Building Trust: Bascom Palmer Eye Institute, Provectus Biopharmaceuticals, and RBS PDAT
Rose Bengal Sodium Photodynamic Antimicrobial Therapy for Eye Infections
This has been more about building trust than affirming a “groundbreaking” medical treatment.
Introduction
There: The 2019 publishing of Bascom Palmer Eye Institute’s (BPEI’s) pilot clinical study of its rose bengal (RB) photodynamic antimicrobial therapy (PDAT) (RB PDAT) for treating infectious keratitis, which is the leading cause of corneal blindness in the world.
To Here: Provectus’s 2024 exclusive worldwide license of BPEI’s PDAT innovation, which would use the Company’s pharmaceutical-grade rose bengal sodium (RBS) (i.e., thus RBS PDAT) and could potentially be used to treat corneal ectasia, infectious scleritis, keratoconus, and other eye diseases and disorders.
The journey from there to here has been about Provectus endeavoring to build trust with the leadership and members of the Ophthalmic Biophysics Center (OBC) at BPEI at the University of Miami (UM) in Miami, Florida, and start with pursuing the commercialization of the OBC’s “groundbreaking” treatment (their words, not ours) of bacterial, fungal, and parasitic (acanthamoeba) infections of the eye using RBS.
Provectus’s charge will be to try to advance to approval(s) the combination of the OBC’s green light source medical device and RBS-based drug product candidate. Trust between the OBC and Provectus should hopefully, naturally facilitate BPEI advocacy of the treatment, its promise, and its potential.
Provectus folks are experts on the RBS molecule, its mechanisms of actions across disease areas, and its drug substance synthesis and drug product manufacturing. BPEI are clearly global experts in eye disease and care. In August 2023, US News & World Report released its rankings for 2023-2024 “Best Hospitals” and BPEI once again topped the chart in ophthalmology, receiving the #1 ranking for the 20th year in a row and the 22nd time; these rankings began 34 years ago.
The Beginning
Provectus’s trust-building started when the OBC’s seminal RB PDAT manuscript was electronically published in the American Journal of Ophthalmology on September 5, 2019; the paper was published in final edited form in the journal’s December 2019 edition. Titled Rose Bengal Photodynamic Antimicrobial Therapy (RB-PDAT) for Patients with Progressive Infectious Keratitis: A Pilot Clinical Study (Naranjo et al. 2019), the paper was the OBC’s sixth piece of writing on the topic of RB PDAT at that time.
The paper described the clinical outcomes of 18 patients who received RB PDAT as an adjunct treatment for severe, progressive, infectious keratitis from January 2016 to March 2018 at BPEI, where the RB used was commercial-grade rose bengal.
Cross-contributors spanned different UM places, including BPEI, OBC at BPEI, the Anne Bates Leach Eye Center (Hospital), the Florida Lions Ocular Pathology Laboratory, and the William Thode Ocular Microbiology Laboratory at the Leonard Miller School of Medicine (MSM), and the Department of Chemistry at UM.
Since 2014, OBC and its UM cross-contributors have published 15 papers and comments about their RB PDAT innovation.1
RB PDAT emerged under the leadership of Jean-Marie Parel, IngETS-G, PhD, FARVO, Director of the OBC. The OBC team and Dr. Parel spent many years advancing their PDAT technology using RB against different types of treatment-naïve and resistant keratitis. The OBC established the merits of its innovation through extensive in vitro testing, pilot in vivo safety and clinical studies, and the scrutiny that comes with numerous peer-reviewed publications and medical conference presentations of RB PDAT’s methodology, datasets, and results.
RB PDAT is also the subject of two international, randomized, double masked, clinical trials for acanthamoeba and fungal (NCT05110001) and bacterial (NCT06271772) keratitis:
NCT05110001 is sponsored by the University of California, San Francisco (UCSF), with collaborators of Aravind Eye Care System (AECS; clinical site), the National Eye Institute (NEI) of the National Institutes of Health (study funder), Stanford University, and Federal University of São Paulo (clinical site), and
NCT06271772 is sponsored by UCSF, with collaborators of AECS (clinical site), Stanford University, and Federal University (clinical site).
BPEI is not explicitly involved in these studies; however, its medical devices (the intellectual property [IP] to which Provectus is licensing) may be being used and the clinical sites may be using RB from Sigma-Aldrich (aka MilliporeSigma). Additionally, the parties are well-known to each other.
