Delving into the Latest Updates on Sovesudil with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

AMA0076, AMA-0076, PHP 201

+ [1]

Target

ROCK

Mechanism

ROCK inhibitors(Rho-associated kinases inhibitors)

Therapeutic Areas

Eye Diseases

Active Indication

Glaucoma

Inactive Indication

Glaucoma, Open-AngleLow Tension Glaucoma

Originator Organization

Amakem NV

Active Organization

Katholieke Universiteit Leuven

Inactive Organization

pH Pharma Co., Ltd.Startup

Amakem NV

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

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Structure/Sequence

Molecular FormulaC23H22FN3O3

InChIKeyPNWBYIFLWUCWKS-UHFFFAOYSA-N

CAS Registry1333400-14-8

A multitude of pharmacological compounds have been shown to lower and control intraocular pressure (IOP) in numerous species of animals and human subjects after topical ocular dosing or via other routes of administration. Most researchers have been interested in finding drug candidates that exhibit a relatively long duration of action from a chronic therapeutic use perspective, for example to treat ocular hypertension (OHT), primary open-angle glaucoma and even normotensive glaucoma. However, it is equally important to seek and characterize treatment modalities which offer a rapid onset of action to help provide fast relief from quickly rising IOP that occurs in certain eye diseases. These include acute angle-closure glaucoma, primary angle-closure glaucoma, uveitic and inflammatory glaucoma, medication-induced OHT, and other secondary glaucomas induced by eye injury or infection which can cause partial or complete loss of eyesight. Such fast-acting agents can delay or prevent the need for ocular surgery which is often used to lower the dangerously raised IOP. This research survey was therefore directed at identifying agents from the literature that demonstrated ocular hypotensive activity, normalizing and unifying the data, determining their onset of action and rank ordering them on the basis of rapidity of action starting within 30-60 min and lasting up to at least 3-4 h post topical ocular dosing in different animal species. This research revealed a few health authority-approved drugs and some investigational compounds that appear to meet the necessary criteria of fast onset of action coupled with significant efficacy to reduce elevated IOP (by ≥ 20%, preferably by >30%). However, translation of the novel animal-based findings to the human conditions remains to be demonstrated but represent viable targets, especially EP₂-receptor agonists (e.g. omidenepag isopropyl; AL-6598; butaprost), mixed activity serotonin/dopamine receptor agonists (e.g. cabergoline), rho kinase inhibitors (e.g. AMA0076, Y39983), CACNA2D1-gene product inhibitors (e.g. pregabalin), melatonin receptor agonists, and certain K⁺-channel openers (e.g. nicorandil, pinacidil). Other drug candidates and targets were also identified and will be discussed.

01 Mar 2022·Acta ophthalmologicaQ3 · MEDICINE

Sovesudil (locally acting rho kinase inhibitor) for the treatment of normal‐tension glaucoma: the randomized phase II study

Q3 · MEDICINE

Article

Author: Kim, Young Kook ; Park, Ki Ho ; Kim, Soojin ; Jeoung, Jin Wook ; Satyal, Sanjeev ; Ha, Ahnul ; Kim, Jaesoon

Abstract:

Purpose:

To evaluate ocular hypotensive efficacy and the safety of sovesudil (formally known as PHP‐201), a novel Rho‐associated protein kinase (ROCK) inhibitor, in patients with normal‐tension glaucoma (NTG).

Design:

Multicentre, prospective, double‐masked, randomized, placebo‐controlled, parallel clinical study.

Methods:

Patients with NTG (unmedicated baseline IOP ≤ 21 mmHg) were randomized in 3 groups and treated with sovesudil in concentrations of 0.25% and 0.5%, or with a placebo three times daily (TID) for 4 weeks. The primary end‐point was the mean diurnal IOP change from the baseline at week 4. Safety was recorded over a 4‐week treatment period and the following 2‐week observation period.

Results:

A total of 119 patients were included in the primary efficacy analysis. The mean diurnal IOP change from the baseline at week 4 was −1.56 mmHg for the high‐dose group, −1.10 mmHg for the low‐dose group and −0.65 mmHg for the placebo group. The difference between the high‐dose and the placebo groups was −0.91 mmHg (95% confidence intervals: −1.73, −0.09). 0.5% sovesudil TID met the criteria for superiority to the placebo. The most frequent ocular adverse event among sovesudil‐treated patients was conjunctival hyperaemia (24.4% for the high‐dose and 17.5% for the low‐dose group) and predominately classified as mild.

