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Beyond palliative relief for severe dry eye disease

Clinical trial shows high molecular weight hyaluronic acid drops improve symptoms and regenerate damaged corneal nerves

Cheryl Guttman Krader

Posted: Thursday, December 3, 2020

Treatment with a preservative-free, lubricating eye drop containing 0.15% high molecular weight hyaluronic acid (HMWHA; Comfort Shield, i.com medical GmbH) provides better symptomatic relief for patients with severe dry eye disease (DED) than existing “optimum” lubricant drops and has a remarkable benefit for promoting corneal nerve growth, according to results of a multi-centre, prospective, randomised clinical trial.

Jutta Horwath-Winter MD, Assistant Professor of Ophthalmology, Medical University Graz, Graz, Austria, was a principal investigator in the study. She told EuroTimes: “Although the TFOS DEWS II Management and Therapy Report states that tear replacement products do not target the underlying pathophysiology of DED, the results of the HYLAN M study show that it in addition to its lubricating properties and effect for increasing tear viscosity, HMWHA apparently has neurotrophic effects.”

Gysbert van Setten MD, PhD, Assistant Professor of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden, was also a principal investigator in the research study and lead author of the published report.

He commented: “HMWHA is nature’s own lubricant, and the 0.15% HMWHA drops closely mimic the features and functions of the natural tear film. Instead of a DED regimen incorporating a plethora of drops and ointments, 0.15% HMWHA could provide a simplified approach, which would be particularly beneficial for older patients.”

Both investigators emphasised that while there are other commercially available artificial tears containing hyaluronic acid, the products are not all equal.

“The benefits of a product containing hyaluronic acid depend more on the molecular weight of the hyaluronic acid than its concentration. There is currently no convincing evidence that any other ocular lubricants lead to neuronal regeneration in DED,” Dr van Setten said.

Dr Horwath-Winter agreed that the properties of hyaluronic acid depend mainly on molecular weight.

“HMWHA has a high water-binding capacity, anti-inflammatory properties and wound healing effects,” she said.

HYLAN M DESIGN AND DATA
The eight-week HYLAN M study included adults who met published criteria for severe DED [Ocular Surface Disease Index (OSDI) ≥33, Oxford corneal fluorescein staining (CFS) score ≥3] and had been on a stable treatment regimen. They were randomised 1:1 to use the HMWHA drops or continue their existing artificial tears.

Eighty-four patients were included in the efficacy analysis. Change in CFS from baseline to week eight was assessed as the primary endpoint and did not show a statistically significant difference between groups.

“Oxford staining gradients are demanding and subjective, and we cannot rule out that these issues confounded the ability to demonstrate a statistically significant benefit of HMWHA treatment despite all of the standardisation implemented in the study. Furthermore, the eight-week treatment period may have been too short to show a benefit. Just as symptoms of DED often manifest before signs, symptoms may improve before DED-related anatomical changes,” said Dr van Setten.

Dr Horwath-Winter noted that the low sub-basal nerve fiber length found in the study population of patients with severe DED might also have been a confounding issue. Trophic support from corneal nerves is important for epithelial renewal, she explained.

The analysis of change in total OSDI score, the key secondary endpoint, showed a 13.5-point statistically significant difference favouring the HMWHA group (P = .001). The HMWHA treatment also had statistically significant benefits compared with the control for improving the OSDI pain subscore, OSDI vision subscore and BCVA.

Both investigators underscored the importance of symptomatic improvement.

“Symptom assessment is a key element in evaluating a DED treatment because of the impact of symptoms on patient well-being,” Dr van Setten said.

Dr Horwath-Winter quoted a conclusion from the recently published Asia Dry Eye Society consensus report, stating: “Therapeutic efficacy should be evaluated by the symptoms such as dry eye-related pain, discomfort or visual disturbances. Functional visual acuity should also be included as an outcome measure in further studies in this field.”

NERVE REGENERATION
Corneal nerve changes were assessed through masked reader review of in vivo confocal laser scanning microscopy images in a subset of 16 patients. The analyses showed corneal nerve fibre length was similar in the two treatment subgroups at baseline, but at study end, it had increased by 51% (P=0.03) in the HMWHA group and was unchanged in the control group.

The investigators commented that the effect of HMWHA treatment on corneal nerve growth correlates well with its benefit for relieving pain. In the absence of significant changes in dry eye signs, they suggested that the therapeutic benefits of the HMWHA drops are likely due to pharmacological effects, including downregulation of ocular inflammation and support of corneal nerve recovery, rather than physical effects like hydration or lubrication.

FUTURE RESEARCH
Because nerve damage is increasingly recognised as a factor in DED pathophysiology, the investigators believe further studies are warranted to investigate the role of HMWHA for improving corneal innervation and function. Ongoing studies include other DED patient subgroups and patients with diabetic keratopathy. There is also interest in investigating its use in patients undergoing surgical procedures that can damage corneal nerves.

The HYLAN M clinical trial results appeared in the Journal of Clinical Medicine [J Clin Med. 2020;9(110:E3536; J. Clin. Med. 2020, 9(12), 3799]