R 835 / Rigel - LARVOL DELTA

Safety and efficacy results from A phase 1b study of R289, a dual irak 1/4 inhibitor, in patients with Relapsed/Refractory (R/R) lower risk myelodysplastic syndrome (LR-MDS). (ASH 2025) - P1/2 | "The median number of prior therapies was 3 (range 1-8); 76% were previouslytreated with luspatercept, 73% with an erythropoiesis stimulating agent, 67% with a hypomethylatingagent, and 6% with imetelstat. R289 was well-tolerated in this elderly, heavily pretreated LR-MDS patient population, themajority of whom were HTB at BL. The incidence of G3/4 cytopenias and infections was low. Allresponding patients had R835 plasma concentrations similar to those at which ≥50% LPS-inducedinhibition of cytokine release was observed in HS, indicating a potential threshold for dose response(≥500 mg QD)."

Clinical • P1 data • Constipation • Gastroenterology • Gastrointestinal Disorder • Hematological Disorders • Hematological Malignancies • Infectious Disease • Inflammation • Myelodysplastic Syndrome • Pneumonia • Respiratory Diseases • HEY1 • IL1R1 • IRAK1 • TLR4

Phase 1b Trial of Irak 1/4 Inhibition for Low-Risk Myelodysplastic Syndrome Refractory/Resistant to Prior Therapies: A Trial in Progress (ASH 2023) - P1/2 | "R289 is a prodrug that is converted to the active drug R835 in the gastrointestinal (GI) tract...The trial is currently recruiting at 9 US sites. The study has enrolled 7 patients in the dose escalation phase."

IO biomarker • P1 data • Anemia • Chronic Myelomonocytic Leukemia • Gastrointestinal Disorder • Hematological Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • CRP • IL1R1 • IRAK1 • IRAK4 • NLRP3 • TLR4 • TNFA

R289, a Dual Irak 1/4 Inhibitor, in Patients with Relapsed/Refractory (R/R) Lower-Risk Myelodysplastic Syndrome (LR-MDS): Initial Results from a Phase 1b Study (ASH 2024) - P1/2 | "R835 is a selective dual inhibitor of IRAK 1/4 that blocks TLR4 and IL-1R-dependent cytokine release in vitro and in vivo...Those with del (5q) must be R/R to lenalidomide...Prior therapies included luspatercept [n=15 (79%)], hypomethylating agent (HMA) [n=15 (79%)]...Further evaluation of 250 mg BID and a 500/250 mg daily split dose is ongoing. An expansion cohort is planned to confirm a recommended phase 2 dose."

Clinical • P1 data • Acute Myelogenous Leukemia • Anemia • Fatigue • Hematological Disorders • Hematological Malignancies • Infectious Disease • Leukemia • Myelodysplastic Syndrome • Oncology • Pneumonia • Respiratory Diseases • IL1R1 • IRAK1 • MYD88 • TLR4

Meta-analyses of clozapine, norclozapine levels and their ratio across three genome wide association studies. (PubMed, Transl Psychiatry) - "We suggest a UGT2B10 missense SNP rs61750900, in perfect linkage disequilibrium with UGT2B10 rs835309, as the probable causal variant. Our study confirms and extends the number of genetic variants affecting clozapine and norclozapine metabolism."

Clinical • Journal • CYP1A1 • CYP1A2 • NFIB

Genetic Variants in Antioxidant Genes Modulate the Relationships Among Obesity-Related Oxidative Stress Markers in Mexican Children. (PubMed, Antioxidants (Basel)) - "We aimed to assess the direct and modulatory effects of SNPs in antioxidant genes (SOD2 rs4880, GPX1 rs1050450, GPX7 rs835337, CAT rs1001179) on the relationships among obesity-related oxidative stress markers in Mexican children...The inverse association between sTAC and TBARS remained significant only in non-carriers of SOD2 rs4880 (p = 0.003) and GPX1 rs1050450 (p = 0.002). Our data evidence that sTAC and TBARS are associated with obesity, showing a negative relationship in Mexican children who are non-carriers of SOD2 rs4880 and GPX1 rs1050450."

Journal • Genetic Disorders • Obesity • GPX1 • GPX7 • SOD2

Association of LPCAT1-rs8352 genetic variant with susceptibility and severity of pediatric bronchial asthma: a case-control study. (PubMed, BMC Pediatr) - "The LPCAT1-rs8352 allele C is associated with pediatric asthma onset and severity. Further research on the LPCAT1 genetic variants may provide a deeper understanding of pediatric bronchial asthma mechanisms and lead to improved management strategies."

Biomarker • Journal • Asthma • Immunology • Pediatrics • Pulmonary Disease • Respiratory Diseases • CRP • LPCAT1

Phase 1b trial of IRAK 1/4 inhibition for low-risk myelodysplastic syndrome refractory/resistant to prior therapies. (ASCO 2024) - P1b | "R289 is a prodrug for R835, a potent and selective inhibitor of IRAK1 and IRAK4 kinases. Statistical analyses will be primarily descriptive. The trial is currently ongoing at 9 US sites."

