rilzabrutinib (SAR444671) / Sanofi - LARVOL DELTA

Efficacy and Safety of Oral Bruton Tyrosine Kinase Inhibitor (BTKi) Rilzabrutinib in Adults with Previously Treated Immune Thrombocytopenia (ITP): A Phase 3, Placebo-Controlled, Parallel-Group, Multicenter Study (LUNA 3) (ASH 2024) - P3 | "In the rilzabrutinib arm, 1 patient with multiple risk-factors had a treatment-related grade 3 peripheral embolism (SAE) and 1 patient died due to pneumonia unrelated to treatment. Conclusion : Pivotal LUNA 3 phase 3 study results in patients with ITP showed that first-in-class BTKi rilzabrutinib has a robust therapeutic effect as shown by rapid and durable platelet response, reduced bleeding and need for rescue therapy, improved physical fatigue and QoL, and favorable safety and tolerability."

Clinical • P3 data • Fatigue • Hematological Disorders • Immune Thrombocytopenic Purpura • Infectious Disease • Pain • Pediatrics • Pneumonia • Respiratory Diseases • Thrombocytopenia • Thrombocytopenic Purpura

Improved Health-Related quality of Life (HRQoL) with Oral Bruton Tyrosine Kinase Inhibitor (BTKi) Rilzabrutinib Vs Placebo in Adults with Previously Treated Immune Thrombocytopenia (ITP): Phase 3 Luna 3 Multicenter Study (ASH 2024) - P3 | "Conclusion : Statistically significant and clinically meaningful improvement in physical fatigue was observed at weeks 13 and 25 with rilzabrutinib vs placebo, with improvements also seen in both durable and non-durable responders and other disease-specific HRQoL endpoints, indicative of potential multiple modalities of action. These HRQoL results provide additional evidence of rilzabrutinib's effects beyond increased platelet counts and reduced bleeding in previously treated adults with ITP."

Clinical • HEOR • P3 data • Fatigue • Hematological Disorders • Immune Thrombocytopenic Purpura • Pediatrics • Thrombocytopenia • Thrombocytopenic Purpura

Bruton Tyrosine Kinase Inhibitor Rilzabrutinib Reduces Vaso-Occlusion and Markers of Inflammation and Adhesion in Transgenic Mice with Sickle Cell Disease (ASH 2024) - "There were no significant differences among treatment groups compared to vehicle for any red blood cell indices. Conclusion : Preclinical data provides evidence that treatment with rilzabrutinib ameliorates inflammation through multiple mechanisms of action and prevents microvascular stasis in Townes SCD mice."

Preclinical • Cardiovascular • Genetic Disorders • Hematological Disorders • Inflammation • Sickle Cell Disease • Thrombosis • CD31 • IL18 • IL1B • NLRP3 • PECAM1 • RELA • TLR4

Part a Efficacy and Safety of Oral Bruton Tyrosine Kinase Inhibitor (BTKi) Rilzabrutinib in Patients with Warm Autoimmune Hemolytic Anemia (wAIHA): Multicenter, Open-Label, Phase 2b Study (ASH 2024) - P2 | "Conclusion : Rilzabrutinib in previously treated patients with primary wAIHA resulted in robust efficacy based on overall and durable Hb response, decreased hemolysis, and clinically meaningful improvement in fatigue. Rilzabrutinib was well-tolerated with a favorable safety profile in patients with wAIHA."

Clinical • P2b data • Anemia • Autoimmune Hemolytic Anemia • Cardiovascular • Complement-mediated Rare Disorders • Fatigue • Hematological Disorders • Immunology • Inflammatory Arthritis • Pain

LUNA3: Study to Evaluate Rilzabrutinib in Adults and Adolescents With Persistent or Chronic Immune Thrombocytopenia (ITP) (clinicaltrials.gov) - P3 | N=194 | Active, not recruiting | Sponsor: Principia Biopharma, a Sanofi Company | Recruiting ➔ Active, not recruiting

Enrollment closed • Hematological Disorders • Immune Thrombocytopenic Purpura • Thrombocytopenia • Thrombocytopenic Purpura

Press Release: ASH: rilzabrutinib demonstrated significant patient benefit in the first positive phase 3 study of a BTK inhibitor in ITP (GlobeNewswire) - P3 | N=193 | LUNA 3 (NCT04562766) | Sponsor: Principia Biopharma, a Sanofi Company | "Positive results from the pivotal LUNA 3 phase 3 study of rilzabrutinib in adults with persistent or chronic immune thrombocytopenia (ITP)....Platelet response was achieved in 65% (n=86) of patients receiving rilzabrutinib compared to 33% (n=23) of patients on placebo. The primary endpoint was met, with rilzabrutinib demonstrating durable platelet response in 23% of ITP adult patients compared to 0% on the placebo arm (p<0.0001), as well as key secondary endpoints including reduced bleeding, number of weeks with platelet response, the need for rescue therapy use, and improved physical fatigue and quality of life measures. These results were presented today at the 66th American Society of Hematology (ASH) Annual Meeting and Exposition in San Diego, December 7-10, 2024."

