Progress in clinical trials of drug treatment for dry eye in the past three years

Recently, Cornea magazine published the positive results of a phase 2b/3 clinical trial of CyclASol 0.
1%, a non-water drop eye solution of CyclASol, which was completed by Novaliq GmbH of Germany, for the treatment of dry eye
.
According to other data, Hengrui Pharmaceuticals obtained the development right of CyclASol 0.
1% in China from Novaliq at the end of 2019, and initiated the clinical application of this product (R&D code: SHR8058) at the end of 2020
.
This article takes this as an opportunity to sort out the clinical trials of the new type of dry eye treatment drugs published in the past three years retrieved in the Pubmed database, and conduct an expanded search and evaluation of key varieties
.
PART 01.
Search and analysis method database: Pubmed Search formula: (("DRY EYES"[Title/Abstract] OR "DRY EYE"[Title/Abstract] OR "EYE DRYNESS"[Title/Abstract]) AND (RANDOMLY[Title /Abstract] OR RANDMISED[Title/Abstract] OR RANDOMIZED[Title/Abstract])) AND (PHASE[Title/Abstract]) Inclusion criteria: clinical trials of drug intervention or secondary analysis (such as pooled analysis, post-hoc analysis) And meta-analysis, etc.
); publication time ≥ 2018
.
PART 02.
Summary of clinical trials and introduction of key varieties 01 Cyclosporine ophthalmic drugs 1.
CyclASol John D Sheppard et al.
[1] a period of 328 dry eye patients The results of a 12-week Phase 2b/3 multicenter, randomized, confirmatory, double-blind, placebo-controlled trial showed that CyclASol 0.
1% outperformed the vehicle in terms of the primary endpoint of total corneal fluorescence staining score at week 4 Control (Δ -0.
8; 95% CI: -1.
3 to -0.
4; P = 0.
0002)
.
This difference reached a statistically significant level after the second week of the trial and remained until the end of the trial
.
The secondary endpoint of the trial (OSDI, Ocular Surface Disease Index) did not reach statistical significance (P = 0.
2634)
.
However, after 4 weeks of treatment, the effect of CyclASol 0.
1% on ocular dryness was statistically significantly better than the vehicle control (Δ -4.
783; 95% CI: -9.
129 to -0.
438; P = 0.
0311)
.
David L Wirta et al[2] conducted a 16-week phase 2 multicenter, randomized placebo-controlled double-blind trial in 207 dry eye patients.
The results showed that during the 16-week treatment, Compared with the vehicle control and Restasis, CyclASo can continuously reduce corneal and conjunctival staining, and it can take effect on the 14th day
.
The mixed effect model analysis results show that the improvement effect of CyclASol on total corneal staining, central corneal staining and conjunctival staining are statistically significantly better than the vehicle control, and the improvement effect on OSDI is also statistically significantly better than that Excipient control
.
There were few ocular adverse reactions in each treatment group
.
According to the announcement issued by Novaliq in mid-August 2021, CyclASol is a non-water drop eye solution developed by the company using its EyeSol patented technology.
In addition to the ESSENCE-1 test whose results have been announced, the other is code-named ESSENCE -2 Phase 3 randomized placebo-controlled double-blind trial also completed the recruitment of 834 subjects in mid-August, and is expected to obtain trial results in the fourth quarter of this year
.
2.
CyclAGel ophthalmic gel (CyclAGel) Wen-Yan Peng et al [3] a 12-week phase 2 exploratory, multi-center, single-blind, randomized trial in 240 dry eye patients The results of the positive control test showed that during the 12-week treatment, CyclAGel can continuously improve ocular dry fraction, corneal fluorescein staining, tear film breakup time and Schirmer test score, but after the baseline is corrected, CyclAGel and Restasis The difference between the groups is not statistically significant, and the results of the full analysis set are consistent with the set of compliance programs
.
In addition, the effect of each CyclAGel treatment group (0.
05%/QD, 0.
05%/BID, and 0.
1%/QD) is better than Restasis.
Among them, the effect of CyclAGel 0.
05%/QD is the most significant
.
There were few ocular adverse reactions during treatment in each group, and no serious drug-related adverse reactions were seen
.
The trial was led by the National Key Ophthalmology Laboratory of Sun Yat-sen University's Sun Yat-Sen Eye Center.
