vecabrutinib (SNS-062) / Viracta Therap - LARVOL DELTA

Clinical Characteristics, Treatment Patterns, and Outcomes of Patients with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) Refractory to Covalent Bruton's Tyrosine Kinase Inhibitor (BTKi) and Exposed to B-Cell Lymphoma 2 Inhibitor (BCL2i) (ASH 2023) - "The therapies received in the first line after BTKi and BCL2i were allogeneic HSCT (4 patients), duvelisib (3 patients), oral CDK9i (2 patients), and 1 patient each with CAR-T, anti-CD20 bispecific antibody, alemtuzumab, vecabrutinib, zanubrutinib; and for patients with RT: venetoclax plus rituximab with anthracycline chemotherapy (2 patients), PI3Ki/PD-1 (1 patient), duvelisib (1 patient) (Figure 1). Patients with CLL/SLL who were failed by BTKi and BCL2i treatment have poor prognosis. Overall response rates to treatment immediately after BTKi and BCL2i treatment are low among doubly refractory patients. More effective treatments are needed to address the unmet therapeutic needs of CLL/SLL patients who are refractory to both BTKi and BCL2i."

Clinical • IO biomarker • B Cell Lymphoma • Bone Marrow Transplantation • Chronic Lymphocytic Leukemia • Leukemia • Lymphoma • Oncology • Richter's Syndrome • Small Lymphocytic Lymphoma • BCL2 • IGH • PD-1 • TP53

NX-5948 and NX-2127 potently degrade a broad array of clinically-relevant BTK mutants that display resistance to inhibitors and other BTK degraders (IWCLL 2023) - P1 | "The C481S and C481R mutations eliminated the anti-proliferative effects of covalent inhibitors ibrutinib, acalabrutinib, and zanubrutinib, whereas the V416L, T474I, and L528W mutations had variable effects on the covalent inhibitors. By contrast, the non-covalent inhibitors pirtobrutinib, vecabrutinib, and fenebruitnib maintained activity against C481S but displayed partially reduced potency against the C481R mutation and dramatically reduced potency against the V416L, T474I, and L528W mutations...These degrader molecules may also have utility in earlier lines of therapy due to their ability to suppress scaffold-mediated BTK signaling. Phase 1a/b trials of NX-5948 and NX-2127 in patients with relapsed or refractory B-cell malignancies are ongoing (NX-5948: NCT05131022; NX-2127: NCT04830137)."

Clinical • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Leukemia • Oncology • BTK • CRBN

Treatment Strategies and Outcomes for Double Refractory chronic lymphocytic leukemia; A single center experience (IWCLL 2023) - "Background: There remains an unmet need for patients with aggressive disease refractory to both Bruton Tyrosine Kinase inhibitors (BTKi) and Venetoclax...Two patients received acalabrutinib and obinutuzumab, one patient had a sustained partial response while the other died due to POD. One patient was started on vecabrutinib and died due to POD. A total of 17 double refractory CLL patients were identified between 2016 and 2021. The median age was 66 years (range 47–80 years), and 10 (58.8%) patients were female. At the time of double refractory status, 15 (88.2%) patients had unmutated IgHV disease, 11 (64.7%) had 17p deletion, while 9 (52.9%) had complex karyotype identified on the CLL fluorescence in situ hybridization (FISH) test."

Clinical • IO biomarker • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • Richter's Syndrome • IGH

Mutations Detected in Real World Clinical Sequencing during BTK Inhibitor Treatment in Chronic Lymphocytic Leukemia (CLL) (IWCLL 2023) - "73 patients had only one BTKi (ibrutinib (IBR), 64; acalabrutinib (ACA), 9). 12 pts had multiple BTKis, 8 with two drugs with IBR first followed by ACA (Nf3, 37.5%), vecabrutinib (Nf1, 12.5%), and PIR (Nf4, 50.0%); and 4 with three or more drugs... Our retrospective report summarizes mutations detected during BTKi treatment and shows that BTK L528W can occur during both covalent and non-covalent BTK inhibitor therapy. Four of six patients who progressed on PIR had T474 mutations. In addition, our results may suggest that activating mutations in RAS/RAF/MAPK pathway are related to BTKi resistance."