P1 data • Hematological Disorders • Hematological Malignancies • Inflammation • Myelodysplastic Syndrome • Oncology • Pain • IL1R1 • IRAK1 • IRAK4 • NLRP3

Integrative Multi-omics Analysis Identifies Genetic Variants Contributing to Non-syndromic Cleft Lip with or without Cleft Palate. (PubMed, Chin J Dent Res) - "Our study identified five SNPs (rs7218002, rs835367, rs77022994, rs961470 and rs17314727) and three susceptibility genes (NTN1, FGGY and LINC01135) associated with NSCL/P. These findings contribute to a better understanding of the genetic factors involved."

Journal • NTN1

Pathophysiology of migraine aura. (PubMed, Handb Clin Neurol) - "In the first genome-wide association study (GWAS) that focused migraine with aura, a single SNP rs835740 reached genome-wide significance. Unfortunately, the SNP did show statistical significance in a later meta-analysis which included GWAS data from subsequent studies. Here, we review the clinical features, pathophysiological theories, and currently available potential evidence for the genetic basis of migraine aura."

Journal • CNS Disorders • Depression • Migraine • Pain • Psychiatry • CACNA1A

R851, a Potent Second Generation IRAK1 and IRAK4 Inhibitor Suppresses IL-6 in Vitro and in Vivo for the Treatment of Rheumatoid Arthritis (ACR Convergence 2023) - "As a result, inhibition of IRAK4 has been investigated as a means of attenuating a range of autoimmune diseases including rheumatoid arthritis, with zimlovisertib demonstrating encouraging results in a Phase 2 rheumatoid arthritis study. Using the knowledge gained in the development of R835, we have identified R851 as a second generation dual IRAK1 and IRAK4 inhibitor. The increased potency in whole blood assays is believed to be driven by a reduction in protein binding. We predict that R851 will require a significantly lower exposures for efficacy in humans which should position this molecule for a chronic condition like rheumatoid arthritis."

Preclinical • Hematological Malignancies • Immunology • Inflammation • Inflammatory Arthritis • Myelodysplastic Syndrome • Oncology • Rheumatoid Arthritis • Rheumatology • IL23A • IL6 • IRAK4 • TLR3 • TNFA

CD147 rs8259T>A Variant Confers Susceptibility to COVID-19 Infection within the Mexican Population. (PubMed, Microorganisms) - "Our results suggest that the CD147 rs8259T>A variant is a risk factor for COVID-19."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases • BSG • CD14

PHASE 1B CLINICAL STUDY OF IRAK 1/4 INHIBITION FOR LOW-RISK MYELODYSPLASTIC SYNDROMES REFRACTORY/RESISTANT TO PRIOR THERAPIES: A TRIAL IN PROGRESS (EHA 2023) - P1b | "R289 is a prodrug that is converted to the active drug R835 in the gastrointestinal (GI) tract. Phase I, Myelodysplastic syndrome, Kinase inhibitor, MDS"

Clinical • P1 data • Gastrointestinal Disorder • Hematological Disorders • Hematological Malignancies • Inflammation • Myelodysplastic Syndrome • Oncology • Pain • IL1R1 • IRAK1 • IRAK4 • NLRP3 • TLR4

Phase 1b clinical study of IRAK 1/4 inhibition for low-risk myelodysplastic syndromes refractory/resistant to prior therapies. (ASCO 2023) - P1b | "R289 is a prodrug that is converted to the active drug R835 in the gastrointestinal (GI) tract. The trial is currently recruiting at 8 US sites. Clinical trial information: NCT05308264."

Clinical • P1 data • Gastrointestinal Disorder • Hematological Disorders • Hematological Malignancies • Inflammation • Myelodysplastic Syndrome • Oncology • Pain • IL1R1 • IRAK1 • IRAK4 • NLRP3 • TLR4

Comparative genomic and phenotypic analyses of the virulence potential in Shiga toxin-producing Escherichia coli O121:H7 and O121:H10. (PubMed, Front Cell Infect Microbiol) - "Consistently, both O121:H7 and O121:H10 strains displayed significant reduced cytotoxicity than either the O157:H7 strain EDL933 or the O121:H19 strain RM8352. In fact, the O121:H7 strain RM8082 appeared to cause minimal cytotoxicity to Vero cells. Our study demonstrated distinct evolutionary lineages among the strains of serotypes O121:H19, O121:H10, and O121:H7 and suggested reduced virulence potentials in STEC strains of O121:H10 and O121:H7."

Journal

Effect modification of greenness on the association between heat and mortality: A multi-city multi-country study. (PubMed, EBioMedicine) - "Our findings can inform communities on the potential health benefits of greenspaces in the urban environment and mitigation measures regarding the impacts of climate change."

