Discovery and development of plasma kallikrein inhibitors for multiple diseases
- June 30, 2022
Up to 50% of patients do not respond optimally to anti-VEGF treatment regimens
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Diabetic Macular Edema (DME) is the leading cause of progressive vision loss in working-age people.
It is currently estimated that approximately 22 million people worldwide have DME, with the prevalence increasing due to the growing global diabetic epidemic.
People who suffer from DME have leaking vessels in the back of the eye. This leakage leads to a thickening of the retina and causes vision problems. DME may cause blurriness in the center of vision, the appearance of dark spots or patches in the field of vision, and colors to look dull. These symptoms may affect the ability to read, write, drive and recognize faces – presenting a significant patient and caregiver burden.
Current treatments for DME include inhibitors of vascular endothelial growth factor (VEGF), steroids and laser therapy.
Up to 50% of patients do not respond optimally to anti-VEGF treatment regimens
While anti-VEGF is the mainstay of therapy, up to 50% of patients do not respond optimally. Moreover, the treatment regimen itself presents a high burden: patients must have intravitreal injections on a frequent basis (can be as often as monthly), resulting in a lack of compliance and an increase in loss of vision.
Oxurion strives to develop therapies that can serve as an alternative for patients who do not respond well to the current standard of care and to lower the treatment burden.
At Oxurion we are dedicated to developing innovative compounds that target VEGF-independent pathways. Research indicates that not all DME patients have elevated VEGF levels. Rather, there are two distinct pathways linked to DME, with elevated plasma kallikrein (PKal) levels also identified as a key driver in the development of DME.
Plasma kallikrein (PKal) is a mediator of vascular leakage, inflammation, micro-hemorrhages and neurodegeneration. The kallikrein-kinin system (KKS) is a metabolic cascade that, when activated, triggers the release of vasoactive kinins. Central to the KKS is the serine protease, PKal. Upon activation, PKal cleaves its substrate, high-molecular-weight kininogen (HK), to release bradykinin (BK), an agonist at the B2 receptor (B2R). BR can be further converted to Des-Arg9-BK, which activates the B1 receptor (B1R). B2R is constitutively expressed and mediates most normal physiological effects of kinins.
The figure was created with BioRender.com.
In contrast, B1R is normally expressed at very low levels; however, it is highly inducible and overexpressed following tissue injury and is involved in chronic inflammation. In the eye, KKS activation increases vascular permeability, retinal thickening, inflammation and neurodegeneration, responses which are exacerbated in diabetic animals. This body of evidence suggests that the KKS plays an important role in the development of DME and that it is a VEGF-independent mediator of the disease.
THR-149 was licensed from Bicycle Therapeutics and is a bicyclic peptide that selectively inhibits human plasma kallikrein (PKal) with an inhibition constant of 0.22 nM. Through the inhibition of the kallikrein-kinin system (KKS), THR-149 prevents the induction of retinal vascular permeability and inflammation.
Scientific publications (Kita T et al. Diabetes 2015;64:3588-3599) show that patients with DME have elevated levels of PKal and that the vitreous level of PKal is less variable than VEGF, making it a potentially more effective target for treating DME. Additionally, THR-149 has the potential to reduce retinal vascular micro-hemorrhages and retinal ganglion cell degeneration via neuroprotection.
THR-149 molecule
The Phase 1 trial was designed to evaluate the safety of a single intravitreal (IVT) injection of THR-149, a novel PKal inhibitor, of 3 ascending dose levels in subjects with visual impairment due to center-involved DME (CI-DME). More information can be found here: NCT03511898
Status: Completed
Topline Data:
The Phase 2 KALAHARI study is a two-part, randomized, prospective, multi-center study assessing multiple injections of THR-149 in DME patients who have previously shown a suboptimal response to anti-VEGF therapy. More information can be found here: NCT04527107
Part A
In Part A of the study, three dose levels of THR-149 (0.005mg, 0.022mg and 0.13mg), each administered in three monthly IVT injections, were evaluated in order to select the best dose for Part B of the study.
Status: Part A completed and highest dose selected for Part B
Topline Data Part A:
Link to video: https://www.modernretina.com/view/high-dose-of-thr-149-delivers-bcva-increase-stable-cst-in-kalahari-study
Phase 2 clinical trial (“KALAHARI”) part B evaluating multiple injections of THR-149 in DME patients with suboptimal response to anti-VEGF therapy compared to aflibercept.The KALAHARI trial is powered (80%) for superiority over anti-VEGF and will also provide preliminary data on use of THR-149 in combination with anti-VEGF therapy.
