A Phase 2 Multicenter, Randomized, Double-masked, Sham-controlled, Reference-arm Study to Evaluate Efficacy and Safety of ONL1204 in Patients With Geographic Atrophy (GA) Associated With Age-related Macular Degeneration (AMD)

The purpose of this study is to collect efficacy and safety information of intravitreal injection for 3 experimental arms, including 2 dose levels of ONL1204 and 2 treatment frequencies in patients with GA associated with AMD.
GA associated with AMD is one of the world's leading causes of visual disability and legal blindness globally. Associated with aging, cigarette smoking, obesity, diets low in certain nutrients, a lifestyle related to cardiac risk, and a growing list of genetic factors, AMD is becoming an increasingly prevalent public health concern, especially as the global population ages. ONL1204 is a first-in-class inhibitor of fragment apoptosis stimulator receptor-mediated cell death that has demonstrated protection of multiple retinal cell types in numerous preclinical models of retinal disease, including models of dry AMD.

Start Date01 Mar 2025

Sponsor / Collaborator

ONL Therapeutics, Inc.

NCT05730218

/ CompletedPhase 2

A Phase 2, Randomized, Sham-Controlled, Single-Masked, Dose-Ranging, Multi-Center Study to Assess the Safety and Efficacy of Intravitreal ONL1204 Ophthalmic Solution in Subjects With Macula-off Rhegmatogenous Retinal Detachment

The goal of this Phase 2 clinical trial is to learn about ONL1204 Ophthalmic Solution in terms of safety and how well the drug works in patients that have a macula-off (central point of vision) rhegmatogenous retinal detachment (RRD). The main questions it aims to answer are:
Does ONL1204 improve vision in macula-off RRD patients when used before retinal detachment repair surgery compared to patients that have surgery alone?
Is ONL1204 safe to use as an add-on drug before retinal repair surgery?
Researchers will observe patients that receive two different dosages of ONL1204 Ophthalmic Solution (50 µg or 200 µg) compared to current standard therapy (no treatment) to see if there are differences in vision and safety outcomes.

Start Date04 Apr 2023

Sponsor / Collaborator

ONL Therapeutics, Inc.

NCT05160805

/ CompletedPhase 1

A Phase 1b Multicenter, Randomized, Single-Masked, Sham-Controlled Study of the Safety and Tolerability of ONL1204 Ophthalmic Solution in Patients with Progressing Open Angle Glaucoma

The purpose of this study is to demonstrate the safety and tolerability of ONL1204 Ophthalmic Solution in patients with progressing open angle glaucoma.
ONL1204 Ophthalmic Solution is a first-in-class inhibitor of fragment apoptosis stimulator (Fas) receptor-mediated cell death that has demonstrated protection of multiple retinal cell types in numerous preclinical models of retinal disease. Apoptosis of retinal ganglion cells is associated with progressive glaucoma. Nonclinical data on ONL1204 Ophthalmic Solution suggest that ONL1204 Ophthalmic Solution may inhibit the cell death pathways in these cells.

Start Date02 May 2022

Sponsor / Collaborator

ONL Therapeutics, Inc.

100 Clinical Results associated with ONL-1204

100 Translational Medicine associated with ONL-1204

100 Patents (Medical) associated with ONL-1204

Literatures (Medical) associated with ONL-1204

01 Dec 2019·Journal of NeuroinflammationQ1 · MEDICINE

A small peptide antagonist of the Fas receptor inhibits neuroinflammation and prevents axon degeneration and retinal ganglion cell death in an inducible mouse model of glaucoma

Q1 · MEDICINE

ArticleOA

Author: Gregory-Ksander, Meredith ; Krishnan, Anitha ; Marshak-Rothstein, Ann ; Kocab, Andrew J ; Zacks, David N