Having seen the pilot clinical study paper very shortly after its publishing, Provectus reached out to Guillermo Amescua, MD, Professor of Clinical Ophthalmology, Medical Director of the Ocular Microbiology Laboratory, and board-certified ophthalmologist at BPEI in September 2019.
The gist of Provectus’s outreach was our desire to introduce the Company and its IP, acknowledge BPEI’s clinical study, indicate that the study may have implicated Provectus’s IP rights, and collaborate with the OBC, BPEI, and UM on RBS PDAT.
The Competition
Avedro (Nasdaq: AVDR) received U.S. Food and Drug Administration (FDA) approval in 2016 for its corneal cross-linking system to treat patients with progressive keratoconus and post-LASIK ectasia. Avedro’s treatment comprised the combination of riboflavin (i.e., vitamin B2), branded as Photrexa, and an ultraviolet light source device, branded as the KXL system).
OBC et al. published four papers (i.e., 2014, 2016, 2020, and 2022) successfully comparing RB PDAT (518 nm wavelength) to riboflavin PDAT (375 nm) for different keratitis isolates.
The pricing structure of Avedro’s treatment (i.e., KXL + Photrexa) in 2017 comprised an $80k device and an $3k drug dose. By comparison, the OBC’s device potentially could be made for $5-10k per device at manufacturing scale and only a few milligrams of Provectus’s RBS potentially could be needed per patient.
In March 2019, Avedro provided full-year revenue guidance of approximately $36-40 million from the sale of its approved treatment.
Glaukos acquired Avedro later in 2019 in an all-stock transaction valued at approximately $500 million. As of today’s stock market close, Glaukos (Nasdaq: GKOS) had a market capitalization of about $4.4 billion.
In 2023, corneal health sales (which primarily comprised Photrexa and KXL systems) represented approximately $77 million (~25%) of Glaukos’s total net sales of approximately $315 million. It would appear that Photrexa/KXL’s compounded annual revenue growth could have been an approximately 21% from 2019-2023.
Why RB-PDAT?
We asked Drs. Parel and Amescua about RB PDAT.
Why did you create RB PDAT? In South Florida, a significant portion of patients receiving standard care for corneal ulcers ultimately require surgical intervention due to the condition's severity, often with a poor visual prognosis. Seeking to provide an alternative approach, we embarked on an experimental journey with various photosensitizers. Our initial trials with riboflavin yielded unsatisfactory results, prompting us to explore rose bengal. Encouragingly, the outcomes improved with this agent, marking our trajectory over the past eight years.
[Substack post note: Eight years represents time since the start of the pilot clinical study. Development of RB PDAT by the OBC has spanned closer to 10 years or more.]
How many people do you believe RB PDAT can positively impact? Infectious keratitis is a significant contributor to worldwide blindness, notably serving as the primary cause of corneal blindness. The PDAT treatment protocol, owing to its widespread availability and accessibility, holds tremendous potential to positively influence the lives of millions afflicted by this condition.
What is the need that RB PDAT addresses? The pharmaceutical industry has shown limited investment in medications for infectious keratitis, resulting in a scarcity of innovation and the emergence of increasingly resistant microorganisms. To propel innovation in this crucial area, PDAT is one potential avenue as an antimicrobial agent specifically tailored to target the evolving resistance mechanisms of these microorganisms.
Where would you take the RB PDAT innovation further? Investigate PDAT's application in strengthening corneal collagen and its potential relevance to treating corneal ectasia. Assess PDAT's efficacy in patients with infectious scleritis, particularly its impact on scleral collagen. Preliminary data suggest potential benefits of PDAT for patients with pseudomonas infections. Ongoing research is also exploring iontophoresis as a method to enhance the penetration of rose bengal deep into the cornea, thereby augmenting treatment efficacy.
Pseudomonas aeruginosa (P aeruginosa)
Dr. Amescua shared the OBC/BPEI/UM’s 15th paper on RB PDAT with Provectus on March 21st, its publication date, titled Clinical Features and Treatment Outcomes of Carbapenem-Resistant Pseudomonas aeruginosa Keratitis (subscription required).
