Compositions comprising PEDF-derived oligopeptides for treatment of dry eye

Abstract

A pharmaceutical composition for the treatment of dry eye comprises a peptide having an amino acid sequence selected from SEQ ID NO: 1-7. The xerophthalmia is accompanied by cataract. A subject suffers from cataract and has accepted surgical treatment.

Description

Background Art Technical Field

[0001] The present invention relates to PEDF-derived short peptide (PDSP) and its use in treating and / or improving dry eye. Background Art

[0003] Dry eye (also called keratoconjunctivitis sicca) is a complex disease that causes symptoms such as discomfort, visual disturbances, and tear film instability, which can damage the ocular surface. Dry eye occurs when the eye does not produce enough tears or when tears evaporate too quickly. It is accompanied by increased tear film osmolarity and inflammation of the ocular surface. The severity of dry eye signs / symptoms varies widely between patients. While some patients experience only mild irritation, others develop severe complications that lead to significant corneal damage and impaired vision.

[0004] Dry eye disease (DED) may be caused by a variety of causes that affect the production of any of the tear components (lipid, aqueous, and mucin) or the stability of the tear film (e.g., rapid evaporation of tears), resulting in tear hyperosmolarity, tear film instability, and insufficient support for the integrity of the ocular surface epithelium. Tear hyperosmolarity conditions may potentially damage the ocular epithelium and stimulate an inflammatory cascade in the ocular epithelium, leading to the loss of surface epithelial cells (including conjunctival goblet cells). The loss of goblet cells reduces mucin secretion, leading to the loss of surface epithelial protection and tear film instability, as well as the development of dry eye and damage to the corneal epithelium. Tear film instability often causes a chronic cycle of ocular surface inflammation and ocular surface damage, leading to DED.

[0005] Currently, patients with DED have few treatment options, including artificial tears, anti-inflammatory drugs, and analgesics. Although these treatments can relieve some symptoms for some patients, there is still a need for better treatment and prevention methods for DED. Summary of the invention

[0006] One aspect of the present invention relates to a pharmaceutical composition for treating dry eye disease (DED). According to one embodiment of the present invention, the pharmaceutical composition for treating dry eye disease (DED) comprises a peptide having an amino acid sequence selected from SEQ ID NO: 1-7. According to an embodiment of the present invention, the subject suffers from DED and cataracts. According to some embodiments of the present invention, the subject suffers from surgically treated cataracts.

[0007] One aspect of the invention relates to a method of treating dry eye disease (DED) in a subject. According to one embodiment of the invention, the method of treating dry eye disease (DED) comprises administering to a subject in need thereof a composition comprising a peptide having an amino acid sequence selected from SEQ ID NO: 1-7. According to some embodiments of the invention, the subject suffers from DED and cataracts. According to some embodiments of the invention, the subject suffers from surgically treated cataracts.

[0008] Other aspects of the invention will be explained using the following description and accompanying drawings. BRIEF DESCRIPTION OF THE DRAWINGS

[0009] Figure 1 A schematic diagram of a treatment plan according to an embodiment of the present invention is shown.

[0010] Figure 2A The therapeutic effects of BRM421 were shown on visual analogue scale (VAS) dryness, VAS burning / stinging, and VAS photophobia. Figure 2B Shows the Qianhe Post-assessment analysis of the therapeutic effect of BRM421 on VAS dryness and VAS burning / stinging.

[0011] Figure 3A The therapeutic effect of BRM421 on diary dryness and diary burn was shown. Figure 3B Shows the Qianhe Post-evaluation analysis of the therapeutic effect of BRM421 on diary (ODS) dryness and ODS burn and ODS stinging.