Beijing Hospital, Henan Eye Hospital and other domestic institutions participated, but no corporate researchers participated
.
Nor did we search for other clinical trials or commercialization information related to cyclosporine ophthalmic gel
.
3.
Cyclosporin A/trehalose compound eye drops Jeongah Shin et al.
[4] a 12-week phase 2 multi-center, randomized, double-blind, parallel project in patients with moderate to severe dry eye , The placebo-controlled test results show that HU00701 (0.
01% cyclosporin A + 3% trehalose), HU007 (0.
02% cyclosporin A + 3% trehalose) have good safety, HU007 can effectively reduce the Corneal staining score of patients with to severe dry eye
.
For the full analysis set, HU00701 (0.
01% cyclosporin A + 3% trehalose), HU007 (0.
02% cyclosporin A + 3% trehalose) and the control group had corneal staining scores from baseline to 12 weeks of treatment There was no statistically significant difference between the groups in the change (primary endpoint).
After 12 weeks of treatment, only the corneal rupture time was statistically significant between the placebo control group and HU00701
.
A total of 15 patients reported 20 adverse reactions, but there was no statistically significant difference between the groups in their incidence
.
Laboratory tests, vital signs, and experience results did not change significantly during the entire research process
.
The researchers of this trial are all from research institutions in South Korea, and no information related to the commercialization of the tested drug has been retrieved yet
.
4.
Cyclosporine 0.
05% nanoemulsion (CN) Chang Hyun Park et al.
[5] a 12-week 4 phase multi-center, randomized, single-blind, active drug control parallel in patients with dry eye Group test results showed that the cyclosporin 0.
05% nanoemulsion (CN), cyclosporin 0.
05% emulsion (CE) and diquafosol treatment group after 12 weeks of treatment have statistically significant changes in corneal and conjunctival staining compared to baseline.
The values ​​are -6.
60, -5.
28 and -6.
63 in order, confirming the non-inferiority of CN compared with CE (95% CI: -0.
15 to 2.
80, Δ>-2.
88)
.
The comparison between the groups after 12 weeks of treatment showed that the reduction of conjunctival staining score in the CN group was significantly higher than that in the CE group
.
The comparison between the CN group and the diquafosol group showed that the tear film rupture time of the CN group and the Schirmer test result had a continuous and statistically significant improvement, while the tear film rupture time of the diquafoxol group was in the 12th place.
A statistically significant improvement occurred only in the first week, and the results of the Schirmer test showed a relatively short-term improvement only in the fourth week
.
The cyclosporin 0.
05% nanoemulsion used in this experiment has been marketed in Korea under the trade name Cyporin N (Taejoon, Seoul, Korea)
.
5.
Cyclosporine 0.
09% Nano Eye Drops (OTX-101) Melissa Toyos et al[6] the results of an 84-day phase 2b/3 randomized, double-blind trial in patients with dry eye It was shown that after 84 days of treatment, the number of subjects (proportions) whose results of Schirmer test in the OTX-101 and vehicle control groups changed from baseline by ≥10mm were 30 (22.
6%) and 12 (10.
6%, P =.
0168), the average changes were 5.
5 ± 8.
0 and 3.
6 ± 6.
0 mm (P = .
0405)
.
Most of the adverse reactions observed during the treatment are mild and do not require treatment
.
John Sheppard et al.
[7] conducted a 12-week phase 3 randomized, double-blind, placebo-controlled trial (+ a 1-year open-label extension trial) in 745 patients with keratoconjunctival sicca.
The results showed that treatment After 12 weeks, the number of subjects (proportion) in the Schirmer test score of the OTX-101 treatment group and the vehicle control group from the baseline was 76 (20.
5%) and 42 (11.
3%) respectively (P= 0.
0005)
.
Moreover, the improvement effect of OTX-101 on the conjunctival staining score was significantly better than that of the vehicle control, (the least squares average of the changes from the baseline were -1.
65 [0.
12] and -1.
12 [0.
12], P=0.
0013) And the proportion of subjects with clear central cornea was also statistically significantly higher than the latter (222 [64.
0%] vs.
199 [55.
3%], P=0.
0179)
.
In the subsequent 1-year extended safety trial, most of the adverse reactions were mild.
Among them, the pain in the administration part was the most common adverse reaction (17 [13.