P3 data • Immune Thrombocytopenic Purpura

NX-5948, a Clinical-Stage BTK Degrader, Achieves Deep Suppression of BCR, TLR, and FcR Signaling in Immune Cells and Demonstrates Efficacy in Preclinical Models of Arthritis and Other Inflammatory Diseases (ACR Convergence 2024) - P1 | "In the established CIA model at 30 mg/kg, 10/12 mice treated with NX-5948 displayed complete resolution of paw swelling, compared to 2/12 mice treated with rilzabrutinib and 7/12 mice treated with ibrutinib. NX-5948 is a clinical stage BTK degrader that potently suppresses BCR, TLR, and FcR signaling in vitro and demonstrates efficacy across multiple disease models. NX-5948 is a clinical stage BTK degrader that potently suppresses BCR, TLR, and FcR signaling in vitro and demonstrates efficacy across multiple disease models. Regardless of model type, NX-5948 displayed comparable or better efficacy than BTK inhibitors, supporting the hypothesis that BTK degradation confers a significant therapeutic benefit over BTK inhibition by removing both kinase and scaffolding functions. These preclinical results support initiation of clinical development of NX-5948 in autoimmune and inflammatory disease settings."

Immune cell • Preclinical • CNS Disorders • Glomerulonephritis • Immunology • Inflammation • Lupus Nephritis • Multiple Sclerosis • Nephrology • Oncology • Rheumatology • Targeted Protein Degradation

Autoimmune Hemolytic Anemias: Challenges in Diagnosis and Therapy. (PubMed, Transfus Med Hemother) - "Therapy is quite different, as steroids and rituximab are effective in the former, but have a lower response rate and duration in the latter...Several new drugs are increasingly used or are in trials for relapsed/refractory AIHAs, including B-cell (parsaclisib, ibrutinib, rilzabrutinib), and plasma cell target therapies (bortezomib, daratumumab), bispecific agents (ianalumab, obexelimab, povetacicept), neonatal Fc receptor blockers (nipocalimab), and complement inhibitors (sutimlimab, riliprubart, pegcetacoplan, iptacopan)...Along with all these variables, there are rare forms like mixed (wAIHA plus CAD), atypical (IgA or warm IgM driven), and DAT negative, where the diagnosis and clinical management are particularly challenging. This article covers the classic clinical features, diagnosis, and therapy of wAIHA and CAD, and focuses, with the support of clinical vignettes, on difficult diagnosis and refractory/relapsing cases requiring novel therapies."

Journal • Review • Anemia • Autoimmune Hemolytic Anemia • Cardiovascular • Complement-mediated Rare Disorders • Hematological Disorders • Immunology • Infectious Disease • Oncology • Rare Diseases • Thrombosis • Transplantation

Therapies for Chronic Spontaneous Urticaria: Present and Future Developments. (PubMed, Pharmaceuticals (Basel)) - "If symptoms persist despite this adjustment, the next step involves the use of omalizumab, a monoclonal anti-IgE antibody, which has shown efficacy in the majority of cases. However, a subset of patients remains refractory, necessitating alternative treatments such as immunosuppressive agents like cyclosporine or azathioprine...Among them, significant attention is being given to drugs that block Bruton's tyrosine kinase (BTK), such as remibrutinib, which reduces mast cell activation. Therapies like dupilumab, which target the interleukin-4 (IL-4) and IL-13 pathways, are also under investigation. Additionally, molecules targeting the Mas-related G protein-coupled receptor X2 (MRGPRX2), and those inhibiting the tyrosine kinase receptor Kit, such as barzolvolimab, show promise in clinical studies...Further research is essential to better elucidate the pathophysiology of CSU and optimize treatment protocols to achieve long-term benefits in managing this condition...."