AbstractBackgroundGlaucoma is a complex, multifactorial disease where apoptosis, microglia activation, and inflammation have been linked to the death of retinal ganglion cells (RGCs) and axon degeneration. We demonstrated previously that FasL-Fas signaling was required for axon degeneration and death of RGCs in chronic and inducible mouse models of glaucoma and that Fas activation triggered RGC apoptosis, glial activation, and inflammation. Here, we investigated whether targeting the Fas receptor with a small peptide antagonist, ONL1204, has anti-inflammatory and neuroprotective effects in a microbead-induced mouse model of glaucoma.MethodsIntracameral injection of microbeads was used to elevate intraocular pressure (IOP) in Fas-deficient (Faslpr) mice and WT C57BL/6J mice that received an intravitreal injection of the Fas inhibitor, ONL1204 (2 μg/1 μl) (or vehicle only), on day 0 or day 7 after microbead injection. The IOP was monitored by rebound tonometry, and at 28 days post-microbead injection, Brn3a-stained RGCs and paraphenylenediamine (PPD)-stained axons were analyzed. The effects of ONL1204 on retinal microglia activation and the expression of inflammatory genes were analyzed by immunostaining of retinal flatmounts and quantitative PCR (qPCR).ResultsRebound tonometry showed equivalent elevation of IOP in all groups of microbead-injected mice. At 28 days post-microbead injection, the RGC and axon counts from microbead-injected Faslprmice were equivalent to saline-injected (no IOP elevation) controls. Treatment with ONL1204 also significantly reduced RGC death and loss of axons in microbead-injected WT mice when compared to vehicle-treated controls, even when administered after IOP elevation. Confocal analysis of Iba1-stained retinal flatmounts and qPCR demonstrated that ONL1204 also abrogated microglia activation and inhibited the induction of multiple genes implicated in glaucoma, including cytokines and chemokines (GFAP, Caspase-8, TNFα, IL-1β, IL-6, IL-18, MIP-1α, MIP-1β, MIP-2, MCPI, and IP10), components of the complement cascade (C3, C1Q), Toll-like receptor pathway (TLR4), and inflammasome pathway (NLRP3).ConclusionsThese results serve as proof-of-principal that the small peptide inhibitor of the Fas receptor, ONL1204, can provide robust neuroprotection in an inducible mouse model of glaucoma, even when administered after IOP elevation. Moreover, Fas signaling contributes to the pathogenesis of glaucoma through activation of both apoptotic and inflammatory pathways.

Cell Death & Disease

Preservation of retinal structure and function in two mouse models of inherited retinal degeneration by ONL1204, an inhibitor of the Fas receptor

Article

Author: Kocab, Andrew J ; Zacks, David N ; Yang, Mengling ; Jia, Lin ; Yao, Jingyu

AbstractDue to the large number of genes and mutations that result in inherited retinal degenerations (IRD), there has been a paucity of therapeutic options for these patients. There is a large unmet need for therapeutic approaches targeting shared pathophysiologic pathways in a mutation-independent manner. The Fas receptor is a major activator and regulator of retinal cell death and inflammation in a variety of ocular diseases. We previously reported the activation of Fas-mediated photoreceptor (PR) cell death in two different IRD mouse models, rd10 and P23H, and demonstrated the protective effect of genetic Fas inhibition. The purpose of this study was to examine the effects of pharmacologic inhibition of Fas in these two models by intravitreal injection with a small peptide inhibitor of the Fas receptor, ONL1204. A single intravitreal injection of ONL1204 was given to one eye of rd10 mice at P14. Two intravitreal injections of ONL1204 were given to the P23H mice, once at P14 and again at 2-months of age. The fellow eyes were injected with vehicle alone. Fas activation, rate of PR cell death, retinal function, and the activation of immune cells in the retina were evaluated. In both rd10 and P23H mice, ONL1204 treatment resulted in decreased number of TUNEL (+) PRs, decreased caspase 8 activity, enhanced photoreceptor cell counts, and improved visual function compared with vehicle treated fellow eyes. Treatment with ONL1204 also reduced immune cell activation in the retinas of both rd10 and P23H mice. The protective effect of pharmacologic inhibition of Fas by ONL1204 in two distinct mouse models of retinal degeneration suggests that targeting this common pathophysiologic mechanism of cell death and inflammation represents a potential therapeutic approach to preserve the retina in patients with IRD, regardless of the genetic underpinning.

