Studies: Drops, drops, drops and drops. TOP1630, NGF, sulglycotide, and xanthan gum
A quick pass through several studies….
It’s almost 8:30 on a Sunday night and I have been thumbing through and writing about far too many journal articles for far too long. This is where i start skimming very rapidly and summarizing in three words or less.
A phase 2 randomized, double-masked, placebo-controlled study of novel nonsystemic kinase inhibitor TOP1630 for the treatment of dry eye disease.
Taylor et al, Clinical Ophthalmology, Feb 2019
Yippee, I get to move this from Column 1 to Column 2 on the Drug Pipeline page. Progress!
To evaluate the safety and efficacy of topical TOP1630, a novel nonsystemic kinase inhibitor, in dry eye disease (DED).
PATIENTS AND METHODS:
A randomized, double-masked, parallel-group trial of 0.1% TOP1630 ophthalmic solution TID or placebo (vehicle without active drug) was conducted in DED subjects (n=61). Key eligibility criteria consistent with enrolling a moderate to severe DED population included >6 months DED history; OSDI© score ≥18; Schirmer's test score ≤10 and ≥1 mm/5 minutes; tear film break-up time >1 and <7 seconds; and dry eye exacerbation in corneal staining and ocular discomfort in a Controlled Adverse Environment (CAE®). After a 7-day run-in period with placebo TID, eligible subjects were randomized to TOP1630 or placebo for 28 days. No supplemental artificial tears or rescue medication were allowed.
TOP1630 was safe, well-tolerated, and efficacious in treating DED symptoms and signs. No serious adverse events (AEs) or withdrawals due to treatment emergent AEs occurred. Drop comfort scores showed TOP1630 to be comfortable and comparable with placebo. Significant symptom improvements were seen for TOP1630 vs placebo for ocular discomfort (P=0.02 post-CAE), grittiness/foreign body sensation (on four independent assessment scales, each P<0.05), worst DED symptom (diary, P=0.06), and ocular pain (VAS, P=0.03). Sign improvements were seen for total ocular surface (all regions), corneal sum, and conjunctival sum staining with TOP1630 compared with placebo (each P<0.05).
TOP1630 had placebo-like tolerability and produced improvements in multiple symptom and sign endpoints in both environmental and challenge settings. The emergent TOP1630 benefit-risk profile for DED treatment is highly favorable and supports further development.
A New Ophthalmic Pharmaceutical Formulation, Topical Sulglycotide, Enhances the Ocular Mucin Secretion in Desiccation Stress-Mediated Dry Eye Disease.
Lee et al, Investigative Ophthalmology and Visual Science, March 2019
Very early stages, but “markedly increased tear product” and “increase in the numbers of goblet cells” and all the other goodies sound promising.
The aim of this study was the investigation of the effect of sulglycotide (SOS), a polysulfated glycopeptide derived from porcine duodenal mucin, for the treatment of dry eye disease.
NOD.B10.H2b mice were exposed to an air draft for 10 days, and, simultaneously, scopolamine hydrobromide was injected subcutaneously. The mice were randomly divided into nine groups as follows: four kinds of SOS formulations and three kinds of commercial medicine. After 10 days of treatment, we estimated the effect of treatment on tear production, epithelium stabilization, mucin secretion, and inflammation.
The desiccation stress significantly decreased tear production and corneal epithelium stabilization, as well as markedly decreased the numbers of goblet cells and mucin-stained cells in conjunctiva. However, the topical 4% SOS eye drops markedly increased tear production and corneal stabilization, which recovered to baseline levels. In addition, topical 4% SOS significantly induced an increase in the numbers of goblet cells and the expression of membrane-associated mucins including MUC1, MUC4, and MUC16, as well as the gel-forming mucin, MUC5AC. Furthermore, SOS formulations provided anti-inflammatory improvement in a dose-dependent manner.
In summary, we suggest that a new ophthalmic pharmaceutical formulation, topical sulglycotide, enhances the ocular mucin secretion in dry eye disease and can be used as a new ophthalmic pharmaceutical material to treat dry eye disease.
Effect of recombinant human nerve growth factor eye drops in patients with dry eye: a phase IIa, open label, multiple-dose study.
