Article

The Promise of Topicals for Retinal Disease

Researchers pursue combination therapies, repurposing, and new directions to chase “the holy grail.”

Topical instillation of eyedrops is the most common route of ophthalmic drug delivery, but the impediments and limitations associated with drug penetration to the posterior segment have thwarted multiple efforts to develop topical treatment for the retina. The challenge that researchers face is identifying molecules that are both effective and small enough to penetrate the eye.

“Topical drops are a pretty high hurdle,” said Joan W. Miller, MD, FARVO, chair of the Department of Ophthalmology at Harvard Medical School and chief of ophthalmology at Massachusetts Eye and Ear in Boston. “The concern is to get enough drug to reach the retina. That’s the limiting factor, because the eye is designed to keep things out.”

Still, said Dr. Miller, “We’ve come a long way in treating retinal disease.” Her research team won the Champalimaud Award for identifying the role of VEGF in ocular disease. That discovery changed the landscape of therapies for AMD, DR, and other retinal disorders. “It was surgical disease that’s now driven by drug treatments. That’s a significant shift.”

The next frontier of drugs includes topicals, with researchers exploring drops with potential to leap that hurdle of delivering medication to the back of the eye.

ADJUVANTS EMERGE

“Topical drops for the treatment of chronic retinal diseases are an elusive holy grail for retinal patients,” said vitreoretinal physician and surgeon Peter A. Karth, MD, MBA. “However, the current topical products in the pipeline seem to be more adjuvant therapy, reducing the number of injections by increasing the interval, rather than standalone replacements for injections.”

Emmett T. Cunningham Jr., MD, PhD, takes a similar view. As a managing director of Clarus Funds, adjunct clinical professor of ophthalmology at Stanford University School of Medicine, and director of the uveitis service at California Pacific Medical Center, he keeps watch on a wide range of emerging treatments. “An effective topical therapy for AMD, DR, or DME would provide enormous dosing and potentially safety benefits,” he said. “But despite several promising attempts, results comparable to intravitreal therapy have yet to be achieved.”

Dr. Karth, an associate with Oregon Eye Consultants and adjunct assistant clinical professor at Stanford University, is convinced that topicals used in combination with existing therapies represent a step forward. “There are several of these topical agents in trials for the treatment of AMD and DME,” he said. “Of particular interest in early trials is squalamine, which has shown promise.”

SQUALAMINE

Squalamine is a compound first isolated from tissues of the dogfish shark and sea lamprey.1 It has anticancer, antiviral, and antimicrobial properties. Over the last few decades, it has been widely researched for lung cancer chemotherapy,2 effectiveness against gram-positive bacteria,3 and even potential benefits in tablet form to disinfect home nebulizers of cystic fibrosis patients.4 New research suggests that squalamine has potential benefit for Parkinson’s disease and related neurologic conditions.5

For ocular use, Ohr Pharmaceuticals initiated a phase 3 trial of topical squalamine (squalamine lactate ophthalmic solution, 0.2%) in combination with injections of ranibizumab (Lucentis; Genentech) for treatment of wet AMD.6 The company anticipates that squalamine could reduce injection frequency, inhibit multiple growth-factor pathways, and have manufacturing cost advantages. In its December 2016 SEC filing, the company stated that the phase 3 trial is proceeding based on the data from its phase 2 clinical trial in wet AMD, which demonstrated a positive treatment effect of squalamine combination therapy in classic choroidal neovascularization and in those with occult neovascularization less than 10 mm2.7

“Based on my clinical experience, Squalamine is a promising drug with the potential to noninvasively improve visual function over the current standard of care,” said David S. Boyer, MD, retina specialist at Retina-Vitreous Associates Medical Group, Beverly Hills, California, and a member of Ohr’s scientific advisory board, in a press release.

In February 2017, disappointing results from the Regeneron phase 2 and Ophthotech phase 3 wet AMD combination studies prompted Ohr Pharmaceuticals to stop enrollment. The study will gather data on the more than 200 patients already enrolled, which will enable the release of results in 2017, earlier than planned. Jason Slakter, MD, CEO of Ohr, said in a conference call that although results from the recent combination studies had created a negative landscape, squalamine differs from the drugs in those studies in its activity, method of administration, patient selection, and previous trial results. Dr. Slakter asserted that the patient population selected for the squalamine phase 3 study was identified in the phase 2 trial as those most likely to benefit from combination therapy, was consistent with the mechanism of squalamine and combination therapy in general, and that squalamine’s biologic activity in the back of the eye had been confirmed by the phase 2 trial.8

GENERICS

A research team from Wills Eye in Philadelphia, Pennsylvania, has been looking at repurposing the common glaucoma drug dorzolamide-timolol, which lowers eye pressure, specifically for patients who don’t respond sufficiently to anti-VEGF treatments alone. In a pilot study, the researchers gave a small group of neovascular AMD patients dorzolamide-timolol drops in addition to monthly anti-VEGF injections. Their study, published last year in JAMA Opthalmology, reported significant improvements.9

Jason Hsu, MD, a retina surgeon at Wills Eye Hospital, said, “We’re moving forward with a multicenter randomized trial. We have IRB approval and are ready to start recruiting. The goal is 50 patients across 5 centers. We’ll be randomizing patients to receive this glaucoma drop vs a placebo artificial tear drop.” Dr. Hsu hypothesizes that reduced aqueous fluid production could reduce drug turnover in the eye, allowing the anti-VEGF more time to be effective.