Clinical • IO biomarker • Real-world • Real-world evidence • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • BRAF • KRAS • MAP2K1 • NF1 • NOTCH2 • NRAS • PLCG2 • SF3B1 • TP53 • XPO1

Leukemic Presentation and Progressive Genomic Alterations of MCD/C5 Diffuse Large B-cell Lymphoma (DLBCL). (PubMed, Cold Spring Harb Mol Case Stud) - "Despite an initial good clinical response to BTK inhibitor ibrutinib, anti-CD20 antibody rituxan, alkylating agent bendamustine, and hematopoietic stem-cell transplant, the lymphoma relapsed, accompanied by morphologic and molecular evidence of disease progression. Finally, the relapsed lymphoma cells showed in vitro resistance to standard BTK inhibitors but sensitivity to vecabrutinib, active against mutated BTK, and to PIM1 inhibitor. In summary, we provide in-depth molecular characterization of a case representing leukemic form of DLBCL and discuss mechanisms that may have contributed to lymphoma progression and development of drug resistance."

Journal • Bone Marrow Transplantation • Diffuse Large B Cell Lymphoma • Hematological Disorders • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Transplantation • CD79B • MYD88 • PRDM1 • TBL1XR1 • TP53

Waldenström's macroglobulinemia - clinical symptoms and review of therapy yesterday, today and tomorrow. (PubMed, Klin Onkol) - "New antiCD20 antibody (obinutuzumab) is of advantage in patients with WM with rituximab intolerance as well as bendamustin and new proteasome inhibitors (ixazomib and carfilzomib) or new BTK inhibitors with lower cardiotoxicity. Many of the abovementioned drugs do not have official registration for WM and can be administrated with the consent of the health care provider only. Thus, this work brings evidence of their efficacy."

Journal • Review • Atrial Fibrillation • Cardiovascular • Hematological Disorders • Hematological Malignancies • Lymphoma • Lymphoplasmacytic Lymphoma • Multiple Myeloma • Oncology • Waldenstrom Macroglobulinemia

NOVEL SPLICE-SITE MUTATION IN PLCG2 ASSOCIATED WITH RESISTANCE TO BTK INHIBITORS (EHA 2023) - " Among the multiple parallel lines of REC-1 cells where resistance to the covalent BTKi: ibrutinib and tirabrutinib, and the non-covalent BTKi: nemtabrutinib, pirtobrutinib, vecabrutinib, fenebrutinib and RN-486 was generated, a novel PLCG2 c.2236-1G>T mutation at the splice site was observed in 2 of 3 tirabrutinib resistant lines with variant allele frequencies (VAF) of 42% and 44%, respectively. Here, we identified a novel PLCG2 splice-site mutation in BTKi resistant REC-1 cells, which led to the deletion of exon 21, most likely impairing the auto-inhibitory regulation of the enzyme and increasing lipase activity of PLCγ2. Similar to other known PLCγ2 mutants, the novel Δ21 PLCγ2 mutant showed resistance to all BTKi tested, due toBTK independent activation of BCR signaling. Our study highlights the importance of sequencing splice sites of PLCG2 in the context of patients who progress under BTKi-based treatments."

Chronic Lymphocytic Leukemia • Oncology • NF-κβ • PLCG2

Extended Abstract: New BTKi (SOHO 2022) - "It has also been studied in combination with idelalisib or entospletinib in CLL and other B-cell lymphomas though without clear benefi t for the combinations over monotherapy16,17. Tirabrutinib is approved in Japan for WM, lymphoplasmacytic lymphoma (LPL), and RRPCNSL, and in South Korea for RR-PCNSL18. TG-1701 is a selective covalent BTKi that has been studied as a monotherapy and in combination with ublituximab and umbralisib with preliminary results suggesting both effi cacy and manageable safety19. Orelabrutinib, another selective covalent BTKi, has been studied as a monotherapy in CLL in addition to other B-cell malignancies, also with favorable safety and effi cacy20,21 and it is approved in China for rel/ref CLL and MCL22. Finally, DTRMWXHS-12 is a covalent BTKi that uniquely is being studied in combination with everolimus and pomalidomide (triplet referred to as DTRM-555), given that this combination was determined to lead to synthetic lethality in both in vivo..."

IO biomarker • Chronic Lymphocytic Leukemia • CNS Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Lymphoplasmacytic Lymphoma • Mantle Cell Lymphoma • Marginal Zone Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Waldenstrom Macroglobulinemia • FLT3 • IL2 • ITK • PLCG2

NX-5948 promotes selective, sub-nanomolar degradation of inhibitor-resistant BTK mutants (AACR 2023) - P1 | "The C481S mutation eliminated the anti-proliferative effects of covalent inhibitors ibrutinib, acalabrutinib, and zanubrutinib, while the V416L, T474I, and L528W mutations dramatically reduced the activity of pirtobrutinib, vecabrutinib, and fenebrutinib. The exceptional potency, selectivity, and activity of NX-5948 against BTK mutants warrant its investigation in clinical settings that develop diverse inhibitor resistance. A phase 1a/b trial of NX-5948 for patients with relapsed or refractory B-cell malignancies is ongoing (NCT05131022)."

