A Two-Week, Randomized, Double-masked Study to Evaluate Safety and Efficacy of Lubricin (150 μg/mL) Eye Drops Versus Sodium Hyaluronate (HA) 0.18% Eye Drops (Vismed®) in Patients with Moderate Dry Eye Disease

doi:10.1016/j.jtos.2016.08.004

The Ocular Surface

Volume 15, Issue 1, January 2017, Pages 77-87

https://doi.org/10.1016/j.jtos.2016.08.004 Get rights and content

Abstract

Purpose

The objective of this clinical trial (NCT02507934) was to assess the efficacy and safety of recombinant human lubricin as compared to a 0.18% sodium hyaluronate (HA) eye drop in subjects with moderate dry eye disease (DED).

Methods

DEWS Grade 2-3 subjects were randomized to use lubricin (N=19, 51.9 ± 11.8 years) or HA (N=20, 61.8 ± 13.3 years). After a saline washout period, subjects administered BID therapy for 7 days, followed by instillation as needed (2–6 drops per eye) for 7 days. Visual analog scale (VAS) including foreign body sensation, burning/stinging, itching, pain, sticky feeling, blurred vision and photophobia were primary outcomes, with secondary endpoints of corneal fluorescein staining, Schirmer test, tear film breakup time (TFBUT), eyelid and conjunctival erythema and number of instillations compared at day 14.

Results

The primary endpoint was met. Lubricin supplementation achieved greater than a 72% reduction from baseline in foreign body sensation (P<.013), burning/stinging, pain, sticky feeling (P<.0432), blurred vision (P<.0013), and photophobia (P<.011) in at least one eye. Lubricin also showed significant improvement in fluorescein staining (OD/OS: 43.8%/50.0%, vs. 26.5%/23.3%, P<.0398, P<.0232), TFBUT (P<.010), SANDE frequency (P<.0435), eyelid erythema (P<.004), conjunctival erythema (P<.0013), and instillations (P<.04) as compared to HA. No treatment-related adverse events occurred during the investigation.

Conclusions

Recombinant human lubricin was shown to produce significant improvement in both signs and symptoms of dry eye disease as compared to HA.

Introduction

Lubricin (PRG4: GenBank NP_005798), a large glycoprotein with a central mucin-like domain, was recently identified as a boundary lubricant that is transcribed, translated, and expressed by human ocular surface tissues.¹ Lubricin dramatically reduces friction between the human cornea and conjunctiva.¹ At a latex-glass interface, bulk human tear film mucins were incapable of lowering the coefficient of friction whereas lubricin was able to significantly ameliorate friction as compared to a saline control.² In addition, lubricin significantly reduced both static and kinetic friction coefficients atop a human donor cornea-lid interface as compared to commercially available hyaluronic acid or saline solutions.¹ Similar reductions in friction were seen at a human donor cornea-PDMS contact lens model interface following lubricin irrigation,³ as well as with commercial silicone hydrogel contact lenses atop human cornea and eyelid interfaces.⁴

Impaired lubricin biosynthesis, which occurs during inflammation,5, 6 is hypothesized to occur during various types of dry eye disease, and is associated with damage to the ocular surface.¹ Pro-inflammatory cytokines common to dry eye, such as IL-1ɑ, IL-1ß, and TNFɑ,7, 8, 9 markedly reduce lubricin expression in other tissues such as articular cartilage.5, 6, 10 An inverse relationship has also been observed between the levels of procathepsin B, neutrophil elastase, and lubricin in the injured knee.¹¹ Preliminary data suggest that cathepsin S, a key proteolytic enzyme released from the lacrimal gland in Sjögren syndrome,¹² degrades lubricin and compromises its function,¹³ while loss of lubricin at the ocular surface resulted in significantly greater staining for PRG4 knockout mice than in wild-type controls.¹ Accordingly, lubricin is thought to be a critical component of a healthy ocular surface glycocalyx, serving as an essential barrier to the development of corneal and conjunctival epitheliopathies.