Sacchetti et al, British Journal of Ophthalmology, April 2019
NGF is a concept I remember following as far back as 2001 when I first join the online community of people with dry eye and eye pain.
Dry eye disease (DED) affects more than 14% of the elderly population causing decrease of quality of life, high costs and vision impairment. Current treatments for DED aim at lubricating and controlling inflammation of the ocular surface. Development of novel therapies targeting different pathogenic mechanisms is sought-after. The aim of this study is to evaluate safety and efficacy of recombinant human nerve growth factor (rhNGF) eye drops in patients with DED.
Forty consecutive patients with moderate to severe DED were included in a phase IIa, prospective, open label, multiple-dose, clinical trial to receive rhNGF eye drops at 20 µg/mL (Group 1: G1) or at 4 µg/mL (Group 2: G2) concentrations, two times a day in both eyes for 28 days (NCT02101281). The primary outcomes measures were treatment-emerged adverse events (AE), Symptoms Assessment in Dry Eye (SANDE) scale, ocular surface staining and Schirmer test.
Of 40 included patients, 39 completed the trial. Both tested rhNGF eye drop concentrations were safe and well tolerated. Twenty-nine patients experienced at least one AE (14 in G1 and 15 in G2), of which 11 had at least 1 related AE (8 in G1 and 3 in G2). Both frequency and severity of DED symptoms and ocular surface damage showed significant improvement in both groups, while tear function improved only in G1.
The data of this study indicate that rhNGF eye drops in both doses is safe and effective in improving symptoms and signs of DED. Randomised clinical trials are ongoing to confirm the therapeutic benefit of rhNGF in DED.
And after all those exciting things, the anticlimax:
Changes in conjunctival epithelial cells after treatment with 0.2% xanthan gum eye drops in mild-moderate dry eye.
Postorino et al, European Journal of Ophthalmology, March 2019.
I’m afraid I can’t muster the three words for this one. Some day perhaps I’ll work up some enthusiasm. I mean, when did “It’s better than celluvisc” become the bar? After all, apparently even seawater diluted with spring water gets us that far.
To study the effects of xanthan gum eye drops on the ocular surface and conjunctival cytology of patients with mild-moderate dry eye.
This prospective, double-masked, controlled trial included 30 patients (age > 60 and Ocular Surface Disease Index score >12 and <33), divided into two groups of 15 subjects and treated with 0.2% xanthan gum eye drops (group 1) or 0.5% carboxymethylcellulose (group 2) qid. After a run-in period with saline qid, patients were evaluated by Ocular Surface Disease Index questionnaire, clinical assessment, and impression cytology at baseline (T0) and after 1 month (T1). For impression cytology, cellularity, cell-to-cell contacts, nucleus/cytoplasm ratio, chromatin aspect, goblet cells distribution, keratinization, and the presence of inflammatory cells were considered. Parameters were scored from 0 (no alterations) to 3 (evident alterations). For statistical analysis, Student's t-test, Wilcoxon rank-sum test, and Mann-Whitney U-test were used.
Clinically, after 1 month of treatment, group 1 showed an improvement of corneal stain (T0 = 1.1 ± 1.4; T1 = 0.5 ± 0.7; p = 0.03) and a reduction of Schirmer I test (T0 = 9.8 ± 6.1; T1 = 5.9 ± 4.1; p = 0.001). In group 2, no differences were found between T0 and T1 for all the clinical tests. For impression cytology, in group 1 cellularity (T0 = 0.6 ± 0.5; T1 = 0.3 ± 0.5; p = 0.05), chromatin aspect (T0 = 1.2 ± 0.4; T1 = 0.8 ± 0.5; p = 0.01), keratinization (T0 = 1 ± 0.7; T1 = 0.5 ± 0.5; p = 0.03), and total score (T0 = 5.8 ± 1.3; T1 = 3.6 ± 1.7; p = 0.003) were significantly ameliorated, while in group 2 only total score improved significantly (T0 = 5 ± 1.4; T1 = 4.3 ± 1.5; p = 0.01). The comparison between groups showed significant amelioration for keratinization in group 1 at T1 (p = 0.02).
The treatment with xanthan gum, a molecule with anti-oxidant and mucoadhesive properties, ameliorated conjunctival epithelium of mild-moderate dry eye patients better than carboxymethylcellulose.