THR-149 / Oxurion, Bicycle Therap - LARVOL DELTA

Recent advances in the discovery and development of drugs targeting the kallikrein-kinin system. (PubMed, J Transl Med) - "The therapeutic impact of targeting the kallikrein-kinin system is no longer limited to the treatment of hereditary angioedema. Ongoing research on other diseases demonstrates the potential of therapeutic interventions targeting the kallikrein-kinin system and will provide further treatment options for patients in the future."

Journal • Review • Cardiovascular • Complement-mediated Rare Disorders • Diabetic Macular Edema • Diabetic Retinopathy • Hereditary Angioedema • Inflammation • Ophthalmology • Rare Diseases • Retinal Disorders

Structure and function of the pseudouridine 5'-monophosphate glycosylase PUMY from Arabidopsis thaliana. (PubMed, RNA Biol) - "The results indicate that Thr149 and Asn308, which are conserved in the PUMY family, are structural determinants for recognizing the nucleobase of ΨMP...Mutational analysis validates the proposed roles of the active site residues in catalysis. Our structural and functional analyses provide further insight into the enzymatic features of PUMY towards ΨMP."

Journal

KALAHARI: A Study to Evaluate THR-149 Treatment for Diabetic Macular Oedema (clinicaltrials.gov) - P2 | N=135 | Completed | Sponsor: Oxurion | Recruiting ➔ Completed

Trial completion • Diabetes • Diabetic Macular Edema • Diabetic Retinopathy • Macular Edema • Metabolic Disorders • Ophthalmology • Retinal Disorders

Switching of newly synthesized linker-based derivatives of non-steroidal anti-inflammatory drugs toward anti-inflammatory and anticancer activity. (PubMed, Bioorg Chem) - "On the other hand, a slight increase in the potency of compound 10 towards anticancer activity may be due to the instantaneous participation of the OH group and carbonyl group to give conventional hydrogen bonds towards THR 149 amino acid residue, which was missing in compound 8...Further, compounds 8 and 10 were subjected to in-vitro COX-2 inhibition and cytotoxicity assay and the results obtained were in accordance with the in-silico study. Thus, compound 8 become more potent towards COX-2 inhibition with IC value of 48.51 µg/ml and compound 10 showed good bioactivity toward cytotoxic activity with IC value of 93.03 µg/ml."

Journal • Oncology • HER-2

KALAHARI: A Study to Evaluate THR-149 Treatment for Diabetic Macular Oedema (clinicaltrials.gov) - P2 | N=126 | Recruiting | Sponsor: Oxurion | Trial completion date: Mar 2023 ➔ Dec 2023 | Trial primary completion date: Mar 2023 ➔ Sep 2023

Trial completion date • Trial primary completion date • Diabetes • Diabetic Macular Edema • Diabetic Retinopathy • Macular Edema • Metabolic Disorders • Ophthalmology • Retinal Disorders

Phase 2 Study of THR-149, a Plasma Kallikrein Inhibitor in Patients With DME Who Respond Suboptimally to Anti-VEGF Treatment (Month 6 Results of Part A of the KALAHARI Study) (ASRS 2022) - No abstract available

Clinical • P2 data

KALAHARI: Part A Results of the Phase 2 Study of THR-149, a Plasma Kallikrein Inhibitor, in Subjects with DME Responding Sub optimally to anti-VEGF Treatment (Macula 2022) - "Three monthly injections of THR-149 were safe and well tolerated. The highest dose of THR-149 (0.13 mg) has been selected for the Part B of the KALAHARI study which is comparing the safety and efficacy of THR-149 to aflibercept in subjects with DME with suboptimal response to anti-VEGFs. Information collected in Part A has been utliized to amend the design of Part B of the KALAHARI study which is currently recruiting."

Clinical • P2 data

Identification of HPCAL1 as a specific autophagy receptor involved in ferroptosis. (PubMed, Autophagy) - "Site-directed mutagenesis aided by bioinformatic analyses revealed that the autophagic degradation of CDH2 requires PRKCQ (protein kinase C theta)-mediated HPCAL1 phosphorylation on Thr149, as well as a non-classical LC3-interacting region motif located between amino acids 46-51. The genetic or pharmacological inhibition of HPCAL1 prevented ferroptosis-induced tumor suppression and pancreatitis in suitable mouse models. These findings provide a framework for understanding how selective autophagy promotes ferroptotic cell death.Abbreviations: ANXA7: annexin A7; ARNTL: aryl hydrocarbon receptor nuclear translocator like; CCK8: cell counting kit-8; CDH2: cadherin 2; CETSAs: cellular thermal shift assays; CPT2: carnitine palmitoyltransferase 2; DAMP, danger/damage-associated molecular pattern; DPPH: 2,2-diphenyl-1-picrylhydrazyl; DFO: deferoxamine; EBNA1BP2: EBNA1 binding protein 2; EIF4G1: eukaryotic translation initiation factor 4 gamma 1; FBL: fibrillarin; FKBP1A: FKBP..."