Journal

Associations of maternal anthropometrics with newborn anogenital distance and the 2:4 digit ratio. (PubMed, Hum Reprod) - "Increased maternal weight and adiposity before and in early pregnancy may lengthen the female AGD, which warrants further investigation."

Journal • Genetic Disorders • Obesity

Rigel Reports Second Quarter 2021 Financial Results and Provides Business Update (PRNewswire) - "During the quarter, Rigel received feedback from the FDA supporting its proposed clinical program to evaluate R289, a pro-drug formulation of R835, in low-risk myelodysplastic syndromes (MDS). Planning is now underway on the Phase 1/2 clinical trial. In June, Rigel entered into a research collaboration with MD Anderson Cancer Center to evaluate Rigel's novel IRAK1/4 inhibitors in a series of preclinical studies of MDS and chronic myelomonocytic leukemia (CMML). The translational research generated from these studies will add to the body of data generated to date on R835 and R289 and further elucidate the therapeutic potential of targeting deregulated innate immune signaling in MDS and CMML."

Licensing / partnership • New P1/2 trial • Chronic Myelomonocytic Leukemia • Hematological Malignancies • Myelodysplastic Syndrome • Oncology

[VIRTUAL] PRECLINICAL EFFICACY OF R835, A NOVEL IRAK1/4 DUAL INHIBITOR, IN RODENT MODELS OF JOINT INFLAMMATION (EULAR 2020) - "R835 is a promising clinical candidate for the treatment of a range of cytokine-driven rheumatological diseases. R835 has proven to have desirable pharmacokinetic properties, was well tolerated and suppressed LPS-induced serum cytokines in healthy volunteers in a recent phase 1 study."

Preclinical • Hematological Disorders • Immunology • Pain • Rheumatoid Arthritis • Rheumatology • IL1B • IL1R1 • TLR4

[VIRTUAL] FIRST-INHUMAN STUDY OF SAFETY, PHARMACOKINETICS AND PHARMACODYNAMICS OF IRAK1/4 INHIBITOR R835 IN HEALTHY SUBJECTS (EULAR 2020) - "R835 was well tolerated after single or multiple dose administrations. The most common AEs were headache and gastrointestinal disturbance. For both of the formulations tested, the PK of R835 was linear and exposure was dose proportional with rapid steady-state attainment following BID administration."

Clinical • P1 data • PK/PD data • Gastrointestinal Disorder • Immunology • Lupus • Rheumatology • CXCL8 • CYP1A2 • IL1B • IL1R1 • IL6 • TLR4

[VIRTUAL] CELL-TYPE SPECIFIC REGULATION OF IL-1R SIGNALING BY R835, A DUAL IRAK1/4 INHIBITOR (EULAR 2020) - "This study has elucidated signaling differences between cell types downstream of the IL-1R. In endothelial cells, as in myeloid cells, the kinase activity of IRAK1 and IRAK4 is required for the activation of all downstream signaling. Unexpectedly, in human fibroblasts, IRAK1/4 kinase activity appears to primarily regulate the JNK pathway, and not the NFkB pathway."

Immunology • CXCL8 • IL1B • IL1R1 • MAPK8 • MYD88 • TLR4

[VIRTUAL] TARGETING IRAK1 AND 4 SIGNALING WITH R835, A NOVEL ORAL SMALL MOLECULE INHIBITOR: A POTENTIAL NEW TREATMENT FOR SYSTEMIC LUPUS ERYTHEMATOSUS (EULAR 2020) - "To our knowledge, R835 is the first dual IRAK1/4 inhibitor to enter clinical development and provides an attractive approach to treat a range of autoimmune and rheumatic diseases, including lupus."

Gene Therapies • Immunology • Lupus • Renal Disease • Rheumatology • Systemic Lupus Erythematosus • IL1R1 • MYD88 • TLR4

[VIRTUAL] R835, A NOVEL IRAK1/4 DUAL INHIBITOR IN CLINICAL DEVELOPMENT, BLOCKS TOLL-LIKE RECEPTOR 4 (TLR4) SIGNALING IN HUMAN AND MOUSE (EULAR 2020) - "Our study demonstrates that R835, through inhibition of IRAK1/4 kinase activity, blocks LPS-induced cytokine production in vitro and in vivo. In a recent phase 1 study, R835 substantially reduced the increase of serum cytokines after an intravenous LPS challenge in healthy volunteers. Importantly, this shows that the pharmacological inhibition of IRAK1/4 pathway by R835 in humans mirrors the results obtained in mice."

Immunology • IL1R1

Rigel announces first quarter 2019 financial results and provides company update (PRNewswire) - "The company's research and development team continues to investigate potential molecules that modulate the immune system, including R835, Rigel's IRAK 1/4 inhibitor currently in Phase 1 development."

Clinical

R 835: Completion of P1 trial in healthy subjects in 2019 (Rigel) - Annual Report 2018

Trial completion date