As Ehlers previously speculated, the friction between cornea and the lid, particularly towards the lid margin, is likely dominated by boundary lubrication, mediated by a film of surface-active substances atop the corneal epithelium.¹⁴ If true, the replenishment of a competent glycocalyx should reduce ocular surface friction and improve signs and symptoms associated with dry eye disease (DED). To test this hypothesis, we sought to determine whether the topical administration of recombinant human lubricin would provide a superior reduction in ocular signs and symptoms as compared to a commercially available 0.18% sodium hyaluronate (HA) eye drop.

Section snippets

Methods: Study Design

This was a 2-week, randomized, double-masked, parallel group and 1-week follow-up study to evaluate tolerability, safety, and efficacy of lubricin eye drops as compared to HA. The trial began on June 26, 2015 and ended on October 6, 2015. (Trial period comprises first visit of first enrolled patient to last visit of last enrolled patients.) Prior to initiation, the Investigator's brochure and all other relevant documentation were reviewed and approved independently by ethics committees of

Results

Forty (40) subjects were screened and included in the investigation. A summary of demographics and disposition is shown in Table 1. All 40 enrolled patients were suffering from dry eye at a DEWS severity level 2 or 3 in at least one eye. The second most frequent underlying condition was Sjögren syndrome (37.5%) followed by hypertension (27.5%) and by autoimmune thyroiditis (20.0%). Other conditions had frequencies ≤17.5%. All randomized subjects were evaluated for safety variables. One subject,

Discussion

Our clinical investigation was designed to assess the efficacy and safety of recombinant human lubricin as compared to an HA eye drop solution in subjects with moderate dry eye disease. Recombinant human lubricin improved the sensation of blurred vision and the total score of ocular symptoms in the left eye, and foreign body sensation, photophobia, and sticky feeling in both eyes significantly more than HA, thus satisfying the primary hypothesis of the clinical investigation. Of note, all

Conclusions

Recombinant human lubricin 150 μg/mL was found to be safe, well tolerated, and generally superior to 0.18% sodium hyaluronate, improving both signs and symptoms in moderate DED subjects. Statistically significant treatment effects and numerous trends towards improvement suggest further studies aimed at elucidating the therapeutic effect of recombinant human lubricin in a larger patient cohort, as well as in more mild-to-severe cohorts, are warranted.

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Cited by (72)