According to the authors (Tribin et al. 2024), “[m]ultidrug-resistant Pseudomonas aeruginosa gained notoriety after the Centers for Disease Control and Prevention (CDC) classified the pathogen as a serious threat in 2019…In February 2023, the CDC, in collaboration with the US Food and Drug Administration, issued a national alert, warning clinicians of an extensively drug-resistant strain of P aeruginosa (VIM-GES-CRPA).”
P aeruginosa was linked to this from October 2023: “U.S. health officials are warning consumers to stop using more than two dozen over-the-counter eye drop products due to the potential risk of eye infection that could lead to vision loss.”
March 2024: As an aside (in cancer), “The Food and Drug Administration (FDA) has issued an advisory ordering the recall of a chemotherapy injectable found to be contaminated with bacteria that cause fatal infections. In its Advisory No. 2024-0532, the agency warned against the sale and use of Trexasaph (generic name: Methotrexate), regardless of its batch manufacturing, after the imported drug with Batch No. I23J001A was found positive with Pseudomonas aeruginosa.”
Tribin et al. 2024 discussed 9 patients with VIM-GES-CRPA (P aeruginosa) treated at BPEI, 2 of whom were treated with RB PDAT. The authors noted that, “[a]dditionally, PDAT is a broad-spectrum therapeutic and has no known microbial resistance in vitro. Our small case series, which used a retrospective design without controls, provides evidence but cannot provide definite support of the potential use of RB-PDAT in similar cases of resistant microbial strains to preserve visual outcomes…The use of RB-PDAT adjunct therapy in this subset of patients without intraocular involvement may improve ocular integrity and visual outcomes.”
RB PDAT in Action
Dr. Amescua provided Provectus with this video clip of a simulation of the RB PDAT procedure.
A Timeline Perspective
Our relationship-building timeline with the OBC included interacting with UM’s Office of Technology Transfer (OTT). Technology transfer offices at universities help manage university IP assets, such as the OBC’s RB PDAT.
Third quarter, 2019 (3Q19). Naranjo et al. 2019 was published. Provectus reached out to Dr. Amescua.
4Q19. OTT connected with Provectus following our outreach.
2Q20. UM and Provectus fully executed a mutual confidential disclosure agreement. The OBC held its first call with Provectus.
3Q20. UM and Provectus fully executed Provectus’s material transfer agreement so that the Company could send RBS to the OBC for its analysis and assessment. The OBC provided Provectus with its analysis of RBS’s purity and composition.
1Q21. The OBC provided the Company with more of its analysis.
2Q21. OTT and Provectus began negotiations of an option license agreement.
1Q22. UM and Provectus fully executed the option agreement.
2Q22. OTT and Provectus fully executed an amendment to the option agreement. Provectus entered into a scientific research agreement with the OBC.
2Q23. OTT and Provectus began negotiations of a license agreement, and developed a mutually acceptable term sheet.
4Q23. OTT and Provectus began drafting definitive agreements for a license agreement transaction.
1Q24. The OBC provided Provectus with its final scientific research report on RBS. OTT and Provectus finalized definitive agreements.
During Provectus’s interactions with OTT, we engaged with six different IP associates and directors.
India
Some of the best ophthalmology work is done in India because of the sheer numbers of patients seen and diverse disease presentation (e.g., American ophthalmology residents and fellows may do rotations or seek training experience at Indian eye centers). See Provectus March 2nd Substack titled Provectus Full-Thickness Cutaneous Wound Healing Poster Presentation at 2024 Society for Investigative Dermatology Annual Meeting. Our recent conversation with Dr. Venkatesh Prajna of Aravind Eye Care System underscored the size and scope of the medical need for RB PDAT in India, China, and elsewhere. India could potentially play a notable or significant role in the development and commercialization of RBS PDAT for the treatment of eye diseases and disorders.
Forward-Looking Statements
The information provided in this Provectus Substack Post may include forward-looking statements, within the meaning of the Private Securities Litigation Reform Act of 1995, relating to the business of Provectus and its affiliates, which are based on currently available information and current assumptions, expectations, and projections about future events and are subject to a variety of risks and uncertainties and other factors that could cause actual events or results to differ materially from those projected in the forward-looking statements. Such statements are made in reliance on the safe harbor provisions of Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934. Forward-looking statements are often, but not always, identified by the use of words such as “aim,” “likely,” “outlook,” “seek,” “anticipate,” “budget,” “plan,” “continue,” “estimate,” “expect,” “forecast,” “may,” “will,” “would,” “project,” “projection,” “predict,” “potential,” “targeting,” “intend,” “can,” “could,” “might,” “should,” “believe,” and similar words suggesting future outcomes or statements regarding an outlook.
