Dry Eye Therapies

Treatments targeting specific causes with new delivery mechanisms on the horizon. Howard Larkin reports from ARVO 2021 in Las Vegas, USA.

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Treatments targeting specific causes with new delivery mechanisms on the horizon. Howard Larkin reports from ARVO 2021 in Las Vegas, USA. Researchers introduced a range of dry eye treatments with novel targets and delivery mechanisms now entering clinical trials at the 2021 ARVO meeting. TARGETING MGD AZR-MD-001 (Azura Ophthalmics) is an ointment containing selenium sulphide applied twice weekly that specifically addresses meibomian gland dysfunction (MGD), which is often the root cause of dry eye symptoms, said Laura Downie, BOptom, PhD, Associate Professor, and Dame Kate Campbell, Fellow, at the University of Melbourne, Australia. MGD is characterised by keratinisation blocking meibomian gland orifices and keratin debris combined with cross-linking of strong disulphide bonds, raising the melting point and viscosity of the meibum. Selenium sulphide targets aberrant keratins and chemically disrupts disulphide bonds, unblocking the glands and thinning secretions, Dr Downie explained. In a phase 2a trial, 0.1%, 0.5%, and 1.0% concentrations of AZR-MD-001 were tested against the medication vehicle alone. A three-month interim analysis of the first 33 patients found the 0.5% and 1.0% concentrations significantly increased the number of functional meibomian glands and improved meibum quality towards a clear liquid secretion while reducing OSDI dry eye symptoms compared with baseline. The 1.0% preparation also improved these outcomes significantly compared with the vehicle control group, and clinically significant improvement in OSDI scores showed a dose-dependent relationship with AZR-MD-001 concentration. Patients tolerated the treatments well, although there was some transient burning, Dr Downie reported. “AZR-MD-001 has potential to be the first effective pharmacotherapy treatment specifically intended for MGD,” Dr Downie said. Full results will be reported later. TARGETING INFLAMMATION PL9643 (Palatin Technologies) is a melanocortin agonist that may be a novel therapeutic target to treat inflammatory ocular diseases, including dry eye. As a first-in-class treatment, it may be faster-acting and more tolerable than current anti-inflammatory treatments, said Kenneth R Kenyon MD, of Tufts University School of Medicine, Boston, USA. The melanocortin peptide receptor systems’ wide range of anti-inflammatory properties includes inhibition of leukocyte activation and protection of tissues from the inflammatory response. PL9643 is a melanocortin pan-agonist that promotes many of these anti-inflammatory effects, Dr Kenyon explained. In a phase 2 trial, researchers tested a 1.0 microgram/mL preparation of PL9643 against a placebo administered three times daily for 12 weeks. The treatment effects on dry eye signs and symptoms did not reach significance in the entire 160-patient study group. However, in a sub-group of 61 patients with moderate to severe dry eye, significant improvements were seen in the primary sign endpoint of corneal staining as well as for conjunctival staining and tear film breakup time at week 12. Trends towards improvement in multiple ocular symptoms, including burning, grittiness, stinging, itching, and foreign body sensation also were noted. Data from week 2 showed significant improvement in overall ocular discomfort. Patients again tolerated treatment well, and there were fewer reported adverse events in the treatment group than the placebo group, Dr Kenyon reported. “These positive results across multiple signs and symptoms of dry eye very enthusiastically support continued development of PL9643 as a therapeutic option for dry eye disease,” Dr Kenyon said. There is a plan for a phase 2/3 trial for this year. NASAL SPRAY TARGETING THE LACRIMAL FUNCTION OC-01 (Oyster Point Pharma, now FDA approved as TYRVAYA™) is a nasal spray containing varenicline, a nicotinic acetylcholine receptor agonist. It activates the trigeminal parasympathetic pathway to activate the lacrimal functional unit to re-establish the natural tear film in patients with dry eye, said Michael Raizman MD of Tufts University School of Medicine, Boston, USA. In addition to the lacrimal glands, varenicline tartrate also stimulates the meibomian glands and goblet cells. The compound is water soluble, diffuses quickly across the nasal mucosa, increases tear production within seconds, and has limited systemic bioavailability, Dr Raizman said. In a phase 3 study