Journal • Review • Cardiovascular • Chronic Spontaneous Urticaria • Dermatology • Immunology • Urticaria • BTK • IL13 • IL4

Evaluation of the Safety Profile of Rilzabrutinib at 12 Weeks in Patients With Chronic Spontaneous Urticaria in the Phase 2 RILECSU Dose-Finding Study (JDP 2024) - No abstract available

Clinical • P2 data • Chronic Spontaneous Urticaria • Dermatology • Immunology • Urticaria

Open Label Two-Arm Study to Evaluate Rilzabrutinib in IgG4-Related Disease Patients (clinicaltrials.gov) - P2 | N=27 | Completed | Sponsor: Principia Biopharma, a Sanofi Company | Active, not recruiting ➔ Completed

Trial completion • Inflammation

RESULT Umbrella Trial in Primary Focal Segmental Glomerulosclerosis/Minimal Change Disease (KIDNEY WEEK 2024) - "We describe the protocol and operational feasibility for the Renal Efficacy Signaling UmbrelLa Trial (RESULT). RESULT is an innovative global Phase 2a randomized, placebo-controlled umbrella trial that simultaneously evaluates the safety and efficacy of 3 novel therapies targeting immunological pathways implicated in primary FSGS/MCD: frexalimab (anti-CD40L monoclonal antibody), SAR442970 (anti-OX40L and anti-TNFα bispecific), and rilzabrutinib (BTK-inhibitor). This global RESULT Phase 2a trial utilizes an innovative efficacy signal-seeking master protocol to simultaneously evaluate 3 immunologically active therapies in FSGS/MCD and is the first umbrella trial in nephrology. Operational feasibility and stakeholder feedback demonstrate high scientific and medical interest, as well as appropriateness of trial design and assessments."

Chronic Kidney Disease • Focal Segmental Glomerulosclerosis • Glomerulonephritis • Pediatrics • CD40LG • TNFSF4

Rilzabrutinib: Regulatory submissions in Japan/China for immune thrombocytopenic purpura in H1 2025 (Sanofi) - Q3 2024 Results

China filing • Japan filing • Immune Thrombocytopenic Purpura • Immunology

Baseline characteristics of adult patients with previously treated immune thrombocytopenia enrolled in the LUNA 3 placebo-controlled Phase 3 study of rilzabrutinib, an oral Bruton's tyrosine kinase inhibitor (DGHO 2024) - P3 | "Eligible patients have primary ITP for a duration of >3 months for adults (age ≥18 years) and >6 months for adolescents (age 12–17 years [age 10–12 years allowed in EU]); 2 averaged platelet counts <30×10 9 /L within 2 weeks before treatment; and previous but unsustained platelet response to corticosteroids (CS) or intravenous immunoglobulin (IVIg)/anti-D, or documented intolerance or insufficient response to standard-of-care ITP therapy. The ongoing LUNA 3 study includes patients with ITP from multiple geographical regions with varying disease characteristics, with ~half having received ≥5 therapies at enrollment."

Clinical • P3 data • Hematological Disorders • Immune Thrombocytopenic Purpura • Pediatrics • Thrombocytopenia • Thrombocytopenic Purpura

RESULT: A Study to Evaluate the Efficacy and Safety of Frexalimab, SAR442970, or Rilzabrutinib in Participants Aged 16 to 75 Years With Primary Focal Segmental Glomerulosclerosis or Minimal Change Disease (clinicaltrials.gov) - P2 | N=84 | Recruiting | Sponsor: Sanofi | Not yet recruiting ➔ Recruiting

Enrollment open • Focal Segmental Glomerulosclerosis • Glomerulonephritis • Lupus Nephritis • Nephrology

New drugs for the treatment of primary immune thrombocytopenia (PubMed, Rinsho Ketsueki) - "Two thrombopoietin receptor agonists (eltrombopag and romiplostim), rituximab or splenectomy have been recommended for the treatment of glucocorticoid-resistant ITP in Japanese guidelines. In addition, the Syk inhibitor fostamatinib and FcRn inhibitor efgartigimod were approved in Japan for refractory ITP in 2023 and 2024, respectively. Clinical trials have also reported promising results for the new thrombopoietin receptor agonist avatrombopag, the BTK inhibitor rilzabrutinib, and the C1s inhibitor sutimlimab. These developments will usher in a new era in the treatment of ITP."

Journal • Hematological Disorders • Immune Thrombocytopenic Purpura • Thrombocytopenia • Thrombocytopenic Purpura • SYK

A 12-Week Safety Assessment of Rilzabrutinib in Patients With Chronic Spontaneous Urticaria From the RILECSU Phase 2 Dose-Ranging Study (EADV 2024) - P2 | "Rilzabrutinib showed an acceptable safety profile and was well tolerated in the 12-week double-blind period of the RILECSU dose-ranging study in adults with moderate to severe CSU. Table: Most common TEAEs through Week 12 (≥ 10% in any group) TEAEs through Week 12, n (%) Placebo (N=40) Rilzabrutinib 400 mg QPM (N=38) Rilzabrutinib 400 mg BID (N=41) Rilzabrutinib 400 mg TID (N=41) Diarrhea 6 (15.0) 3 (7.9) 12 (29.3) 12 (29.3) Nausea 2 (5.0) 5 (13.2) 7 (17.1) 8 (19.5) Headache 0 2 (5.3) 6 (14.6) 4 (9.8) Abdominal pain 2 (5.0) 1 (2.6) 5 (12.2) 0"

