ND-2110 / Roche, Nimbus Therap - LARVOL DELTA

Preclinical Activity of IRAK4 Kinase Inhibitor CA-4948 Alone or in Combination with Targeted Therapies and Preliminary Phase 1 Clinical Results in Non-Hodgkin Lymphoma (ASH 2018) - P1; "...In preclinical studies, CA-4948 demonstrates pharmacodynamic and antitumor activity in in vitro and in vivo models with MYD88 alterations, and was previously shown to have a synergistic anti-tumor activity when combined with venetoclax in vivo...Interestingly, neither CA-4948, ibrutinib, nor the combination had anti-tumor activity in Z-138 and GRANTA-591 xenograft models, consistent with these cell lines having activated NF-κB through the alternative NIK signaling pathway...Conclusion : These results provide a rationale for CA-4948 BID dosing and incorporating the use of an ex-vivo whole-blood TLR-stimulation assay as a surrogate PD response biomarker, the former of which will be evaluated in the current Ph1 dose escalation soon and the latter of which is currently being implemented in the Ph1 trial for patients with advanced NHL. The murine xenograft results further support exploration of CA-4948 as monotherapy and in combination with canonical and alternative...

Combination therapy • IO biomarker • P1 data • Biosimilar • Diffuse Large B Cell Lymphoma • Hematological Disorders • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

Phase 1 Study of CA-4948, a Novel Inhibitor of Interleukin-1 Receptor-Associated Kinase 4 (IRAK4) in Patients with R/R Non-Hodgkin Lymphoma (NHL) (SOHO 2019) - P1; "Preliminary PD data has shown on target reduction of NF-kB-associated factors such as IL-6 post-TLR stimulation ex vivo, similar to murine studies.Conclusions CA-4948 demonstrates excellent PK, PD and safety in patients, with characterization of MTD and RP2D ongoing. Clinical trial: NCT03328078."

Clinical • IO Biomarker • P1 data

Phase 1 study of CA-4948, a novel inhibitor of interleukin-1 receptor-associated kinase 4 (IRAK4) in patients (pts) with r/r non-Hodgkin lymphoma. (ASCO 2019) - P1; "Current dose/schedule is well tolerated with preliminary PK and PD effects at the initial dose level. MTD has not been reached. Clinical trial information: NCT03328078"

Clinical • IO biomarker • P1 data • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

Comparative transcriptome analyses define genes and gene modules differing between two Populus genotypes with contrasting stem growth rates. (PubMed, Biotechnol Biofuels) - "This study illustrated that active division and expansion of vascular cambium cells and secondary cell wall deposition of xylem cells contribute to stem radial increment and biomass accumulation, and it identified relevant genes for these complex growth traits, including a BELL transcription factor gene PeuBELL15. This provides genetic resources for improving and breeding elite genotypes with fast growth and high wood biomass."

Journal

[VIRTUAL] HIGH SPECIFIC IMMUNE RESPONSE AND LOW T-CELL ACTIVATION IN CHILDREN WITH COVID-19 (CROI 2021) - " VL did not differ by age (18507 [326-339315], 6723 [3427-114587], and 21106 [162-152500] copies/5µl, in group A, B and C, respectively; overall, p=0.955)... Levels of SARS-CoV-2 did not differ among age classes, but adults displayed a higher T cell activation and a lower production of anti-SARS Nabs than children. Conversely, younger infected children had the highest production of anti-SARS Nabs and the lowest non-specific T cell activation, most likely due to their higher expression of regulatory T cells."

Clinical • IO biomarker • Infectious Disease • Novel Coronavirus Disease • Pediatrics • Respiratory Diseases • CD4 • CD8 • FOXP3 • IL2RA • IL7R

Phosphorylation of Microglial IRF5 and IRF4 by IRAK4 Regulates Inflammatory Responses to Ischemia. (PubMed, Cells) - "IRAK4 signaling is critical for microglial inflammatory responses and a potential therapeutic target for neuroinflammatory diseases including cerebral ischemia."

