Rose Bengal Photodynamic Antimicrobial Therapy for Infectious Keratitis

An article by Salomon Merikansky, MD and Guillermo Amescua, MD of Bascom Palmer Eye Institute

In the current November 2024 issue of Corneal Physician magazine, Bascom Palmer Eye Institute (BPEI) ophthalmologists in Miami, FL wrote an article about rose bengal (RB) photodynamic antimicrobial therapy (PDAT) (RB PDAT) titled, “Rose Bengal Photodynamic Antimicrobial Therapy for Infectious Keratitis.”

The article presently positions RB PDAT as a valuable treatment option for patients who fail standard of care (SOC) (i.e., appropriate topical/systemic antimicrobial medication); in other words, in an adjunct (i.e., with SOC) or refractory (i.e., second-line) setting. The article also discusses a National Institutes of Health-sponsored, double-masked, prospective, randomized clinical trial of RB PDAT for the treatment of fungal and Acanthamoeba keratitis in a first-line setting (having the acronym REAGIR¹ and trial identifier NCT05110001). 

Co-author Dr. Merikansky is currently completing a CorneaResearch and Ocular Microbiology Fellowship at BPEI. He has a strong clinical interest in corneal infections and diseases. Dr. Amescua is a professor of clinical ophthalmology and a cornea, cataract, and uveitis surgeon at BPEI. He also serves as the medical director of the Ophthalmic Biophysics Center and the Ocular Microbiology Laboratory. Dr. Amescua has a patent application related to the RB PDAT technology.  

The article itself almost reads like an investment thesis in plain English.

Please note that we draw directly and liberally from (i.e., copy several parts of) the article in our comments below.

The problem.

Infectious keratitis (IK), or an infection of the cornea, is a potentially vision-threatening, ophthalmic emergency due to rapid progression and devastating complications. It is a significant public health issue in the U.S. as a common cause of corneal blindness and the fifth leading cause of overall blindness. IK can be caused by a variety of microorganisms, including bacteria, fungi, viruses, and parasites.

The main risk factor for corneal infections in the so-called developed world is contact lens use, as microorganisms can adhere to the contact lens surface and transfer to a damaged or compromised corneal epithelial layer. Leading risk factors in the so-called developing world include contact lens wear, ocular trauma, and environmental factors (e.g., eye contact with soil).

The market opportunity.

Based on limited, dated, and non-comprehensive incidence data of microbial keratitis of ~28 cases per 100,000 people per year, there are an estimated 75,000 cases in the U.S. each year.² Incidence rates can vary in developed countries from approximately 6 in Australia, to ~28 in the U.S., to ~40 in the U.K., all per 100,000 people per year. In India, incidence varies from 113 to ~800 cases per 100,000 people per year, or approximately 1.6 to 11.2 million.³ Market size? In a classic top-down, Internet-of-the 1990s/2000s market sizing exercise, annual global cases could be more than ~80 million.⁴

Competitive landscape.

Despite existing treatment guidelines and advancements in antimicrobial therapies, the management of severe cases of infectious keratitis remains a complex challenge. The emergence of antibiotic-resistant organisms coupled with limited access to appropriate treatments has led to a significant increase in severe ocular complications, which can ultimately result in permanent vision loss or even enucleation.

Over the last 20 years, corneal collagen crosslinking (CXL) with riboflavin has been explored for IK management, called photo-activated chromophore for keratitis corneal crosslinking (PACKCXL). PACK-CXL was found to have some success against bacterial strains, but less efficacy against fungal infections. This gap led to BPEI’s exploration, discovery, and advancement of RB as a more effective photosensitizing agent [than riboflavin].

RB PDAT’s competitive advantage.

Over the past decade, RB PDAT has been explored by BPEI as a potential treatment for IK. The in vitro inhibitory effect against many microorganisms has been tested extensively, with data presented in over 20 peer-reviewed publications⁵ and numerous medical conference presentations (both oral and poster).

In vivo safety studies have confirmed that despite inducing damage to the invading infectious cells, RB PDAT is safe for the eye, showing the preservation of the corneal endothelium, limbal stem cell niche (LSCN), iris, and keratocytes, as well as the photoreceptors in the retina.