Status : Part B is currently enrolling patients
Study Design:
Powered for superiority of THR-149 versus aflibercept at Month 3
Provide preliminary data on use of THR-149 in combination with anti-VEGF therapy through a flip over injection at Month 3
More info on the Kalahari study can be found here: https://www.kalahari-trial.com/eng-usa
University VitaSalute
Retina Vitreous Associates Medical Group
Co-Chair, Cole Eye Institute
Sierra Eye Associates
Hôpital de la Croix-Rousse
Moorfields Eye Hospital
Oxurion looks forward to playing an important role in the treatment of retinal disorders, including diabetic macular edema (DME).
Our novel therapeutic THR-149, which is independent of the VEGF pathway, has the potential to be first in class and to be the new standard of care for DME patients who respond suboptimally to anti-VEGF therapies.
University VitaSalute
Francesco Bandello is Professor and Chairman at the Department of Ophthalmology University Vita-Salute, Scientific Institute San Raffaele, Milan, Italy. He is Past President Academic Dean of “Corso di Laurea Specialistica/Magistrale in Medicina e Chirurgia” at the same University.
Professor Bandello is Past President of EURETINA, President of Academia Ophthalmologica Europea and Vice-President of EuroLam.
Prof. Bandello is Editor-in-Chief of the European Journal of Ophthalmology and former board member of the Club Jules Gonin and Macula Society. He is member of the Executive Board of ESASO Foundation (European School for Advanced Studies in Ophthalmology) and S.I.S.O (Società Italiana Scienze Oftalmologiche); member of the Academia Ophthalmologica Internationalis and the Accademia Nazionale di Medicina.
Prof. Bandello is co-author of 12 books and he serves as a peer reviewer for grant applications for the NEI. He has authored or co-authored 904 Pub-Med articles and he served as trained Principal Investigator in several clinical trials performed following ICH/GCP and mainly concerning retinal diseases.
Retina Vitreous Associates Medical Group
Dr. David S. Boyer is a board-certified ophthalmologist specializing in the treatment of diseases of the retina and vitreous. He is Senior Partner at Retina-Vitreous Associates Medical Group with offices in Los Angeles, Beverly Hills, North Hollywood, Torrance, Pasadena, and Tarzana, California. Dr. Boyer is an Adjunct Clinical Professor of Ophthalmology with the University of Southern California/Keck School of Medicine in Los Angeles, CA. He has an extensive research background and is currently an investigator for various clinical trials (includeing THR-149 KALAHARI trial). He is one of the leading retinal clinical researchers in the country for new treatments in macular degeneration and diabetic macular edema. A widely published author and avid lecturer, Dr. Boyer lectures nationally and internationally on retinal research and the innovative approach to the treatment of retinal diseases.
Co-Chair, Cole Eye Institute
Peter K. Kaiser, M.D. graduated magna cum laude with Highest Honors from Harvard College and magna cum laude from Harvard Medical School. He completed an internal medicine internship at Massachusetts General Hospital, an ophthalmology residency at the Massachusetts Eye and Ear Infirmary, and a vitreoretinal fellowship at Bascom Palmer Eye Institute where he was awarded a Heed Ophthalmic Fellowship , before joining the vitreoretinal department of the Cole Eye Institute at the Cleveland Clinic Foundation, Cleveland, Ohio where he is the Chaney Family Endowed Chair in Ophthalmology Research and Professor of Ophthalmology at the Cleveland Clinic Lerner College of Medicine.
As a National Eye Institute and National Institute of Health RO1-funded principal investigator, Dr. Kaiser leads a team involved in the evaluation of vascular biology in age-related macular degeneration (AMD) and diabetic retinopathy (DR). In addition, Dr Kaiser is actively involved in clinical research having served as Study Chairman for numerous major, multi-center, international clinical trials, and principal investigator in over 60 trials evaluating new treatments for AMD, DR, and other retinal disorders. He is the director of Center for Ocular Research and Evaluation (CORE). Dr. Kaiser has been honored to receive the Lew R. Wasserman Award from the Research to Prevent Blindness and the Macula Society’s Young Investigator Award. Complementing his research endeavors, Dr. Kaiser serves on numerous scientific advisory boards and addresses his research interests as an invited speaker at national and international conferences. He is a major contributor to the medical literature having authored 7 textbooks, 30 book chapters, and more than 400 peer-reviewed manuscripts. He is Editor-in-Chief of Retinal Physician, Associate Editor of International Ophthalmology Clinics, and serves on the editorial boards of American Journal of Ophthalmology, Retina, Retina Today, and Ocular Surgery News. Dr. Kaiser has been recognized by American Society of Retina Specialists Honor and Senior Honor Awards, along with the American Academy of Ophthalmology Achievement, Senior Achievement, and Lifetime Achievement Awards. He has been listed as one of the “Best Doctors in America” every year since 2002 and named one of the “150 Top Innovators in Retina” by Ocular Surgery News, selected as a charter inductee of the Retina Hall of Fame in 2017, and appeared on the biannual Ophthalmologist’s “Power List” in 2016, 2018, and 2020 as one of the top 100 most influential people in the world of ophthalmology. He is the team ophthalmologist for the Cleveland Cavaliers (National Basketball Association).
