AR-13503 / DSM Biomedical, Alcon - LARVOL DELTA

Computational Pharmaceutics: Glaucoma drug discovery and development using AutoGrow4's genetic algorithm, ROx, ADMET Predictor, and OCAT (ARVO 2024) - "Using netarsudil and its active metabolite (AR-13503) as benchmarks, the goal is to identify compounds that represent improvements over existing therapies. Analysis of the five graphs revealed five compounds as potential candidates. These compounds were deemed most optimal in terms of potency (mean Vina score = -9.1) and druggability (mean corneal permeability = 280.144). The next phase of this project will involve building an OCAT model of netarsudil in GastroPlus 9.8.3 to predict the ocular pharmacokinetics of the candidate-like leads."

Glaucoma • Ophthalmology

Two functional forms of corneal endothelial cell replacement therapies in a non-human primate model of corneal endothelial dysfunction (ARVO 2024) - "Rho-associated protein kinase inhibitor (ROCKi; AR-13503 - 5μM (ARVO-2023)) was supplemented in all procedures... This current study using NHP showed that both preparations of cadaveric donor-derived CECs are robust in yielding functional primary CECs for corneal endothelial cell injection therapy."

Preclinical • Ophthalmology

Injury to Cone Synapses by Retinal Detachment: Differences from Rod Synapses and Protection by ROCK Inhibition. (PubMed, Cells) - "Functional restoration of the photopic b-wave, indicating cone-bipolar neurotransmission, is also improved with ROCK inhibition. Successful protection of both rod and cone synapses with AR13503 suggests this drug will (1) be a useful adjunct to subretinal administration of gene or stem cell therapies and (2) improve recovery of the injured retina when treatment is delayed."

Journal • CNS Disorders • Retinal Disorders

Effects of Rho-Associated Kinase (Rock) Inhibitors (Alternative to Y-27632) on Primary Human Corneal Endothelial Cells. (PubMed, Cells) - "We then evaluated nine ROCK inhibitors for their effects on primary CECs, before narrowing it down to the two most efficacious compounds-AR-13324 (Netarsudil) and its active metabolite, AR-13503-and assessed their impact on cellular proliferation in vitro. Lastly, an ex vivo corneal wound healing study showed a comparable wound healing rate for the final healed area in corneas exposed to Y-27632 or AR-13324. (4) In conclusion, we were able to demonstrate that various classes of ROCKi compounds other than Y-27632 were able to exert positive effects on primary CECs, and systematic donor-match controlled comparisons revealed that the FDA-approved ROCK inhibitor, AR-13324, is a potential candidate for cellular therapeutics or as an adjunct drug in regenerative treatment for corneal endothelial diseases in humans."

Journal • Ophthalmology • Transplantation

Protection of cone synapses with a ROCK inhibitor after retinal detachment (ARVO 2023) - "We previously reported that rod spherules retract causing synaptic disjunction and that retraction can be reduced by a Rho kinase (ROCK) inhibitor (AR13503, Halasz et al...Layman Abstract (optional): Provide a 50-200 word description of your work that non-scientists can understand. Describe the big picture and the implications of your findings, not the study itself and the associated details."

Ophthalmology • Retinal Disorders

The use of rho-associated kinase inhibitors for corneal endothelial cell replacement therapeutics (ARVO 2023) - "Purpose The aim of this study is to assess the use of the active metabolite (AR-13501) of a regulatory-approved rho-associated coiled-coil kinase (ROCK) inhibitor (Netarsudil) for corneal endothelial cellular therapeutics within a rabbit model of bullous keratopathy (BK)...Results Our results showed that both Group A rabbits (receiving expanded CECs in AR-13503) and Group B rabbits (receiving SNEC-harvested CECs in AR-13503), had comparable CCT throughout each time-points assessed to those of the positive control rabbits in Y-27632 (Figure 1)...Layman Abstract (optional): Provide a 50-200 word description of your work that non-scientists can understand. Describe the big picture and the implications of your findings, not the study itself and the associated details."

Cataract • Ophthalmology

A Study Assessing AR-13503 Implant in Subjects With nAMD or DME (clinicaltrials.gov) - P1 | N=18 | Completed | Sponsor: Aerie Pharmaceuticals | Active, not recruiting ➔ Completed

Trial completion • Age-related Macular Degeneration • Diabetic Macular Edema • Macular Degeneration • Ophthalmology • Retinal Disorders • Wet Age-related Macular Degeneration

EVALUTAION OF VARIOUS RHO-ASSOCIATED KINASE (ROCK) INHIBITORS ON THE ATTACHMENT AND PROLIFERATION OF PRIMARY CORNEAL ENDOTHELIAL CELLS (ARVO 2022) - "Both classes of Aminofurazan and Benzodiazapiene ROCKi had a negative impact on HCEnCs at 30mM, whereas the Y-39983 molecule were detrimental to the HCEnCs from 10mM. We were able to demonstrate that various ROCKi evaluated including Ripasudil (K-115) and Netarsudil (AR-13324 and AR-13503) were comparable in their capacity to improve cellular attachment of HCEnCs at various concentrations. Subsequent evaluation revealed the Netarsudil molecules to aid proliferation of HCEnCs even when used at lower concentrations to Y-27632. Further functional assessment of Netarsudil within a cell injection rabbit model of bullous keratopathy is currently on going."