Frontiers in NeurologyQ3 · MEDICINE

The Role of Neuroinflammation in Glaucoma: An Update on Molecular Mechanisms and New Therapeutic Options

Q3 · MEDICINE

ReviewOA

Author: Malinverni, Lorenza ; Rolle, Teresa ; Ponzetto, Antonio

Glaucoma is a multifactorial optic neuropathy characterized by the continuous loss of retinal ganglion cells, leading to progressive and irreversible visual impairment. In this minireview, we report the results of the most recent experimental studies concerning cells, molecular mechanisms, genes, and microbiome involved in neuroinflammation processes correlated to glaucoma neurodegeneration. The identification of cellular mechanisms and molecular pathways related to retinal ganglion cell death is the first step toward the discovery of new therapeutic strategies. Recent experimental studies identified the following possible targets: adenosine A2A receptor, sterile alpha and TIR motif containing 1 (neurofilament light chain), toll-like receptors (TLRs) 2 and 4, phosphodiesterase type 4 (PDE4), and FasL-Fas signaling (in particular ONL1204, a small peptide antagonist of Fas receptors), and therapies directed against them. The continuous progress in knowledge provides interesting data, although the total lack of human studies remains an important limitation. Further research is required to better define the role of neuroinflammation in the neurodegeneration processes that occur in glaucomatous disease and to discover neuroprotective treatments amenable to clinical trials. The hereinafter reviewed studies are reported and evaluated according to their translational relevance.

News (Medical) associated with ONL-1204

13 Sep 2024

·www.globenewswire.com

ONL Therapeutics Closes $65 Million in Oversubscribed Series D Financing

Funds will advance the development of ONL1204 Ophthalmic Solution with the initiation of a Phase 2 global study for the treatment of geographic atrophy (GA) associated with dry age-related macular degeneration (AMD)ANN ARBOR, Mich., Sept. 13, 2024 (GLOBE NEWSWIRE) -- ONL Therapeutics, Inc., a clinical-stage biopharmaceutical company developing novel therapies for protecting the vision of patients with retinal disease, today announced that it has secured $65M in Series D financing. Johnson & Johnson Innovation – JJDC, Inc. led the round that was backed by a consortium of investors that included Bios Partners, Novartis Venture Fund, and Visionary Ventures, amongst others. “We are grateful to our new and returning investors who are making it possible for the company to achieve its vision of helping patients see the future,” commented David Esposito, chief executive officer of ONL Therapeutics. “This new round of funding provides an exciting opportunity for our company to advance the clinical development program for ONL1204.” ONL Therapeutics will continue to work alongside Johnson & Johnson’s Specialty Ophthalmology research and development team to provide a forum for sharing input to the company’s ongoing clinical development plans. ONL Therapeutics is the first and only clinical-stage company focused on the unique mechanism of action (MOA) preventing Fas-mediated death of retinal cells and inflammatory signaling pathways, the root causes of vision loss and blindness. In a Phase 1b clinical trial of ONL1204 Ophthalmic Solution in patients with GA associated with dry AMD, patients treated with ONL1204 showed reductions in the rate of growth of the GA lesion with either a single injection or two injections (90 days apart) after 6 months of treatment compared to sham patients. A consistent treatment effect was seen when comparing treated eyes versus fellow eyes. “This new round of funding builds on the University of Michigan’s support of ground-breaking biomedical research that will enable us to further advance our unique and differentiated clinical program in GA, a disease that is responsible for nearly one in five cases of blindness caused by macular degeneration,” said David Zacks, M.D., Ph.D., co-founder and chief scientific officer of ONL Therapeutics. “With the unique MOA of ONL1204 addressing neuroprotection and our compelling Phase 1 clinical data, we are excited for the potential to bring a new innovation to GA patients around the world.” About ONL1204 Ophthalmic SolutionONL1204 is a novel, first-in-class small molecule Fas inhibitor designed to protect key retinal cells, including photoreceptors, from cell death that occurs across a range of retinal diseases and conditions. Death of these retinal cells, through both direct and inflammatory signaling pathways, is the root cause of vision loss and the leading cause of blindness. The company’s later-stage clinical development program for ONL1204 includes a Phase 2 study in the U.S. for the treatment of macula-off retinal detachment (NCT05730218), a condition for which the compound has been granted orphan drug designation by the United States Food and Drug Administration (FDA). The company has also conducted a Phase 1b clinical trial in patients with geographic atrophy (GA) associated with age-related macular degeneration (AMD) (NCT04744662) and a Phase 1b clinical trial in patients with progressing open-angle glaucoma (NCT05160805) at sites in Australia and New Zealand. About ONL TherapeuticsONL Therapeutics (ONL) is a clinical-stage biopharmaceutical company committed to developing first-in-class therapeutics to protect and improve the vision of patients with retinal disease. By advancing a breakthrough technology designed to protect key retinal cells from Fas-mediated cell death, ONL is pioneering a new approach to preserving vision. For more information about ONL Therapeutics, please visit www.onltherapeutics.com.

