Methods and compositions for the treatment of glaucoma and related conditions

Abstract

Provided herein are compositions and formulations for alleviating problems associated with uncontrolled intraocular pressure (IOP) in the eye, comprising the administration of trabodenoson. Administration of trabodenoson reverses or halts the progression of glaucoma and other related disorders. Trabodenoson also restores the function of pressure sensors in the eye.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 63 / 391,303, filed July 21, 2022, along with supplements filed July 30, 2022, September 5, 2022, October 1, 2022, November 29, 2022, and March 11, 2023, and U.S. Provisional Application No. 63 / 491,070, filed March 19, 2023, the entire contents of which are incorporated herein by reference.

[0002]

[0001] Embodiments of the present disclosure generally relate to novel pharmaceutical compositions, formulations, dosing regimens, and methods of making and using them to treat glaucoma and related conditions. Provided herein are methods involving the use of trabodenoson to regulate and treat uncontrolled intraocular pressure. [Background technology]

[0003] Glaucoma is a multifactorial, slowly progressive neurodegenerative disease and the leading cause of irreversible blindness worldwide, with an estimated 118.5 million patients worldwide by 2025. Neuroprotection against glaucomatous vision loss is a widely sought-after goal, but has yet to achieve effective outcomes. Intraocular pressure (IOP) is currently the only modifiable risk factor for the disease, and controlling IOP can slow disease progression and reduce vision loss. There are more than 10 FDA-approved IOP-lowering drugs (e.g., VYZULTA®, ROCKLATAN®, RHOPRESSA®) that are effective as symptomatic relief in reducing IOP in patients with early- to intermediate-stage glaucoma. However, as glaucoma disease progresses, patients become treatment non-responders (a condition referred to as refractory glaucoma), at which point high-risk invasive glaucoma drainage procedures, such as trabeculectomy or tube shunts, become unavoidable. Unfortunately, such treatments typically fail at a 50% rate within 3-5 years for a variety of reasons, including postoperative surgical complications. Ultimately, approximately 25-30% of glaucoma patients become legally blind due to uncontrolled IOP or IOP dysfunction in the advanced or late stages of glaucoma.

[0004] The fundamental root cause of IOP dysfunction or uncontrolled IOP is related to pressure sensor damage and degradation, which results in the failure of the pressure sensor to self-regulate outflow through the trabecular meshwork (TM) in patients with glaucoma or ocular hypertension (OH). In early to mid-stage glaucoma, mild damage to the TM causes functional irregularities, while in late-stage glaucoma with severe damage to the TM, it causes engine failure. The TM is responsible for 85-90% of outflow drainage.

[0005] Traditionally, IOP-lowering eye drops have been used as a mainstay of glaucoma disease management (symptom relief) tools. Such eye drops function to compensate for the deficiencies of pressure sensor irregularities in early- to mid-stage glaucoma. Patient poor compliance (>50% non-compliance) leads to IOP instability and fluctuations, which further accelerates disease progression and ultimately becomes irreversible. New generation minimally invasive glaucoma surgery (MIGS) addresses patient poor compliance and thus slows disease progression, but does not repair the pathological processes of pressure sensors that occur as a result of aging, oxidative damage, or parainflammation.

[0006] DURYSTA® is a bimatoprost sustained-release (SR) biodegradable DURYSTA® is an intracameral implant and the first and only FDA-approved SR drug delivery product for long-term management of IOP stability. DURYSTA® elevates matrix metalloproteinase (MMP) levels in the ciliary muscle and iris, which then induces degradation of collagen, fibronectin, and lamina within the extracellular matrix (ECM), potentially resulting in improved uveoscleral outflow or trabecular meshwork outflow. DURYSTA® led to a "drug holiday" of at least 8 months in 80% of treated patients, and up to 3 years in some individuals. The AMERTIS-II Phase 3 clinical trial of DURYSTA® further demonstrated the benefit of visual field stabilization over 20 months, including an 8-month drug holiday after 12 months of API induction with three consecutive implants. DURYSTA® not only solves patient compliance issues, but also saves patients additional prescription drug costs and, importantly, halts glaucoma disease progression. Despite the promise of DURYSTA®, its clinical application is limited by bimatoprost-induced endophthalmitis, which often results in an alarming rate of corneal endothelial loss (20% loss in less than two years compared with a 0.6% loss per year under standard conditions). Such sight-threatening side effects are time- and dose-dependent and proportional to the MMP therapeutic effect. Given the risk of such adverse side effects, the FDA permits only single implants and not repeat applications. A single implant only resulted in 28% of patients being off the drug for up to 20 months after a 4-month API induction (Phase 2 clinical trial results).

[0007] What is needed are compositions and methods for alleviating complications caused by elevated IOP. Ideally, such compositions and methods should be easy to administer, long-lasting, and safe. Furthermore, such compositions and methods should preferably be able to reverse and halt the pathological conditions associated with elevated IOP in patients with glaucoma and related conditions. Also needed are compositions that do not cause undesirable side effects. Summary of the Invention [Means for solving the problem]

[0008] In one embodiment, the present disclosure relates to compositions and formulations comprising trabodenoson as an IOP treatment (rather than simply an IOP symptom reliever) for patients with glaucoma, including ocular hypertension (OHT), primary open-angle glaucoma (POAG), normal-tension glaucoma (NTG), primary angle-closure glaucoma (PACG), secondary glaucoma, and congenital glaucoma. In one embodiment, trabodenoson restores the function of pressure sensors in the trabecular meshwork (TM) of glaucomatous human eyes.

[0009] Without wishing to be bound by theory, trabodenoson is believed to act by selectively binding to adenosine A1 receptors (A1R) in the TM and ciliary body (CB) at optimal doses, triggering three independent signaling pathways for IOP control. Trabodenoson's action is particularly desirable in situations where the TM is damaged or where pressure sensors are worn out, resulting in functional irregularities (blockage or dysfunction of the outflow engine). Trabodenoson controls IOP through both slow and fast modes of action, with the slow mode via A1R activation in TM cells, resulting in upregulation of MMPs, including the potent MMP-14 and MMP-2, in the TM. The biological effects of MMPs are to remove ECM debris (e.g., type IV collagen, fibronectin, and lamina) and open mesh pores in rigid aging TM, thereby altering TM tissue texture by increasing elasticity and water conductance (similar to MMPs in Bruch's membrane rejuvenation), thus improving oxygenation to the pressure-sensing cell lining in the inner wall of Schlemm's canal. Pressure-sensing cells resemble the monolayer retinal pigment epithelium (RPE) with phagocytic properties, derived from the neural crest, which has limited self-renewal capacity upon injury in the adult mammalian eye. The lifespan and health of such pressure-sensing cells determine TM durability by controlling outflow. Activation of A1R also triggers G protein-coupled plasma membrane hyperpolarization, which places TM endothelial cells (or pressure-sensing cells) in a quiescent state and reduces calcium influx, restoring cellular homeostasis (similar to its neuroprotective role in RGC cells), which is of strategic importance for TM health and longevity.

[0010] Both MMP-induced basement membrane rejuvenation and adenosine-induced neuroprotection synergistically improve pressure sensor function in disease states, thus improving IOP performance in patients with glaucoma. The use of trabodenosone in clinical settings demonstrated a continuous IOP improvement over time, an aspect not previously observed with other IOP-lowering medications for symptomatic relief. Surprisingly, such IOP pattern behavior was unique, robust, and reproducible in early and advanced glaucoma, including PGA poor responders. The fast mode is thought to be mediated by a vascular effect, where A1R-induced G protein-coupled intracellular signaling crosstalks with muscarinic receptor 2 (M2) in contractile tissues in the TM and CB (mimicking the pilocarpine effect), and pulsatile IOP synchronizes with the cardiac pulse, which has diurnal variations, in both healthy and glaucoma-affected eyes. The fast mode vascular effect exhibits a "bell"-shaped IOP dose-response curve, requiring an optimal dose or sweet spot to achieve maximum IOP reduction. Pressure-sensing cells are sensitive to oxidative damage and shear stress, and their function is nitric oxide (NO) dependent or sensitive, which in turn determines optimal trabodenosone dosing.

[0011] Provided herein is a unique dosing regimen that includes administering trabodenoson at a clinically optimal dose. In certain embodiments, the clinically optimal dose of trabodenoson is determined by its complex mechanism of action (fast vs. slow modes). In one embodiment, a single instillation of 0.6% trabodenoson ophthalmic solution results in maximum IOP reduction, peaking in a "bell" shape. In one embodiment, under the positive influence of MMP activation, the optimal dose of trabodenoson ophthalmic solution comprises about 0.8%-6%, 1.0-3%, 1.0-1.5%, or 1.2%-1.5%, or 1.5%. In one embodiment, for sustained-release products, the API loading dose and release rate that results in an API concentration similar to that of aqueous humor includes a drop-in dose (1.5%). The "bell"-shaped IOP-lowering response curve is a guideline (rule) for optimal dosing of any trabodenoson-related product for treating glaucoma (IOP) while attempting maximum IOP reduction.

[0012] IOP is physiologically controlled by a system of pressure-sensing cells in the TM and associated underlying basement membrane (BM). Similar to the neural crest-derived RPE (retinal pigment epithelium) and corneal endothelium, which have limited self-renewal after injury or oxidative damage in the adult human eye during aging, these pressure-sensing cells comprise what are often referred to as TM endothelial cells, which form a cobblestone-like texture and form a single layer lining the inner wall of Schlemm's canal. The episcleral veins (EVPs) function as valves that control outflow through the TM (pressure sensors).

[0013] In one embodiment of the present invention, the novel dosing regimen described herein results in drug holiday. Drug holiday for IOP-related disorders is achieved when a patient's TM indicates a healthy state with restored pressure sensor function to the extent that no prescription medication or treatment is required to maintain the patient's IOP at standard target levels or below 21 mmHg. The invention described herein exceeds the efficacy of DURYSTA® (bimatoprost sustained-release intracameral implant), leading to sustained drug holiday of 8 months to up to 3 years. While not wishing to be bound by theory, trabodenosone is a more potent MMP stimulator (with emphasis on MMP-14, as it is the most potent of the MMP family) with anti-inflammatory activity via activation of oxidative macrophages, resulting in a longer drug holiday than DURYSTA®. Furthermore, trabodenosone's cytoprotection or neuroprotection of pressure-sensing cells is an inherent attribute of its therapeutic efficacy, superior to proinflammatory prostaglandin analogs (PGAs) in the SR system, such as DURYSTA®.

[0014] Without wishing to be bound by theory, the induction time and duration of drug withdrawal are believed to be determined by two important aspects: first, the stage of glaucoma disease, and second, the efficacy and duration of treatment. Regarding the stage of glaucoma disease, an important consideration depends on the recoverability and durability of the pressure sensor, or the quality of the sensor. Based on existing evidence, it is believed that a minimum of 50–70% of pressure-sensing cells may still be present in the glaucomatous eye to achieve full functional recovery and a stable drug withdrawal period of 6–12 months or longer. Patients at the same disease stage may have different and complex cell biological capabilities. Therefore, a given treatment may result in complete recovery in some patients and partial recovery in others, with the duration ranging from 3 months to up to 3 years or longer depending on the number of remaining pressure-sensing cells and their metabolic state. Regarding the second aspect, therapeutic efficacy, this aspect is generally related to the enzymatic strength and neuroprotective efficacy of MMPs. In contrast to prior art prescription drugs such as DURYSTA®, which lack neuroprotection of pressure-sensing cells (and actually increase intraocular inflammation and metabolic stress, thereby compromising the health of pressure-sensing cells), the sustained release of trabodenosone is significantly more potent for treating glaucoma and related conditions. As described herein, the sustained release of trabodenosone is more effective than the administration of other prior art prescription drugs, particularly as a withdrawal induction agent. The longer the induction time, the more stable and sustained the withdrawal may be. Furthermore, the increased efficacy of trabodenosone compared to prior art drugs such as DURYSTA® Sustained-release formulations can induce drug withdrawal at a faster rate (e.g., 1-3 months) for a higher percentage of patients (80-90%), including those with more advanced glaucoma (e.g., those on three or four prescription medications). For example, with 3-5 month sustained-release trabodenosone, 50-80% of patients with moderate glaucoma can achieve a drug withdrawal of 6-24 months (or more), respectively. Longer-term sustained-release dosing results in a higher percentage of patients experiencing a sustained drug withdrawal compared to shorter-term sustained-release formats (e.g., for severe glaucoma, 6 months may be better than 3 months).While not wishing to be bound by the following theory, compared to trabodenosone eye drops, the sustained release administration is more potent than the eye drops.

[0015] In one embodiment, the invention contemplated herein has advantages over prior art formulations, either as eye drop formulations or sustained-release formulations (e.g., as implants), because trabodenoson is the only drug in eye drop formulations that can upregulate MMPs and the only MMP therapeutic that does not increase intraocular inflammation (prostaglandin analogs are pro-inflammatory), making trabodenoson a leading choice and best candidate for intraocular sustained-release drug delivery products (such as anterior chamber rods). Trabodenoson is also a potent vasodilator with excellent therapeutic effects against age-related pathological processes involved in glaucoma and age-related macular degeneration (AMD). [Brief explanation of the drawings]

[0016] [Figure 1] Table 2 presents data related to trabodenson ophthalmic solution investigated in a randomized controlled clinical trial undergoing dose escalation from Phase 1 / 2 to Phase 3 in patients with POAG / OH, including a combination study in latanoprost ophthalmic solution poor responders. A total of 819 patients or human subjects were studied for 2 weeks to 3 months at doses starting at 0.15% BID, increasing to 6% QD, and up to 18% single doses. This demonstrated excellent systemic clinical safety and ocular tolerability, with low conjunctival hyperemia (mild to moderate): 2.56% compared to 50% with Rhopressin. Maximum IOP reduction was 6-7 mmHg at 1.5% BID on Day 28, with potential switching to QD. A phase 3 clinical trial failed to meet the IOP endpoint at 3 months, but the 6% QD arm demonstrated incremental increases in IOP reduction (or improvement) over 3 months with clinical significance compared to placebo (data source: Clinicaltrial.gov).