A structural and functional comparison between two recombinant human lubricin proteins: Recombinant human proteoglycan-4 (rhPRG4) vs ECF843
2023, Experimental Eye Research
Proteoglycan 4 (PRG4, lubricin) is a mucin-like glycoprotein present on the ocular surface that has both boundary lubricating and anti-inflammatory properties. Full-length recombinant human PRG4 (rhPRG4) has been shown to be clinically effective in improving signs and symptoms of dry eye disease (DED). In vitro, rhPRG4 has been shown to reduce inflammation-induced cytokine production and NFκB activity in corneal epithelial cells, as well as to bind to and inhibit MMP-9 activity. A different form of recombinant human lubricin (ECF843), produced from the same cell line as rhPRG4 but manufactured using a different process, was recently assessed in a DED clinical trial. However, ECF843 did not significantly improve signs or symptoms of DED compared to vehicle. Initial published characterization of ECF843 showed it had a smaller hydrodynamic diameter and was less negatively charged than native PRG4. Further examination of the structural and functional properties of ECF843 and rhPRG4 could contribute to the understanding of what led to their disparate clinical efficacy. Therefore, the objective of this study was to characterize and compare rhPRG4 and ECF843 in vitro, both biophysically and functionally.
Hydrodynamic diameter and charge were measured by dynamic light scattering (DLS) and zeta potential, respectively. Size and molecular weight was determined for individual species by size exclusion chromatography (SEC) with in-line DLS and multi-angle light scattering (MALS). Bond structure was measured by Raman spectroscopy, and sedimentation properties were measured by analytical ultracentrifugation (AUC). Functionally, MMP-9 inhibition was measured using a commercial MMP-9 activity kit, coefficient of friction was measured using an established boundary lubrication test at a latex-glass interface, and collagen 1-binding ability was measured by quart crystal microbalance with dissipation (QCMD). Additionally, the ability of rhPRG4 and ECF843 to inhibit urate acid crystal formation and cell adhesion was assessed.
ECF843 had a significantly smaller hydrodynamic diameter and was less negatively charged than rhPRG4, as assessed by DLS and zeta potential. Size was further explored with SEC-DLS-MALS, which indicated that while rhPRG4 had 3 main peaks, corresponding to monomer, dimer, and multimer as expected, ECF843 had 2 peaks that were similar in size and molecular weight compared to rhPRG4's monomer peak and a third peak that was significantly smaller in both size and molar mass than the corresponding peak of rhPRG4. Raman spectroscopy demonstrated that ECF843 had significantly more disulfide bonds, which are functionally determinant structures, relative to the carbon-carbon backbone compared to rhPRG4, and AUC indicated that ECF843 was more compact than rhPRG4. Functionally, ECF843 was significantly less effective at inhibiting MMP-9 activity and functioning as a boundary lubricant compared to rhPRG4, as well as being slower to bind to collagen 1. Additionally, ECF843 was significantly less effective at inhibiting urate acid crystal formation and at preventing cell adhesion.
Collectively, these data demonstrate ECF843 and rhPRG4 are significantly different in both structure and function. Given that a protein's structure sets the foundation for its interactions with other molecules and tissues in vivo, which ultimately determine its function, these differences most likely contributed to the disparate DED clinical trial results.
Novel drug delivery systems for the management of dry eye
2022, Advanced Drug Delivery Reviews
Dry eye disease (DED) is a frequently observed eye complaint, which has recently attracted considerable research interest. Conventional therapy for DED involves the use of artificial tear products, cyclosporin, corticosteroids, mucin secretagogues, antibiotics and nonsteroidal anti-inflammatory drugs. In addition, ocular drug delivery systems based on nanotechnology are currently the focus of significant research effort and several nanotherapeutics, such as nanoemulsions, nanosuspensions, microemulsions, liposomes and nanomicelles, are in clinical trials and some have FDA approval as novel treatments for DED. Thus, there has been remarkable progress in the design of nanotechnology-based approaches to overcome the limitations of ophthalmic formulations for the management of anterior eye diseases. This review presents research results on diagnostic methods for DED, current treatment options, and promising pharmaceuticals as future therapeutics, as well as new ocular drug delivery systems.
Stepwise Approach to the Diagnosis and Management of Dry Eye and Ocular Surface Disease
2022, Advances in Ophthalmology and Optometry
Current trends in pharmaceutical treatment of dry eye disease: A review
2022, European Journal of Pharmaceutical Sciences
Dry eye disease (DED), keratoconjunctivitis sicca or dysfunctional tear syndrome, is the most prevalent ophthalmic disease which affects a substantial segment of people worldwide with increasing frequency. It is considered a multifactorial disease of the ocular surface and tear film, characterized by a variation of signs and symptoms. The symptoms range from mild to severe itching, burning, irritation, eye fatigue, and ocular inflammation that may lead to potential damage to the cornea, conjunctiva and even vision loss. Correspondingly, depending on the different manifestations and pathophysiology, the treatment must be tailored specifically to each patient by targeting the specific mechanisms implicated in their disease. Currently, there are several medical products and techniques available or under investigation for the treatment of DED. The present article focused on the pathophysiology of DED, the new diagnostic approach and the recently developed drug delivery systems or devices reducing the progress of the disease and treating the causes.
Questionnaire Design and Use to Assess Dry Eye Disease
2022, Dry Eye Disease
Symptomology is critical to the diagnosis of dry eye disease and is what separates it from general ocular surface disease. As the screening element of the diagnosis of dry eye, standardization is essential and the two TFOS DEWS II accepted questionnaires are the Ocular Surface Disease Index (cut-off ≥13 out of 100) or the DEQ-5 (cut-off ≥6 out of 22). This chapter identified that none of the existing questionnaires meet current best practice for patient reported outcome design and none stand out for their sensitivity. Hence, the choice of questionnaire for monitoring treatment should be based on the respondent burden (related to the number of questions) and recall frequency (to fit with the follow-up schedule).
Treatment of Dry Eye Disease in the United States
2022, Dry Eye Disease
The treatment of patients with dry eye disease is based upon the severity of the patient's disease and symptoms. In addition, since there are several factors that can contribute to dry eye symptoms, it is critical to address the underlying cause including evaporative dry eye, aqueous deficiency, and inflammation. The treatment of dry eye should follow a stepwise approach based upon the patient's symptoms and the underlying physiology of their condition. The goals of treating dry eye disease are to improve patients' symptoms and quality of life, decrease inflammation, and prevent ocular surface damage. There has been a large expansion in treatment modalities available to treat the different causes of dry eye disease. For patients with symptoms that are refractory to conservative measures and lubricants, there are several prescription medications that can be utilized including antiinflammatory agents and antibiotics. In addition, blood products are increasingly being used that have shown relief in symptoms and signs of dry eye disease. In-office procedures can also play a helpful role in managing evaporative dry eye disease. For patients with advanced disease, contact lenses, amniotic membrane transplant, and neurostimulation can be considered. Furthermore, surgical procedures can help ameliorate symptoms for certain patients. Lastly, there is ongoing research on devices and novel therapeutics that are currently in clinical trials. While dry eye disease affects millions of patients, the advances that have been made in treating dry eye disease help decrease the burden of disease on patients' lives.