Phase 1Orphan Drug

13 Sep 2024

·endpts.com

Valneva raises about €61M; Immuneering details new Phase 2a data

Plus, news about ONL Therapeutics, Cidara Therapeutics, Emergent BioSolutions, Vico Therapeutics and Centessa: Valneva gets €61.2M private placement: Valneva said the funds will go toward supporting ongoing Phase 3 and Phase 4 studies of its chikungunya vaccine and commercialization of that shot. It will also use the money to help fund planned Phase 2 trials for its Shigella and Zika vaccine candidates. Immuneering’s small Phase 2a dataset: The company said two of five first-line pancreatic cancer patients responded to its experimental drug, called IMM-1-104, which is designed to inhibit the MAPK pathway and “achieve universal-RAS activity.” One patient had a complete response and another had an unconfirmed partial response. Its stock $IMRX was up about 55% on Friday morning. ONL Therapeutics closes $65M Series D: Johnson & Johnson Innovation led the round . The funds will be used to advance the company’s ONL1204 program, a small molecule Fas inhibitor that aims to protect retinal cells across different eye diseases like macula-off retinal detachment and geographic atrophy. Cidara Therapeutics restructures, lays off 30% of workforce: The biotech took the measures after J&J returned a flu drug earlier this year . Cidara raised $240 million in a PIPE financing in conjunction with the move in April. The reprioritization, announced Thursday, will see the company solely focus on the flu drug, called CD388, and seek partners for its oncology pipeline. Cidara had 69 employees as of April. Emergent BioSolutions gets BARDA award for Ebola, settles case: The company will get $41.9 million to scale up its commercial efforts for Ebanga, its Ebola drug. Separately, Emergent said Friday it had agreed to pay $40 million — mostly from its insurance — to settle a class action lawsuit brought in 2021. Emergent’s shares $EBS were up about 6% on Friday morning. Vico Therapeutics presents interim Phase 1/2a Huntington’s data: The private Dutch biotech said six patients saw a 28% decrease, on average, in CSF mutant huntingtin protein after 12 weeks. There was also no effect on neurofilament light chain. Vico raised a $60 million Series B in January. Centessa Pharmaceuticals upsized its offering to $225 million from $150 million.

Phase 2Clinical ResultVaccine

10 Sep 2024

·www.globenewswire.com

ONL Therapeutics to Present at the 57th Annual Scientific Meeting of The Retina Society and EURETINA Innovation Spotlight