BPEI has treated over 130 patients and the outcomes have been promising. In 2019, a pilot clinical study at BPEI involving 18 patients with severe IK was conducted to translate non-clinical findings into clinical practice, demonstrating a 72% success rate. Aravind Eye Hospital in Madurai, India has also reported treating over 100 patients with RB PDAT. 

Risks and challenges.

The limited sample size and microbial diversity of BPEI’s pilot clinical study precluded definitive conclusions. A larger dataset, such as that from the REAGIR trial, would enable a more comprehensive evaluation of the clinical efficacy of RB PDAT.

Key catalyst.

The REAGIR trial will provide critical insights into the future viability of RB PDAT for treating IK.

As noted above, REAGIR is a National Institutes of Health-sponsored, double-masked, prospective, randomized clinical trial of RB PDAT for the treatment of fungal and Acanthamoeba keratitis in a first-line setting (i.e., SOC + RB PDAT vs placebo + RB PDAT) involving 330 patients enrolled and treated in India (at Aravind Eye Hospital).

Business model & strategy.

The University of Miami has entered into a licensing agreement with Provectus Biopharmaceuticals (that’s us!), a company that specializes in pharmaceutical-grade RB. This represents a strategic partnership aimed at accelerating the development and commercialization of PDAT for the treatment of IK, benefiting patients worldwide through an effective partnership that combines cutting-edge research with industry expertise.

Ocular Microbiology and Immunology Group (OMIG)

Alongside the American Academy of Ophthalmology (AAO) 2024 annual meeting on October 18-21 in Chicago, IL, the OMIG 2024 annual meeting will be held on October 18.

Team members from several different elements of BPEI — the Department of Ophthalmology, the Ophthalmic Biophysics Center, Surgical and Research Services, the Ocular Microbiology Laboratory, and the Ocular Pathology Laboratory — will make two presentations at OMIG.

First, “Long-Term Graft Survival after Rose Bengal Photodynamic Antimicrobial Therapy for Infectious Keratitis and Keratoplasty;” Purpose: To evaluate the long-term graft survival outcomes for patients undergoing a therapeutic penetrating keratoplasty (TPK), optical penetrating keratoplasty (OPK), and deep anterior lamellar keratoplasty (DALK) following adjunct treatment with Rose Bengal Photodynamic Antimicrobial Therapy (RB-PDAT) for severe, progressive, infectious keratitis.

Second, “Rose Bengal Photodynamic Therapy (PDAT) for Mycobacterium abscessus Keratitis: In Vitro Efficacy and Clinical Outcomes;” Purpose: Evaluate the efficacy of RB PDAT to inhibit Mycobacterium abscessus clinical strains. The clinical outcomes of seven patients with culture proven Mycobacterium abscessus keratitis who underwent RB-PDAT are also presented.

We previously noted that BPEI will make a presentation at AAO 2024, “Rose Bengal Photodynamic Antimicrobial Therapy as Adjunct Therapy for Pseudomonas Necrotizing Scleritis.”

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1. Rose bengal Electromagnetic Activation with Green Light for Infection Reduction 

2. The number of annual cases probably should be closer to ~86,000, where the math is 27.6 cases/100,000 people times a 2010 U.S. population of ~309 million.

3. The math is 113 or 800 cases/100,000 people times a 2020 India population of ~1.396 billion.

4. The ratio of developed to undeveloped populations in the world is approximately 1:5; that is, ~16% of the global population lives in developed countries and ~84% lives in developing countries. Take the average of the Australian, American, and English incidence rates (as a proxy for the developed world) and the low-end of the Indian incidence rate (as a proxy for the developing world), weight them accordingly to arrive at a blended global incidence rate of ~100 cases per 100,000 people per year, and use a 2024 global population of approximately 8.2 billion.

The math is 25 * 0.16 + 113 * 0.84 or ~100 cases/100,000 people per year times ~8.2 billion.

5. Microbial inhibition has been observed in the following species: (bacteria) Staphylococcus aureus, Pseudomonas aeruginosa, and Nocardia spp.; (fungi) Candida spp., Fusarium spp., Paecilomyces spp., Pseudallescheriaboydii, Curvularia lunata; and (parasites) Acanthamoeba spp.