Ophthalmology

A Study Assessing AR-13503 Implant in Subjects With nAMD or DME (clinicaltrials.gov) - P1; N=18; Active, not recruiting; Sponsor: Aerie Pharmaceuticals; Recruiting ➔ Active, not recruiting; Trial completion date: Jan 2022 ➔ May 2022

Clinical • Enrollment closed • Trial completion date • Age-related Macular Degeneration • Diabetic Macular Edema • Macular Degeneration • Ophthalmology • Retinal Disorders • Wet Age-related Macular Degeneration

[VIRTUAL] Novel corticosteroid class reduces inflammation and lowers IOP in animal models (ARVO 2021) - " CS covalently linked to AR-13503, the active metabolite of netarsudil, were designed to deliver physiologically relevant levels of each drug to tissues of the ocular surface. CS are invaluable tools in ophthalmology but carry significant risks with long-term use. Our new class of CS with ROCKi activity demonstrated a reduced risk of inducing elevated IOP while retaining anti-inflammatory efficacy comparable to CS used in the clinic."

Preclinical • Dry Eye Disease • Ocular Inflammation • Ophthalmology • FN1

[VIRTUAL] Ocular pharmacokinetics of a novel class of corticosteroids with ROCK inhibitory activity and potential for reduced steroid-associated risks (ARVO 2021) - " Multiple compounds were synthesized to contain a steroid covalently linked to the active metabolite of netarsudil, AR-13503. We have developed a novel corticosteroid with inhibitory activity against ROCK and, thus, strong potential to reduce risks associated with conventional corticosteroids. Our data demonstrate the favorable pharmacokinetic profile of ROCK-steroid compounds for topical anti-inflammatory applications."

PK/PD data • Glaucoma • Ocular Inflammation • Ophthalmology • FN1

A Study Assessing AR-13503 Implant in Subjects With nAMD or DME (clinicaltrials.gov) - P1; N=18; Recruiting; Sponsor: Aerie Pharmaceuticals; N=59 ➔ 18; Trial completion date: Sep 2021 ➔ Jan 2022; Trial primary completion date: Sep 2021 ➔ Jan 2022

Clinical • Enrollment change • Trial completion date • Trial primary completion date • Age-related Macular Degeneration • Complement-mediated Rare Disorders • Diabetic Macular Edema • Macular Degeneration • Ophthalmology • Retinal Disorders • Wet Age-related Macular Degeneration

A Study Assessing AR-13503 Implant Alone and in Combination With Aflibercept in Subjects With nAMD or DME (clinicaltrials.gov) - P1; N=59; Recruiting; Sponsor: Aerie Pharmaceuticals; Active, not recruiting ➔ Recruiting; N=108 ➔ 59

Clinical • Combination therapy • Enrollment change • Enrollment open • Age-related Macular Degeneration • Complement-mediated Rare Disorders • Diabetic Macular Edema • Macular Degeneration • Ophthalmology • Retinal Disorders • Wet Age-related Macular Degeneration

A Study Assessing AR-13503 Implant Alone and in Combination With Aflibercept in Subjects With nAMD or DME (clinicaltrials.gov) - P1; N=108; Active, not recruiting; Sponsor: Aerie Pharmaceuticals; Recruiting ➔ Active, not recruiting

Clinical • Combination therapy • Enrollment closed • Age-related Macular Degeneration • Complement-mediated Rare Disorders • Diabetes • Diabetic Macular Edema • Gene Therapies • Genetic Disorders • Macular Degeneration • Macular Edema • Metabolic Disorders • Ophthalmology • Rare Diseases • Retinal Disorders • Wet Age-related Macular Degeneration

Aerie Pharmaceuticals reports first quarter 2020 financial results and provides business update (Aerie Pharmaceuticals Press Release) - "The AR-1105...was fully enrolled ahead of schedule in October 2019 with a readout expected in the second half of 2020. The first-in-human clinical trial for AR-13503...commenced in the third quarter of 2019 for neovascular age-related macular degeneration and DME (diabetic macular edema). Aerie currently expects to commence enrollment of the Phase 2 clinical trial in the second half of 2020, with a readout expected in 2021....Aerie also plans to file a Prior Approval Supplement with the FDA in second-quarter 2020 to obtain FDA approval to manufacture Rhopressa® in Athlone for commercial distribution in the U.S. market....An opinion from the EMA’s Committee for Medicinal Products for Human Use on the MAA for Roclanda® is expected in the fourth quarter of 2020. Topline data from the Rocklatan® Mercury 3 Phase 3 clinical trial in Europe is expected potentially in late 2020, the results of which will help determine commercial prospects in the region."