ANN ARBOR, Mich., Sept. 10, 2024 (GLOBE NEWSWIRE) -- ONL Therapeutics, Inc., a clinical-stage biopharmaceutical company developing novel therapies for protecting the vision of patients with retinal disease, today announced that the company plans to present clinical data at the upcoming 57th Annual Scientific Meeting of The Retina Society and EURETINA Innovation Spotlight (EIS). The Retina Society Meeting is scheduled for September 11-15, 2024, at the Four Seasons Hotel Ritz Lisbon in Lisbon, Portugal, while the EIS Meeting will take place September 18, 2024, at the International Barcelona Convention Center (CCIB) in Barcelona, Spain. Details of the Retina Society Meeting presentations are as follows: Title:Fas Inhibition with ONL1204 for the Treatment of Geographic Atrophy: Results from a Phase 1b StudyPresenter:Lejla Vajzovic, M.D.Associate Professor of OphthalmologyDuke University Eye CenterTime/Date:10:44 a.m. Western European Summer Time (WEST) on Saturday, September 14, 2024 Title:FAS Inhibition with Intravitreal ONL1204 for the Treatment of Macula-off Rhegmatogenous Retinal Detachment: Results from a Phase 2 StudyPresenter:Durga Borkar, M.D., MMCiAssociate Professor of OphthalmologyDuke University Eye CenterTime/Date:12:46 p.m. WEST on Saturday, September 14, 2024 Details of the EIS Meeting presentation are as follows: Title:Targeting Fas Pathway: ONL Therapeutics’ Approach to Dry AMD (as part of Session 1: Non-neovascular AMD and IRDs)Presenter:David N. Zacks, M.D., Ph.D.Professor, Ophthalmology and Visual Sciences, University of Michigan Chief Scientific Officer, ONL TherapeuticsTime/Date:1:05 – 1:40 p.m. Central European Summer Time (CEST) on Wednesday, September 18, 2024 About ONL1204 Ophthalmic SolutionONL1204 is a novel, first-in-class small molecule Fas inhibitor designed to protect key retinal cells, including photoreceptors, from cell death that occurs across a range of retinal diseases and conditions. Death of these retinal cells, through both direct and inflammatory signaling pathways, is the root cause of vision loss and the leading cause of blindness. The company’s later-stage clinical development program for ONL1204 includes a Phase 2 study in the U.S. for the treatment of macula-off retinal detachment (NCT05730218), a condition for which the compound has been granted orphan drug designation by the United States Food and Drug Administration (FDA). The company has also conducted a Phase 1b clinical trial in patients with geographic atrophy (GA) associated with age-related macular degeneration (AMD) (NCT04744662) and a Phase 1b clinical trial in patients with progressing open-angle glaucoma (NCT05160805) at sites in Australia and New Zealand. About ONL TherapeuticsONL Therapeutics (ONL) is a clinical-stage biopharmaceutical company committed to developing first-in-class therapeutics to protect and improve the vision of patients with retinal disease. By advancing a breakthrough technology designed to protect key retinal cells from Fas-mediated cell death, ONL is pioneering a new approach to preserving vision. For more information about ONL Therapeutics, please visit www.onltherapeutics.com.

Phase 1Phase 2Orphan DrugClinical Result

100 Deals associated with ONL-1204

R&D Status

10 top R&D records.

to view more data

Indication	Highest Phase	Country/Location	Organization	Date
Age Related Macular Degeneration	Phase 2	-	ONL Therapeutics, Inc.	01 Mar 2025
Geographic Atrophy	Phase 2	-	ONL Therapeutics, Inc.	01 Mar 2025
Retinal Detachment	Phase 2	United States	ONL Therapeutics, Inc.	04 Apr 2023
Rhegmatogenous retinal detachment - macula off	Phase 2	United States	ONL Therapeutics, Inc.	04 Apr 2023
Glaucoma, Open-Angle	Phase 1	Australia	ONL Therapeutics, Inc.	02 May 2022
Glaucoma, Open-Angle	Phase 1	New Zealand	ONL Therapeutics, Inc.	02 May 2022
Glaucoma, Angle-Closure	Preclinical	-	ONL Therapeutics, Inc.	20 Nov 2023
Retinitis Pigmentosa	Preclinical	United States	ONL Therapeutics, Inc.	-

Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT03780972 (CTgov)	Phase 1	Rhegmatogenous retinal detachment - macula off	14	Collection of ocular fluids+ONL1204 (Cohort 1 Dose A)	jsglctmitg(kmkyetfguc) = innqkthrlr piouqfjevt (syxfpublfm, svigjrbpjw - hesqpfnuur) View more	-	24 Sep 2024
NCT03780972 (CTgov)	Phase 1	Rhegmatogenous retinal detachment - macula off	14	Collection of ocular fluids+ONL1204 (Cohort 2 Dose B)	jsglctmitg(kmkyetfguc) = pawwgnqjsf piouqfjevt (syxfpublfm, ntrakvmrql - nccojpfipd) View more	-	24 Sep 2024
NCT03780972 (ARVO2023)	Phase 1	Rhegmatogenous retinal detachment - macula off Fas-regulated cytokines	14	ONL1204	(ljxikjdocn) = lirytyldtr cjaqxmuyxz (ctdtnkxeyl )	Positive	23 Apr 2023

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