All Eyes on Bascom Palmer

Preliminary results for the Steroids for Corneal Ulcers Trial II presented at AAO 2024: Negative effects of corneal cross-linking on patients with bacterial infectious keratitis

According to Altamirano et al. 2020¹, photodynamic therapy (PDT) has been used for numerous applications in ophthalmology (n.b., the authors of this paper are from Bascom Palmer Eye Institute). As it relates to Provectus, Bascom Palmer’s rose bengal (RB) photodynamic antimicrobial therapy (PDAT) (RB PDAT, aka RB PDT) competes with corneal collagen cross-linking (CXL), which combines photosensitizer chemical riboflavin (i.e., vitamin B2)) and an ultraviolet (UV) light source device, for the treatment of infectious keratitis (IK).

Photo-Activated Chromophore for Keratitis Corneal Cross-Linking (CXL for short)

CXL using UV light and riboflavin to treat IK is also referred to as Photo-Activated Chromophore for Keratitis Corneal Cross-Linking (PACK-CXL), and was approved by the U.S. Food and Drug Administration (FDA) as a first-line treatment for progressive keratoconus and post-LASIK ectasia².

Also according to Altamirano et al. 2020, the first publication describing the use of CXL in the context of human corneal infections was by Iseli et al. in 2008. Since then, several case reports, case series, and prospective non-randomized studies on the use of CXL for corneal infections have been reported.

The standard of care (SOC) for IK has been the use of topical antibiotics (i.e., antibiotic eye drops). There are several different types of IK, such as bacterial, viral, fungal, and parasitic, and microbes can become drug-resistant.

Steroids for Corneal Ulcers Trial (SCUT)

In the mid- to late-2000s, a randomized, placebo-controlled, double-masked, multi-center clinical trial was run to determine if topical corticosteroids in combination with SOC antibiotics (i.e., steroids as an adjunctive therapy) could better treat bacterial IK:

• Treatment arm: topical moxifloxacin (antibiotic) + topical prednisolone phosphate (steroid), and

• Control arm: topical moxifloxacin + topical placebo

This trial was called the Steroids for Corneal Ulcers Trial (SCUT) (study design and baseline characteristics³). SCUT was funded by the National Institutes of Health’s (NIH’s) National Eye Institute (NEI), and enrollment centers included:

• the Aravind Eye Care System (Madurai, Tirunelveli, and Coimbatore, India),

• Dartmouth-Hitchcock Medical Center, and

• the Francis I. Proctor Foundation at the University of California, San Francisco (UCSF).

Of the 500 patients enrolled, however, 97% were in India. The endpoint of the study was 3-month best spectacle-corrected visual acuity (BSCVA).

According to Srinivasan et al. 2012⁴, SCUT showed no overall difference in 3-month BSCVA (and no safety concerns) with adjunctive corticosteroid therapy for bacterial corneal ulcers. That is, adjunctive topical corticosteroid use does not improve 3-month vision in patients with bacterial corneal ulcers.

Steroids and Cross-linking for Ulcer Treatment Trial (SCUT II)

In the 2020s, collaborators from UCSF (one of whom later moved to Stanford University) and Aravind undertook an NIH NEI-funded international, randomized, double-masked, sham and placebo-controlled clinical trial to determine the benefit of adjunctive CXL (using UV light and riboflavin) and/or topical steroids in addition to topical antibiotic drops for the treatment of bacterial IK:

• Treatment arm #1: topical moxifloxacin (antibiotic) + topical difluprednate (steroid) + CXL,

• Treatment arm #2: topical moxifloxacin + topical difluprednate + sham CXL (i.e., placebo), and

• Control arm: topical moxifloxacin plus topical placebo plus sham CXL.

The trial was called the Steroids and Cross-linking for Ulcer Treatment Trial (SCUT II)⁵. Patients were to have been enrolled at:

• Aravind Eye Hospitals in in Coimbatore, Madurai, Pondicherry, and Tirunelveli, India,

• the Proctor Foundation clinic at UCSF,

• Bascom Palmer, and

• Kaiser Permanente Northern California medical facilities.

The endpoint of the study was 6-month BSCVA. The study leaders hypothesized that (i) CXL would in better 6-month BSCVA compared to antibiotic alone (i.e., Treatment arm #1 vs Control arm), and (ii) early topical steroids would improve 6-month BSCVA compared to antibiotic alone (i.e., Treatment arm #2 vs Control arm). CXL using UV light and riboflavin was donated to the study by Avedro (NASDAQ: ACDR), which developed the treatment (and achieved an approval of it for first-line progressive keratoconus and post-LASIK ectasia in 2016) and was acquired by Glaukos (NASDAQ: GKOS)⁶ in 2019.

