rilzabrutinib (SAR444671) / Sanofi - LARVOL DELTA

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

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

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 • Rheumatoid Arthritis • Rheumatology • Targeted Protein Degradation

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

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 | Not yet recruiting | Sponsor: Sanofi

New P2 trial • Focal Segmental Glomerulosclerosis • Glomerulonephritis • Lupus Nephritis • Nephrology

BTKi of Varying Specificity are Potent Inhibitors of Platelet ITAM Signaling Pathways (ISTH 2024) - "Washed platelets were prepared and treated with DMSO vehicle or one of five BTKi drugs (ibrutinib, zanubrutinib, acalabrutinib, remibrutinib, and rilzabrutinib) before activating platelets with collagen-related peptide (3 µg/ml CRP; GPVI pathway), fucoidan (100 µg/ml, CLEC-2 pathway), and ristocetin (0.5 mg/ml, GPIb pathway). Aggregation induced by low-dose CRP was completely inhibited by the addition of all BTKi at 2 µM and all but acalabrutinib at 400 nM (Figure 1). Aggregation induced by fucoidan and by R6H8 were inhibited by all the BTKi at 400 nM, including acalabrutinib. Aggregation induced by T6 or ristocetin was not inhibited by the three BTKi tested."

Cardiovascular • Hematological Disorders • Thrombocytopenia • Thrombosis

ZANUBRUTINIB AND ELTROMBOPAG AS SECOND-LINE TREATMENTS FOR PATIENTS WITH IMMUNE THROMBOCYTOPENIA: AN OPEN-LABEL, RANDOMIZED, CONTROLLED, PHASE 2 TRIAL (EHA 2024) - P2 | "Despite the variety of availablesubsequent treatments, such as thrombopoietin receptor agonists, rituximab, recombinant humanthrombopoietin, and splenectomy, neither durable responses nor long-term remissions are guaranteed...reported that rilzabrutinib, an oral BTK inhibitor used as a second-line treatment for refractory ITP, couldlead to an overall response of 40%... Zanubrutinib plus eltrombopag showed an encouraging response rate and tolerability in patients withrefractory ITP. This finding suggested that BTK inhibitors such as zanubrutinib might be promising candidatesfor patients with corticosteroid-resistant or refractory primary immune thrombocytopenia."

Clinical • P2 data • Hematological Disorders • Thrombocytopenia • Thrombocytopenic Purpura

BASIC CHARACTERISTICS OF ADULT PATIENTS WITH PREVIOUSLY TREATED IMMUNE THROMBOCYTOPENIA ENROLLED IN LUNA 3 PHASE 3 PLACEBO-CONTROLLED STUDY OF RILZABRUTINIB, AN ORAL BRUTON TYROSINE KINASE INHIBITOR (EHA 2024) - P3 | "Patients should have previous but unsustained response (platelet count ≥50×109/L) to corticosteroids (CS) orintravenous immunoglobulin (IVIg)/anti-D, or documented intolerance or insufficient response to anyappropriate courses of standard-of-care ITP therapy. The ongoing LUNA 3 multicenter, phase 3 study includes ITP patients from multiplegeographical regions with varying disease characteristics, with ~half having received ≥5 therapies atenrollment. This pivotal study is designed to provide placebo-controlled evidence for the efficacy and safety ofrilzabrutinib in patients with primary ITP who had insufficient response to or were intolerant of prior ITPtherapies. **"

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

EFFECTS OF ORAL BRUTON TYROSINE KINASE INHIBITOR RILZABRUTINIB ON THE PLATELET VARIABILITY INDEX SCORE IN PATIENTS WITH IMMUNE THROMBOCYTOPENIA: PHASE 2 STUDY (EHA 2024) - P2 | "Among previously treated patients with ITP who responded to rilzabrutinib, PVI scores from baseline decreasedas platelet counts increased with treatment, whereas this was not observed in non-responders. These resultsmay indicate more stable platelet counts and an overall reduction in disease severity with continuedrilzabrutinib treatment."

Clinical • P2 data • Hematological Disorders • Thrombocytopenia • Thrombocytopenic Purpura

LONG-TERM SAFETY AND EFFICACY OF RILZABRUTINIB, AN ORAL BRUTON TYROSINE KINASE INHIBITOR, IN PATIENTS WITH IMMUNE THROMBOCYTOPENIA (ITP): INTEGRATED PHASE 2 PART A AND PART B (EHA 2024) - P2 | "Pooled analyses of LTE patients demonstrated high and durable platelet counts withrilzabrutinib monotherapy or with concomitant ITP medication. Patients discontinuing concomitant ITP therapymaintained high platelet counts. Rilzabrutinib remains well tolerated with continued treatment in previouslytreated patients with ITP."

Clinical • P2 data • Hematological Disorders • Infectious Disease • Influenza • Respiratory Diseases • Thrombocytopenia • Thrombocytopenic Purpura

CLINICAL PREDICTORS OF RESPONSE TO THE ORAL BRUTON TYROSINE KINASE INHIBITOR RILZABRUTINIB IN PREVIOUSLY TREATED PATIENTS WITH IMMUNE THROMBOCYTOPENIA: POOLED ANALYSIS OF PHASE 2 STUDY (EHA 2024) - P2 | "008) and no prior rituximab (P=0. In patients who received prior ITP therapies, the strongest predictors of response to rilzabrutinib were higherbaseline platelet counts and no prior use of TPO-RA, suggesting that patients who were more treatment naivewere more likely to respond to rilzabrutinib therapy. Continued evaluation of potential predictors of responsein larger sample sizes is warranted to further support these findings."

P2 data • Retrospective data • Hematological Disorders • Thrombocytopenia • Thrombocytopenic Purpura

Sustained efficacy of a case with refractory primary immune thrombocytopenia after treatment with Zanubrutinib (ISTH 2024) - "Bruton’s tyrosine inhibitor (BTKi) Rilzabrutinib has been reported to be effective in chronic or persistent ITP...During the following year, he had tried low dose of decitabine, rituximab, cyclosporine A and Oseltamivir without effect... His platelet count increased after around 10 days. Since then, the corticosteroid was tapered. Now he was treated with 80mg/d of Zanubrutinib and very low dose of cyclosporin and 20mg of Avatrombopag."

Clinical • Hematological Disorders • Immunology • Respiratory Diseases • Thrombocytopenia • Thrombocytopenic Purpura

Pooled Analysis of the Efficacy and Safety of Oral Bruton Tyrosine Kinase Inhibitor Rilzabrutinib in Patients With Previously Treated Immune Thrombocytopenia: Phase 2 Study (ISTH 2024) - P2 | "As of 31Jan2023, 71 ITP patients from part A (n=45) and part B (n=26) were included. At enrollment, patients had a median age of 52 years (range, 19-75), median duration of ITP for 7.3 years (range, 0.4-52.5), and 32% were splenectomized. Twenty-nine (41%) patients met the primary endpoint (ie, responders), including 10/24 (42%) patients receiving rilzabrutinib monotherapy and 19/47 (40%) rilzabrutinib with concomitant ITP therapy."

P2 data • Retrospective data • Hematological Disorders • Thrombocytopenia • Thrombocytopenic Purpura