[0017] [Figure 2]Optimal dosing is demonstrated and a graph showing optimal trabodenoson eye drop dosing: 1.5% vs. 0.6% is provided. A Phase 2 trabodenoson dose-escalation study demonstrated a "bell"-shaped IOP dose-response curve (green bar) with 0.6% BID reaching the peak of the curve, and a dose-dependent IOP reduction (blue bar) with 1.5% BID being more effective than 0.6% BID at day 14 in normalizing diurnal fluctuations in patients with glaucoma. This is the first to recognize the two components associated with the dual MOA of trabodenoson administered at therapeutic doses (ranges). Figure 2A shows that a single dose of 0.6% trabodenoson eye drops instilled into the eyes of normotensive Dutch-belted pigmented rabbits led to an immediate IOP reduction of 25% to 27% from baseline in 2 hours, with a return to baseline by 6 hours. This study determined the trabodenoson dosing regimen, which is twice daily at initiation. Figure 2B: A 14-day phase 2 clinical trial of escalating doses of trabodenosone in patients with POAG / OH demonstrates a "bell"-shaped dose-response curve (green bars) with 0.6% BID peaking at the apex, superior to 0.15% BID and 0.3% BID (left) and 1.5% BID (right). The green bars represent IOP reduction from baseline IOP, and the blue bars represent IOP reduction from day -1 circadian IOP, with the corresponding IOP response curves dependent on the time to steady state and dose. At day 14, 1.5% BID is more effective than 0.15%, 0.3%, and 0.6% BID. In the 1.5% BID cohort, the mean IOP reduction at day 28 is superior to the mean IOP reduction at day 14. Although 0.6% peaks in the bell-shaped dose-response curve, under the positive influence of trabodenosone-derived MMP treatment, 1.5% BID is more effective than 0.6% BID in normalizing diurnal variation in patients with glaucoma.Figure 2 is from T.G. Qiu. Trabodenoson on trabecular meshwork rejuvenation: a comprehensive review of clinical data. Expert Opin Investig Drugs. 2021 Mar;30(3):227-236. doi:10.1080 / 13543784.2021.1873276. Published by: Informa Ltd and Taylor & Francis Groups. Intellectual property and copyright @2021 All rights reserved by the corresponding author.

[0018] [Figure 3] This figure demonstrates that the clinical dosing principle of trabodenosone is governed by its dual mechanism of action, via a fast mode of vascular effects and a slow mode of biological effects of MMPs. The slow mode, via its derived MMP treatment, leads toward a steady state depending on time, dose, and disease stage (Figure 3A). The fast mode exhibits a "bell"-shaped dose-response curve requiring a sweet spot or optimal dose to achieve maximum IOP reduction, and IOP values remain consistent over time (Figure 3B). The clinical readout of IOP reduction with trabodenosone is the sum of the IOP reductions provided by the fast and slow modes, and the maximum sum of IOP reduction changes over time as a result of therapeutic improvements in MMPs that alter IOP values (Figure 3C).

[0019] [Figure 4]This figure provides an illustration of optimal trabodenosone dosing (1.5% vs. 0.6%) and time-course dynamics (three scenarios). Dose selection summary: Under the positive influence of trabodenosone-derived MMP treatment, the previously identified optimal dose is no longer 0.6% as the sweet spot at the start, but rather demonstrates time-course dynamics at a given disease stage. Dose selection is based on the efficacy of trabodenosone MMP treatment leading toward drug withdrawal (early-to-mid-stage) and the need to rapidly remove ECM debris and prevent irreversible damage to pressure sensors (advanced or late-stage). 1.5% is more effective than 0.6%. Three different clinical scenarios are presented, showing doses of 0.6% BID followed by 1.5% BID to track each other toward the finish line (steady state) where drug withdrawal is possible. Figure 4A: The first scenario shows that 1.5% BID reaches steady state (off-drug) at an early time point (e.g., 4-8 months), while 0.6% BID is still running (ramp-up) and has not yet reached steady state, resulting in a higher total IOP reduction with 1.5% BID than with 0.6% BID in a given patient population. 1.5% is more effective than 0.6% in treating patients with severe glaucoma. Figure 4B: The second scenario shows that 0.6% BID reaches steady state (off-drug) at a later time point (e.g., 8-12 months), potentially resulting in a higher total IOP reduction than 1.5% BID, which reached steady state earlier with stable IOP. Figure 4C: A third scenario is one in which 1.5% BID and 0.6% BID have a transition overlap where the total IOP reduction for both doses is the same or similar over a very short period of time. This transition point could be early (e.g., 1-4 months) when the IOP at 1.5% is ramping up due to MMP effects, but the vascular effect of 0.6% is beneficial over 1.5% before both doses reach steady state. Alternatively, it could be later (e.g., 6-9 months) when 1.5% BID achieves a stable IOP (flat curve) and the IOP with 0.6% BID is still ramping up to the point where it may exceed the maximum achieved by 1.5% BID. During this kinetics, there is a contact point where both doses achieve the same total IOP reduction before 0.6% BID reaches steady state (drug off).Note that the 4-8, 8-12, and 1-3 or 6-9 month time points are given for illustrative purposes and do not reflect actual real-world time in patients. While BID dosing can be switched to QD after a period for both doses, BID is used consistently throughout this figure for comparative purposes. The eye drops and sustained-release (SR) share the same dynamic pattern: 1.5% BID is more effective than 0.6% BID in reaching steady state (or drug holiday), especially in the treatment of severe glaucoma. The sustained-release (SR) formulation is more effective than its eye drop formulation (at the same API concentration in aqueous humor). The timeline for patients to achieve drug withdrawal (steady state) depends on the formulation (SR vs. eye drops) and disease severity. While 0.6% BID may achieve slightly higher IOP reduction (total) later, from a therapeutic standpoint, 1.5% is more effective and reaches drug withdrawal sooner. Therefore, 1.5% is superior to 0.6% as an IOP treatment for glaucoma patients, especially those with severe disease who require immediate repair of pressure sensors before irreversible cell apoptosis (cell loss) is reached to a degree that exceeds their functional compensation threshold (unknown). Based on preclinical and clinical evidence (Figure 8), 6% likely lies at the bottom of the bell-shaped IOP dose-response curve, while 3% lies in the middle of the slope shown in this figure. Trabodenosone-induced neurovascular modulation may be NO-sensitive or -dependent.

[0020] [Figure 5]We present data related to a study demonstrating the unique IOP pattern behavior of trabodenosone in patients with POAG / OH. This panel demonstrated unique and powerful IOP therapeutic improvement in patients with early-to-moderate POAG / OH, including PGA poor responders. Such unique pattern behavior distinguishes trabodenosone from current FDA-approved IOP medications, such as ROCK inhibitors, Rhopressin, PGAs (lantanoprost, bimatoprost, travoprost, Vyzulta), beta-blockers, CAIs, and brimonidine, almost all of which are symptom-relieving and exhibit a flat IOP reduction curve over time, while Vyzulta and Rescula show some mild and limited therapeutic effect, but only in a subset of patients (NTG) or in selected individuals, respectively (Figures 5E and 5F). Trabodenosone's unique time course of IOP improvement is the result of its MMP therapy and neuroprotection of pressure-sensing cells via TM rejuvenation and repair of TM pressure sensors, which is demonstrated for the first time in this study. IOP profiles for latanoprost, travoprost, bimatoprost, unoprost, and rhopressin can be found in randomized controlled clinical trials (AS Khouri et al. 2019, ES Ancient et al. 2005, DR Fung et al. 2014) and are generally characterized as flat curves over a 6- to 12-month time course in patients with POAG / OH. Figure 5A: Phase 3 travodenosone monotherapy in patients with mild POAG / OH with baseline IOP <= 24 mmHg administered at a high dose of 6% QD resulted in sustained IOP improvement over 3 months with clinical significance compared to placebo (Figure 5A is from T.G. Qiu. Expert Opin Investig Drugs. 2021 Mar;30(3):227-236. Published by Informa Ltd and Taylor & Francis Groups. Intellectual property and copyright © 2021 by the corresponding author. All rights reserved).Figure 5B provides data related to the following: A phase 2 trabodenoson dose-escalation study in patients with POAG / OH with baseline IOP >21 mmHg shows incremental increases in IOP reduction (improvement) with 1.5% BID eye drops, that day 28 performed better than day 14 (0.9 mmHg improvement at 2 weeks), and that BID dosing switches occurred as early as day 29. (Figure 5B from Myers JS, et al. Journal of Ocular Pharmacology and Therapeutics 2016 32:8,555-562. https: / / www.liebertpub.com / doi / 10.1089 / jop.2015.0148. Copyright 2016, The Authors and Mary Ann Liebert, Inc. Publishers) Figure 5C: Trabodenosone add-on to lantanoprost in POAG / OH patients, including latanoprost poor responders, also showed robust and sustained IOP improvement over 12 weeks with a dosing regimen of 1.5% BID for 8 weeks, followed by a switch to 3.0% QD for the next 4 weeks. All three clinical trials (Phase 2 and 3) demonstrated the same unique IOP pattern behavior (IOP improvement) over time with the potential for dosing switching from BID to QD, indicating improved patient TM durability after trabodenosone treatment (Figure 5C from Inotek Pharma IPO S-1 form, 2014). Figure 5D shows DURYSTA®-derived MMP treatment in a preclinical normotensive canine model. The IOP-lowering profile was dose-dependent, with 22 μg being superior to the 12 μg API loading dose, but there was no improvement over time. There were also three possible reasons for the lack of improvement over time in clinical trials (not shown): 1) it may be related to its increased intraocular inflammation, including IOP performance; 2) DURYSTA® does not have a neuroprotective benefit on pressure-sensing cells or the TM endothelium; and 3) SR rapidly reached steady state within the first week or two.(Source: Lee SS, et al. J Ocul Pharmacol Ther. 2019 Apr;35(3):138-144. doi:10.1089 / jop.2018.0095.) Figure 5E. The IOP reduction profile of Vyzulta (latanoprost bunod) over 12 months (12M) in patients with NTG showed no benefit of NO delivery with only a slight improvement (approximately 0.6 mmHg) within the first 12 weeks, followed by a flattening of the curve for the remainder of the 12M study (Figure 5E is adapted from Kawase, K. et al. Adv Ther 33, 1612–1627 (2016). Copyright © 2016 Author(s). https: / / link.springer.com / article / 10.1007 / s12325-016-0385-7#rightslink.) Figure 5F shows examples of Rescula eye drop-induced IOP “therapeutic” profiles in two individual patients with refractory glaucoma, suggesting that slow-moderated cumulative improvement over time from weeks or months depends on disease severity, with no drug breaks reported in Rescula users. When administered to patients with early-to-moderate glaucoma or those without “active” intraocular inflammation, the IOP-lowering profile of Rescula showed a flat curve similar to that of a symptom-relieving medication (reference: E.S. Arcieri et al. Arch Ophthalmol. 2005;123(2):186–192). Figure 5F is from Qiu TG (2015) J Clin Exp Ophthalmol 6:473 Copyright @ Author 2015.

[0021] [Figure 6]Data related to studies demonstrating the beneficial effects of trabodenosone treatment on severe glaucoma and glaucoma conditions are provided. As shown herein, trabodenosone is more effective in patients with more severe glaucoma compared to patients with less severe glaucoma, and is more effective in POAG than in OH. IOP improves with treatment time in both mild and advanced POAH / OH. Figure 6A: A phase 2 clinical trial demonstrated that prescribed 1.5% BID trabodenosone eye drops resulted in greater IOP reduction in patients with POAG than in patients with OH in the initial population. (Figure 6A from Qiu TG. Expert Opin Investig Drugs. 2021 Mar;30(3):227-236, Copyright @ 2021 Authors) Figure 6B: A Phase 2 clinical trial showed that trabodenosone eye drops administered at 1.5% BID provided greater IOP reduction in patients with baseline IOP >25 mmHg than in patients with baseline IOP >21 mmHg at Day 14 (>7 mmHg vs. 6.5 mmHg), with better IOP improvement over the 28-day treatment period than at Day 14 (Data Source: Inotek Pharma OIS 2012). Figure 6C: A Phase 2 clinical trial of trabodenosone add-on for lantanoprost poor responders demonstrated robust incremental IOP improvement over the 12-week treatment period with a dosing switch from 1.5% BID*8 weeks to 3% QD*4 weeks. Furthermore, trabodenoson is more effective in patients with POAG than in lantanoprost poor responders (data source: Inotek Pharma 2014 S-1 Form).

[0022] [Figure 7]We present data related to trabodenosone treatment in pressure sensors via neuroprotection and ECM rejuvenation in the TM. As shown herein, trabodenosone treatment provides neuroprotection to pressure-sensing cells (neuronal lineage cells) while simultaneously removing ECM debris through potent MMP-14 upregulation, leading to subsequent degradation of type IV collagen and fibronectin in the thickened ECM of the trabecular meshwork in glaucomatous eyes. Both mechanisms of action synergistically lead to rejuvenation and repair of pressure sensors, which has not previously been understood or reported. (Figure 7A) In a preclinical NAION mouse model administered trabodenosone 6% eye drops BID for a period of time, EM morphological evaluation of cross sections of the optic nerve bundle demonstrated a significant reduction in axonal loss and myelination damage observed in treated eyes compared to placebo controls. The TM endothelium is a cobblestone-like monolayer with self-contact inhibition in cell culture, similar to the RPE; both originate from the neural crest and loss of self-renewal capacity in the adult mammalian eye (W.D. Stamer et al., Exp. Eye. Res. 2017 May;158:112-123). A1R activation-induced neuromodulation is inhibitory in nature through its G protein-coupled plasma membrane hyperpolarization, which increases K-ATP conductance and inhibits calcium influx and the release of excitatory neurotransmitters such as glutamate and dopamine, thereby directing neurons toward quiescence. The evidence for trabodenosone's neuroprotection of RGCs is applicable to its cytoprotection of pressure-sensing cells in the TM, where placing these cells in a quiescent state is essential for replenishing cellular metabolic capacity (rejuvenation) (Figure 7A, adapted from Yan Guo, et al.; Trans. Vis. Sci. Tech. 2019;8(6):47, doi: https: / / doi.org / 10.1167 / tvst.8.6.47. Copyright © 2019 The Authors, Published by ARVO Journal). Figure 7B / 7C: In vitro cultured human TM cell models demonstrated the biological activity of trabodenosone, upregulating MMP-14 expression and subsequently downregulating type IV collagen and fibronectin.Figure 7D: In a preclinical aged mouse model, 6% trabodenoson treatment led to ECM remodeling with opening of TM mesh pores and enlarged ECM spaces compared to placebo-treated eyes (Figure 7B / Figure 7C / Figure 7D are adapted from: Li G, Stamer WD et al. Trabodenoson, an Adenosine Mimetic With A1 Receptor Selectivity Lowers Intraocular Pressure by Increasing Conventional Outflow Facility in Mice. Invest Ophthalmol Vis Sci. 2018 Jan 1;59(1):383-392. https: / / doi.org / 10.1167 / iovs.17-23212. Copyright 2018 Authors, Published by ARVO Journal). The TM is a sponge-like tissue that constitutes the ECM, and outflow resistance is at the junction where it transitions to the basement membrane (BM) underlying the single-layered endothelium that forms the inner wall of Schlemm's canal. In healthy eyes, the BM is made up of fibronectin, lamina, and type IV collagen. In glaucoma eyes, pathological ECM material is present, with deformed proteoglycans deposited on the BM and solidifying TM mesh pores. Trabodenosone-derived MMP-14 treatment removes ECM debris, opening mesh pores and leading to ECM texture changes with increased elasticity and hydraulic conductance, similar to the effects of MMP-9 treatment in retinal Bruch's membrane (Figure 9). The therapeutic effect of CHA(A1R)-derived MMPs on TM rejuvenation was first discovered by Dr. Qiu in 2015. Trabodenosone is a more potent MMP stimulator than MMP-14, the most potent MMP in the family. Its therapeutic efficacy in aged mice is consistent with its therapeutic efficacy in patients with severe conditions.

