Melanocortin Receptor Agonist PL9588

 

Palatin Technologies, Inc. (NYSE American: PTN), a biopharmaceutical company developing first-in-class medicines based on molecules that modulate the activity of the melanocortin receptor system, announced the development of a new molecule to lower intra-ocular pressure (IOP). The company gave this information through a poster entitled, “Melanocortin Receptor Agonist PL9588 Reduces Intraocular Pressure in Normotensive Rabbits” at the Association of Research in Vision and Ophthalmology (ARVO) Annual Conference.

Topically administered PL9588 showed reductions in IOP with magnitudes similar or greater to the positive controls, latanoprost, and timolol, which are FDA-approved for treating glaucoma. The IOP-lowering effect of a single topical dose of PL9588 persisted for 24 hours. A therapeutic melanocortin agonist could provide new options for treatment, both as a single agent or in combination with a standard of care. Palatin's data provides support for the continued development of PL9588 with the aim of providing a novel, once-daily treatment for glaucoma.

Melanocortins are hormone agonists that include several melanocyte-stimulating hormones (MSHs) and adrenocorticotropin hormones. These exert their effect through binding to melanocortin receptors (MCrs). Melanocortin agonism contributes to the resolution of inflammation through multiple pathways.

The melanocortin receptor ("MCr") system has effects on inflammation, immune system responses, metabolism, food intake, and sexual function. There are five melanocortin receptors, MC1r through MC5r. Modulation of these receptors, through the use of receptor-specific agonists, which activate receptor function, or receptor-specific antagonists, which block receptor function, can have medically significant pharmacological effects. Many tissues and immune cells located throughout the body, including the gut, kidney, and eye, express melanocortin receptors, empowering our opportunity to directly activate natural pathways to resolve disease inflammation.

Drugs based on melanocortin agonists have been approved by the FDA for treating several conditions, including inflammatory/autoimmune diseases, rare forms of genetic obesity, and female sexual dysfunction. In the eye, they are being evaluated for dry eye disease, uveitis, and diabetic retinopathy. With the development of this new molecule (PL9588) for use in glaucoma, a new pathway is being explored in the management of this disease.

https://palatin.com/

INÊS FIGUEIREDO PEREIRA: RESEARCHER IN FOCUS

 

Dr. Inês Figueiredo Pereira is an Assistant Professor in the Microsystems group at the Eindhoven University of Technology (TU/e), Netherlands. She is credited with two different minimally invasive smart glaucoma implants.

Dr. Inês Figueiredo Pereira

 

Her expertise encompasses biomaterials, micro and nanotechnology, microfabrication, sensors and actuators, soft microvalves, stimuli-responsive materials, and microfluidics. Her research is dedicated to the advancement of wearable and implantable medical devices for healthcare applications, with a specific focus on enhancing diagnostics, disease prevention, and improving treatment outcomes.

As part of her research, she performed numerical simulation studies to assess the feasibility of using a glaucoma implant with an adjustable hydrodynamic resistance to regulate IOP in glaucoma patients. The model determines the ideal hydrodynamic resistance that a glaucoma implant must have to overcome the two most common postoperative complications–bleb scarring and hypotony. 

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0273672

“Results from the simulations provided valuable insights that allowed for the development of a magnetically actuated glaucoma implant that can be non-invasively and repeatedly adjusted to different IOP conditions even after implantation,” notes Figueiredo Pereira.

 

Smart glaucoma implant

https://doi.org/10.1038/s41378-023-00561-9

Adjustment is achieved by integrating a magnetic microvalve in the implant, which can open or close fluidic channels, and thus change the hydrodynamic resistance of the implant when needed, and all by using a simple external magnet. “With this valving system, the IOP can be tuned according to a patient’s needs,” says Dr. Figueiredo Pereira.

Working of the smart glaucoma implant

She also developed a new biodegradable and minimally invasive glaucoma implant, which is approximately the same size as the world’s smallest medical device known to be implanted in the human body, which is the iStent Inject W from the company Glaukos. “The implant from Glaukos is a permanent and metallic implant, whereas ours is inspired by their implant but it is based on a polymer material (polycarbonate-bisamide or PC-BA) making it biodegradable’, remarks the researcher.