Sierra Eye Associates
Arshad M. Khanani, MD, MA, FASRS is a Managing Partner, Director of Clinical Research, and Director of Fellowship at Sierra Eye Associates and Clinical Associate Professor at the University of Nevada, Reno School of Medicine.
Dr. Khanani founded the clinical research department at Sierra Eye Associates, which is now one of the leading clinical research centers in the country. He has served as a principal investigator for over 100 clinical trials and has been a top enroller in the country for multiple Phase 1-3 trials. In addition, Dr Khanani has been the first one to perform surgical procedures in multiple surgical clinical trials dealing with sustained delivery and gene therapy. He has over 75 scientific publications.
Dr. Khanani also serves as a member of numerous national and international clinical trial steering committees as well as scientific advisory boards with the goal of bringing new treatment options for patients with retinal diseases. Dr. Khanani is frequently invited as a guest speaker at national and international meetings.
Dr. Khanani is an elected member of the Macula Society, Retina Society and has received numerous awards of distinction. In 2019, he received the Nevada Business Magazine Healthcare Heroes Physician of the Year award for his continued dedication to the field of ophthalmology. He has received the Senior Honor Award from the American Society of Retina Specialists (ASRS) and was also awarded the prestigious ASRS Presidents’ Young Investigator Award in 2021.
Hôpital de la Croix-Rousse
Laurent Kodjikian, MD PhD FEBO, is the Former-President of the French Society of Ophthalmology (SFO). He is Knight of the National Order of the Legion of Honor Chevalier de l’Ordre and Legion d’Honneur; since 1st January 2021. He is Professor of Ophthalmology and Chair of Ophthalmology at the Lyon-Est medicine university, University of Lyon, France, and Associate Chair of the Department of Ophthalmology, Croix-Rousse Teaching Hospital, Lyon, France. Since 2005, Professor Kodjikian has been on the Boards of the French Agency for Drug Security (ANSM, ex-AFSSAPS) and the National French Health Agency (HAS). Since 2009, he has also been an Expert on Clinical Research Projects in University Hospitals for the French Health Minister. Since 2013, he has been administrator of the national French Ophthalmological Society (SFO), Associate General Secretary since 2016 and current president since 2018. He is a member of numerous scientific societies (ARVO, AAO, Euretina, Club Jules Gonin, SFO). Professor Kodjikian’s research focus is on medical and surgical retina (especially AMD, DR, RVO) and in infections and inflammations (uveitis). He has been involved in more than 80 clinical trials, examining especially novel therapies for AMD and diabetic retinopathy. He has contributed to more than 359 peer-reviewed publications in the ophthalmic literature. Professor Kodjikian is author or co-author of 8 books. He was or is reviewer for 53 journals (including famous journals like The Lancet). He currently belongs to the Editorial Board of the Journal of Clinical Medicine (JCM) and Journal Français d’Ophtalmologie.
Moorfields Eye Hospital
Dr. Adnan Tufail is a leading ophthalmologist in London, specializing in medical retina disorders and cataract surgery in the context of retinal diseases. He is the clinical and research lead at Moorfields Eye Hospital for age-related macular degeneration (AMD), co-leads the €16 million Macustar Consortium, which unites industry and academia to drive dry AMD research, and is the clinical lead of the largest-ever UK Medical Research Council grant to develop novel non-VEGF anti-angiogenic therapies.
Dr. Tufail’s current areas of clinical research include novel drug and cell therapies for AMD, diabetic retinopathy and myopic degeneration, as well as a number of rare and complex retina disorders. Professor Tufail has published extensively in clinical and scientific journals and is invited to lecture widely around the world.
Lariboisere University Hospital
Ramin Tadayoni, MD, PhD, is Professor of Ophthalmology at the Université Paris Cité, France’s leading multidisciplinary university, and Department Chairman at 3 Parisian hospitals, Lariboisiere, Saint Louis and Rothschild Foundation Hospitals, in France.
In addition to his clinical and management activities, Professor Tadayoni has authored over 200 scientific articles as well as other contributions to the written literature in the field of retina. He is also the leader of French government funded EviRed research program on artificial intelligence for diabetic retinopathy, EURETINA President Elect, past President of the French-speaking Retina Specialists Society (CFSR) and elected as associate of the “French National Academy of Surgery”.
Professor Tadayoni was graduated as medical doctor and ophthalmologist from Paris V University. He completed his vitreoretinal fellowship at Lariboisiere University Hospital, Paris. He also pursued his PhD at Paris VII University, and Paris Vision Institute. He was later awarded HDR, the highest academic degree in France, and the American Academy of Ophthalmology Achievement Award. He is very committed to education and has the honor of having trained several clinical vitreoretinal and research fellows.