Clinical • P2 data • Atrial Fibrillation • Cardiovascular • Chronic Spontaneous Urticaria • Dermatology • Hematological Disorders • Immunology • Infectious Disease • Pain • Urticaria • BTK

Rilzabrutinib reduces biomarkers related to itch and disease severity in chronic spontaneous urticaria and atopic dermatitis (EADV 2024) - P2 | "Significant improvements in weekly ISS7 and relative change in weekly average of daily PP-NRS scores were observed with rilzabrutinib in patients with CSU and AD, respectively. Rilzabrutinib reduces biomarkers associated with itch and disease severity in CSU and AD, suggesting that rilzabrutinib has the potential to treat itch-related conditions."

Biomarker • Atopic Dermatitis • Chronic Spontaneous Urticaria • Dermatitis • Dermatology • Immunology • Pruritus • Urticaria

Rilzabrutinib improves itch in atopic dermatitis (EADV 2024) - P2 | "Rapid improvement in absolute and relative change in weekly average of daily PP-NRS was demonstrated with rilzabrutinib.** RNA-seq and gene set enrichment data show rilzabrutinib dampens itch signalling not only through inhibition of pruritogen secretion but also by reducing neurosensory signalling, suggesting that rilzabrutinib could be an attractive drug for the treatment of itch-related conditions."

Atopic Dermatitis • Dermatitis • Dermatology • Immunology • Pruritus • BTK

Late Breaking Abstract - Efficacy of high- and low-dose rilzabrutinib from a phase 2 study (ERS 2024) - P2 | "Rilzabrutinib was associated with reduced LOAC as well as significant and clinically meaningful improvement in asthma control over 12 weeks vs placebo."

Clinical • Late-breaking abstract • P2 data • Asthma • Immunology • Respiratory Diseases

Rilzabrutinib, a potent and selective Bruton's tyrosine kinase inhibitor, suppresses reactive oxygen species production and CD11b activation in human eosinophils (ERS 2024) - "This study is the first to demonstrate that BTK plays a novel role in human eosinophil activation and ROS generation elicited by IL-5 and LPS. These findings provide preclinical support for the therapeutic potential of rilzabrutinib in treating inflammatory diseases in which eosinophils play an integral role."

Asthma • Immunology • Inflammation • Respiratory Diseases • IL5 • ITGAM • TLR4

Selective Btk inhibition by PRN1008/PRN473 blocks human CLEC-2 & PRN473 reduces venous thrombosis formation in mice. (PubMed, Blood Adv) - "Treatment with ibrutinib is associated with increased bleeding due to off-target inhibition of Src family kinases (SFKs). PRN473 significantly reduced the number of thrombi in podoplanin positive vessels following Salmonella infection and the presence of IVC thrombosis following vein stenosis. The potent inhibition of human platelet CLEC-2, and reduced thrombosis in in vivo models, together with the lack of off-target SFK inhibition and absence of bleeding reported in rilzabrutinib treated immune thrombocytopenia patients, suggest Btk inhibition as a promising antithrombotic strategy."

Journal • Preclinical • Cardiovascular • Hematological Disorders • Immunology • Infectious Disease • Primary Immunodeficiency • Thrombocytopenia • Thrombocytopenic Purpura • Thrombosis • Venous Thromboembolism • PDPN

Novel treatments for immune thrombocytopenia: targeting platelet autoantibodies. (PubMed, Expert Rev Hematol) - "Treatments outlined in this review include a) FcRn antagonists (efgartigimod), b) complement inhibitors (sutimlimab), c) B-cell directed therapies such as BTK inhibitors (rilzabrutinib), anti-BAFF agents (belimumab, ianalumab), and Syk inhibitors (fostamatinib, sovleplenib), d) plasma-cell directed therapies (daratumumab, bortezomib), and e) cellular therapeutic products. Platelet antibodies are often elusive in ITP; yet novel treatments targeting this pathway reinforce their role in the pathogenesis of this autoimmune platelet disorder."

Journal • Review • Hematological Disorders • Immunology • Thrombocytopenia • Thrombocytopenic Purpura • SYK

Rilzabrutinib: Regulatory submissions in US/EU for immune thrombocytopenic purpura in H2 2024 (Sanofi) - Q2 2024 Results

EMA filing • FDA filing • Immunology • Thrombocytopenic Purpura

Rilzabrutinib: Data from P2b trial (NCT05002777) in patients with warm autoimmune hemolytic anemia in H2 2024 (Sanofi) - Q2 2024 Results

P2b data • Autoimmune Hemolytic Anemia • Immunology