Diffuse Large B Cell Lymphoma • Hematological Malignancies • Oncology • BTK • CRBN

Next Generation Small Molecules in Chronic Lymphocytic Leukemia (SOHO 2019) - "With the regimen of venetoclax plus obinutuzumab, approximately 88% of patients were progression free at 24 months.4 While the definite duration of treatment will likely allow for retreatment at disease progression, the depth and duration of subsequent remissions is unknown...In the phase III NCTN study E1912, which evaluated ibrutinib plus rituximab in the frontline treatment of younger patients, 3 year progression free survival (PFS) was 89%...While clinical studies are early, and new agents are coming forward rapidly, there are four agents that have been or are currently in clinical development.GDC-0853 is a highly selective reversible inhibitor of BTK...As well, in the TCL1 mouse model of CLL as well as the TCL1/Myc model of aggressive lymphoma in the setting of CLL, ARQ-531 out-performed ibrutinib.10 This drug is currently in phase 1 testing, with the maximal tolerated dose (MTD) yet to be identified, and favorable toxicity profile thus far. At a dose of 65 mg, 4/6..."

IO biomarker • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Mantle Cell Lymphoma • Oncology

Favorable Modulation of Chimeric Antigen Receptor T Cells Safety and Efficacy By the Non-Covalent BTK Inhibitor Vecabrutinib (TCT-ASTCT-CIBMTR 2022) - P1b/2 | "The Bruton’s tyrosine kinase (BTK) inhibitor, ibrutinib, has been shown to favorably modulate CART functions. Mechanistically, total RNA sequencing of activated CART19 incubated with vecabrutinib highlighted a significant enhanced expression of multiple genes involved in the PI3K/AKT (proliferation) and Th1 pathways (cytotoxicity) (Fig.1M, N). Conclusion We demonstrate that vecabrutinib is a potent and a novel strategy to favorably modulate CART19 functions by increasing their efficacy and decreasing toxicity."

CAR T-Cell Therapy • Clinical • Hematological Malignancies • Inflammation • Lymphoma • Mantle Cell Lymphoma • Oncology • CD19 • IL10 • IL2 • IL6 • ITK • LAMP1

PRECLINICAL VALIDATION OF VECABRUTINIB (SNS-062) EFFICIENCY AGAINST BTK-C481S MUTATED LYMPHOMAS (EHA 2018) - P1b/2; "Ibrutinib, the first in class BTK inhibitor has proven to be highly efficient in chronic lymphocytic leukemia or mantle cell lymphoma, and is thought to be of potential interest in the Activated B cell subtype of diffuse large B cell lymphomas (ABC-DLBCL). These preclinical data suggest that vecabrutinib is a highly specific and potent drug that is able to overcome the resistance due to BTK C481S mutations. Given its very favorable pharmacokinetic and safety profile, a phase 1b/2 dose escalation and cohort expansion clinical trial has been recently launched in patients with previously treated B-lymphoid malignancies."

Preclinical • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Indolent Lymphoma • Mantle Cell Lymphoma

Favorable Modulation of Chimeric Antigen Receptor T Cells Safety and Efficacy By the Non-Covalent BTK Inhibitor Vecabrutinib (ASH 2021) - P1b/2 | "The Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib has been shown to favorably modulate CART phenotype and function through downregulation of inhibitory receptors and enhancement of CART cell efficacy in preclinical models and early clinical studies. In summary, we demonstrate for the first time that using the reversible BTK inhibitor, vecabrutinib, is a potent and a novel strategy to favorably modulate CART19 function by increasing their efficacy and decreasing toxicity. Further studies are currently underway to compare the effect of reversible versus irreversible BTK/ITK inhibition on CART functions and to further validate the mechanisms responsible for the observed effects."

CAR T-Cell Therapy • Clinical • Hematological Disorders • Hematological Malignancies • Inflammation • Lymphoma • Mantle Cell Lymphoma • Oncology • CD19 • IL10 • IL2 • IL6 • ITK • LAMP1 • TNFA

Vecabrutinib Is Efficacious In Vivo in a Preclinical CLL Adoptive Transfer Model (ASH 2018) - P1b/2; "However resistance to the BTK inhibitor ibrutinib has been shown to emerge in a subset of CLL patients. Of interest, the immunosuppressive Tregs, which protect the tumor from immune surveillance were decreased in various tissue compartments; however, a decrease in the effector CD8 T cells might impact anti-tumor immunity if there is a consistent effect upon drug treatment. Vecabrutinib antitumor activity and effects on T-cell populations in vivo in this preclinical CLL model are intriguing, merits further investigation and supports the ongoing phase 1b/2 study in patients with previously treated B-lymphoid malignancies (NCT03037645)."