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: Sources of Support: This study was supported by Dompé farmaceutici s.p.a., Italy, and Lμbris BioPharma, Boston MA and conducted by the contract research organization CROSS Sa - Switzerland. The sponsors had no role in the data collection or statistical analysis, but designed the study and prepared the manuscript. The final decision on content was retained by the authors.

: The authors wish to acknowledge the following financial interests: Dompé: Employee (FM). Lμbris BioPharma: Equity (ERT, GDJ, TAS, BDS, DAS), Patents (ERT, GDJ, TAS, BDS, DAS), Consultant (TAS), Director (ERT, BDS). TearLab Corporation: Equity (BDS), Patents (BDS), Employee (BDS).

: Single-copy reprint requests to Flavio Mantelli, MD, PhD or Benjamin D. Sullivan, PhD (addresses below).

^∗: These authors equally contributed to the work and appear in alphabetical order.

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Original ResearchA Two-Week, Randomized, Double-masked Study to Evaluate Safety and Efficacy of Lubricin (150 μg/mL) Eye Drops Versus Sodium Hyaluronate (HA) 0.18% Eye Drops (Vismed®) in Patients with Moderate Dry Eye Disease

Abstract

Purpose

Methods

Results

Conclusions

Introduction

Section snippets

Methods: Study Design

Results

Discussion

Conclusions

Tribol Int

Osteoarthritis Cartilage

Biochem Biophys Res Commun

Ophthalmology

Ophthalmology

Ophthalmology

Adv Colloid Interface Sci

Osteoarthritis Cartilage

Transcription, translation, and function of lubricin, a boundary lubricant, at the ocular surface

JAMA Ophthalmol

Characterization of a bovine synovial fluid lubricating factor. II. Comparison with purified ocular and salivary mucin

Connect Tissue Res

Dose-dependent and synergistic effects of proteoglycan 4 on boundary lubrication at a human cornea-polydimethylsiloxane biointerface

Eye Contact Lens

Bioregulation of lubricin expression by growth factors and cytokines

Eur Cell Mater

Tear proteomic analysis of patients with type 2 diabetes and dry eye syndrome by two-dimensional nano-liquid chromatography coupled with tandem mass spectrometry

Invest Ophthalmol Vis Sci

Blueberry component pterostilbene protects corneal epithelial cells from inflammation via anti-oxidative pathway

Sci Rep

Upregulation of NLRP3 inflammasome in the tears and ocular surface of dry eye patients

PLoS One

Decreased lubricin concentrations and markers of joint inflammation in the synovial fluid of patients with anterior cruciate ligament injury

Arthritis Rheum

Original Research
A Two-Week, Randomized, Double-masked Study to Evaluate Safety and Efficacy of Lubricin (150 μg/mL) Eye Drops Versus Sodium Hyaluronate (HA) 0.18% Eye Drops (Vismed®) in Patients with Moderate Dry Eye Disease