“As a clinician and someone very interested in research, I think it’s common to say you try 100 things and 99% of time they don’t work, but that one time you get a positive signal, it’s very exciting,” said Dr. Hsu. “The hope is this will be helpful for patients, if our larger study indeed proves this drug is helpful.” His team also plans to explore the benefits of the glaucoma drop for retinal vein occlusion and diabetic macular edema.

“We’re entering an interesting era of combination therapy,” said Dr. Hsu. “If this is confirmed to have a real positive effect, it’s a cost-effective eyedrop that’s generic and already on the market. It’s exciting if we can find new uses for old drugs and adapt previously approved drugs for new uses to help patients.”

ALTERNATIVE DIRECTIONS

Overseas, a pilot study at the University of Sassari in Italy, published November 2016 in the European Journal of Ophthalmology, suggested benefits of using topical bromfenac, a nonsteroidal anti-inflammatory drug, twice a day in patients with newly diagnosed DME.10

An article in the January 2017 issue of Journal of Molecular Medicine describes an animal study that hints at new opportunities for the topical pipeline. Using eye drops in mouse models, researchers from the Medical University of South Carolina in Charleston, were able to bypass the outer blood-retina barrier to deliver treatment that reduced VEGF-dependent RPE pathophysiology.11 They foresee potential application of this approach in wet and dry AMD.

Ophthalmic researchers continue to push forward and learn more about the pathways behind vision deterioration. As a result, new opportunities and treatment alternatives could one day reduce injections and expand topical delivery. RP

REFERENCES

  1. Zasloff M, Adams AP, Beckerman B, et al. Squalamine as a broad-spectrum systemic antiviral agent with therapeutic potential. Proc Natl Acad Sci USA. 2011;108(38):15978-15983.
  2. Herbst RS, Hammond LA, Carbone DP, et al. A phase I/IIA trial of continuous five-day infusion of squalamine lactate (MSI-1256F) plus carboplatin and paclitaxel in patients with advanced non-small cell lung cancer. Clin Cancer Res. 2003;9(11):4108-4115.
  3. Alhanout K, Malesinki S, Vidal N, Peyrot V, Rolain JM, Brunel JM. New insights into the antibacterial mechanism of action of squalamine. J Antimicrob Chemother. 2010;65(8):1688-1693.
  4. Djouhri-Bouktab L, Alhanout K, Andrieu V, et al. Soluble squalamine tablets for the rapid disinfection of home nebulizers of cystic fibrosis patients. J Cyst Fibros. 2012;11(6):555-559.
  5. Perni M, Galvagnion C, Maltsev A, et al. A natural product inhibits the initiation of α-synuclein aggregation and suppresses its toxicity. Proc Natl Acad Sci USA. 2017 Jan 17.
  6. Efficacy and safety study of squalamine ophthalmic solution in subjects with neovascular AMD (MAKO). https://clinicaltrials.gov/ct2/show/NCT02727881
  7. United States Securities and Exchange Commission. Annual report under section 13 or 15(d) of the securities exchange act of 1934 For the fiscal year ended September 30, 2016: Ohr Pharmaceutical, Inc. Available at: http://ir.ohrpharmaceutical.com/all-sec-filings#document-15442-0001387131-16-008696
  8. Helzner J. Ohr “pauses” phase 3 AMD study. Ret Physician. February 22, 2017. Available at: http://www.retinalphysician.com/issues/2017/january-2017/ohr-pauses-phase-3-amd-study
  9. Sridhar J, Hsu J, Shahlaee A, et al. Topical dorzolamide-timolol with intravitreous anti-vascular endothelial growth factor for neovascular age-related macular degeneration. JAMA Ophthalmol. 2016;134(4):437-443.
  10. Pinna A, Blasetti F, Ricci GD, Boscia F. Bromfenac eyedrops in the treatment of diabetic macular edema: a pilot study. Eur J Ophthalmol. 2016 Nov 16. [Epub ahead of print].
  11. Obert E, Strauss R, Brandon C, et al. Targeting the tight junction protein, zonula occludens-1, with the connexin43 mimetic peptide, αCT1, reduces VEGF-dependent RPE pathophysiology. J Mol Med (Berl). 2017. [Epub ahead of print].