The safety and efficacy of Provectus’s drug agents and/or their uses under investigation have not been established. There is no guarantee that the agents will receive health authority approval or become commercially available in any country for the uses being investigated or that such agents as products will achieve any revenue levels.
Due to the risks, uncertainties, and assumptions inherent in forward-looking statements, readers should not place undue reliance on these forward-looking statements. The forward-looking statements contained in this Provectus Substack Post are made as of the date hereof or as of the date specifically specified herein, and the Company undertakes no obligation to update or revise any forward-looking statements, whether because of new information, future events, or otherwise, except in accordance with applicable securities laws. The forward-looking statements are expressly qualified by this cautionary statement.
Risks, uncertainties, and assumptions include those discussed in the Company’s filings with the U.S. Securities and Exchange Commission, including those described in Item 1A of Provectus’ Annual Report on Form 10-K for the period ended December 31, 2022 and the Company’s Quarterly Report on Form 10-Q for the period ended September 30, 2023.
1: Arboleda A, Miller D, Cabot F, Taneja M, Aguilar MC, Alawa K, Amescua G, Yoo SH, Parel JM. Assessment of rose bengal versus riboflavin photodynamic therapy for inhibition of fungal keratitis isolates. Am J Ophthalmol. 2014 Jul;158(1):64-70.e2. doi: 10.1016/j.ajo.2014.04.007. Epub 2014 Apr 29. PMID: 24792103; PMCID: PMC4075940.
2: Halili F, Arboleda A, Durkee H, Taneja M, Miller D, Alawa KA, Aguilar MC, Amescua G, Flynn HW Jr, Parel JM. Rose Bengal- and Riboflavin-Mediated Photodynamic Therapy to Inhibit Methicillin-Resistant Staphylococcus aureus Keratitis Isolates. Am J Ophthalmol. 2016 Jun;166:194-202. doi: 10.1016/j.ajo.2016.03.014. Epub 2016 Mar 23. PMID: 27016125.
3: Amescua G, Arboleda A, Nikpoor N, Durkee H, Relhan N, Aguilar MC, Flynn HW, Miller D, Parel JM. Rose Bengal Photodynamic Antimicrobial Therapy: A Novel Treatment for Resistant Fusarium Keratitis. Cornea. 2017 Sep;36(9):1141-1144. doi: 10.1097/ICO.0000000000001265. PMID: 28691942; PMCID: PMC5546001.
4: Martinez JD, Naranjo A, Amescua G, Dubovy SR, Arboleda A, Durkee H, Aguilar MC, Flynn HW, Miller D, Parel JM. Human Corneal Changes After Rose Bengal Photodynamic Antimicrobial Therapy for Treatment of Fungal Keratitis. Cornea. 2018 Oct;37(10):e46-e48. doi: 10.1097/ICO.0000000000001701. PMID: 30028750; PMCID: PMC6131034.
5: Naranjo A, Pelaez D, Arrieta E, Salero-Coca E, Martinez JD, Sabater AL, Amescua G, Parel JM. Cellular and molecular assessment of rose bengal photodynamic antimicrobial therapy on keratocytes, corneal endothelium and limbal stem cell niche. Exp Eye Res. 2019 Nov;188:107808. doi: 10.1016/j.exer.2019.107808. Epub 2019 Sep 17. PMID: 31539544.
6: Naranjo A, Arboleda A, Martinez JD, Durkee H, Aguilar MC, Relhan N, Nikpoor N, Galor A, Dubovy SR, Leblanc R, Flynn HW Jr, Miller D, Parel JM, Amescua G. Rose Bengal Photodynamic Antimicrobial Therapy for Patients With Progressive Infectious Keratitis: A Pilot Clinical Study. Am J Ophthalmol. 2019 Dec;208:387-396. doi: 10.1016/j.ajo.2019.08.027. Epub 2019 Sep 5. PMID: 31493402; PMCID: PMC7184264.