[0023] [Figure 8]Trabodenosone 3% QD is superior to 6% QD in terms of a "bell"-shaped IOP dose reduction curve, which is a rapid mode of vascular effect. The A1R's vascular effect is mediated by Gi protein-coupled muscarinic M2 neurovascular regulation through increased carbon monoxide (NO), similar to the acetylcholine (Ach) effect on muscle relaxation by increased NO. The A1R acts through Gi protein activation, which couples cAMP production to induce vasorelaxation (dilation) with A1R-mediated NO production. The target receptor is likely via M2 parasympathetic innervation on vascular or contractile tissues, such as TM smooth muscle cells, and TM endothelial cells, which are most sensitive to NO. Figure 8A / 8B: Trabodenosone eye drops were administered at 3% QD and 6% QD doses for 7 consecutive days in young and old C57 mice, respectively. On day 1, 6% QD trabodenosone appeared more effective in old mice than in young mice administered at 3% QD, consistent with clinical trials in patients as a result of MMP effects. It is also noteworthy that while IOP reduction with 3% QD persisted over 7 days, the IOP-lowering effect of 6% QD in old mice slowly decreased by day 7, with 6% QD likely falling to the bottom of the bell-shaped IOP dose-response curve. Mouse eyes have a very thin sclera, which enhances drug delivery to the pars plana and vitreous cavity (small), resulting in high cumulative cAMP levels and exceeding optimal NO levels. Trabodenosone's vascular effects are dose-sensitive. The results of this study were misinterpreted in previous publications, and this is the first time that it has been noted that trabodenosone dosing in IOP reduction may be related to its NO effect. 3% is better than 6% in IOP reduction in mouse models. Similar findings were seen in patients (Figure 8A / 8B from Li G, W.D. Stamer et al. Invest Ophthalmol Vis Sci. 2018 Jan 1;59(1):383-392, doi:10.1167 / iovs.17-23212. Copyright © 2018 The Authors, published by ARVO Journals).Figure 8C: A phase 2 clinical trial of trabodenosone in fixed-dose combination with lantanoprost also found that 3% QD trabodenosone performed better than 6% QD in combination with 0.005% QD lantanoprost, but both appeared less effective than 0.005% QD lantanoprost alone, likely due to a conflict between PGA and A1R in vascular effects: one dilating, the other vasoconstricting (Source: Inotek Pharmaceuticals, Clinical Trial Identifier: NCT02829996).

[0024] [Figure 9]We provide evidence of MMPs' role in Bruch's membrane rejuvenation. Figures 9A and 9B show that MMP-2 increases the hydraulic conductance of aging Bruch's membrane from human donor eyes. MMP-9 is more potent than MMP-2, and its treatment shifts the hydraulic conductance curve of Bruch's membrane in 60-year-old donor tissue to regain the hydraulic conductance of 40-year-old Bruch's membrane by increasing its elasticity. (Figures 9A and 9B are from Ahir A, Guo L, Hussain AA, Marshall J. Expression of metalloproteinases from human retinal pigment epithelial cells and their effects on the hydraulic conductivity of Bruch's membrane. Invest Ophthalmol Vis Sci. 2002 Feb;43(2):458-65. Copyright © 2002 Publisher ARVO.) Figure 9C shows that nanopulse laser stimulates limited regeneration of host RPE cells accompanied by increased MMP production in Bruch's membrane, resulting in subretinal fluid breakdown in patients with DME. Clinical efficacy demonstrates a slow accumulation mode with sustained therapeutic effects (improved visual acuity). This is a pattern of MMP treatment behavior in retinal specialties, similar to that observed in the trabodenosone-derived MMP treatment outcome of IOP improvement (slow accumulation mode). MMP and the basement membrane (BM) are important common threads in connecting retinal blepharitis to glaucoma. Bruch's membrane is a type of BM. (Figure 9C from Qiu TG. Expert Opin Investig Drugs. 2021 Mar;30(3):227-236. Copyright @ 2021 Authors)

[0025] [Figure 10]We demonstrate that DURYSTA®-derived MMP led to drug withdrawal with functional recovery of the pressure sensor in patients with mild to moderate glaucoma, but the drug withdrawal period was unstable, likely due to increased intraocular inflammation driven proportionately by the high levels of SR API released within the AC. Figure 10A: Ph2 clinical trial: DURYSTA® with 4.2 months of API release led to 68%, 40%, and 28% of patients with mild-to-moderate POAG / OH being off-drug at 2, 8, and 20 months, respectively, and its MOA is thought to result in ECM remodeling and TM rejuvenation toward full functional recovery of the pressure sensor via high concentrations of bimatoprost-induced MMP upregulation (e.g., MMP-9) (Figure 10A is from Craven ER, et al. Drugs. 2020 Feb;80(2):167-179, https: / / link.springer.com / article / 10.1007 / s40265-019-01248-0#rightslink. Copyright @ 2019 The Authors, Published by Springer Nature). Figure 10B: In an in vitro human TM cell culture model, high concentrations (10 μg / mL) of bimatoprost and latanoprost upregulate MMP-9 expression (Figure 10B from Li X, et al. PLoS One. 2016 Mar 24;11(3):e0151644, doi:10.1371 / journal.pone.0151644. Copyright @ The Authors, 2016). Figure 10C: Elevated cytokines and pro-inflammatory molecules (e.g., TNFα, interleukins) in aqueous humor in patients with uveitis, diabetic retinopathy, and others result in clinically significant corneal endothelial loss (CEL), which is linear in a dose- or disease severity-dependent manner. (Figure 10C from Yagi-Yaguchi, Y. et al. Sci Rep 7 13603 (2017). https: / / doi.org / 10.1038 / s41598-017-14131-3. Copyright @ 2017 Authors, published by Springer Nature.)

[0026] [Figure 11-12]Trabodenosone for Drug-Release Parameter Estimation. Scientific Rationale: Drug-release reflects the health of the TM and the full functional recovery of pressure sensors in glaucomatous eyes. This reflects the complex biological ability of pressure-sensing cells to self-regulate IOP without the additional assistance of symptom-relieving IOP prescription medications. Drug-release parameters are determined by two important aspects. One aspect is related to the stage of glaucoma, which defines the likelihood of pressure sensor recovery (it is estimated that a minimum of 50-70% of pressure-sensing cells must remain in glaucomatous eyes to achieve full functional recovery and a stable drug-release period of 6-12 months or more). Parameters should include the percentage of patients: for example, 50%-80% at the start (1-3 months or 3-6 months of induction) and the drug-release period (3-6 months, 12-24 months, or 3-5 years). The other aspect is related to treatment efficacy and treatment time. Efficacy includes MMP efficacy and neuroprotective efficacy. Durysta does not have a neuroprotective role on pressure-sensing cells and also increases inflammation and metabolic stress on pressure-sensing cells. Therefore, Trabodenosone is much more potent than SR PGAs such as Durysta. Because the therapeutic effect of Trabodenosone increases over treatment time, its SR is more effective than eye drops as a withdrawal inducer. High-concentration eye drops are more effective than low-concentration eye drops; for example, 1.5% is more effective as a withdrawal inducer than 0.6%. 3% is more therapeutically effective as a withdrawal stabilizer than 1.5% without the need for a maximum target of IOP reduction.

[0027] In principle, the Trabo-SR (sustained-release trabodenosone) format, compared with Durysta, can induce drug withdrawal at a faster rate in a higher percentage of patients with more advanced glaucoma (e.g., patients on three to four prescription medications, or eyes with glaucoma that have undergone unsuccessful trabeculectomy or IDose implants) with a longer duration of treatment. Furthermore, for trabodenosone, a longer SR induction drives a higher percentage of patients to a more sustained drug withdrawal compared with a short-term SR format (e.g., in severe glaucoma, 6M is better than 3M). However, Durysta's MMP therapeutic efficacy is compromised by its proportionally increased sight-threatening side effects on corneal and TM health.

[0028] Clinical Evidence: Figures 11-12A: Durysta SR single-dose implants (4.2M 10µg and 15µg API loading doses) resulted in an estimated 68%, 47% (estimated), 40%, and 28% of patients on drug off at 6M, 9M, 12M, and 2M, respectively. Figures 11-12B: Durysta API time course induction of drug off: 4.2M Durysta SR single implants with 10µg and 15µg API loading doses resulted in 40% of patients on drug off at 12M, and 12 months of API with three consecutive 10µg implants resulted in 80% of patients on drug off. 8 months of API (one or two trabodenosone implants) resulted in an estimated 60% of patients on drug off. Figures 11-12C: Trabodenoson administered as a low-dose eye drop (1.5% BID) led to a unique dosing switch from BID to QD as early as day 29 in mild-to-moderate POAG / OH and at week 8 in latanoprost poor-responders. Dose switching is a clinical biomarker of TM durability, a precursor to drug discontinuation.

[0029] Real-World Potential: Figure 11D provides data showing the estimated effect of trabodenoson ophthalmic solution administration on drug-free duration. When combined with SR MMP as a loading dose (e.g., DURYSTA®) in patients with glaucoma, the estimated drug-free period for trabodenoson ophthalmic solution was: 50% of patients at 12 months or 80% of patients at 24 months were able to achieve a sustained drug-free period of at least 6 months and up to 3 years. Trabodenoson ophthalmic solution also stabilized and extended drug-free periods for up to 12 months or more in patients with Durysta SR MMP induction (67% drug-free period induction with Durysta, although 27% were short-lived at less than 2 months). Figure 12D shows the estimated withdrawal of trabodenosone SR (ACrod) as a withdrawal-inducing agent with 3-5 months of API in patients with glaucoma. It is estimated that 50-80% of patients with 1-2 months of drug can achieve stable withdrawal for 6-24 months of drug withdrawal persistence. 2-3 M API may induce withdrawal in newly diagnosed early glaucoma.

[0030] [Figure 13]Figure 13A shows the trabecular meshwork as a sponge-like tissue composed of contractile tissue, forming an outflow drainage system with aqueous humor exiting the Schlemm's canal toward the episcleral veins, and episcleral venous pressure (EVP) functions as an IOP regulator governed by the pressure sensor (Figure 13A is from Kay Lam, et al., Anatomy of the Aqueous Outflow Drainage Pathways. Book Title: Minimally Invasive Glaucoma Surgery (pp. 11-19). Jan 2021. Copyright: Author @ CCASng, K. Barton). Figure 13B shows pressure-sensing cells forming a monolayer lining on the inner wall of the SC and underlying BM, forming a functionally and anatomically integral part of the pressure sensor. At the JCT, the ECM, along with the BM, also plays an important role in maintaining and supporting the metabolic health and function of pressure-sensing cells. Outflow resistance in the TM is thought to be located in the JCT region. MMP treatment helps clear ECM debris and pathological proteoglycans in dense junction regions by improving elasticity and hydraulic conductance, which subsequently increases oxygenation of pressure-sensing cells, rejuvenating their metabolic capacity and contributing to sensor longevity. Trabodenosone-induced neuroprotection of pressure-sensing cells by placing them in a quiescent state is unique and important for preventing cells from undergoing apoptosis or necrosis under oxidative stress or metabolic inflammation. (Figure 13B is from Keller KE, Peters DM. Pathogenesis of glaucoma: Extracellular matrix dysfunction in the trabecular meshwork—A review. Clin Exp Ophthalmol. 2022 Mar;50(2):163-182).

[0031] All figures published in cited open access journals are covered by the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (http: / / creativecommons.org / licenses / by-nc / 4.0 / ) and are copyrighted either courtesy of the corresponding author or publisher. DETAILED DESCRIPTION OF THE INVENTION

[0032] The following detailed description is exemplary and explanatory and is intended to provide further explanation of the disclosure set forth herein. Other advantages and novel features will become readily apparent to those skilled in the art from the following detailed description of the disclosure. Texts and references cited herein include U.S. Provisional Patent Application Nos. 63 / 491,070 and 63 / 391,303, which are incorporated in their entirety.

[0033] Also incorporated herein in their entireties are U.S. Patent Nos. 7,423,144, 8,501,708, 9,522,160, 9,370,530, and U.S. Patent Application No. 2016 / 0158268.

[0034] As used herein, the term "subject" should be taken to include subjects, for example, medical or surgical subjects, such as humans and other animals, in need of therapeutic intervention.

[0035] Abbreviation: A1R: adenosine A1 receptor AAV: adeno-associated virus AC: anterior chamber of the eye Ach: acetylcholine (Ach) ADON: autosomal dominant optic atrophy AMD: Age-related macular degeneration ARTEMIS1: A phase 3, randomized, 20-month trial of bimatoprost implant in primary open-angle glaucoma. ARTEMIS 2: A phase 3, randomized, 20-month study of the efficacy and safety of bimatoprost implants in patients with primary open-angle glaucoma and ocular hypertension. API: Active Pharmaceutical Ingredient ARVO: Association for Research in Vision and Ophthalmology BID: Twice a day BM: Bruch's membrane BM: basement membrane C3: Complement factor 3 CB: Ciliary body CEL: Corneal endothelium loss CHA: cycloheylendenosine CFTR: Cystic fibrosis transmembrane conductance regulator CM: Corneoscleral network DME: Diabetic macular edema ECD: endothelial cell density ECM: extracellular matrix ERK: extracellular signal-regulated kinase EVP: episcleral venous pressure GA: geographic atrophy IND: Investigational New Drug IOP: Intraocular pressure IVT: Intravitreal JCT: juxtacanalicular tissue LBN: Latanoprost Bunod LCA: Leber congenital amaurosis LHON: Leber's hereditary optic neuropathy MATrX-1: A Study of Trabodenoson in Adults with Ocular Hypertension or Primary Open-Angle Glaucoma MIGS: Minimally Invasive Glaucoma Surgery MMP: matrix metalloproteinase MOA: Mechanism of Action 6M: 6 months or 6 months MS: multiple sclerosis mTOR: mechanistic target of rapamycin NAION: Non-arteritic anterior ischemic optic neuropathy NO: Nitric oxide NTG: normal tension glaucoma OH: ocular hypertension PACG: Primary angle-closure glaucoma PGA: Prostaglandin analogue POAG: Primary open-angle glaucoma POC: Proof of Concept PXF: false desquamation QD: Once a day. RD: retinal detachment RGC: retinal ganglion cell ROCKi: Rho kinase inhibitor RP: Retinitis pigmentosa RPE: retinal pigment epithelium 2RT Laser: Retinal Rejuvenation (2RT) Laser, SC: Schlemm's canal SLT: Selective Laser Trabeculoplasty SR: Sustained release TID: 3 times a day TM: Trabecular meshwork TNF: tumor necrosis factor UM: uveoscleral meshwork VEGF: Vascular endothelial growth factor

[0036] In one embodiment, provided herein are novel methods and dosing regimens for improving intraocular pressure, comprising administering a composition comprising trabodenoson. The chemical structure of trabodenoson (formerly known as INO-8775) is shown below: [ka]

[0037] Without wishing to be bound by the following theory, it is believed that trabodenosone acts by binding to adenosine A1 receptors, which are distributed in ocular tissues as shown below.