Conclusions:

Sovesudil 0.25% and 0.5% TID showed statistically significant IOP‐lowering effects and 0.5% concentration’s IOP‐lowering effects met the superiority criteria in comparison with the placebo at week 4. Sovesudil was well tolerated with mild adverse events including relatively low incidence of conjunctival hyperaemia in patients with NTG.

29 Apr 2020·Current medicinal chemistryQ2 · MEDICINE

Rho-kinase (ROCK) Inhibitors - A Neuroprotective Therapeutic Paradigm with a Focus on Ocular Utility

Q2 · MEDICINE

Review

Author: Piplani, Poonam ; Abbhi, Vasudha

Background::

Glaucoma is a progressive optic neuropathy causing visual impairment and Retinal Ganglionic Cells (RGCs) death gradually posing a need for neuroprotective strategies to minimize the loss of RGCs and visual field. It is recognized as a multifactorial disease, Intraocular Pressure (IOP) being the foremost risk factor. ROCK inhibitors have been probed for various possible indications, such as myocardial ischemia, hypertension, kidney diseases. Their role in neuroprotection and neuronal regeneration has been suggested to be of value in the treatment of neurological diseases, like spinal-cord injury, Alzheimer’s disease and multiple sclerosis but recently Rho-associated Kinase inhibitors have been recognized as potential antiglaucoma agents.

Evidence Synthesis::

Rho-Kinase is a serine/threonine kinase with a kinase domain which is constitutively active and is involved in the regulation of smooth muscle contraction and stress fibre formation. Two isoforms of Rho-Kinase, ROCK-I (ROCK β) and ROCK-II (ROCK α) have been identified. ROCK II plays a pathophysiological role in glaucoma and hence the inhibitors of ROCK may be beneficial to ameliorate the vision loss. These inhibitors decrease the intraocular pressure in the glaucomatous eye by increasing the aqueous humour outflow through the trabecular meshwork pathway. They also act as anti-scarring agents and hence prevent post-operative scarring after the glaucoma filtration surgery. Their major role involves axon regeneration by increasing the optic nerve blood flow which may be useful in treating the damaged optic neurons. These drugs act directly on the neurons in the central visual pathway, interrupting the RGC apoptosis and therefore serve as a novel pharmacological approach for glaucoma neuroprotection.

Conclusion::

Based on the results of high-throughput screening, several Rho kinase inhibitors have been designed and developed comprising of diverse scaffolds exhibiting Rho kinase inhibitory activity from micromolar to subnanomolar ranges. This diversity in the scaffolds with inhibitory potential against the kinase and their SAR development will be intricated in the present review. Ripasudil is the only Rho kinase inhibitor marketed to date for the treatment of glaucoma. Another ROCK inhibitor AR-13324 has recently passed the clinical trials whereas AMA0076, K115, PG324, Y39983 and RKI-983 are still under trials. In view of this, a detailed and updated account of ROCK II inhibitors as the next generation therapeutic agents for glaucoma will be discussed in this review.

100 Deals associated with Sovesudil

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Glaucoma, Open-Angle	Phase 3	KR	pH Pharma Co., Ltd.Startup	01 Nov 2021
Low Tension Glaucoma	Phase 2	KR	pH Pharma Co., Ltd.Startup	06 Mar 2017
Glaucoma	Phase 1	GB	Amakem NV	01 Sep 2013

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


PHP-201 (APAO2019)	Phase 2	Glaucoma	119	PHP-201 0.25%	yrfzjgkoxy(lwxirafgsp) = 1 (2.63%) of 38 patients for the placebo group, 7 (17.5%) of 40 patients for 0.25% group, and 10 (24.4%) of 41 patients for 0.5% group istyqzwljp (bsssafgjym )	Positive	06 Mar 2019
				PHP-201 0.5%
ARVO2013	Not Applicable	-	5	AMA0076	fngfhvmuvp(javhdzrjqa) = Hyperemia was observed with all concentrations of Y-39983 whereas only mild hyperemia was induced after administration of AMA0076 0.4% (highest concentration used) xssxymxiyz (krenvrcigt )	-	01 Jun 2013
				Y-39983
ARVO2012	Not Applicable	Ocular Hypotension	-	AMA0076 0.1% + 0.01% BAK	cyylzqlkxj(bmoufztmwi) = zjatiuxfzt afrncobvqg (ovgrwfdpgx )	Positive	01 Mar 2012
				AMA0076 0.3% + 0.01% BAK	cyylzqlkxj(bmoufztmwi) = pswbafzvba afrncobvqg (ovgrwfdpgx )