7: Durkee H, Arboleda A, Aguilar MC, Martinez JD, Alawa KA, Relhan N, Maestre-Mesa J, Amescua G, Miller D, Parel JM. Rose bengal photodynamic antimicrobial therapy to inhibit Pseudomonas aeruginosa keratitis isolates. Lasers Med Sci. 2020 Jun;35(4):861-866. doi: 10.1007/s10103-019-02871-9. Epub 2019 Dec 23. PMID: 31872325; PMCID: PMC7261617.
8: Naranjo A, Arboleda A, Martinez JD, Durkee H, Aguilar MC, Relhan N, Nikpoor N, Galor A, Dubovy SR, Flynn HW Jr, Miller D, Parel JM, Amescua G, Leblanc R. Reply to Comment on: Rose Bengal Photodynamic Antimicrobial Therapy for Patients With Progressive Infectious Keratitis: A Pilot Clinical Study. Am J Ophthalmol. 2020 Jun;214:198-200. doi: 10.1016/j.ajo.2020.02.001. Epub 2020 Apr 7. PMID: 32276724.
9: Altamirano D, Martinez J, Leviste KD, Parel JM, Amescua G. Photodynamic Therapy for Infectious Keratitis. Curr Ophthalmol Rep. 2020 Dec;8:245-251. doi: 10.1007/s40135-020-00252-y. Epub 2020 Sep 12. PMID: 34540359; PMCID: PMC8445507.
10: Peterson JC, Arrieta E, Ruggeri M, Silgado JD, Mintz KJ, Weisson EH, Leblanc RM, Kochevar I, Manns F, Parel JM. Detection of singlet oxygen luminescence for experimental corneal rose bengal photodynamic antimicrobial therapy. Biomed Opt Express. 2020 Dec 10;12(1):272-287. doi: 10.1364/BOE.405601. PMID: 33520385; PMCID: PMC7818961.
11: Martinez JD, Arrieta E, Naranjo A, Monsalve P, Mintz KJ, Peterson J, Arboleda A, Durkee H, Aguilar MC, Pelaez D, Dubovy SR, Miller D, Leblanc R, Amescua G, Parel JM. Rose Bengal Photodynamic Antimicrobial Therapy: A Pilot Safety Study. Cornea. 2021 Aug 1;40(8):1036-1043. doi: 10.1097/ICO.0000000000002717. PMID: 34190718; PMCID: PMC8504203.
12: Adre E, Durkee H, Arboleda A, Alawa K, Maestre J, Mintz KJ, Leblanc RM, Amescua G, Parel JM, Miller D. Rose Bengal and Riboflavin Mediated Photodynamic Antimicrobial Therapy Against Selected South Florida Nocardia Keratitis Isolates. Transl Vis Sci Technol. 2022 Jan 3;11(1):29. doi: 10.1167/tvst.11.1.29. PMID: 35044443; PMCID: PMC8787600.
13: Sepulveda-Beltran PA, Levine H, Altamirano DS, Martinez JD, Durkee H, Mintz K, Leblanc R, Tóthová JD, Miller D, Parel JM, Amescua G. Rose Bengal Photodynamic Antimicrobial Therapy: A Review of the Intermediate-Term Clinical and Surgical Outcomes. Am J Ophthalmol. 2022 Nov;243:125-134. doi: 10.1016/j.ajo.2022.08.004. Epub 2022 Aug 8. PMID: 35952754.
14: Arboleda A, Durkee H, Miller D, Aguilar MC, Alawa K, Relhan N, Amescua G, Parel JM. Variations in irradiation energy and rose bengal concentration for photodynamic antimicrobial therapy of fungal keratitis isolates. Lasers Med Sci. 2024 Feb 21;39(1):72. doi: 10.1007/s10103-024-04014-1. PMID: 38379056.
15: Tribin FE, Lieux C, Maestre-Mesa J, Durkee H, Krishna K, Chou B, Neag E, Tóthová JD, Martinez JD, Flynn HW Jr, Parel JM, Miller D, Amescua G. Clinical Features and Treatment Outcomes of Carbapenem-Resistant Pseudomonas aeruginosa Keratitis. JAMA Ophthalmol. 2024 Mar 21. doi: 10.1001/jamaophthalmol.2024.0259. Epub ahead of print. PMID: 38512246.