[0038] Table 1: Adenosine A1 receptor distribution in ocular tissues [Table 1]

[0039] As shown in Figure 1, trabodenoson eye drops have previously been investigated in randomized controlled clinical trials undergoing dose escalation from Phase 1 / 2 to Phase 3 in patients with POAG / OH, including a combination study in latanoprost eye drop poor responders. Table 2, shown in Figure 1, provides a summary of the clinical trials of trabodenoson (INO-8775) eye drops in glaucoma. This clinical trial series examined the efficacy of trabodenoson-derived MMP treatment in patients with mild to moderate or advanced glaucoma, including PGA poor responders. Unlike Rhopress, both trabodenoson treatment and IOP reduction arms do not have an upper limit of baseline IOP <= 24 mmHg, making trabodenoson more effective in patients with high baseline IOP or more severe conditions. Improvement in IOP over time is an important pattern behavior of trabodenoson treatment in glaucoma.

[0040] Figures 2 and 3 provide details about the unique findings demonstrating optimal dosing at 1.5% versus 0.6%. A Phase 2 trabodenosone dose-escalation study demonstrated a "bell"-shaped IOP dose-response curve (green bar) where 0.6% BID peaked the curve (0.15%, 0.3%, 0.6%, 1.5%, 3%, 4.5%, and 6%), and a dose-dependent IOP reduction (blue bar) where 1.5% BID was more effective than 0.6% BID at day 14 for normalizing diurnal fluctuations (0.15%, 0.3%, 0.6%, and 1.5%) in patients with glaucoma. 3% was better than 6% in terms of IOP reduction. This is the first to recognize two components associated with the dual MOA of trabodenosone administered at therapeutic doses (ranges).

[0041] This disclosure provides the first evidence that trabodenosone has been associated with IOP reduction, but the mechanism by which it does so has not previously been understood. As discovered by the inventors, trabodenosone has a significant impact in producing a vascular effect, which is the primary driving force behind IOP reduction (maximum), while the MMP effect does not have a direct effect on the contractile tissue or blood vessels that improves IOP, opens mesh pores, and increases outflow capacity; instead, it removes debris and alters the tissue texture of the TM, thereby improving the suitability of the contractile tissue to reduce IOP. The dual effect of fast-mode vascular effect (contractility) is synergistic with its slow-mode action via MMP treatment.

[0042] The novel findings of the present invention include the demonstration that trabodenosone is dose-sensitive to its vascular effects: 3% is better than 6% at reducing IOP, and 0.6% is better than 1.5% at the beginning, before its MMP therapeutic effect ramps up. The present invention also demonstrates that trabodenosone induces fast-mode IOP reduction via vascular effects (which may be NO-dependent) and therefore requires an optimal dose (bell-shaped). 3% performs better than 6% at reducing IOP (preclinical and clinical evidence). See Figure 8, which shows that 3% trabodenosone has a "bell"-shaped IOP dose reduction curve, fast-mode via vascular effects, superior to 6% (Figures 8A and 8B).

[0043] Some blood vessels in the body are innervated by parasympathetic fibers (e.g., coronary vessels). These nerves release ACh, which binds to muscarinic receptors on smooth muscle and / or endothelium. A1R's vascular effects are mediated by Gi protein-coupled muscarinic M2 neurovascular regulation, which increases the effects of NO, similar to the effects of ACh on muscle relaxation by increased NO. A1R acts through Gi protein activation, which couples cAMP production to cause vasorelaxation (dilation) accompanied by A1R-mediated NO production. The target receptor is likely via M2 parasympathetic innervation on vascular or contractile tissues, such as TM smooth muscle cells, and TM endothelial cells, which are most sensitive to NO. Brimonidine has the opposite effect, causing vasoconstriction via norepinephrine (NE)-mediated vasoconstriction, whereas sympathetic innervation is present in vascular endothelium and / or smooth muscle cells. Preclinical studies have demonstrated that trabodenosone is more potent in rescuing and protecting RGCs and outer layer photoreceptors from apoptosis compared to brimonidine, which lacks any effect on outer layer photoreceptor cells in ischemia-reperfusion rodent models (W McVicar 2015 ARVO).

[0044] The discovery by Professor John Marshall of the effect of MMPs on Bruch's membrane rejuvenation and its clinical application of 2RT in specialized retinal treatment provides further understanding of trabodenosine-derived MMPs in TM basement membrane rejuvenation. Both Bruch's membrane and BM in TM share common molecular structures and glycoprotein components: fibronectin, type IV collagen, and laminin. 2RT and SLT also share similar actions through the recruitment or regeneration of new cells in the adjacent regions (RPE or TM endothelium) that upregulate MMPs, resulting in long-term therapeutic effects lasting up to several years after a single treatment in early POAG / OH.

[0045] Prior art medications, such as bimatoprost SR intracameral implants (DURYSTA®), upregulate MMPs that release high concentrations of API in target tissues (iris and CB). A single implant resulted in drug withdrawal in 68% of patients, but more than half of the induction patients required rescue medication at 12–24 months (not stable), likely due to a proportional increase in intraocular inflammation caused by high levels of SR API. Bimatoprost, like other prostaglandin analogues, is inherently proinflammatory (all commercially available PGA eye drops, including next-generation VYZULTA and ROCKLATAN, carry FDA labels warning about the risks associated with cystoid macular edema (CME) and increased intraocular inflammation with low-dose eye drop formulations). DURYSTA® delivers 4,400-fold higher API to target tissues compared to bimatoprost eye drops (0.03% QD) administered on day 7. Three consecutive implants of DURYSTA® resulted in 80% of patients remaining drug-free for more than 8 months; however, such repeated treatments led to an alarming rate of corneal endothelial cell loss (CEL) (20% loss in 20 months compared to 1% loss per year in normal aging) (Reference: DURYSTA® Pivotal Ph 3 Clinical Trials: ARMERTIS-1 and ARMERTIS-2) (See Figure 10).

[0046] Drug holiday reflects the health of the TM and the complete functional recovery of pressure sensors in glaucomatous eyes. This reflects the complex biological ability of pressure-sensing cells to self-regulate IOP without the need for additional symptom-relieving IOP prescription medications. Determining drug holiday parameters is based on two key aspects. First, the stage of glaucoma defines the likelihood of pressure sensor recovery (it is estimated that a minimum of 50-70% of pressure-sensing cells must remain in glaucomatous eyes to achieve complete functional recovery and a stable drug holiday of 6-12 months or more). This parameter includes the percentage of patients: 50%-80% at the start (1-3 months or 3-6 months of induction) and the drug holiday period (3-6 months, 12-24 months, or 3-5 years). Second, treatment efficacy and treatment time. Efficacy includes MMP efficacy and neuroprotective efficacy. DURYSTA® does not have a neuroprotective role on pressure-sensing cells and also increases inflammation and metabolic stress on pressure-sensing cells. Therefore, trabodenosone is much more potent in SR than PGAs such as DURYSTA®. Because the therapeutic effect of trabodenosone increases with treatment time, its SR is more effective as a withdrawal inducer than eye drops.

[0047] In principle, extended-release trabodenosone can induce drug withdrawal at a faster rate in a higher percentage of patients with more advanced glaucoma (e.g., patients on three prescription medications) with a longer duration of treatment compared to DURYSTA®. Extended-release trabodenosone also drives a higher percentage of patients into more sustained drug withdrawal compared to shorter-duration extended-release formats (e.g., 6M is superior to 3M in severe glaucoma). However, the therapeutic benefits of DURYSTA® MMP are commensurately increased by its sight-threatening side effects on previously unrecognized corneal and TM health conditions, compromising the efficacy of that MMP.

[0048] According to previous studies, as shown in Figure 11A, persistence of drug off with DURYSTA® SR single dose implants (4.2M 10µg and 15µg API loads) led to 68%, 47% (estimated), 40%, and 28% of patients being off at 6M, 9M, 12M, and 24M, respectively. Figure 11B provides a DURYSTA® API time course derivation of drug off. 4.2M DURYSTA® SR single implants with 10µg and 15µg API loads led to 40% of patients being off at 12M, and 12 months of API with three consecutive 10µg implants led to 80% of patients being off. It was estimated that 8 months of API (1 or 2 consecutive implants) would result in approximately 60% of patients being off. In contrast, Figure 11C shows that trabodenoson administered as a low-dose eye drop (1.5% BID) led to a unique dosing switch from BID to QD as early as day 29 in mild-to-moderate POAG / OH and at week 8 in latanoprost poor-responders. Dose switching is a clinical biomarker of TM durability, a precursor to drug discontinuation.

[0049] In one embodiment, provided herein are novel methods and dosing regimens for improving intraocular pressure, comprising administering a composition comprising trabodenoson to a subject in need thereof at a dose of 1.0-3.0%, 1.0-2.0%, or 1.2-1.5%, or 1.5%. The optimal dose range provides peak IOP reduction in a "bell"-shaped dose-response curve, with an initial peak at 0.6% and a subsequent catch-up at 1.5% (or 1.0%-1.5%). In one embodiment, administration of the trabodenoson composition enables a unique IOP pattern with continuous IOP improvement toward a steady state. The pattern behavior includes a slow mode of action that is time-, dose-, and stage-dependent. In one embodiment, the invention described herein is beneficial for subjects with early or advanced POAG / OH, including poor PGA non-responders. In one embodiment, the claimed invention is not limited to symptomatic relief but is based on therapeutic improvements, including but not limited to improving or restoring trabecular meshwork function and therefore its effects on longevity through the dual action of BM rejuvenation of neuroprotection and pressure-sensing cell metabolic capacity.

[0050] In one embodiment, the claimed invention normalizes diurnal IOP irregularities, with 1.5% BID eye drops being more effective than 0.6% BID eye drops in patients with glaucoma. In one embodiment, the invention is effective in reversing mild to moderate impairment of sensory cell metabolic activity in early to intermediate stage glaucoma with mild to moderate TM pathology, and in another embodiment, the invention is more effective in halting disease progression and treating advanced stage glaucoma with moderate to severely damaged TM, further preventing the need for high-risk glaucoma drainage surgery.

[0051] While not wishing to be bound by any theory, the claimed invention is believed to be effective because it simultaneously activates three independent signaling pathways via G protein-coupled muscarinic M2 receptor activation in the TM and CB, cell hyperpolarization in the TM endothelium, and specific binding affinity to the A1R, which triggers MMP14 / MMP2 upregulation in the TM. Furthermore, at optimal dose ranges, trabodenosone is believed to induce A1R activation, leading to neuroprotection or cytoprotection of pressure-sensing cells in the TM of glaucomatous eyes. Such neuroprotection or cytoprotection occurs by inhibiting calcium influx through G protein-coupled cell membrane hyperpolarization, restoring cellular homeostasis in TM endothelial cells (or pressure-sensing cells). Cell hyperpolarization represents a metabolic quiescent state of the sensing cells with cytoprotective benefits. It is M2 receptor activation, rather than the biological effects of its derived MMPs, that leads to IOP reduction via contractile tissue during movement, a previously misunderstood concept. Its enzymatic degradation helps improve the compliance of contractile tissue in response to the overriding IOP regulation of pressure sensors. Such an integrated functional relationship between MMP upregulation in the TM / CB and M2 activation is revealed for the first time in the present invention.

[0052] Without wishing to be bound by theory, it is believed that at optimal dosing, trabodenosone provides maximum IOP reduction through M2 receptor activation. Its vascular effects are sensitive to NO, which also requires optimal doses (e.g., 0.6%-1.5%, 1.0%-1.5%). Trabodenosone-induced upregulation of MMP14 / MMP2 leads to changes in basement membrane (BM) texture by increasing elasticity and water conductance (similar to MMPs in Bruch's membrane rejuvenation). Furthermore, increased TM water conductance is thought to increase oxygenation and metabolic waste excretion in pressure-sensing cells in patients with pathological TM.

[0053] In one embodiment, a composition containing trabodenosone, e.g., in the form of eye drops, is administered once daily, twice daily, three times daily, four times daily, once weekly, twice weekly, or three times weekly. In one embodiment, 1.5% (or 1.0-1.5%, 1.5-3%) trabodenosone eye drops may be initially administered twice daily as a loading dose, followed by a once-daily dose. In certain embodiments, the loading dose duration may be determined based on the disease state, from early to advanced stage of glaucoma. In some cases, the loading dose duration may include 1-12 weeks, 2-10 weeks, 4-8 weeks, and increments therebetween. Switching from BID to QD dosing is a precursor to drug withdrawal and is unique as a result of its potent therapeutic effect.

[0054] As a resting or maintenance agent, trabodenosone ophthalmic dosing does not require maximum IOP reduction or strict compliance; for example, dose ranges can be 1.5% to 3% QD, 3% QD, 1.5% BID, or 3% QD every other day, or three times a week. Evening doses are better than morning doses.

[0055] In one embodiment, a composition comprising trabodenoson is administered as a sustained-release (SR) formulation to prevent and treat IOP dysfunction in glaucoma. For maximum IOP therapeutic benefit with clinically meaningful IOP reduction, the sustained-release product should ideally provide an API concentration in the aqueous humor equivalent to the same API concentration (range) achieved via eye drops at a given optimal dose (range). In one embodiment, the optimal dose (range) of the trabodenoson eye drops determines the API loading dose and release rate. In one embodiment, the sustained-release formulation of the present invention can be fabricated using polymer-based PLGA and / or PEG biodegradable or non-biodegradable materials.

[0056] In one embodiment, the sustained-release formulation is provided in a form that is minimally invasive in shape, size, and dimensions and / or administered via outpatient procedures. The form can be an injectable rod, disc, coil, stent, or other equivalent format known to those skilled in the art. In one embodiment, an intracameral "rod" form can be fabricated using biodegradable materials to fit a 27-30G needle with a length of 0.5-1.0 mm. The API lifespan or sustained-release drug for a single implant can include a duration of 3-6 months, 6-12 months, 12-24 months, or 1-3 months. In one embodiment, the sustained-release formulation can be delivered via various routes, such as intracameral, intravitreal, suprachoroidal, subtenon, peribulbar, ocular surface, or punctal plugs, via minimally invasive methods. The sustained-release formulation can also be fabricated via medical coating techniques, such as drug-eluting stents, drug-eluting contact lenses, and drug-eluting intraocular lenses.

[0057] To minimize clinical side effects associated with SR formulations, the biodegradable polymer degradation rate and API release rate should be induced so that both are eliminated from the aqueous system simultaneously, within 2–3 days, or at most 7 days apart. Care must be taken to avoid prolonged periods of API precipitation or empty implants where the API is not retained within the AC, as seen in Durysta (Phase 3 study). The significant advantage of the Trabodenosone SR AC rod is its repeated dosing without stimulating intraocular inflammation. However, the dosing interval must be based on the individual eye's drug-free period and implant visibility to ensure a desirable, targeted pharmacokinetic API release profile.

