to Address Unmet Needs in ITP

Current therapeutic strategies and perspectives in refractory ITP: What have we learned recently?

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