Product Overview

Resolv ER™

There is no cure for diabetic retinopathy (DR) and current treatments, such as anti-VEGF injections for chronic treatment for diabetic macular edema (DME) and DR and panretinal laser therapy, provide only temporary relief. Kato Pharmaceuticals is developing a first-in-class treatment for DR using urea as the active pharmaceutical ingredient (API) for intravitreal injection. Urea acts to disrupt the hydrogen bonds between the vitreous and the retina, inducing a total posterior vitreous detachment (PVD) that inhibits the progression of retinal damage due to DR and other age-related pathologies of the eye. By using this therapeutic, patients suffering from these pathologies may avoid invasive surgery and preserve vision.

Because the volume of drugs that can be delivered to the eye is limited by the size of the organ, and because ophthalmic formulations dissipate relatively quickly once introduced into the vitreous, delivering and maintaining therapeutic doses of drugs to the macula and adjacent tissues has been a great challenge for ophthalmic drug developers and clinicians. There exists a need for ophthalmic drug formulations that can deliver a therapeutically effective dose to the back of the eye over an extended period of time for the treatment of chronic diseases, such as AMD, DME, and DR, among others.

Liposomes represent a promising injectable delivery system for intravitreal administration as they are a biodegradable, biocompatible carrier that can provide sustained release for prolonged periods. By controlling their size and structure, one can tailor the intravitreal elimination kinetics of the liposome carrier and the encapsulated API. This will optimize liposome formulations to be used in delivering a sustained release of urea to the vitreoretinal interface to cause a total PVD within the clinically acceptable duration (30-60 days)

Extended Release Formulation

  • Basic drug formulation rapidly dissipates throughout ocular tissues with only 20% reaching the retina with a dwell time +/- 4 hours.
  • Liposome loaded Resolv ER™ in buffer is designed to deliver an initial bolus of API then drug continuously at the vitreo-retinal interface over the next 24-36 hours.
  • Half-life of ~ 4 hours at the vitreo-retinal interface
  • Additional injections for non-responders, if warranted, can be safely administered.

In-Vitro Release Rate – ResolvER™ 40% Encapsulated Urea

Release Rate – ResolvER™ 40% Encapsualted Urea in Retina Tissue

Release Rate – Resolv ER™ 40% Encapsulated Urea

Mechanism of Action

Urea in concentrations of 10 molar or greater acts as a powerful protein denaturant.  Vitreous collagen fiber networks anchor the vitreous and retina by binding onto proteins, laminin, and fibronectin, found in the internal limiting membrane (ILM) of the retina. Resolv ER™ acts at the back of the eye to denature collagen fibrils by disrupting the water network which acts to stabilize the collagen strands by hydrogen bonding. By delivering concentrated Urea at the vitreoretinal border region, Resolv ER™ acts to disrupt the hydrogen bonds within the triple helix structure of the collagen strands and cause the strands to unravel.  The denatured collagen fibers are no longer able to bind to the fibronectin and laminin on the ILM. As a result, a posterior vitreous detachment (PVD) is induced once the collagen networks of fibrils separate from the ILM of the retina.

References
1. Li X, Shi X, Fan J.Posterior vitreous detachment with plasmin in the isolated human eye. Graefes Arch Clin Exp Ophthalmol. 2002;240(1): 56–62.
2. Fincham GS, James S, Spickett C, et al.Posterior Vitreous Detachment and the Posterior Hyaloid Membrane. Ophthalmology. 2017.
3. Bennion BJ, Daggett V.The molecular basis for the chemical denaturation of proteins by urea. Proceedings of the National Academy of Sciences of the United States of America. 2003;100(9):5142-5147. doi:10.1073/pnas.0930122100.

Supporting Publications

Prospective assessment of proliferative diabetic retinopathy with observations of posterior vitreous detachment

The purpose was to study the relation between posterior vitreous detachment (PVD) and progression of diabetic retinopathy (DR), based on our observation that proliferative DR is rare in patients with complete PVD. The medical records of 403 patients with diabetes were reviewed for the relation between progressive DR and the status of PVD and HbA(1c) over 3 years. There was no progression of DR over 3 years of eyes with complete PVD with collapse. Complete PVD is a strong negative risk factor for DR. The PVD status in patients with diabetes should be evaluated.

https://www.ncbi.nlm.nih.gov/pubmed/16779571

Intellectual Property

Issued U.S. Patents:

  1. U.S. 6,462,071 Method patent for use of urea derivatives in treatment of ophthalmic disorders. Agents for IVT administration to treat or prevent disorders of the eye.
  2. U.S. 7,008,960 Method patent for use of urea derivatives for causing liquefaction of the vitreous. Agents for IVT administration to treat or prevent disorders of the eye.
  3. U.S. 8,691,874 Formulation for Resolvine. Treatment of Ophthalmic disorders using Urea.
  4. U.S. 7,977,385 Agents for corneal administration to treat or prevent disorders of the eye. 
  5. U.S. 11,052,158 Delivery of Urea to the cells of the macula and retina using liposome constructs.
  6. Foreign counterpart patents issued in Australia, Canada, India, Israel, Japan, Mexico, New Zealand, Russia and Singapore, EP, AE, BR, Chinese, CA, HK, KR
  7. Patents Pending
  1. PCT/US2016/35842 directed to extended-release urea compositions.
  2. PCT/US2017/047643 directed to delivery of urea to cells of the retina using liposome constructs.
  3. U.S. 62/546,992 directed to delivery of drugs to cells of the retina using liposome constructs.
  4. U.S. 2019/0184030 delivery of urea using liposome constructs to the macula and retina (is the continuation of U.S. 16/326,195, serial number 17/334,278).
  5. U.S. 17/231793 (filed 04/15/2021)