2%] vs.
42 [32.
6%])
.
Visual inspection, intraocular pressure examination, slit lamp examination and fundus examination showed no safety problems
.
Damien F Goldberg et al.
[8] conducted an 84-day phase 3 randomized, multicenter, placebo-controlled, double-blind trial in 744 dry eye patients.
The results showed that after 84 days of treatment, OTX-101 The subjects whose scores in the Schirmer test increased ≥10 mm from baseline in the group were significantly higher than those in the placebo control group (16.
6% vs 9.
2%; P <0.
001)
.
Compared with the placebo control group, corneal staining (days 28, 56 and 84) and conjunctival staining (days 56 and 84) in the OTX-101 group were significantly improved
.
The overall symptom scores of the OTX-101 and placebo control groups were significantly lower than baseline (by about 30%), but there was no significant difference between the groups
.
OTX-101 0.
09% has good safety and tolerability, and the adverse reactions that occurred during the treatment were mild
.
Previously, OTX-101 was approved by the FDA in August 2018 for the trade name, Cequa, and the licensee is Sun Pharmaceuticals
.
6.
Cyclosporine 0.
05% ophthalmic emulsion (CsA OE) Di Chen et al.
[9] carried out a 3-month 3-month multi-center, randomization in 240 moderate to severe Chinese dry eye patients , Double-blind, placebo-controlled results showed that the total effective rate of CsA OE at each follow-up time point was statistically significantly better than that of the vehicle control, and the total effective rate of the two groups after 3 months of treatment was 70.
6% and 27.
8%
.
The dry eye symptoms and OSDI in the CsA OE group were significantly improved from day 28 and day 7, respectively (P< .
05)
.
The OSDI of the CsA OE group on the 56th day and the 84th day was significantly better than the placebo control (P = .
0061, <.
001)
.
The drug-related adverse reactions in the CsA OE group and the placebo control group were 5% and 2.
5%, respectively (P = .
4061).
Among them, eye pain was the most common, and both were mild to severe, while visual acuity, intraocular pressure or No harmful effects were seen in the vital signs
.
Although the test drug used in the trial and Restasis is the same as the cyclosporine 0.
05% ophthalmic emulsion, there is no public data indicating that pharmaceutical companies participated in or funded the trial
.
7.
0.
1% cyclosporine cationic ophthalmic emulsion (CsA CE) Andrea Leonardi et al.
[10] a total of 734 moderate to severe dry eye patients, a 6-month phase 3 clinical trial analysis results It was found that the total population receiving CsA CE treatment, patients with severe dry eye and Sjogren syndrome patients with severe dry eye are significantly more likely to become CFS-OSDI responders than those receiving excipient intervention.
The OR value is OR 1.
66 (95% CI: 1.
11~2.
50; P=0.
015), 1.
80 (95CI: 1.
04~ 3.
19; P=0.
038) and 3.
37 (95CI: 1.
20~11.
19; P=0.
030)
.
But for the total population of Sjogren syndrome, the difference between the groups was not statistically significant (OR 1.
77, 95% CI 0.
89~3.
66; P=0.
109)
.
In addition, compared with excipients, CsA CE can significantly reduce the expression of median human leukocyte antigen-DR at the 6th month of treatment (P=0.
002)
.
The active test substance used in this experiment is Ikervis of Santen Pharmaceutical
.
02 The results of a 15-day phase 1 randomized, open-label, single-center, two-way crossover trial conducted by Jeffrey Nau et al.
[11] in healthy volunteers for varanclin administered through the nasal cavity showed that varanclin was 0.
12 After a single dose of mg nasal spray, the peak systemic exposure level (mean plasma Cmax) was 0.
34 ng/mL, and the median peak time Tmax was 2.
0h
.
In contrast, the values ​​of the above two parameters for a single oral dose of 1 mg of varenicline were 4.
63 ng/mL and 3.
0 h, respectively
.
The exposure level (Cmax) and total exposure level (AUC0-∞) of varanclin 0.
12 mg nasal spray after a single dose are equivalent to 7.
0% and 7.
5% of 1 mg oral administration, respectively
.
In addition, according to the information disclosed by Oyster Point Pharma, Inc.