Preclinical • Biosimilar • Chronic Lymphocytic Leukemia • Graft versus Host Disease • Hematological Disorders • Hematological Malignancies • Indolent Lymphoma • Leukemia • Non-Hodgkin’s Lymphoma • Oncology

Resistance to the Non-Covalent BTK Inhibitor Pirtobrutinib (ASH 2022) - "In WES analysis, patient #1 had 16 samples evaluated prior to, during, and at relapse on acalabrutinib, vecabrutinib and pirtobrutinib...Patient #2 had 10 samples evaluated prior to, during and at relapse on ibrutinib and pirtobrutinib...In this study, we demonstrate that ex vivo efficacy of pirtobrutinib declines as patients' CLL starts to progress, in concert with the development of gatekeeper and alternative site BTK mutations that lead to resistance to pirtobrutinib. Interestingly, many of the second-site BTK mutations fail to activate BTK phosphorylation but are still associated with downstream activation of phospho-AKT and phospho-ERK; the mechanism of this activation remains to be elucidated."

Oncology • CCL3 • PLCG2 • SF3B1 • TP53

Novel BTK Mutations Conferring Resistance to Non-Covalent BTK Inhibitors and Alternative Treatment Strategy (ASH 2022) - "Here,we generated and comprehensively characterized BTK and PLCG2 mutations conferring resistance to ibrutinib and five different non-covalent BTKi namely pirtobrutinib (LOXO-305), vecabrutinib (SNS-062), nemtabrutinib (ARQ-531), fenebrutinib (GDC-0853), and RN-486. We also found that cells harboring these novel BTK mutations showed differential sensitivity to the covalent vs. non-covalent BTKi. We further demonstrate the potential of venetoclax as follow up treatment upon resistance to non-covalent BTKi."

IO biomarker • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Mantle Cell Lymphoma • Oncology • PLCG2

Phase 1b dose-escalation study of the selective, noncovalent, reversible Bruton's tyrosine kinase inhibitor vecabrutinib in B-cell malignancies. (PubMed, Haematologica) - "Not available."

Journal • P1 data • Hematological Malignancies • Oncology

Outcomes of Chronic Lymphocytic Leukemia and Richter Transformation Following Discontinuation of Non-Covalent Bruton’s Tyrosine Kinase Inhibitors (ASH 2021) - "These agents (pirtobrutinib, ARQ-531, SNS-062) reversibly bind BTK and overcome acquired resistance to covalent BTKis (cBTKi). In this first study to report outcomes of CLL and RT pts who have discontinued a ncBTKi, several important themes have emerged. For venetoclax naive CLL pts, venetoclax appears to be a promising strategy following ncBTKi discontinuation supporting the ability to stay within the BTKi class prior to switching to venetoclax. Cellular therapies including CAR T-cell therapy and allo SCT had a high ORR and warrant further investigation (80% of pts had prior cBTKi, ncBTKi and venetoclax and 100% had prior cBTKi and ncBTKi)."

IO biomarker • Bone Marrow Transplantation • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • Richter's Syndrome • Transplantation • IGH • TP53

Efficacy of Vecabrutinib Treatment in a Murine Model of Sclerodermatous Graft-Versus-Host-Disease (ASH 2021) - "In conclusion, vecabrutinib treatment demonstrated efficacy and beneficially regulated B cell and T cell immune subsets in a preclinical murine model of sclerodermatous cGVHD. Studies to further evaluate differences between vecabrutinib and ibrutinib treatment are ongoing."

IO biomarker • Preclinical • Alopecia • Bone Marrow Transplantation • Chronic Graft versus Host Disease • Conjunctivitis • Fibrosis • Graft versus Host Disease • Immune Modulation • Immunology • Inflammation • Ocular Infections • Ocular Inflammation • Ophthalmology • Scleroderma • Systemic Sclerosis • Transplantation • CD4 • CD8 • CD86 • CXCR5 • FOXP3 • GZMB • IL10 • IL2RA • IL4 • PD-1 • SDC1

Viracta Therapeutics Presents Preclinical Vecabrutinib Data in Oral and Poster Presentations at ASH 2021 (PRNewswire) - "Vecabrutinib enhanced the efficacy of CAR T-cells in a murine mantle cell lymphoma model. Vecabrutinib inhibited the secretion of pro-inflammatory cytokines known to play a role in the cytokine release syndrome associated with CAR T-cell therapy. Vecabrutinib significantly reduced chronic graft-versus-host disease (cGVHD) symptoms in a murine disease model."