  

Biodegradable implant

“We anticipate that our implant will slowly degrade and then be absorbed by the body over time, leaving behind a natural pathway for fluid drainage,” says Figueiredo Pereira. “This biodegradable glaucoma implant provides a promising new approach for restoring outflow in a more natural way.” 

PUBLICATIONS:

https://www.tue.nl/en/research/researchers/ines-figueiredo-pereira

https://doi.org/10.1038/s41433-021-01595-x

https://research.tue.nl/nl/publications/a-model-for-designing-intraocular-pressure-regulating-glaucoma-im/?_gl=1*qrvniu*_ga*MTA5OTgwODE3Ny4xNjk0NDQ2MDgz*_ga_JN37M497TT*MTY5NTE5Nzc4NS41LjEuMTY5NTE5ODEyOS41MC4wLjA

https://www.tue.nl/en/news-and-events/news-overview/deze-glaucoomimplantaten-zijn-slim-en-veel-gemakkelijker-in-te-brengen

NANOTECHNOLOGY UPDATE

 

Dr. Hu Yang, a Missouri S&T (USA) professor who is pioneering new glaucoma treatments was recently awarded the National Institutes for Health’s R01 grant, which will provide his research team with $2.5 million in funding over the next five years.

Dr. Hu Yang

Yang and his fellow researchers have developed a treatment that could eventually allow patients to only use eye drops once per week instead of daily, and it should also be more effective than current regimens.

Yang’s treatment involves a nanoparticle delivery system that delivers more ophthalmic medications into the eye. With current eye drops, only about 2% of the treatment reaches its targeted location.

A nanoparticle eyedrop model

The new formulation will deliver more than one type of medication, Yang says. The medications will work to drain blockages in the eyes, while also reducing the production of aqueous humor, which is a fluid in the eye that can cause pressure.

Yang’s current NIH grant project is for five years, but since he has developed multiple iterations of the treatment over the past several years, he says it would still be possible to begin clinical trials before the current project is completed.

“This treatment should make a significant difference for patients with glaucoma, so we obviously would like to see them benefit from it as soon as possible,” he says. “We have worked on this for several years and are highly optimistic about its potential efficacy.”

MINIject GLAUCOMA DEVICE

 

MINIject® is a minimally-invasive glaucoma surgery (MIGS) device for patients with open-angle glaucoma developed by iSTAR Medical SA, Wavre, Belgium.

MINIject® is a MIGS implant targeting the supraciliary space.

MINIject® is designed to reduce IOP by enhancing natural outflow from the anterior chamber to the supraciliary space. Implantation is predictable in a single-step procedure using a deployment wheel. The device is inserted into the nasal quadrant of the eye through a 2 mm clear corneal incision. The unique flexible design conforms to the shape of the eye.

The MINIject is 5 mm in length with an oblong cross-sectional design measuring 1.1×0.6 mm. A green ring positioned at 0.5 mm from the tip of the device allows for accurate positioning in the anterior chamber.

MINIject®’s biocompatible, soft and flexible porous structure delivers multiple benefits:

• iSTAR Medical’s proprietary STAR® material exhibits outstanding anti-fibrotic and anti-inflammatory properties.
• Porous implant enables a natural flow of aqueous humor, helping reduce fibrosis, minimize scarring and increase durability.
• Conforms to the eye’s anatomy and bio-integrates with surrounding tissue to sustain long-term drainage efficacy.

Another advantage of the device is that it is implanted far away from the cornea (only 0.5mm in the anterior chamber).

CLINICAL DATA:

Clinical data of MINIject® in stand-alone trials at two-year follow-up has shown:

• 35-40% mean IOP reduction after two years
• Meaningful IOP reduction to <15mmHg in most patients
• Approximately half of patients drop-free
• Low rate of complications
• No needling or bleb-management required
• Favorable endothelial cell density safety at two years

In a study by Philippe Denis, Christoph Hirneiß, Georges M Durr, et al, the study cohort had mean baseline IOP of 23.2±2.9 mmHg using a mean of 2.0±1.1 glaucoma medications. The primary endpoint at 6 months was met, with a signification reduction in IOP of 9.0 mmHg.