[0058] The novel methods and dosing regimens for improving intraocular pressure described herein can address the problems caused by intraocular pressure associated with glaucoma. Glaucoma can be early, intermediate, or advanced, late stage glaucoma. In certain embodiments, the glaucoma is POAG / OH, refractory POAG / OH, advanced POAG / OH, end-stage POAG / OH, primary open-angle glaucoma (POAG), primary angle-closure glaucoma (PACG), normal-tension glaucoma, angle-closure glaucoma, uveitic glaucoma, or pseudoexfoliation glaucoma, steroid-induced elevated IOP or glaucoma, or congenital glaucoma.

[0059] In certain embodiments, administration of a composition comprising trabodenoson is in conjunction with an additional therapeutic intervention, which may include surgical intervention or laser treatment. In certain embodiments, the additional intervention comprises administration of a drug selected from the group consisting of Xalatan® latanoprost, Lumigan®, bimatoprost, Travatan Z®, travoprost, and Zioptan™, tafluprost, Vyzulta™ (latanoprost), beta-blockers, timolol, alpha agonists, Alphagan® P, brimonidine, Iopidine®, carbonic anhydrase inhibitors, Trusopt®, dorzolamide, Azopt®, brinzolamide, Diamox, acetazolamide, Neptazane® (methazolamide), Rho kinase inhibitors, Rhopressa®, Rocklatan, netarsudil or Cosopt®, Omlonti, or ripasudil. In certain embodiments, trabodenoson improves the IOP performance of Rhopressa®, Rocklatan®, Omlonti®, or Ripasudil in advanced or end-stage glaucoma. In certain embodiments, administration of a composition containing trabodenoson is performed after trabeculectomy or tube shunting in advanced, late-stage glaucoma after SLT, Ellios laser, or transscleral laser administration. In certain embodiments, administration of a composition containing trabodenoson is performed after MIGS implantation, with or without cataract removal. MIGS devices may include stents, Hydrus, MicroShunt, Trabectome, Istent Infinity, and iDose, respectively, in early-moderate and refractory glaucoma. Trabodenoson eye drops are a desirable solution for stabilizing and extending Durysta drug withdrawal in patients who have received an unstable drug withdrawal (e.g., less than two months).

[0060] In one embodiment, the present invention includes a method for repairing intraocular pressure sensors, comprising administering a composition comprising trabodenoson at a dose of 1.0-2.0%, 1.0-1.5%, 1.5%, or 3% to a subject in need thereof. In one embodiment, administration of the composition results in upregulation of MMP14, cytoprotection of pressure-sensing cells, anti-inflammatory effects on the trabecular meshwork / repair of the trabecular meshwork, vasodilation, or neuromodulation. In one embodiment, repair of the TM includes reduced inflammation, reduced extracellular matrix, restored trabecular meshwork elasticity, and / or reduced mesh pore blockage. TM rejuvenation and repair restores pressure sensor function in glaucomatous eyes, leading to a drug holiday that allows for long-term cessation of IOP-reducing therapy.

[0061] In one embodiment, drug withdrawal in glaucoma patients can be induced with either trabodenosone eye drops and / or sustained-release formulations. In one embodiment, trabodenosone is provided via a sustained-release biodegradable AC rod, which can be used as a loading dose delivery of MMP-14 therapeutic agent to rapidly induce drug withdrawal. Drug withdrawal can occur as early as three months in early glaucoma and last up to three years. Such trabodenosone AC rods induce drug withdrawal in treated or refractory glaucoma patients, with an estimated 1-3, 3-6, or 6-12 months of API presence (preferably 2-4 months).

[0062] In certain embodiments, the trabodenoson AC rod may be inserted periodically into a given eye, for example, every 3 to 6 months, every 6 to 9 months, every 9 to 12 months, or yearly, every 2 years, or every 3 years, or less frequently, depending on the stage of disease and the duration of sustained release of the API. Furthermore, trabodenoson eye drops may be used as a withdrawal inducer with a fixed BID dosing regimen, either as monotherapy or in combination with eye drops or the current standard of care for MIGS. In certain embodiments, trabodenoson eye drops are used as a "relay" withdrawal inducer after the MMP loading dose delivered by the trabodenoson AC rod or DURYSTA®. The eye drops may be used as a withdrawal inducer with a fixed BID dosing regimen, either as monotherapy or in combination with the current standard of care for MIGS or eye drops. Once a patient reaches a drug holiday with SR MMP or MMP instillation, there is no need for IOP control or reduction, at which point trabodenosone dosing and regimens can be more flexible, e.g., 3% QD, may be preferred. In one embodiment, trabodenosone ophthalmic solution at higher doses (e.g., 1.5%-3%) can be used as a drug holiday maintenance or stabilizer with a flexible dosing regimen (BID, QD, or every other day or three times a week, not requiring strict compliance).

[0063] Trabodenosone ophthalmic solution (1.5%, or 1.0-1.5%) has excellent benefits for treating untreatable or refractory elevated IOP in conditions with severe intraocular inflammation, such as uveitic glaucoma, pseudoexfoliation glaucoma, steroid-induced elevated IOP, or glaucoma, in patients with sustained-release steroid intraocular implants, such as Iluvein or Ozurdex implants, or YUTIQ®, and these patients also have sight-threatening ocular comorbidities, such as diabetic retinopathy or diabetic macular edema, retinal vein occlusion, and panuveitis.

[0064] Due to its superior therapeutic efficacy and clinical safety profile, which is not as good as that of Durysta or other PGA-related SR intraocular implants, the Trabodenosone SR AC rod offers excellent benefits for the treatment of advanced to late-stage glaucoma, including but not limited to POAG / OH patients. The Trabodenosone SR AC rod may provide 24 / 7 therapeutic recovery of pathological TM before pressure-sensing cell death reaches a threshold of cell loss toward an irreversible stage (e.g., >50% loss). The speed of recovery without compromising safety is important for this glaucoma patient population.

[0065] Optimal trabodenoson dosing, unique molecular traits, and unique IOP pattern behavior in patients with glaucoma.

[0066] Trabodenoson is an adenosine mimetic that specifically binds to the A1 receptor (A1R). It is the first IOP "treatment" agent with the ability to repair and restore pressure sensor function in patients with glaucoma. At the same time, it can effectively reduce IOP by 6-7 mmHg at 28 days in patients with early POAG / OH, with the potential for incremental IOP reduction over time (a unique pattern). When administered at an optimal dose or dose range (specifically, optimal API concentration in aqueous humor), trabodenoson can simultaneously stimulate three independent signaling pathways: G protein-coupled cell membrane hyperpolarization (resting phase), MMP14 / MMP-2 upregulation in the TM, and activation of muscarinic receptor 2 in the ciliary body and TM (similar to pilocarpine in M3 activation, but without miosis).

[0067] In particular, the biological effects of trabodenosone induce TM texture changes through increased tissue elasticity and water conductance, similar to the MMP-2-driven Bruch's membrane rejuvenation in the retina. Bruch's membrane is a type of basement membrane (BM) and shares a similar molecular structure with BM, composed of type IV collagen, laminin, and fibronectin. BM health depends on constant ECM remodeling through an appropriate ratio of MMPs and TIMPs (tissue inhibitors of metalloproteinases). As senescent MMPs are downregulated, ECM degradation slows, BM thickens, and mesh pores solidify, resulting in stiffening of TM tissue and loss of its youthful elasticity and water conductance. Trabodenosone triggers MMP-14 upregulation, accelerating ECM turnover, clearing mesh pores, and increasing BM water conductance, thereby further improving oxygenation to pressure-sensing cells via the BM / ECM. Trabodenosone, with its cytoprotective properties and neuroprotection against pressure-sensing cells, synergistically enhances patient response to other IOP prescription medications, such as ROCK inhibitors, especially in advanced glaucoma. Due to its dual effects of cytoprotection and BM rejuvenation, trabodenosone is a more potent therapeutic agent than prior art treatments, such as DURYSTA®, which require very high API concentrations to trigger MMP upregulation (but without MMP14 and MMP2 release). Commercially available PGA eye drops do not upregulate MMPs in aqueous humor (JY Heo, YHOoi, DJ Rhee, 2020).

[0068] MMP-14, derived from trabodenosine, is a membrane-type MMP subfamily enzyme with a molecular weight of approximately 66 kDa. It is one of the most potent MMP enzymes, and removes various types of ECM debris from thickened and stiff BM, including glycoproteins (fibronectin, vitronectin, laminin, and tenascin), proteoglycans and GAGs (decorin, versican, and hyaluronan [HA]), collagens (types I, III, IV, V, and VI), elastic fiber components (MAGP-1, fibrillin), and myocilin, a glaucoma-associated protein frequently found in human glaucoma eyes. Its downregulation or deficiency is associated with premature aging. Upregulation of MMP-14 is associated with macrophage activation in aging tissues and its resulting anti-inflammatory activity, distinguishing it from pro-inflammatory PGAs. Bimatoprost- and travoprost-SR-induced MMP upregulation increases in proportion to the increase in intraocular inflammation, and even with a single implant, clinically visible or measurable intraocular inflammation in the AC, such as AC flare, adhesions, or changes in peri-implant pigmentation, is observed (Ocular Therapeutics and Allergan study reports). PGAs require high concentrations to stimulate MMP upregulation, and MMP1, MMP3, and MMP-9 are the most commonly reported MMP phenotypes in in vitro cultured TM models. None of the PGA eye drops upregulates MMPs. DURYSTA® does not upregulate MMP-14 or MMP-2, even at high doses.

[0069] Unique pattern behavior leads to medication switching, which is a precursor to drug withdrawal. Low-dose trabodenosone eye drops (1.5%) contain therapeutic efficacy for improving pressure sensor durability, as evidenced by a dosing switch from BID to QD as early as 29 days, which is unique to trabodenosone. Such dosing switches are seen in early and advanced glaucoma, including PGA poor responders. Its inherent MMP therapy and cytoprotection enable continuous IOP reduction (or improvement) depending on time, dose, and disease stage. This unique IOP-lowering pattern behavior, the unique identity of trabodenosone as an IOP medication, is driven by its unique MOA and molecular phenotype, and, unlike Vyzulta, Rescula, or Rhopressa, offers very limited therapeutic benefit to patients. Such IOP pattern behavior is robust, reproducible, and repeatable across early and advanced stages of glaucoma. Such sustained IOP improvement allows for medication switching, initially reported as a precursor to drug withdrawal, as seen in DURYSTA® sustained-release (SR) MMP treatment efficacy in patients with glaucoma.

[0070] Trabodenosone IOP-lowering profile differs between therapeutic and symptomatic treatments Travondenosone's unique IOP pattern behavior with time-course improvement is based on a therapeutic profile resulting from a perfect match between the drug's MoA and the underlying pathological causes of diseases associated with elevated or uncontrolled IOP or IOP dysfunction. Such therapeutic pattern behavior is driven by its unique molecular characteristics and dosing regimen. In contrast, most available therapies for glaucoma (including RHOPRESSA®, VYZULTA®, and other IOP-lowering medications) are directed at alleviating IOP symptoms, demonstrating a flat IOP reduction profile over time, with IOP reductions at weeks 1 and 12 consistent for patients in the same group or stage. In a 12-month study in a Japanese population with normal-tension glaucoma (NTG), Vyzulta's NO-donor arm demonstrated mild improvement (<1.0 mmHg) during the first 12 weeks, followed by flattening. NTG is considered a subset of POAG with independent IOP risk factors.

[0071] Trabodenosone is particularly preferred because its therapeutic effects—not only remove ECM debris through the biological effects of MMPs but also have a unique cytoprotective effect by restoring TM endothelial homeostasis, synergistically improving the lifespan of pressure sensors—apply to all stages of glaucoma (early, intermediate, late, or advanced), and all types and conditions of glaucoma involving ECM thickening and stiffening in the TM, including POAG, NTG, PACG, secondary glaucoma, uveitic glaucoma, steroid-induced IOP elevation or glaucoma, refractory glaucoma, and congenital glaucoma.

[0072] Identification of the dosing principle and optimal dose of trabodenoson: 1.5% vs. 0.6%. The dosing principle of trabodenoson compositions is governed by a fast versus slow mode of action, with the fast mode of action resulting in a "bell" shaped dose-response curve requiring an optimal dose to achieve maximum IOP reduction (Figure 3). A single dose instillation of 0.6% trabodenoson peaks in the "bell" shaped IOP dose-response curve.

[0073] This fast mode of action is due to vascular effects mediated by A1R activation in the CB or TM via G protein-coupled M2 receptor activation, similar to pilocarpine via M3 receptor activation, which leads to IOP reduction but without miosis. Like most IOP-lowering drugs with symptomatic relief, the fast mode of action is synchronized with the pulsatile heart rate, as is blood pressure, and IOP is also pulsatile, with circadian rhythms and diurnal variations or fluctuations. Trabodenosone or INO-8775 reduces heart rate in rats via a rapid increase in atrioventricular (AV) node (resting) potassium conductance. Reference: Mor, Michal E. et al. 2013.

[0074] In glaucoma, patients experience greater diurnal IOP fluctuations than normal individuals without glaucoma or OH. These diurnal IOP irregularities in glaucomatous eyes are caused by functional irregularities in the pressure sensor. As glaucoma progresses from early to intermediate and then late stages, the functional performance of the pressure sensor deteriorates over time if sensory cell loss reaches a threshold (unknown, e.g., 70% loss around the circle), at which point the patient becomes a non-responder and invasive drainage surgery becomes inevitable. Similar to corneal endothelial loss, which reaches a threshold (500–1000 cells / mm²) and leads to corneal edema or decompensation and blurred vision, in TM, there is a threshold of pressure-sensing cell loss (edema or cavities) before the outflow engine is completely shut down (irreversible damage) and the patient becomes a non-responder to prescription medication. During the normal aging process, TM endothelium is lost at a rate of 0.58% per eye per year (similar to the 0.6% loss of corneal endothelium per year under normal physiological conditions). In glaucoma eyes, this process is accelerated, with intraocular inflammation and metabolic stress accelerating cell apoptosis. For example, it is estimated that a 60-year-old patient with glaucoma would require 70% of the average number of TM cells for that age to achieve complete recovery or withdrawal, with approximately 750,000 cells present at age 20 and approximately 400,000 at age 80.

[0075] The slow mode of action is the trabodenosone treatment arm, which shows time-, dose-, and stage-dependent progression with a steady state (Figure 3A). In clinical trials, trabodenosone eye drops took more than 3 months to reach a steady state in early POAG / OH with very mild damage. 0.6% has previously been identified as the sweet spot that peaks in the "bell"-shaped dose-response curve at the onset. However, surprisingly, under the positive influence of its MMP treatment and neuroprotection on the pressure sensor, higher doses such as 1.5% BID (or 1.0-1.5%) were more effective than 0.6% in normalizing diurnal IOP irregularities and leading to earlier drug withdrawal. Higher doses (1.5% BID) are also more effective in treating severe disease states that require timely repair to avoid major irreversible damage (cell apoptosis) to the pressure sensor. Figures 4A / 4B / 4C show three different scenarios: 0.6% BID and 1.5% BID (example of a high dose) towards the finish line: steady state.