Preclinical • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

Viracta Therapeutics Reports Third Quarter 2021 Financial Results and Provides Corporate Update (PRNewswire) - “Continued the global expansion of pivotal NAVAL-1 trial; multiple U.S. and international sites now open for enrollment. NAVAL-1 (Nanatinostat in Combination with Valganciclovir) is a global, multicenter, open-label Phase 2 basket trial….The Company anticipates providing an update on the initial cohort(s) that have expanded into Stage 2 in the second half of 2022….The Company anticipates providing an update on the initial cohort(s) that have expanded into Stage 2 in the second half of 2022….The Company anticipates providing an update on the initial cohort(s) that have expanded into Stage 2 in the second half of 2022. Announced an upcoming oral presentation at the 2021 ASH Annual Meeting featuring final results from VT3996-201, the Phase 1b/2 trial of Nana-val in R/R EBV+ lymphoma. Data indicate that Nana-val was well tolerated and shows promising efficacy in patients with R/R EBV+ lymphoma….Anticipated 2021 Milestones and...

P1/2 data • Preclinical • Lymphoma • Oncology • Solid Tumor

Viracta Therapeutics Announces Upcoming Oral and Poster Presentations at the 2021 American Society of Hematology Annual Meeting (PRNewswire) - P1b/2, N=65; NCT03397706; Sponsor: Viracta Therapeutics, Inc; "Final results from Viracta's Phase 1b/2 trial evaluating Nana-val in R/R EBV+ lymphoma will be presented....Data to be featured in the oral presentation relate to vecabrutinib, a selective, reversible, non-covalent inhibitor of Burton's tyrosine kinase (BTK) and interleukin-2-inducible kinase (ITK). These data demonstrate that using vecabrutinib is a novel strategy to modulate CD19-targeted chimeric antigen receptor (CAR) T cell functions by increasing their efficacy, and decreasing their toxicity, while maintaining their proliferative potential...Data to be featured in the oral presentation relate to vecabrutinib, a selective, reversible, non-covalent inhibitor of Burton's tyrosine kinase (BTK) and interleukin-2-inducible kinase (ITK). These data demonstrate that using vecabrutinib is a novel strategy to modulate CD19-targeted chimeric antigen receptor (CAR) T cell functions..."

P1/2 data • Preclinical • Hematological Malignancies • Oncology

Viracta Therapeutics Announces Upcoming Oral and Poster Presentations at the 2021 American Society of Hematology Annual Meeting (PRNewswire) - "Viracta Therapeutics...today announced the acceptance of two abstracts for oral presentation and one for a poster presentation at the upcoming 2021 American Society of Hematology (ASH) Annual Meeting, which will be held from December 11-14, 2021, both in Atlanta, Georgia and virtually.....The poster presentation will feature data showing that vecabrutinib treatment demonstrated efficacy and beneficially regulated B cell and T cell immune subsets in a preclinical murine model of sclerodermatous chronic graft-versus-host disease."

Preclinical • Chronic Graft versus Host Disease • Epstein-Barr Virus Infections • Graft versus Host Disease • Hematological Malignancies • Lymphoma

Evaluation of vecabrutinib as a model for non-covalent BTK/ITK inhibition for treatment of chronic lymphocytic leukemia. (PubMed, Blood) - "Lastly, combination treatment of vecabrutinib with venetoclax was found to augment treatment efficacy, significantly improve survival and lead to favourable reprogramming of the microenvironment in the murine Eµ-TCL1 model. Thus, non-covalent BTK/ITK inhibitors such as vecabrutinib may be efficacious in C481S BTK mutant CLL, while preserving the T-cell immunomodulatory function of ibrutinib."

Journal • Chronic Lymphocytic Leukemia • Hematological Malignancies • Immune Modulation • Inflammation • Leukemia • Oncology • CD4 • CD8 • IL2 • ITK

"Pre-clinical data for #vecabrutinib in @BloodJournal Non-covalent BTKi inhibitory effect on C481S BTK mutants in vitro - ITK inhibitory activity (cf ibrutinib) - vecabrutinib + venetoclax synergstic But Sunesis cancelled phase II as lack of adequate efficacy in phase Ib in #CLL" (@tobyeyre82)

P1 data • P2 data • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • BTK