, the first author of the clinical trial, the varanclin nasal spray developed by the company for the treatment of dry eye has completed phase 3 clinical trials, and its NDA review is in progress , The expected PDUFA is mid-October 2021
.
03 Sodium hyaluronate-related ophthalmic drugs 1.
Preservative-free sodium hyaluronate/thiochondroitin eye drops (SH/CS-PF) Filiberto García-Félix et al.
[12] a project carried out in patients with dry eye The results of a phase 4 multicenter, prospective, double-blind trial showed that after 90 days of treatment, subjects in the SH/CS-PF, Systane® Ultra (PEG/PG) and Systane® Ultra PF (PEG/PG-PF) groups The average density of goblet cells increased by 28.
4%, 21.
4%, and 30.
8% from the baseline, respectively, and there was no statistically significant difference between the groups
.
The proportions of test eyes with grade 0-I squamous metaplasia in the above three intervention groups were 85.
5%, 87.
9% and 93.
2%)
.
Tear film rupture time (increased by 1.
24 ± 2.
3s, 1.
27 ± 2.
4s, and 1.
39 ± 2.
3s from baseline), OSDI score (decreased from baseline by -8.
81 ± 8.
6, -7.
95 ± 9.
2 and -8.
78 ± 9.
8) and Schirmer test The results (increased by 1.
38 ± 4.
9, 1.
50 ± 4.
7, and 2.
63 ± 5.
9 from the baseline) also showed similar improvements, but there was no statistically significant difference between the groups
.
There were no significant safety or tolerability issues in each group
.
The SH/CS-PF used in this experiment is Humylub? Ofteno PF provided by Laboratorios Sophia in Mexico
.
2.
Sodium hyaluronate/trehalose eye drops Serge Doan et al.
[13] carried out an 84-day phase 3 randomization, controlled, single-blind, multicenter in 105 patients with moderate to severe dry eye The test results showed that after 84 days of treatment, the proportion of subjects with OSDI<19 in the sodium hyaluronate/trehalose group was significantly higher than that in the sodium hyaluronate group (78.
8% versus 58.
5%; p = .
025)
.
The experiment was funded by Laboratoires Théa, France, which is developing a series of trehalose products
.
04RASP inhibitor reproxalap David Clark et al.
conducted a 12-week phase 2b randomized, double-blind, placebo-controlled trial in 300 dry eye patients [14].
Among them, reproxalap showed a dose-dependent improvement in the signs and symptoms of dry eye
.
Among them, the most significant symptomatic improvement was seen in dry eyes (0.
25%, P = .
047), and the most significant objective improvement was seen in fluorescein staining of the nasal area (0.
25%, P = .
030)
.
The number of subjects reporting a dryness score of 0 in the 0.
25% reproxalap group was significantly higher than that in the placebo control group (P = .
012)
.
At the first visit in the second week after baseline, the symptoms of comprehensive dry eye improved (0.
25%, P <.
0001)
.
The safety indicators have not been significantly improved
.
According to Aldeyra's announcement, the current highest clinical research phase of Reproxalap for the treatment of dry eye is phase 2b, and the clinical development of the drug for the treatment of allergic conjunctivitis has completed a phase 3 clinical trial
.
The results of a parallel group, double-blind, randomized phase 3 clinical trial involving 318 subjects [15] showed that Reproxalap can effectively relieve ocular itching symptoms in patients with allergic conjunctivitis
.
Aldeyra said that the FDA has not yet approved a drug that can be used to treat allergic conjunctivitis and dry eye at the same time.

.
05 Loteprednol 0.
25% eye drops (KPI-121 0.
25%) Michael Korenfeld et al[16] conducted a pooled analysis of phase 2 and phase 3 clinical trials involving 2868 dry eye patients and found that the administration part Disease is the most common adverse reaction.
The incidence of KPI-121 0.
25% in the treatment group and placebo control group was 5.
2% and 4.
4%, respectively
.
The incidence of other adverse reactions in the KPI-121 0.
25% group were all ≤0.
8%
.
KPI-121 0.
25% of the treatment group and the placebo control group had a lower incidence of adverse reactions related to glucocorticoid-related intraocular pressure increase (0.
6% vs 0.
2%)
.
KPI-121 was developed by Kala Company and was approved by the FDA in October 2020 under the trade name EYSUVIS.
It is the first short-term treatment drug for dry eye approved by the FDA
.