involving 758 subjects, patients receiving 0.6 mg/mL (0.03 mg) and 1.2 mg/mL (0.06 mg) of varenicline three times daily saw a high statistically significant rise in Schirmer’s test scores of 10mm or more compared with placebo at day 28. The percentages of eyes showing 10mm improvement or more in the 0.03 mg, 0.06 mg, and vehicle control groups were 47.3%, 49.2%, and 27.8%, with mean changes of 11.3mm, 11.5mm, and 6.3mm, respectively. As early as day 14, patients in the treatment groups saw a significant improvement over placebo in 0–100 Eye Dryness Scores, regardless of their baseline symptom severity. Safety and tolerability were excellent, with sneezing after dosing the most common side effect. The results suggest OC-01 would benefit a broad population of dry eye disease in the real world, and the nasal administration may be an advantage, Dr Raizman noted. “Nasal sprays are well accepted by patients for treating many problems. Eye drops can be difficult to administer for some patients.” INJECTED IMMUNOMODULATOR Sirolimus is an immunomodulating drug commonly prescribed in oral form to prevent rejection of solid organ transplants. A patented subconjunctival injection preparation in which the water-soluble active ingredient is loaded in liposomes could help control immune-modulated inflammation in dry eye. This could reduce the need for topical immunosuppressants and related topical adverse effects and long-term use of corticosteroids with the attendant risks of glaucoma and cataract, said Alejandro Navas MD, PhD of the Institute of Ophthalmology “Conde de Valenciana” at the National University of Mexico, Mexico City. In a phase 2 trial involving 38 eyes in 19 patients, both treated and sham groups showed significant reductions in OSDI scores and conjunctival hyperaemia. The treatment group also showed significant improvements in corneal and conjunctival staining, lipid layer interferometry, and inferior meibomian gland dropout. No local or systemic adverse effects related to the medication were reported, and the administration route was well accepted. Other studies have shown intravitreal sirolimus reduces inflammation for non-infectious uveitis, Dr Navas noted. Loading the active ingredient in liposomes helps extend delivery time. “These findings suggest subconjunctival sirolimus could reduce signs and symptoms in patients with moderate to severe dry eye disease.” NEUROTROPHIC AND REGENERATIVE PEPTIDE BRM421 (BRIM Biotechnology) is a synthetic peptide derived from Pigment Epithelium-Derived Factor (PEDF) with neurotrophic and stem-cell regenerative properties. It has shown an ability to promote the growth and expansion of limbal epithelial stem cells after severe ocular wounding better than PEDF in animal models. By speeding up the cornea repair process through stimulation of corneal stem cell proliferation and differentiation, and improving tear quality through the increase of mucin secretion resulting from goblet cell growth, it may reverse corneal damage and improve signs and symptoms of moderate to severe dry eye, said Pin-Yen Huang MD of BRIM Biotechnology, Taipei, Taiwan. In a five-week first-in-human study involving 157 patients comparing a topical preparation of BRM421 with a vehicle control, the treated group of patients with moderate to severe dry eye syndrome showed a significant improvement in total fluorescein corneal staining scores. The treated group also showed improvement in dryness symptoms on the Ora Calibra Ocular Discomfort and 4-Symptom scale on day 14, with improved tear film break-up time on day 29. A second-in-human study involving 220 patients was shortened to three weeks due to the rapid onset of effects in the first study. It found a trend towards improvement in signs and significant improvement in symptoms, including VAS-eye dryness and VAS-burning scales, as well as VAS-photophobia on day eight. Post-hoc analysis showed greater improvement among patients with more severe baseline disease, and the drug had a strong safety profile with no patients withdrawing due to adverse events, Dr Huang reported. “The quick onset, especially in symptom improvement, is quite consistent,” Dr Huang said. “BRM421’s unique mechanism of action gives it the potential to treat not only moderate to severe dry eye syndrome but possibly severe corneal wounds.” Laura Downie ldownie@unimelb.edu.au Kenneth R Kenyon kenrkenyon@cs.com Michael Raizman mraizman@tuftsmedicalcenter.org Alejandro Navas dr.alejandro.navas@gmail.com, alejandro. navas@institutodeoftalmologia.org Pin-Yen Huang shihya.chang@brimbiotech.com, yichun.chen@ brimbiotech.com