Commercial • Enrollment status • P2 data • P3 data • Age-related Macular Degeneration • Diabetic Macular Edema • Glaucoma • Macular Degeneration • Macular Edema • Ophthalmology • Retinal Disorders • Wet Age-related Macular Degeneration

Novel corticosteroids with inhibitory activity against ROCK reach target ocular tissues and reduce inflammation in EIU (ARVO 2020) - "Dexamethasone, prednisolone, fluocinolone, and triamcinolone were linked to various ROCK inhibitors including the active metabolite of netarsudil, AR-13503. Low doses of these novel compounds reduce inflammation in EIU to levels comparable to clinically relevant treatments today.Conclusions Covalently linked ROCK-steroid compounds retain their anti-inflammatory efficacy. The potential for these compounds to provide lower risk profiles than conventional corticosteroids deserves further investigation."

A novel corticosteroid with ROCK inhibitory activity can reduce ocular inflammation and lower IOP in animal models (ARVO 2020) - "We postulate that ROCK inhibition concomitant with steroid use may decrease the risk of elevated IOP associated with ophthalmic steroid use and utilize a novel compound to explore this hypothesis.Methods A novel compound consisting of triamcinolone linked to the ROCK inhibitor AR-13503, the active metabolite of netarsudil, was generated. IOP was reduced in rabbits treated with the ROCKi-steroid topically.Conclusions A novel ROCKi-steroid (AR-13503-triamcinolone) provided both anti-inflammatory and IOP-lowering activity in animal models. Simultaneous delivery of a steroid with a ROCK inhibitor in this manner deserves further study to evaluate the potential to reduce the risk of steroid-induced glaucoma in patients who require chronic steroid treatment."

Preclinical

Reassessing Aerie Pharmaceuticals (SeekingAlpha) - "AR-13503 is an inhibitor of Rho kinase and Protein kinase C designed to treat wet age-related macular degeneration...Dosing is underway in a Phase 1 trial evaluating the safety and tolerability of the drug in patients with neovascular age-related macular degeneration or diabetic macular edema. The estimated completion date is September 2021."

Trial completion date • Trial status

A Study Assessing AR-13503 Implant Alone and in Combination With Aflibercept in Subjects With nAMD or DME (clinicaltrials.gov) - P1; N=102; Recruiting; Sponsor: Aerie Pharmaceuticals; Not yet recruiting ➔ Recruiting

Clinical • Combination therapy • Enrollment open

Aerie Pharmaceuticals initiates first-in-human clinical trial of AR-13503 sustained release intravitreal implant in patients with neovascular age-related macular degeneration and diabetic macular edema (Aerie Pharmaceuticals Press Release) - "Aerie Pharmaceuticals, Inc....today announced the commencement of patient dosing in a first-in-human clinical trial of AR-13503 Sustained Release (SR) Implant in patients with neovascular age-related macular degeneration (nAMD) or diabetic macular edema (DME)."

Trial status

Aerie Pharmaceuticals reports second quarter 2019 financial results, updates full-year 2019 guidance and provides business update (Aerie Pharmaceuticals Press Release) - "...the clinical trial for AR-13503 (Rho kinase and Protein kinase C inhibitor implant) set to commence shortly for wet age-related macular degeneration and DME (diabetic macular edema)."

New trial

A Study Assessing AR-13503 Implant Alone and in Combination With Aflibercept in Subjects With nAMD or DME (clinicaltrials.gov) - P1; N=102; Not yet recruiting; Sponsor: Aerie Pharmaceuticals; Phase classification: P1/2 ➔ P1

Clinical • Combination therapy • Phase classification

"Aerie Pharmaceuticals expects to start in-human trials in Q2 of AR-13503 multi-kinase inhibitor sustained-release implant, after @US_FDA gave thumbs-up to its IND. https://t.co/h6KiF3ixu6" (@OISTWEETS)

Aerie Pharmaceuticals announces acceptance of its Investigational New Drug Application for AR-13503 sustained release implant (Businesswire) - "Aerie Pharmaceuticals...today announced that the U.S. Food and Drug Administration (FDA) has reviewed the Investigational New Drug Application (IND) for AR-13503...and it is now in effect, allowing Aerie to initiate human studies in the treatment of neovascular age-related macular degeneration (nAMD) and diabetic macular edema (DME). The IND was submitted in March 2019. Aerie expects to initiate a first-in-human clinical study later in the second quarter of 2019."

IND • New trial

Ocular Tissue Distribution and Duration of Release of AR-13503 Following Administration of AR-13503 Sustained Release Intravitreal Implant in Rabbits and Miniature Swine (ARVO 2019) - "A similar ocular tissue distribution pattern was observed in minipigs after intravitreal injection of AR-13503 Implant, with the exception of the ICB, where AR-13503 levels were similar to those in the retina and RPE/choroid. Conclusions These results demonstrated that single intravitreal administration of AR-13503 Implant was well tolerated and has the potential to deliver effective levels of AR-13503 to the retina and RPE/choroid for a period of 5-6 months for the treatment of nAMD and DME."