Journal • Immunology • Inflammation • IL4 • MYD88

Targeting IRAK4 disrupts inflammatory pathways and tumor microenvironment in chronic lymphocytic leukemia regardless MYD88 mutational status (AACR 2018) - "A significant reduction in monocyte absolute counts in spleen and skewing to inflammatory Ly6C+ monocytes in peritoneal cavity was detected after ND2158 treatment, thereby disrupting the support for tumor cells.CONCLUSION. Our findings support pharmacological inhibition of IRAK4 as a potential therapeutic strategy in CLL cells regardless of their MYD88 mutational status, indicating that TLR signaling plays an important role in CLL cells development and CLL tumor microenvironment."

Biomarker • IO Biomarker • Tumor microenvironment • Chronic Lymphocytic Leukemia • Indolent Lymphoma

[VIRTUAL] TREATMENT PATTERNS IN PULMONARY ARTERIAL HYPERTENSION: CHANGES IN CLINICAL PRACTICE OVER TIME USING REAL-WORLD EVIDENCE FROM THE COMBINED OPUS/ORPHEUS DATA SETS (CHEST 2020) - P=N/A | " As of Sept 2019, the OPUS/OrPHeUS PAH follow-up set comprised 4428 patients, of whom 2318 (52%) initiated macitentan pre-GL and 2110 (48%) initiated macitentan post-GL. The majority of patients initiating macitentan received combination therapy at baseline and 6 months post-baseline across all years reported. However, these proportions remained relatively constant over time, despite recommendations for increased use of combination therapy in the 2015 ESC/ERS PAH GL. CLINICAL IMPLICATIONS: Despite the recommendations in the 2015 ESC/ERS PAH Guidelines for increased use of combination therapy, a substantial proportion of patients still initiate and are maintained on monotherapy."

Clinical • HEOR • Real-World Evidence • Hypertension • Pulmonary Arterial Hypertension

Factors affecting calving ease in Egyptian buffalo. (PubMed, Reprod Domest Anim) - "A total of 9627 records from 1999 MP and 2110 PP recorded during the period from 1988 to 2018 was considered...Direct and maternal heritabilities of CE in PP and MP were 0.06 and 0.01, respectively. The low heritability of CE indicated that direct selection may not be an effective method to improve CE trait in Egyptian buffalo."

Journal

Targeting IRAK4 disrupts inflammatory pathways and delays tumor development in chronic lymphocytic leukemia. (PubMed, Leukemia) - "In the Eµ-TCL1 adoptive transfer mouse model of CLL, ND2158 delayed tumor progression and modulated the activity of myeloid and T cells. Our findings show the importance of TLR signaling in CLL development and suggest IRAK4 as a therapeutic target for this disease."

IO Biomarker • Journal • Chronic Lymphocytic Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology

Phosphorylation of IRF5/4 by IRAK4/MyD88 Regulates Microglial Inflammatory Responses to Ischemia (ISC 2020) - "Phosphorylation of IRF5/4 by IRAK4 was determined with IRAK4 inhibitor (ND-2158)...Manipulation of IRF5/4 signaling potentially represents a novel therapeutic strategy for stroke. 1"

IL10 • IL1B • IL4 • IL6 • IRF4

TARGETING IRAK4 DISRUPTS INFLAMMATORY PATHWAYS AND DELAYS TUMOR DEVELOPMENT IN CHRONIC LYMPHOCYTIC LEUKEMIA (EHA 2019) - "We further observed a decrease in NF-κB and STAT3 signaling, cytokine secretion, proliferation and migration of primary CLL cells from MYD88-mutated and –unmutated cases. In the Eµ-TCL1 adoptive transfer mouse model of CLL, ND2158 delayed tumor progression and modulated the activity of myeloid and T cells. Conclusion Our findings show the importance of TLR signaling in CLL development and suggest IRAK4 as a therapeutic target for this disease."

IO Biomarker