Journal • Oncology • Pancreatic Cancer • Pancreatitis • Targeted Protein Degradation • ARNT • ARNTL • CDH2 • EIF4G1 • FBL • GPX4 • HMGB1 • MAP1LC3B • MPO • mTOR • PRKAR1A • PTGS2 • SLC7A11 • SPTA1 • SPTAN1 • UBE2M

Phase 1 Dose-Escalation Study of Plasma Kallikrein Inhibitor THR-149 for the Treatment of Diabetic Macular Edema. (PubMed, Transl Vis Sci Technol) - "THR-149 was safe and well tolerated; preliminary efficacy in terms of BCVA improvement was observed. This work bridges the gap between basic research and clinical care by providing first in human safety and preliminary efficacy data, supporting the further investigation of THR-149 as a potential treatment for DME."

Journal • P1 data • Diabetic Macular Edema • Diabetic Retinopathy • Immunology • Inflammation • Ophthalmology • Retinal Disorders

Targeting Plasma Kallikrein With a Novel Bicyclic Peptide Inhibitor (THR-149) Reduces Retinal Thickening in a Diabetic Rat Model. (PubMed, Invest Ophthalmol Vis Sci) - "These data demonstrate that repeated THR-149 administration reduces several DME-related key pathologies such as retinal thickening and neuropil disruption in the diabetic rat. These observations indicate that modulation of the PKal pathway using THR-149 has clinical potential to treat patients with DME."

Journal • Preclinical • Diabetic Macular Edema • Immunology • Inflammation • Metabolic Disorders • Ocular Inflammation • Ophthalmology • IL6 • VIM

Current Clinical Trials in Diabetic Macular Edema: Various therapies are in development (Retin Physician) - "Diabetic macular edema (DME) represents a leading causes of irreversible legal blindness in the industrialized world. Therapeutically, corticosteroids were utilized early in the treatment of DME. Intravitreal (IVT) corticosteroids, which reduce inflammatory cytokines and act on several pathogenic pathways in DME, have proven effective for the management of DME, supplementing focal laser."

Online posting

Systemic exposure following intravitreal administration of therapeutic agents: an integrated pharmacokinetic approach. 1. THR-149. (PubMed, J Pharmacokinet Pharmacodyn) - "We show that the model accurately describes circulating levels of THR-149, a plasma kallikrein inhibitor in development for the treatment of diabetic macular edema. We hypothesize that the model based on the rabbit eye has broader relevance to the human eye and can be used to analyze systemic exposure of a variety of drugs delivered in the eye."

Journal • PK/PD data • Diabetic Macular Edema • Infectious Disease • Ophthalmology

[VIRTUAL] OXURION NV (BIO 2021) - "Oxurion is aiming to build global franchise in treatment of retinal vascular disorders based on the successful development of its two novel therapeutics: - THR-149, a plasma kallikrein inhibitor being developed as potential new standard of care for the 40% of DME patients who respond sub-optimally to anti-VEGF therapy. Positive topline results in a Ph1 clinical study assessing THR-687 as treatment for DME were announced in 2020. THR-687 expected to enter a Phase 2 clinical trial in mid-20"

Age-related Macular Degeneration • Complement-mediated Rare Disorders • Diabetes • Diabetic Macular Edema • Macular Degeneration • Metabolic Disorders • Ophthalmology • Retinal Disorders • Retinal Vein Occlusion • Wet Age-related Macular Degeneration

A Rare Potential Pathogenic Variant in the BDNF Gene is Found in a Brazilian Patient with Severe Childhood-Onset Obesity. (PubMed, Diabetes Metab Syndr Obes) - "As a result, three missense variants [p.(Thr2Ile), p.(Val66Met), and p.(Arg209Gln)] and four synonymous variants (p.Leu107=, p.Thr149=, p.Ala150=, and p.Ser213=) were identified...This polymorphism has also a protective effect on metabolic syndrome susceptibility. Additionally, we described for the first time a rare potentially pathogenic BDNF variant in a Brazilian patient with severe obesity and childhood-onset."

Clinical • Journal • Genetic Disorders • Metabolic Disorders • Obesity • BDNF

KALAHARI: A Study to Evaluate THR-149 Treatment for Diabetic Macular Oedema (clinicaltrials.gov) - P2; N=122; Recruiting; Sponsor: Oxurion

New P2 trial • Diabetes • Diabetic Macular Edema • Diabetic Retinopathy • Metabolic Disorders • Ophthalmology • Retinal Disorders

Oxurion NV Reports First Patient Dosed in Phase 2 study evaluating THR-149 for treatment of Diabetic Macular Edema (DME) (GlobeNewswire) - P2, N=122; KALAHARI (NCT04527107); Sponsor: Oxurion; '"Starting this clinical trial is an important step towards potentially bringing THR-149, a novel and promising plasma kallikrein inhibitor, to patients with DME. DME is a leading cause of adult visual loss globally and new approaches are needed for the up to 40% of patients who do not respond optimally to anti-VEGF monotherapy. These patients may benefit from therapeutics with new mechanisms of action such as inhibition of plasma kallikrein. THR-149 has shown encouraging early clinical data and I look forward to the results from this robust Phase 2 clinical study.'"

Media quote • P2 data