V565 / VHsquared - LARVOL DELTA

TYRA-200: Next generation inhibitor designed to potently target FGFR2 alterations and resistance mutations (ACS-Fall 2025) - "The therapeutic landscape for FGFR2-driven cancers was significantly advanced by the approval of pan-FGFR inhibitors futibatinib (Lytgobi) and pemigatinib (Pemazyre), which have demonstrated efficacy in treating locally advanced or metastatic cholangiocarcinoma with FGFR2 fusions or rearrangements. However, the effectiveness of these treatments has been hampered by the emergence of multiple resistance mutations, which are often polyclonal and affect critical regions in the FGFR2 kinase domain, such as the gatekeeper residue (V565), molecular brake (N550, E566, K642) and other key variants...TYRA-200 is undergoing evaluation in a Phase 1 clinical trial focused on patients with advanced or metastatic intrahepatic cholangiocarcinoma that have FGFR2 activating gene alterations and have exhausted standard therapies due to resistance. This study aims to assess the potential of TYRA-200 as a viable treatment alternative for these patients, representing a crucial step toward..."

Biliary Cancer • Cholangiocarcinoma • Solid Tumor • FGFR2

Understanding and Overcoming Resistance to Selective FGFR inhibitors Across FGFR2-Driven Malignancies. (PubMed, Clin Cancer Res) - "At progression to FGFR inhibitors, FGFR2-driven malignancies are characterized by high intra- and inter-patient molecular heterogeneity, particularly in cholangiocarcinoma. Resistance to FGFR inhibitors can be overcome by sequential, molecularly-oriented treatment strategies across FGFR2-driven tumors."

Journal • Biliary Cancer • Cholangiocarcinoma • Gastrointestinal Cancer • Oncology • Solid Tumor • BICC1 • FGFR2 • PIK3CA • TSC1

Differences in Intraoperative Fluoroscopic Radiation Exposure During Ankle Fracture Open Reduction and Internal Fixation Between Orthopaedic Surgery and Podiatry. (PubMed, J Am Acad Orthop Surg Glob Res Rev) - "In addition, trimalleolar ORIF with syndesmotic repair performed by orthopaedic surgery had a significantly lower mean total radiation dose compared with those performed by podiatry (244.6 mRad v 565.6 mRad; P = 0.009). Patients and surgical teams are exposed to markedly less radiation in isolated malleolar and trimalleolar fracture ORIF with syndesmosis repair when performed by an orthopaedic surgeon as compared with those performed by a podiatrist."

Clinical • Journal • Retrospective data • Surgery • Musculoskeletal Diseases • Orthopedics

The irreversible FGFR inhibitor KIN-3248 overcomes FGFR2 kinase domain mutations. (PubMed, Clin Cancer Res) - "Thus, KIN-3248 is a novel FGFR1-4 inhibitor whose distinct activity profile against FGFR kinase domain mutations highlights its potential for the treatment of ICC and other FGFR-driven cancers."

Journal • Biliary Cancer • Bladder Cancer • Cholangiocarcinoma • Gastrointestinal Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • FGFR2 • FGFR3

Landscape of Clinical Resistance Mechanisms to FGFR Inhibitors in FGFR2-Altered Cholangiocarcinoma. (PubMed, Clin Cancer Res) - "These data support secondary FGFR2 mutations as the primary mode of acquired resistance to FGFR inhibitors-most commonly N550 and V565 mutations. Thus, development of combination strategies and next-generation FGFR inhibitors targeting the full spectrum of FGFR2 resistance mutations will be critical."

Journal • Biliary Cancer • Cholangiocarcinoma • Gastrointestinal Cancer • Oncology • Solid Tumor • FGFR2

"V565 gatekeeper mutation is Futibatinib resistant too.." (@RenoHemonc)

First patients entered into Phase II trial of VHsquared’s lead Vorabody product V565 HARBOR study of novel anti-TNFα oral domain antibody taking place in North America & Europe - "Arthur Kaser...said, ‘Inflammatory bowel diseases are debilitating conditions in clear need of new therapeutic approaches, so I’m delighted to be involved in this exciting trial. The profile of V565 offers a step change in approach to IBD management, potentially resulting in substantial disease modification early in its course, reducing progression, improving quality of life and bringing significant benefits to patients.’"

Media quote

HarbOR: A Six Week Efficacy, Safety and Tolerability Study of V565 in Crohn's Disease (clinicaltrials.gov) - P2; N=125; Completed; Sponsor: VHsquared Ltd.; Recruiting ➔ Completed

Clinical • Trial completion • Crohn's disease • Gastroenterology • Immunology • Inflammatory Bowel Disease • CRP

Preclinical development of a bispecific TNFα/IL-23 neutralising domain antibody as a novel oral treatment for inflammatory bowel disease. (PubMed, Sci Rep) - "In ex vivo cultures of colonic biopsies from IBD patients, treatment with V565 or V900 inhibited tissue phosphoprotein levels and with a combination of the two, inhibition was even greater. These results support further development of V56B2 as an oral therapy for IBD with improved safety and efficacy in a greater proportion of patients as well as greater convenience for patients compared with traditional monoclonal antibody therapies."

Journal • Preclinical • Crohn's disease • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • Ulcerative Colitis • TNFA

Oral Anti-Tumour Necrosis Factor Domain Antibody V565 Provides High Intestinal Concentrations, and Reduces Markers of Inflammation in Ulcerative Colitis Patients. (PubMed, Sci Rep) - "Immunostaining revealed V565 tissue penetration and association with inflammatory cells, while decreased phosphoproteins after 7d oral dosing was consistent with V565-TNFα engagement and neutralising activity. Overall these results are encouraging for the clinical utility of V565 in the treatment of IBD."

Clinical • Journal • Crohn's disease • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammatory Bowel Disease • Oncology • Oral Cancer • Ulcerative Colitis

Preclinical Development of a Novel, Orally-Administered Anti-Tumour Necrosis Factor Domain Antibody for the Treatment of Inflammatory Bowel Disease. (PubMed, Sci Rep) - "V565 activity was evaluated in TNFα-TNFα receptor-binding ELISAs as well as TNFα responsive cellular assays and demonstrated neutralisation of both soluble and membrane TNFα with potencies similar to those of adalimumab. In an ex vivo human IBD tissue culture model, V565 inhibition of tissue phosphoprotein levels and production of inflammatory cytokine biomarkers was similar to infliximab, demonstrating efficacy when present at the disease site. Taken together, results of these studies provide confidence that oral V565 dosing will be therapeutic in IBD patients where the mucosal epithelial barrier is compromised."

Biomarker • Journal • Preclinical

Oral delivery of the anti-TNFα domain antibody, V565, results in high intestinal and faecal concentrations with minimal systemic exposure in cynomolgus monkeys. (PubMed, Drug Dev Ind Pharm) - "These results suggest that mini-tablets with a 24% Eudragit enteric coating are suitable for targeted release of orally delivered V565 in the intestine for topical treatment of IBD."

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