06 Recombinant human nerve growth factor eye drops (rhNGF) Marta Sacchetti et al.
[17] a 28-day phase 2a prospective, open-label, multiple-dose trial in 40 patients with moderate to severe dry eye The results show that both doses of rhNGF have good safety and tolerability
.
A total of 29 subjects had at least one adverse reaction, and 11 subjects had at least one drug-related adverse reaction
.
The frequency and severity of dry eye symptoms and ocular surface damage were significantly improved in the two groups, while tear function was only improved in the high-dose group
.
07 Recombinant Dehydroribonucleic Acid (DNase) Eye Drops Christine Mun et al.
[18] Results of an 8-week Phase 1/2 placebo-controlled randomized trial in patients with lacrimal dry eye It was shown that the tolerability and adverse reaction characteristics of the DNase treatment group and the placebo control group were similar.
Only the corneal staining of the DNase treatment group showed a statistically and clinically significant decrease relative to baseline after 8 weeks of treatment, and OSDI was relative to There was also a significant decrease in baseline (median decrease was 27.
3)
.
The test drug used in this trial is Genentech's Pulmozyme, and Genentech also provided financial support for the trial
.
08 Non-systemic kinase inhibitor TOP1630 eye drops Mike Taylor et al.
[19] carried out a 28-day phase 2 randomized, double-blind, parallel group trial in patients with dry eye.
The results showed that TOP1630 has good results.
It is safe and tolerable, and can effectively treat the signs and symptoms of dry eye
.
During the treatment, no serious adverse reactions were seen, and no subjects were withdrawn due to adverse reactions
.
The eye drop comfort score results show that TOP1630 has good comfort and is comparable to placebo
.
TOP1630 is better than placebo in improving eye discomfort, grit/foreign body sensation, worst dry eye symptoms and eye pain, and it also has better improvement effects on the total ocular surface, total cornea and summary membrane fluorescein staining.
Compared with placebo
.
This product was developed by TopiVert in the UK
.
In addition, the OT202 eye drops jointly submitted by Ou Kang Vision Biomedical (Shanghai) Co.
, Ltd.
and Zhuhai Essex Biopharmaceutical Co.
, Ltd.
on July 27 for a clinical trial application is also a tyrosine kinase inhibitor type of dry eye drug
.
PART 03.
Summary The analysis results in this article found that the new dry eye drugs that have published clinical trial results in the past three years include: Ophthalmic drugs that have been approved for marketing: cyclosporin 0.
05% nanoemulsion, cyclosporin 0.
09% nano eye drops (OTX-101), cyclosporine 0.
05% ophthalmic emulsion, sodium hyaluronate/thiochondroitin eye drops without preservatives (SH/CS-PF), loteprednol 0.
25% eye drops (KPI- 121 0.
25%) Ophthalmic drug under NDA review: varanclin for nasal administration
.
Ophthalmic drugs in phase 3 clinical trials: CyclASol, sodium hyaluronate/trehalose eye drops
.
Ophthalmic drugs in phase 2 or earlier clinical trials: cyclosporine ophthalmic gel (CyclAGel), cyclosporin A/trehalose compound eye drops, reproxalap, recombinant human nerve growth factor eye drops (rhNGF) ), Recombinant Dehydroribonucleic Acid (DNase) Eye Drops, Non-systemic Kinase Inhibitor TOP1630 Eye Drops
.
It should be pointed out that because this article is based on the clinical trials published in PUBMED and has strict restrictions on the types of clinical trials, it is inevitable that there will be omissions in the screening of drugs in the clinical trial stage, and we hope that the majority of readers Don't hesitate to supplement
.
References: 1.
John D Sheppard et al.
A Water-free 0.
1% Cyclosporine A Solution for Treatment of Dry Eye Disease: Results of the Randomized Phase 2B/3 ESSENCE Study.
Cornea.
2021 Oct 1;40(10):1290 -1297.
2.
David L Wirta et al.
A Clinical Phase II Study to Assess Efficacy, Safety, and Tolerability of Waterfree Cyclosporine Formulation for Treatment of Dry Eye Disease.
Clinical Trial Ophthalmology.
2019 Jun;126(6):792-800 .
doi: 10.
1016/j.
ophtha.
2019.
01.
024.
Epub 2019