[0076] An optimal dose is required not only to ensure IOP reduction at the peak of the "bell" shaped dose-response curve, but also to achieve a maximum or optimal "therapeutic" effect via G protein-coupled vasodilation or nitric oxide (NO)-releasing muscle relaxation.

[0077] Trabodenoson ophthalmic solution dosing and regimen As described herein, the present invention includes administering trabodenoson in optimal dosage ranges of about 0.15%-6%, 0.6%-6%, or 3-6%, 1.0-2.0%, 1.5-3%, or preferably 1.0-1.5%, 1.2-1.5%, or specifically 1.2% or 1.5%.

[0078] In one embodiment, the dosing regimen is BID at the start of monotherapy and can be switched to QD at weeks 2-4, 4-8, 8-12, 3-6, 6-9, or 12-24 depending on the need, disease stage, and, for example, the use of a drug-withdrawal inducer. The regimen requires a BID fixed-dose regimen at the start. While switching to QD at the above time points is possible, it is recommended to continue the drug until drug-withdrawal is achieved. For a drug-withdrawal maintenance agent or add-on to MIGS or other glaucoma surgery or laser treatment in patients whose IOP is under control, the trabodenoson ophthalmic dosing regimen can be flexible, either BID or QD, or 3-5 times per week, and compliance is not required. Depending on its clinical utility or purpose, the clinically effective dose range of trabodenoson for a drug-withdrawal stabilizer or maintenance agent can be expanded, as needed, from 1.5% QD to 3% QD.

[0079] In one embodiment, for at least one trabodenoson ophthalmic formulation: the concentration of trabodenoson will be the same throughout all preclinical and clinical trials, optimally 1.5% (or 1.2%, or 1.0-1.5%, or 1.0-0.02%, or 1.5%-3.0%, or 3-6%). The ophthalmic formulation can be made in a nanoparticle ophthalmic formulation format, a microparticle suspension, or an emulsion. The formulation may further include dextran or fluoride salts, or other lipid materials. The ophthalmic formulation can be made in an aqueous solution, lipid emulsion, or other suspension formulation. The ophthalmic formulation may or may not contain a preservative.

[0080] Trabodenosone on IOP pressure sensor longevity and TM health in glaucoma Components of the TM Pressure Sensor: The trabecular meshwork is a porous, sponge-like, avascular tissue composed of ECM contractile tissue terminating in a basement membrane and overlying endothelial cells, forming a single layer lining on the inner wall of Schlemm's canal. For decades, cutting-edge pharmacological research and drug development has focused on the juxta-Schlemm's canal (JCT) region, where outflow resistance exists. However, Rho kinase inhibitors (ROCK inhibitors) such as Rhopressa relax the JCT by regulating the dynamics of actin filaments (cytoskeleton) in the contractile tissue in the TM, widening the ECM space in the JCT region and increasing outflow through the TM. Few studies have achieved the paramount need for pressure sensor control of such contractile activity. Even in the absence of significant cell loss, if pressure-sensing cells are under extreme oxidative stress, Rhopressa fails to function, resulting in non-responders. Trabodenosone, on the other hand, has the potential to repair and rejuvenate these metabolically impaired cells before they undergo irreversible cell apoptosis. For example, in a patient with a Hydrus intraocular stent implant in which one-quarter of the pressure-sensing cells are metabolically impaired or dead, trabodenosone has the potential to protect and prevent the remaining three-quarters of cells from apoptosis as the disease progresses toward later stages, but current IOP agents lack an adequate MOA to rejuvenate, repair, and restore the function of these sensing cells.

[0081] The present inventors demonstrate, for the first time, that IOP control at the pressure sensor at the distal end of the TM, comprised of the TM endothelium and the underlying BM, is based on the trabodenosine A1R targeting site of action, resulting in IOP improvement in patients. Similar to blood pressure, which has a pressure sensor in the heart, IOP also has a pressure sensor in the TM. It comprises two components: the pressure-sensing cells, which are cobblestone-like, neural-lineage cells that form a monolayer lining on the inner wall of Schlemm's canal (sometimes referred to as TM endothelium or Schlemm's canal endothelial cells). These are shear stress sensors that respond to oxidative stress and are sensitive to NO levels, maintaining IOP homeostasis (Fiona McDonnel et al., 2021). The second component is the basement membrane (BM) underlying the TM endothelium. In healthy TM, this is composed of type IV collagen, lamina, and fibronectin. Depending on the elastic water conductance of the underlying Bruch's membrane, it provides essential support for the health and longevity of RPE cells, as well as the health and longevity of sensory cells that lack self-renewal upon injury in the adult eye. MMP2 and MMP-14 are the primary MMPs for TM cells to control IOP homeostasis in response to mechanical stretch via the mTOR pathway (J Bradley et al in 2003).

[0082] MMP-14 is a potent enzyme that helps clear mesh pores and remove ECM debris in the BM through proteolysis of fibronectin, lamina, and type IV collagen deposited in glaucomatous eyes, including glycoproteins (fibronectin, vitronectin, laminin, and tenascin), proteoglycans and GAGs (decorin, versican, hyaluronan [HA]), collagens (types I, III, IV, V, and VI), fibrous components (MAGP-1, fibrillin), and myocilin, a glaucoma-associated protein frequently found in human glaucomatous eyes that deposits in the TM sheath and lamina.

[0083] Root cause of elevated or uncontrolled IOP in glaucoma: This invention also reveals for the first time that pressure sensor dysfunction, wear, or malfunction is the rate-limiting and primary root cause associated with elevated or uncontrolled IOP in patients with glaucoma, further informing future therapeutic development for the clinical management of IOP in glaucoma. Pressure sensor dysfunction in glaucoma is the result of TM endothelial cell senescence and apoptosis, along with underlying BM thickening and stiffening as a result of age-related oxidative stress, metabolic inflammation, or parainflammation, as well as RPE loss and Bruch's membrane aging (thickening or atrophy) as rate-limiting in dry AMD. Neurovascular inflammation is involved in both the anterior and posterior parts of the eye with glaucomatous vision loss. In the anterior eye, pressure-sensing cell apoptosis (advanced stage) or functional irregularities occur in the early stages of the disease. Pressure-sensing cells are neural lineage cells that share neuronal biology. In the posterior eye, neuroinflammation affects the health of RGCs, causing cell apoptosis. Oxidative stress and metabolic inflammation lead to glutamate excitotoxicity in both neurons. Trabodenosone exerts its neuroprotection through G protein-coupled cell hyperpolarization, restoring cellular homeostasis and thus reducing oxidative stress or damage to RGCs and pressure-sensing cells. Trabodenosone has demonstrated its neuroprotection against RGC apoptosis in two preclinical models through multiple direct RGC protection and indirect neurovascular regulation involving Müller glia, astrocytes, and microglia. More importantly, it enhances potent vascular effects (dilation).

[0084] Trabodenoson and Refractory Glaucoma Refractory glaucoma refers to a clinical condition in which glaucoma patients do not respond well to current symptom-relieving medications. It can be the result of advanced or late-stage POAG / OH and PACG, or of uveitis, PXF, or steroid-induced glaucoma, or of congenital glaucoma. The trabodenosone treatment regimen of the present invention offers significant benefits for this group of patients with severe ECM coagulation or fibrosis and impaired or damaged pressure sensors (for which no effective treatments are currently available). Approximately 25-30% of POAG / OH patients suffer from an inflammatory predisposition accompanied by increased levels of pro-inflammatory molecules, such as TNFα, NF-kappa B, interleukins, and bradykinin, circulating in the bloodstream. Some patients also suffer from genetic predispositions, such as mutations in the optineurin gene (see G Qiu 2015). These proinflammatory molecules or cytokines enter the anterior chamber from the bloodstream, exposing the TM pressure sensor to constant metabolic stress or parainflammation (subthreshold inflammation) along with aging-related oxidative stress. These risk factors accelerate sensor cell apoptosis and underlying BM thickening, as well as fibrotic coagulation of TM mesh pores, collectively leading to blockage of the TM outflow engine in the late stages of glaucoma. Such inflamed aqueous humor is often the underlying cause associated with failed filtering surgery as a result of bleb fibrosis. Both CYPASS® and DURYSTA® cause corneal endothelial death at an alarming rate in the same subset of "inflamed" glaucomatous eyes, a phenomenon that has previously received little attention.

[0085] Uveitic glaucoma involves more severe intraocular inflammation than advanced POAG / OH, causing severe damage to pressure sensors, especially during acute attacks of disease recurrence. Steroids are the primary treatment for uveitis, but they further exacerbate the pathological process in TM. Most cases of uveitic glaucoma are intractable, and no effective treatment is currently available.

[0086] Pseudoexfoliation syndrome (PES) is a systemic disorder in which abnormally high concentrations of fibrous proteinaceous material are produced in ocular tissues. It is the most common cause of secondary glaucoma worldwide and the most common cause of unilateral glaucoma. The resulting PES responds poorly to medical therapy compared with other types of glaucoma and can lead to rapid progression of optic nerve damage. Prevalence can range from 0.6% in the population aged 52–62 to 5% in the population aged 75 or older.

[0087] Steroid-induced IOP elevation is the result of ECM accumulation in the TM, thickening of the BM, and dysfunction of pressure sensors. It is often transient, and while most patients can be treated with standard-of-care IOP-lowering medications, approximately 4-5% of patients may become prescription drug non-responders with recurrent IOP spikes and ultimately develop refractory glaucoma requiring high-risk glaucoma drainage surgery, a condition commonly seen in Iluvein and recurrent Ozurdex users. MMP therapeutic eye drops are a superior option to MMP-based gene therapy for steroid-induced IOP spikes.

[0088] Trabodoenoson eye drops delivering MMP are the optimal choice for steroid-induced IOP spikes or glaucoma for a wide range of target populations, including patients with needs resulting from cataract surgery and retinal gene therapy requiring short-term steroid treatment, as well as patients with DME or uveitis requiring long-term steroid treatment. In contrast, other sustained-release products, such as DURYSTA®, can lead to complications such as severely inflamed aqueous humor in patients with DME or uveitis requiring long-term steroid treatment (e.g., Ozurdex or Iluvein patients).

[0089] Primary angle-closure glaucoma (PACG) often has an acute onset, resulting in adhesions or microfibrosis around the TM in a patchy or punctate pattern that damages pressure sensors throughout the day and night. Protecting the health and longevity of remaining pressure sensors is crucial for patients undergoing trabeculectomy or tube shunting, or standard treatment with either laser or eye drop therapy. PACG accounts for 74% of the glaucoma population, approximately one-third of the POAG population, but is responsible for 50% of glaucoma blindness and is often seen in small Asian eyes with shallow ACs. The DURYSTA® implant (27G, 1.0mm) may be too large for small eyes with PACG. In contrast, trabodenosone provides more potent MMP intervention with neuroprotection, allowing for the creation of smaller "rods" with comparable slow-release durations, which may be advantageous for PACG patients.

[0090] Normal-tension glaucoma (NTG): NTG is a subgroup of POAG, but patients' IOP is less than 21 mmHg. Vision loss in NTG patients is associated with both pressure-independent and pressure-dependent risk factors, such as neurovascular abnormalities, with the former being the primary causative factor and no effective treatment available. Trabodenosone offers significant advantages over current standard-of-care medications (symptom-relieving eye drops) with comprehensive therapeutic potential that addresses underlying causes related to both the anterior and posterior glaucoma of the eye.

[0091] Trabodenosone treatment in combination with current standard of care. In advanced glaucoma, trabodenosone (eye drops or SR) can be used in combination with first-line PGA drugs such as Vylzulta, ROCKLATAN, lantanoprost, travoprost, or bimatoprost, and second-line IOP-lowering drugs such as Rhopressa, timolol, brimonidine, or CAI, as a "triple" or two-drug combo to address difficult, refractory cases. Preferably, the combination of trabodenosone with a ROCK inhibitor such as Rhopressa may improve or enhance the IOP-lowering efficacy of Rhopressa by restoring or improving pressure sensor function in this late-stage group or in non-responders. In patients requiring two to four prescription medications, trabodenosone treatment can reverse disease progression to a point where fewer medications are needed or halt disease progression toward a stage where all medications fail and high-risk surgery becomes inevitable. For progressive or refractory glaucoma, trabodenoson (eye drops or SR) may also be effective as an add-on for patients with MIGS, such as microshunts, and trabeculectomies, or tube shunts.

[0092] Trabodenosone Therapeutic Agent as a Drug Withdrawal Inducer or Stabilizer The term "drug holiday" was originally used to describe cancer patients undergoing chemotherapy who were in remission and no longer required treatment. In glaucoma IOP management, drug holiday reflects the health of the TM in glaucomatous eyes and indicates the functional recovery of the pressure sensor to the point where prescription medications are no longer required to maintain IOP at normal or target levels. Drug holiday also reflects the complex metabolic ability of the pressure sensor to self-regulate IOP in response to shear stress stretching in patients with glaucoma.

[0093] The discovery of trabodenosone-derived MMPs, leading to the possibility of drug withdrawal, is based on the shared common thread of upregulation of a key enzyme protein, MMP, in specialized retinal and glaucoma treatments: 1) DURYSTA®-derived MMP therapy results in sustained drug withdrawal in patients, a previously incompletely understood clinical phenomenon; 2) retinal rejuvenation laser (2RT)-induced MMP-2 upregulation in patients with dry AMD and subretinal fluid degradation in patients with DME demonstrated sustained clinical efficacy over 6-12 months; and 3) SLT laser for glaucoma also results in long-term clinical IOP control via a similar mechanism as 2RT laser, through MMP upregulation. While the biological effects of DURYSTA®-derived MMPs have been described by leading experts in the field as a single anatomical change that triggers ECM remodeling, few recognize that MMP-induced ECM remodeling leads to TM rejuvenation through texture changes in the BM. MMP treatment has the power to transform a 60-year-old Bruch's membrane into a 40-year-old by increasing hydraulic conductance, helping to restore its youthful elasticity, ultimately leading to tissue oxygenation and metabolic exchange.

[0094] Whether a glaucoma patient can achieve a drug holiday and the duration of that holiday depends on the reversibility of the TM, essentially the quantity and quality of pressure-sensing cells (rate-limiting), as well as the efficacy and duration of treatment. For example, trabodenosone SR is more effective than DURYSTA® SR for a given stage of disease, and trabodenosone SR formulations are also more effective than eye drops in driving patients toward drug holiday and repairing severe TM damage, such as in refractory glaucoma. A single implant of DURYSTA® SR may be more effective than trabodenosone eye drops (pulse delivery), while repeated implants may impair pressure sensor function due to increased intraocular inflammation (ARMETIS-1 and 2Ph3 clinical trials).