Preliminary results of SCUT II were presented by Stanford’s Jennifer Rose-Nussbaumer, MD, a board-certified ophthalmologist and fellowship-trained cornea specialist, at the 2024 annual meeting of the American Academy of Ophthalmology (AAO 2024) in Chicago, IL, held October 18-21.

In this video linked here from AAO 2024, Gerami Seitzman, MD and Cornea Subspecialty Day co-chair Christina Prescott, MD, PhD discussed the findings from SCUT II, notably the negative effects of CXL for the treatment of bacterial IK (i.e., vision and scarring worsened).

You can access Dr. Rose-Nussbaumer’s presentation here (sign-up required). She observed that:

• Steroids (vs SOC) improved vision (primary outcome) by a half-line (-0.04, log scale), but the outcome was not statistically significant (p=0.58),

• CXL (vs steroids) worsened vision by a half-line (0.04), but the outcome was not statistically significant (p=0.62),

• Steroids (vs SOC) improved scarring (secondary outcome) (-0.23 mm), but the outcome was not statistically significant (p=0.65), and

• CXL (vs steroids) worsened scarring (0.5 mm), and the outcome was statistically significant (p=0.02).

In summary, she observed that CXL worsened pain, increased corneal scarring, had no impact on microbiologic cure rate (CXL could not sterilize could sterilize the surface of the eye), may reduce vision, and may reduce corneal perforation or therapeutic keratoplasty (TPK) (a good thing).

Interestingly, Dr. Rose-Nussbaumer surveyed experts in the field of cornea (a total of 34 people), who thought of the SCUT II trial that (i) steroids would improve vision (76%) and (ii) CXL would not (71%). Her team also did an analysis using artificial intelligence (AI) (a total of 10 models), which predicted that both steroids and CXL would improve vision (90% in both cases).

Next Up

So, in regards to Provectus and its prospective clinical-stage ophthalmology start-up spinout, “EyeCo,” the ophthalmology community awaits the results of the NIH NEI-funded REAGIR study, a double-masked, sham-controlled trial of RB PDT for the treatment of fungal and acanthameoba keratitis⁷. REAGIR is the acronum for the Rose Bengal Electromagnetic Activation with Green Light for Infection Reduction (REAGIR) study (NCT05110001).

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1. 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.

2. FDA approves first corneal cross-linking system for treatment (July 2016).

3. Srinivasan M, Mascarenhas J, Rajaraman R, Ravindran M, Lalitha P, Glidden DV, Ray KJ, Hong KC, Oldenburg CE, Lee SM, Zegans ME, McLeod SD, Lietman TM, Acharya NR; Steroids for Corneal Ulcers Trial Group. The steroids for corneal ulcers trial: study design and baseline characteristics. Arch Ophthalmol. 2012 Feb;130(2):151-7. doi: 10.1001/archophthalmol.2011.303. Epub 2011 Oct 10. PMID: 21987581; PMCID: PMC3830555.

4. Srinivasan M, Mascarenhas J, Rajaraman R, et al. Corticosteroids for Bacterial Keratitis: The Steroids for Corneal Ulcers Trial (SCUT). Arch Ophthalmol. 2012;130(2):143–150. doi:10.1001/archophthalmol.2011.315.

5. Radhakrishnan N, Prajna VN, Prajna LS, Venugopal A, Narayana S, Rajaraman R, Amescua G, Porco TC, Lietman TM, Rose-Nussbaumer J. Double-masked, sham and placebo-controlled trial of corneal cross-linking and topical difluprednate in the treatment of bacterial keratitis: Steroids and Cross-linking for Ulcer Treatment Trial (SCUT II) study protocol. BMJ Open Ophthalmol. 2021 Nov 29;6(1):e000811. doi: 10.1136/bmjophth-2021-000811. PMID: 34901464; PMCID: PMC8634009.

6. The closing market capitalization of GKOS on October 25, 2024 was approximately $7.15 billion.

7. Prajna V, Prajna L, Sharma S, de Freitas D, Höfling-Lima AL, Varnado N, Abdelrahman S, Cavallino V, Arnold B, Lietman T, Rose-Nussbaumer J. A double-masked, sham-controlled trial of rose bengal photodynamic therapy for the treatment of fungal and acanthameoba keratitis: Rose Bengal Electromagnetic Activation with Green Light for Infection Reduction (REAGIR) Study. Res Sq [Preprint]. 2024 Jul 2:rs.3.rs-4165312. doi: 10.21203/rs.3.rs-4165312/v1. Update in: Trials. 2024 Aug 28;25(1):566. doi: 10.1186/s13063-024-08376-3. PMID: 39011096; PMCID: PMC11247944.