The mean reduction in IOP 24 months after surgery was 40.7% compared with baseline, to a mean diurnal IOP of 13.8 ±3.5 mmHg at 24 months.

The most frequent adverse events were anterior chamber reaction (8/26 patients, 30.8%), visual acuity reduced (8/ 26, 30.8%), VF defect (7/26, 26.9%), IOP elevation (5/26, 19.2%) and lenticular opacities (5/26, 19.2%).

SPYGLASS DRUG DELIVERY PLATFORM

 

A new drug delivery platform for anti-glaucoma medication has been developed by Dr. Malik Y. Kahook, professor of ophthalmology and the Slater Family Endowed Chair in Ophthalmology at the University of Colorado School of Medicine, USA.

Known as the SpyGlass Drug Delivery Platform, it is implanted with the SpyGlass intra-ocular lens (IOL) into the capsular bag via standard cataract surgical technique.

The SpyGlass drug delivery platform consists of a single-piece, hydrophobic acrylic IOL and two drug eluting pads that slide over each haptic and securely attach at the haptic junction. With the drug pads securely attached, the IOL and pads are loaded into a standard IOL injector. The lens is advanced and injected through a sub 2.4 mm incision and implanted directly into the capsular bag.

The drug pads remain outside the visual axis and continuously elute directly into the aqueous humor, which carries the active drug to targeted tissues.

The pads elute Bimatoprost for three years into the eye, providing sustained delivery of the drug for effective glaucoma management.

Pre-clinical testing found compelling IOP lowering in normotensive beagles with 3 doses compared to 0.03% topical bimatoprost. In NZW rabbits there was no detectable systemic exposure and no drug related adverse events even at 10x the maximum dose up to 9 months.

A prospective study was performed to evaluate the safety and efficacy of the sustained release bimatoprost implant with SpyGlass IOL in patients with ocular hypertension or mild to moderate open-angle glaucoma. The results of the study at 3 months reported 45% mean IOP reduction across all doses and all patients became off topical IOP-lowering therapy.

VYZULTA

 

VYZULTA® (latanoprostene bunod ophthalmic solution, 0.024%) is a unique anti-glaucoma medication, indicated in patients with open-angle glaucoma and ocular hypertension.

The drug is manufactured by Bausch + Lomb, USA.

It is a combination of latanoprost acid and nitric oxide.

Latanoprost opens up the interstitial spaces to improve uveoscleral outflow of aqueous.

Nitric oxide improves the permeability of the trabecular meshwork and improves aqueous outflow through the conventional pathway.

In two Phase 3 studies, VYZULTA produced significant IOP reduction from baseline in high-pressure-range patients (mean diurnal IOP of 26.7 mmHg) as well as greater reduction from baseline vs timolol. Upto 9.1 mmHg of IOP reduction from baseline was achieved. More than 30% mean diurnal IOP reduction was also noted in these studies.

Two Phase 3, randomized, multicenter, double-masked, parallel-group, 3-month studies were conducted comparing the IOP-lowering effect of once-daily VYZULTA vs twice-daily timolol 0.5% in patients with open-angle glaucoma or ocular hypertension: APOLLO (VYZULTA, n=284; timolol, n=133) and LUNAR (VYZULTA, n=278; timolol, n=136). VYZULTA demonstrated a mean IOP reduction of 7.5-9.1 mmHg from baseline across 9 evaluated time points over 3 months.

In the Phase 2 dose-ranging VOYAGER study, VYZULTA delivered significantly greater mean IOP reduction vs Xalatan (latanoprost) 0.005%.

As compared to xalatan, 45% more patients achieved a mean diurnal IOP of less than 18 mmHg. This is a significant benchmark as IOP <18 was found to be associated with lesser visual field progression in the Advanced Glaucoma Intervention Study.

At 52 weeks, VYZULTA achieved 26.3% reduction from baseline IOP. Multiple studies have apparently shown 30-40% patients having sustained IOP of <21 mmHg over one year of use.

The agent is used once daily in the evening.

SIDE EFFECTS:

The side effects of VYZULTA are largely similar to those seen with Latanoprost and Timolol.

However, the discontinuation rate due to the adverse effects was less than 1% in the studies reported.

https://www.vyzulta.com/