[0095] The induction time and duration of drug withdrawal are directly linked to the reversibility of pressure sensors, which is determined by the stage or severity of the disease and the extent of damage: for example, 25%, 50%, 75%, or 80% loss of pressure-sensing cells (apoptosis) around the circumference of Schlemm's canal. The therapeutic efficacy of the drug, along with its duration of treatment, is another important parameter that determines the induction time and durability of drug withdrawal. Cell loss and reversibility (unknown): It is not known exactly what percentage (%) of remaining pressure-sensing cells is required to achieve stable drug withdrawal for, for example, three or six months or more in patients with glaucoma. Pressure sensors appear to be metabolically very robust. For example, 15% of patients with Hydrus implants suffer significant damage to one-quarter (1 / 4) of the circle of pressure-sensing cells, while the remaining three-quarters of cells may compensate for this one-quarter cell loss, and some individuals appear to still function normally without the need for additional prescription medication in the second year. Although it is unclear whether the remaining 75% of cells without Hydrus contact are sufficient for self-regulation when fully restored by trabodenosone MMP treatment, it is estimated that 70% of functional sensing cells are sufficient to compensate for damage in glaucomatous eyes for a given time when pressure is under control.

[0096] The quantity and quality of sensory cells are rate-limiting for pathological processes associated with elevated or uncontrolled IOP, and the potential for TM recovery is determined by the minimum number of sensory cells that can compensate for losses during the chronic and prolonged progression of glaucoma. Similar to the corneal endothelium, there is a threshold of cell loss at which the cornea decompensates due to edematous changes that blur vision. During the normal aging process, TM endothelium is lost at a rate of 0.58% per eye per year. In glaucomatous eyes, this process is accelerated, with intraocular inflammation and metabolic stress accelerating cell apoptosis. While there is no established information regarding the thresholds of approximately 750,000 cells at 20 years of age and approximately 400,000 cells at 80 years of age, it is estimated that a 60-year-old patient with glaucoma would require 70% of the average number of TM cells for that age to achieve complete recovery or drug cessation.

[0097] For the same group of patients with POAG / OH on one to two prescription medications as the DURYSTA®-treated population, it is expected that at least 80% of this group will be able to achieve a stable drug-free period of 6 months or more with a single trabodenoson SR implant. Specifically, for the same group of patients with POAG / OH on one to two prescription medications, a 3-month MMP induction (single implant) is expected to lead to more than 28% of patients (e.g., 50%) achieving a stable drug-free period of more than 20 months. Specifically, it is estimated that a single trabodenoson implant with a 3-5 month SR API duration will enable 60-70% of patients on one to two prescription medications to achieve a stable drug-free period of 6 months to up to 3 years. It is estimated that a single trabodenoson implant (for small eyes) with a 1-3 month SR API duration will enable 50% of patients on one to two prescription medications to achieve a stable drug-free period of 6 months to up to 3 years in some individuals. A single trabodenosone implant with a 3-5 month SR API duration in patients with advanced disease who were on two to three prescription medications led to a drug-free period of six months or more in more than 50% of patients due to the induction of MMPs. For patients with more advanced glaucoma who were on two to three prescription medications, three to four prescription medications, or who required high-risk glaucoma drainage procedures such as tube shunts or trabeculectomies, the trabodenosone SR implant (AC rod) could reduce medication from three to four to two to three, or from two to three to one to two, or replace such risky invasive procedures, which often fail in >50% of cases over a three to five-year period. The trabodenosone SR implant (e.g., AC rod) is more effective than its eye drop formulation in this advanced or refractory stage of glaucoma. Trabodenosone SR implants (e.g., AC rods) have advantages over DURYSTA® in advanced glaucoma (2-4 prescription medications) due to their anti-inflammatory and vasodilatory benefits. Trabodenosone can be made in smaller SR sizes, which could fill a market gap in primary angle-closure glaucoma, where DURYSTA® is not recommended.DURYSTA® significantly increases intraocular inflammation at an alarming rate, causing sight-threatening side effects, and for clinical safety reasons, only single implants are permitted (limitations). Patients with advanced glaucoma should be treated with caution.

[0098] Trabodenoson sustained-release product target profile In one embodiment, the sustained-release device containing trabodenosone comprises a "rod" shape, suitable for use in the eye, with a preferred size of 0.5-1.0 mm, fitting a 30-gauge needle (or 27-30-gauge), and made of a biodegradable material (e.g., PLGA or PEG) for outpatient intracameral injection. In one embodiment, the device should be re-administered or repeatable at the end of the drug holiday. In one embodiment, the API loading dose and diurnal release rate or velocity are designed to allow for a 3-6 month API SR duration, which may lead to 80% of treated patients achieving a minimum of 5-6 months and a maximum of 3 years of stable drug holiday, depending on disease stage (early vs. advanced). In an embodiment, for the SR product, the diurnal release rate (velocity) of the API is optimized according to the optimal API concentration in the aqueous humor, as determined by the optimal eye drop dosing (1.5% BID) at week 4, preferably (between weeks 1 and 4). The optimal API concentration in aqueous humor delivered by trabodenosone SR or eye drops should be the same within small variations. Such optimal API concentrations in AC or aqueous humor should be the same in preclinical animal models (rabbits, dogs, monkeys) and in human patients. At such optimal API concentrations in aqueous humor within AC, trabodenosone leads to maximum IOP reduction (≥6–7 mmHg) with maximum therapeutic efficacy.

[0099] In certain embodiments, the sustained-release trabodenosone devices contemplated herein include devices and formats that can be delivered, administered, implanted, or otherwise administered to a patient intracamerally, intravitreally, suprachoroidally, peribulbarly, subtenonally, subconjunctivally, retrobulbarly, or via a drug-eluting contact lens or ring, or punctal plug. SR formats can be in a variety of shapes and sizes, including rods, discs, stents, and rectangles. In one embodiment, an SR intracameral implant can be fabricated in sizes ranging from 27 to 30 g and lengths ranging from 0.5 to 1.0 mm. A 30 g implant is preferred. SR formats can also be fabricated using medical coating technologies, such as iDose drug-eluting stents, drug-eluting contact lenses, and drug-eluting intraocular lenses (Spyware).

[0100] According to certain embodiments, the IOP profile induced by trabodenoson eye drops is delayed, with a ramp-up time of approximately 4 weeks to achieve 6-7 mmHg, and may take 3 months or more to reach a steady state where maximum IOP reduction is achieved in early-to-mid-stage glaucoma. The IOP profile induced by the trabodenoson SR AC rod is estimated to have a rapid onset, with a ramp-up time shorter than the 4 weeks required for the eye drops, due to continuous MMP exposure. Trabodenoson eye drops deliver MMP twice daily, and require a longer time to induce drug withdrawal in the same group of patients compared with DURYSTA® MMP and the trabodenoson SR AC rod, which deliver MMP continuously. While there is no direct standard for the time required for eye drop MMP induction to achieve drug withdrawal, MMP efficacy with trabodenoson eye drops occurred as early as day 29 following a switch from BID to QD dosing. When using the MMP loading dose delivered by DURYSTA® (currently available), it is estimated that within 12 to 24 months of BID dosing, 50 to 80% of patients on one to two prescription medications can achieve a stable drug-free period of 4 to 6 months or more. Trabodenosone ophthalmic solution is most suitable as a drug-free period induction or stabilizer used in combination with SR MMP delivery by DURYSTA® or the trabodenosone AC rod. Patients who have not yet achieved a drug-free state can be continuously induced with MMP therapy using trabodenosone ophthalmic solution, and trabodenosone ophthalmic solution can be used as a maintenance or stabilizer for 12 to 24 months. In total, it is estimated that 50 to 80% of patients can achieve a stable drug-free period of 6 months or more.

[0101] Because trabodenoson is a much more potent MMP stimulator, with MMP-14 being the most potent MMP in the family, and because it also has direct cytoprotection against pressure-sensing cells, trabodenoson "treatment" achieves longer drug withdrawal in patients with more severe or late-stage glaucoma with the same API induction time. Trabodenoson has an excellent clinical safety profile and is the only drug withdrawal induction agent that does not increase intraocular inflammation.

[0102] The sustained-release (SR)-derived API dose concentration in aqueous humor should be the same as the API concentration delivered by the eye drop in the first 30 seconds after instillation after 4-6 weeks of multiple-dose BID treatment, regardless of delivery route, product prototype material, or SR duration. The API loading dose and release rate (circadian) are determined by the API concentration in aqueous humor whose site of action occurs within the AC tissues (TM and CB). The optimal dose ensures maximum treatment outcome, with IOP reduction reaching its maximum steady-state state between 3-12 months, 6-12 months, 3-6 months, or 1-3 months.

[0103] Trabodenosone treatment in the posterior eye - Trabodenosone and wet age-related macular degeneration (AMD): Trabodenosone in reducing atrophic lesions in patients with wet AMD after long-term anti-VEGF therapy. Trabodenosone was initially developed for the treatment of cardiovascular disease, pain, and inflammation, as well as diabetes. There are numerous Phase 1-3 clinical trials based on this adenosine A1R-associated drug for the treatment of cardiovascular disease and diabetes. Adenosine A1R-targeted therapy has also been investigated in stroke models and ischemia-reperfusion models in the eye (elevated IOP model). A1R is most abundant in neurons in the brain and retina, but is also present in microglia, astrocytes, oligodendrocytes, and Müller cells. A1R is densely distributed in the inner retinal layers (RGC cells and nerve bundles) but is less abundant in the photoreceptor layer. In at least one optic nerve crush model, trabodenosone eye drops demonstrated neuroprotection for both the inner RGC layer of neurons and the outer layer of neurons (photoreceptors) in the ischemia-reperfusion model, whereas brimonidine did not protect against photoreceptor loss. Furthermore, in a mouse model of NAION, which involves the pathological process of ischemia and reperfusion, trabodenosone has been observed as a potent neuroprotective agent for rescuing RGC cells. In a rat model of light injury, which mimics one aspect of AMD disease progression, oxidative damage, trabodenosone also demonstrated a role in rescuing photoreceptor cell loss, likely through indirect targeting of Müller glia-driven anti-inflammatory pathways and choroidal vasoregulation or vasodilation. Its neurovascular regulation is important for eliminating outer segment shedding during severe light injury. Based on these studies, trabodenosone is a candidate for the treatment of atrophic lesions in wet AMD. The primary pathology in wet AMD associated with Lucentis overkill is choroidal ischemia around macular lesions. Eye drops with a formulation capable of delivering APIs to the choroid and outer layers of the retina should be effective in reducing such atrophic lesions, as evidenced by clinical trials of Rescula in this indication. Both drugs share a commonality: they are neurovascular modulators with high permeability to scleral tissue. [Example]

[0104] Example 1 Trabodenosone treatment for patients with early-to-mid-stage POAG / OH. Trabodenosone sustained-release (SR) AC rods can be used as a loading dose, followed by trabodenosone eye drops as a maintenance agent for those who achieve drug withdrawal, or as a withdrawal inducer for those who do not achieve drug withdrawal with the loading dose and require additional MMPs to drive pressure sensor repair and recovery toward full recovery. The endpoint can be the percentage of patients who achieve drug withdrawal within 3 to 6 months (or 1 to 3 months) with trabodenosone AC rods alone. Due to its therapeutic effect, the IOP ramp-up time with SR is faster than with 1.5% ophthalmic solution, which takes 4 weeks to achieve a 6-7 mmHg reduction. Furthermore, during a 3-6 month trabodenosone SR duration, it is estimated that more than 80% of treated patients can achieve a stable drug-free period of 6 months or more. The IOP reduction profile is equivalent to that of second-line medications such as Rhopressin or latanoprost, with a diurnal IOP reduction of 7 mmHg or more compared to the baseline starting at week 2, followed by clinical IOP endpoints at weeks 6 and 12. The remaining 20% of patients who receive a trabodenosone SR loading dose and are destined for drug-free periods can be supplemented with trabodenosone ophthalmic solution (1.5% ophthalmic solution), and it is estimated that these patients can achieve a stable drug-free period of 6 months or more within 6-12 months.

[0105] Trabodenosone SR duration: Preclinical studies with Durysta in a normal canine model have shown that one month of MMP SR treatment can lead to steady state. Trabodenosone administered for one to three months (or three to five months) of SR may be sufficient to induce a stable drug-free period of three to six months or more in 60 to 70% of patients. In patients with advanced glaucoma with more severe TM damage, longer MMP induction and two or more implants, e.g., two consecutive implants of one to three months each, or one implant with a 3 to 5 month API release, may be required.

[0106] If trabodenosone AC rods are not available, DURYSTA® can be used as an alternative to the MMP loading dose for testing trabodenosone ophthalmic solution as a withdrawal inducer. Clinical endpoints and study design can be similar to those described above for the use of trabodenosone SR AC rods.

[0107] A: Clinical endpoints of the Trabodenosone SR AC Rod clinical trial: The primary endpoint is the percentage of patients achieving stable drug withdrawal (minimum 3-6 months) after a single implant with a SR duration of 3-6 months. Rhopressa eye drops will be used as a positive control. The co-primary endpoint will be a comparable 3-month IOP reduction profile at all time points: 8:00 AM, 10:00 AM, and 2:00 PM at weeks 2, 6, and 12, compared to current second-line eye drops, such as Rhopressa or timolol eye drops.

[0108] B: Clinical Trial Endpoints for Trabodenosone Eye Drops as a Withdrawal Induction: Withdrawal parameters will be tested using Durysta or Trabodenosone SR (if available) as an MMP loading dose followed by Trabodenosone eye drops (1.5% BID). This will be a superiority trial compared to second-line IOP eye drops such as Rhopressa or Timolol. The primary endpoint is the percentage of patients achieving stable withdrawal at the 12-month endpoint after a 4-month Durysta SR loading dose of MMP treatment. Co-primary endpoint: During the induction period with trabodenoson ophthalmic solution, IOP will be measured at weeks 2, 4, 8, 12, and monthly until drug withdrawal is achieved or the 12-month endpoint, and all IOP reduction points will need to be maintained (except week 2, given the slow onset of action of trabodenoson ophthalmic solution) or compared with the second-line IOP ophthalmic solution, timolol or Rhopressa, as appropriate.

[0109] Example 2 Trabodenosone Treatment for Refractory Glaucoma (Late-Stage POAG / OH). Trabodenosone (SR or eye drops) is used as a "triple" combination for patients with late-stage POAG / OH or refractory glaucoma, e.g., trabodenosone (SR or eye drops) + Rhopressa + brimonidine vs. bimatoprost (SR or eye drops) + Rhopressa + brimonidine (positive control).

[0110] Clinical endpoints for Trabodenosone SR AC Rod vs. Durysta as a triple combination: 12 months of trabodenosone-derived MMP treatment resulting in IOP improvement will be the primary endpoint measured by the percentage of patients who improve or maintain their respective IOP and visual field stability without the need for a fourth prescription medication or invasive glaucoma surgery as a result of disease progression. Secondary endpoint: Percentage of patients requiring fewer prescription medications at the 12-month endpoint after SR implant with MMP treatment. Secondary endpoint: IOP reduction at weeks 2, 4, 8, and 12 compared to the positive control (matched).

[0111] A clinical trial of trabodenosone eye drops plus Rhopressa plus brimonidine compared with bimatoprost plus Rhopressa plus brimonidine in patients with refractory glaucoma requiring three prescription medications at entry. The primary endpoint will be a 12-month and 24-month extension to compare the percentage of patients in the two treatment groups who require the addition of a fourth prescription medication or inevitably require trabeculectomy or tube shunting due to worsening VF or a change in target IOP that prompts such a treatment decision. IOP reduction during treatment must meet the target IOP criteria defined for each study eye or individual, which may vary. Specifically, IOP will be measured at weeks 2, 4, 8, and 12, and then monthly until the 12- or 24-month study endpoint.

[0112] Expected Results: In this late-stage group, trabodenoson SR is more effective than Durysta at correcting pressure sensor malfunction and dysfunction. Therefore, a higher percentage of patients should achieve significant IOP improvement at 12 months with the SR regimen compared with Durysta SR. In the trabodenoson triple therapy trial, trabodenoson is expected to outperform the MMP treatment positive control arm, which does not have trabodenoson or whose IOP worsens over time, a historically well-known fact. Over the 12- to 24-month period, some individuals may progress more quickly than others to the point where they need to further lower their respective target IOP by adding a fourth prescription medication or undergoing surgical options. In principle, IOP improvement with SR trabodenoson will be faster than IOP improvement with trabodenoson ophthalmic solution.

Claims

1. A pharmaceutical composition for reducing or eliminating irregularities in intraocular pressure (IOP) in a person suffering from glaucoma or at risk of developing glaucoma, and for enabling subsequent discontinuation of the drug, The aforementioned pharmaceutical composition is a pharmaceutical composition for topical administration to the eyes of a subject. The aforementioned pharmaceutical composition contains travodenoson at a concentration of approximately 1.0% to approximately 2.0%. A pharmaceutical composition comprising a load dose effective in repairing and restoring pressure sensor function and enabling subsequent discontinuation of the drug.

2. The pharmaceutical composition according to Claim 1, The pharmaceutical composition is a pharmaceutical composition intended to be administered in a drug regimen that includes a loading dose period and a maintenance period. The aforementioned loading dose period is a period during which the pharmaceutical composition containing travodenoson at a concentration of approximately 1.0% to approximately 2.0% is administered topically to the eye twice a day. The aforementioned maintenance period is the period during which normalized IOP is maintained with reduced exposure to travodenoson, and during this maintenance period, the need for strict medication compliance decreases. Pharmaceutical composition.

3. The pharmaceutical composition according to Claim 1, The pharmaceutical composition, containing a loading dose at the start and travodenoson at a concentration of approximately 1.0% to approximately 2.0%, is administered twice daily for approximately 3 to 24 months. Optionally, after at least approximately four weeks of the loading dose period, the administration can be reduced to once daily while continuing the pressure sensor function recovery process throughout the remainder of the loading dose period. This repairs and restores the pressure sensor function, reduces or eliminates IOP irregularities, and enables subsequent drug discontinuation. A pharmaceutical composition intended for use under specific dosage and administration instructions.

4. The pharmaceutical composition according to claim 1, wherein a dose of travodenoson exhibits a bell-shaped response curve in which the IOP peak decreases at 0.6%, and under the favorable effect of travodenoson-mediated matrix metalloproteinase (MMP) therapy, a range of about 1.0% to about 2.0% is more effective in normalizing the irregularity of circadian rhythmic IOP.

5. A pharmaceutical composition for normalizing the irregularity of intraocular pressure (IOP) in a person suffering from glaucoma or at risk of developing glaucoma, The aforementioned pharmaceutical composition is a pharmaceutical composition for topical administration to the eyes of a subject. It contains travodenoson at a concentration of approximately 1.0% to approximately 2.0%. A pharmaceutical composition administered as a rejuvenating or repairing agent for pressure sensors, This is a pharmaceutical composition intended for use in combination with standard IOP-lowering therapy. This is a pharmaceutical composition intended for administration in a flexible dosing regimen, either twice a day or once a day. A pharmaceutical composition characterized by a low need for strict medication compliance.

6. The pharmaceutical composition according to claim 5, This pharmaceutical composition is intended to be administered in combination with current standard treatments selected from beta-blockers, Rho kinase inhibitors, prostaglandins, minimally invasive glaucoma surgery, glaucoma laser treatment, or invasive glaucoma drainage surgery in advanced stages. A pharmaceutical composition administered as a rejuvenating or repairing agent for pressure sensors, This prevents the treated eye from becoming unresponsive, unresponsive, or having IOP dysfunction in advanced stages of the disease. Pharmaceutical composition.

7. The pharmaceutical composition according to claim 5, This is a pharmaceutical composition intended for use in combination with a bimatoprost sustained-release anterior chamber implant or a travoprost sustained-release anterior chamber implant. Travodenoson functions as MMP maintenance therapy, extending the IOP drug-free period and achieving long-term IOP stability. Pharmaceutical composition.

8. A pharmaceutical composition according to claim 1 or 5, A pharmaceutical composition characterized by causing a significant improvement in intraocular pressure upon administration, thereby restoring pressure sensor function or improving the metabolic capacity of pressure-sensing cells.

9. A pharmaceutical composition according to claim 1 or 5, The aforementioned glaucoma includes refractory glaucoma, uveoid glaucoma, steroid-induced elevated intraocular pressure or glaucoma, diabetic glaucoma, pigmented glaucoma, pseudoexfoliation glaucoma, and other glaucomas with extracellular matrix (ECM) lesions associated with secondary glaucoma that are currently difficult to treat with standard medications. The aforementioned pharmaceutical composition provides removal of ECM debris in the column network, as well as restoration and recovery of pressure sensor function. The administration of the aforementioned pharmaceutical composition is more effective in managing severe glaucoma accompanied by significant ECM lesions. Pharmaceutical composition.

10. A pharmaceutical composition according to claim 1 or 5, The aforementioned glaucoma is normal-tension glaucoma. The aforementioned pharmaceutical composition is for reducing or eliminating irregularities in intraocular pressure. Pharmaceutical composition.

11. A pharmaceutical composition according to claim 1 or 5, This is a pharmaceutical composition for treating glaucoma that has progressed to the chronic phase following acute-onset primary angle-closure glaucoma. The aforementioned pharmaceutical composition further comprises a composition having anti-inflammatory activity and MMP enzyme degrading activity via the same. Pharmaceutical composition.

12. The pharmaceutical composition according to claim 1 or 5, wherein the administration of travodenoson as a pressure sensor rejuvenation agent reduces the need for multiple glaucoma treatments or surgery or glaucoma laser treatment.

13. The pharmaceutical composition according to claim 1 or 5, wherein the administration of travodenoson as a pressure sensor rejuvenator reduces or replaces the need for invasive, high-risk tube shunt and trabeculectomy in a subject, and optionally the subject has advanced or terminal glaucoma.

14. The pharmaceutical composition according to claim 1 or 5, wherein the administration of travodenoson as a pressure sensor rejuvenator reduces or replaces the need for minimally invasive glaucoma surgery on a subject, such as ist, hydrus, or glaucoma laser treatment, and optionally the subject is in the early to moderate stage of glaucoma.

15. The pharmaceutical composition according to claim 1 or 5, wherein the pharmaceutical composition is an eye drop formulation provided as a suspension, emulsion, or clear solution, and optionally the eye drop formulation is a nanoparticle eye drop formulation or a lipid eye drop formulation, and optionally the eye drop formulation comprises a polylactic acid-glycolic acid copolymer (PLGA), polyethylene glycol (PE), hydrogel, other biodegradable polymers, or a combination thereof.

16. A pharmaceutical composition for normalizing the irregularity of intraocular pressure, This is intended to induce a disease-free drug-free period after the loading dose period. It is intended to be administered as a sustained-release (SR) formulation or system. Contains an effective amount of travodenoson, This is to ensure that the daily concentration of the active pharmaceutical ingredient (API) of travodenoson in the aqueous humor or target tissue is equivalent to the concentration achieved by travodenoson eye drop formulations administered at a concentration of approximately 1% to 2%. Pharmaceutical composition.

17. The pharmaceutical composition according to claim 16, The administration of the sustained-release (SR) formulation or system comprises three components: a) an API loading dose of travodenoson, b) a daily API release rate or rate of travodenoson, and c) duration of API release of travodenoson. The API loading dose of travodenoson is predetermined by the API circadian release rate and API release duration. The aforementioned API circadian release rate is predetermined by the effective dose range of travodenoson eye drops. The API release duration is determined by the travodenoson-mediated IOP withdrawal induction time during a given disease stage. Regardless of the size, shape, dimensions, delivery route, or material of the API carrier, the composition method for travodenoson designed as a sustained-release system or formulation is characterized by being determined by the three main parameters mentioned above. Pharmaceutical composition.

18. The pharmaceutical composition according to claim 16, The pharmaceutical composition is a sustained-release formulation, The aforementioned sustained-release formulation releases travodenoson in a daily amount that ensures the same level of aqueous humor exposure as when an eye drop formulation containing approximately 1.0% to approximately 2.0% is administered twice a day. Pharmaceutical composition.

19. The pharmaceutical composition according to claim 16, wherein the API release duration is determined by the drug withdrawal induction time, and the drug withdrawal induction time is selected from the group consisting of 1 to 3 months, 2 to 3 months, 3 to 6 months, 6 to 12 months, and up to 3 years.

20. The pharmaceutical composition according to claim 16, wherein administration of travodenoson by a sustained-release formulation or system induces a drug-free period of approximately 3 to 6 months in 80% or more of the treated subjects, and the drug-free period lasts for approximately 6 to 12 months, 1 to 3 years, 3 to 5 years or longer, depending on the stage of glaucoma or the condition of the individual eye.

21. The pharmaceutical composition according to claim 16, Sustained-release travodenoson is administered in an optimal dose range under a flexible dosing regimen as a drug-free interval inducer or stabilizer, and is a pharmaceutical composition intended to induce a disease-free interval through the administration of travodenoson-mediated MMP treatment, i) a minimally invasive glaucoma surgical device, optionally an isten, hydrus, or microshunt; ii) advanced glaucoma drainage surgery, optionally trabeculectomy, or tubular shunt; iii) treatment with a bimatoprost anterior chamber implant, a travoprost SR implant, or other sustained-release drug delivery system; or iv) eye drops for current symptom relief, optionally a prostaglandin analog, optionally latanoprost bunad, travoprost, and / or bimatoprost, optionally a Rho kinase inhibitor, a β-blocker, brimonidine, and / or carbonic anhydrase inhibitor.

22. The pharmaceutical composition according to claim 16, A pharmaceutical composition in which a sustained-release (SR) dose of travodenoson functions as a drug-freezing inducer, followed by the administration of travodenoson eye drops, the travodenoson eye drops stabilizing or extending the drug-free period in the subject by maintaining or protecting the health and lifespan of pressure-sensing cells.

23. The pharmaceutical composition according to claim 16, A sustained-release (SR) travodenoson formulation allows for regular, repeated administration, and in rapidly progressing cases and advanced stages of the disease, more frequent loading doses of travodenoson with an SR formulation or system are necessary compared to cases with slow progression or early stages of the disease, with the administration interval depending on the stage of the disease and the possibility of recovery of pressure sensors in the individual eye, administered every 6 to 12 months, every 1 to 2 years, every 2 or 3 years, or longer, optionally, the administration does not cause corneal endothelial cell loss in the subject, and the administration of travodenoson with a sustained-release formulation or system induces drug withdrawal in the subject within approximately 3 to 6 months, optionally, the subject has refractory glaucoma, and the drug withdrawal period lasts approximately 6 to 12 months or up to 3 years or longer, in this pharmaceutical composition.

24. The pharmaceutical composition according to claim 16, A pharmaceutical composition to be administered in combination with additional therapeutic interventions, The aforementioned additional therapeutic interventions include surgical intervention, laser therapy, or pharmacological drugs. The aforementioned pharmacological drug is selected from the group consisting of latanoprost, bimatoprost, travoprost, tafluprost, latanoprostenbunod, timolol, brimonidine, apraclonidine, dorzolamide, brinzolamide, acetazolamide, metazolamide, netaludil, and a combination of timolol and dorzolamide. Herein, the pharmaceutical composition reduces or eliminates the need for current IOP-lowering drugs, or replaces the need for invasive drainage surgery in the advanced stages of the disease. Pharmaceutical composition.

25. The pharmaceutical composition according to claim 1, 5, or 16, wherein the glaucoma is early, moderate, advanced, or terminal glaucoma.

26. The pharmaceutical composition according to claim 1, 5, or 16, wherein the subject or eye has primary open-angle glaucoma, primary closed-angle glaucoma, normal-tension glaucoma, or secondary glaucoma not limited to uveal glaucoma, diabetic glaucoma, traumatic glaucoma, neovascular glaucoma, steroid-induced elevated intraocular pressure, or glaucoma, and / or congenital glaucoma, optionally, the pharmaceutical composition is effective in treating IOP dysfunction or clinically uncontrollable IOP in subjects with refractory glaucoma, non-responders or poor responders, or advanced or end-stage glaucoma.

27. ​​A pharmaceutical composition for treating choroidal ischemia associated with retinitis pigmentosa (RP) and exudative age-related macular degeneration (AMD) occurring after long-term anti-vascular endothelial growth factor (anti-VEGF) therapy in a target eye, wherein the pharmaceutical composition is for administering a composition of travodenoson into the suprachoroid space, (i) via an eye drop formulation, or (ii) as a sustained-release (SR) formulation or SR system, according to a sufficient dose concentration and dosing regimen, wherein choroidal ischemia and parainflammation are major pathological processes identified in the atrophic lesions of RP and exudative AMD, and the pharmaceutical composition addresses the underlying causes of these diseases by exerting vasodilatory and anti-inflammatory effects.

28. A pharmaceutical composition for restoring pressure sensor function in order to normalize intraocular pressure (IOP) in the eye of a subject suffering from or at risk of developing glaucoma, The intraocular pressure of the subject is controlled by one or more interventions for IOP reduction. The aforementioned pharmaceutical composition contains travodenosone as a matrix metalloproteinase (MMP) therapeutic agent that rejuvenates the basement membrane beneath the pressure-sensing cells of the trabecular network. This restores the pressure sensor function and enables a disease-free drug-free period. The pharmaceutical composition is intended to be administered topically as eye drops twice or once daily at a concentration of about 1% to about 3%, or via a sustained-release (SR) formulation or system that provides a travodenoson exposure substantially equivalent to a topical administration of about 1% to about 3% travodenoson, thereby gradually restoring pressure sensor function and reducing or eliminating irregularities in intraocular pressure (IOP) in the target eye.

29. The pharmaceutical composition according to claim 28, wherein the administration of travodenoson eye drops can be carried out flexibly and there is little need for strict medication compliance.

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