[0012] Figure 4A The therapeutic effect of BRM421 on VAS burning / stinging in subjects without cataract was shown. Figure 4B The therapeutic effect of BRM421 on VAS burning / stinging in subjects with cataracts was shown. Figure 4C The therapeutic effect of BRM421 on VAS burning / stinging in subjects with cataract who did not undergo surgery was shown. Figure 4D The therapeutic effect of BRM421 on VAS burning / stinging in subjects with cataracts who underwent surgery was shown. Figure 4E The therapeutic effect of BRM421 on VAS dryness in subjects without cataract was shown. Figure 4F The therapeutic effect of BRM421 on VAS dryness in subjects with cataracts is shown. Figure 4G The therapeutic effect of BRM421 on VAS dryness in subjects with cataract who did not undergo surgery was shown. Figure 4HThe therapeutic effect of BRM421 on VAS dryness in subjects with cataracts who underwent surgery was shown.

[0013] Figure 5A Corneal damage repair in subjects without cataracts is shown. Figure 5B It showed that corneal damage repair was significantly improved in the BRM421 group compared with the placebo group. Figure 5C The BRM421 group showed significant improvement in corneal damage repair in patients with cataracts who did not undergo surgery compared to the placebo group. Figure 5D The BRM421 group showed a slight improvement in corneal damage repair compared to the placebo group in patients with cataracts who underwent surgery. DETAILED DESCRIPTION

[0014] Human pigment epithelium derived factor (PEDF) is a secreted protein containing 418 amino acids with a molecular weight of about 50 kDa. PEDF is a multifunctional protein with many biological functions (see U.S. Patent Application Publication No. 2010 / 0047212). It was found that different peptide regions of PEDF are responsible for different functions. For example, a 34-mer fragment (residues 44 to 77 of PEDF) has been identified to have anti-angiogenic activity, while a 44-mer fragment (residues 78 to 121 of PEDF) has been identified to have neurotrophic properties.

[0015] U.S. Patent Application No. 2010 / 0047212 discloses that PEDF can promote the self-renewal of stem cells. U.S. Patent No. 9051547 and U.S. Patent No. 9617311 disclose that PEDF fragments (residues 93-121 of PEDF) with a length of 20-39 amino acids can promote stem cell proliferation and wound healing. These PEDF-derived short peptides are referred to as PDSP in this specification. The PDSP used in the present invention is listed in Table 1 below:

[0016] Table 1

[0017]

[0018] Embodiments of the present invention relate to PDSP and its use in preventing and / or treating dry eye disease (DED). In preclinical studies, all PDSPs listed in Table 1 are effective in preventing and / or treating DED. The following specific examples will use the clinical trial results of 29-mer (SEQ ID NO: 3, hereinafter referred to as "BRM421") to illustrate the embodiments of the present invention, and other PDSPs listed in Table 1 also have similar effects. It will be understood by those skilled in the art that the results of BRM421 are for illustration only and are not intended to limit the scope of the present invention.

[0019] Use a controlled hostile environment A multicenter, randomized, double-blind, placebo-controlled clinical study was conducted by Ora, Inc. (Ora, Inc., Andover, MA, USA) to evaluate the safety and efficacy of BRM421 eye drops (OS) in subjects with DED. Use controlled stress on the eye surface to exacerbate the signs and symptoms of DED in a safe and controlled manner.

[0020] Figure 1 The study schedule consisting of 4 visits per week is shown. During the first visit (day -7 ± 1), subjects were screened and Before evaluation, exposure to exist After randomization, the subjects were evaluated and a placebo run-in period (7 ± 1 day) was started. During the 7-day study run-in period before randomization (for subject selection purposes), all subjects received bilateral placebo OS three times a day (TID). Before being evaluated, exposed to and in These assessments formed the baseline measurements. Subjects were then randomized to receive either BRM421 eye drops (OS) or placebo OS (vehicle) three times a day (TID) from Visit 2 to Visit 4 for 14 days.

[0021] During these follow-up visits, the subjects were assessed for symptomatic efficacy. Specifically, the visual analogue scale (VAS) was measured by asking the subjects to rate each ocular symptom caused by ocular dryness. The symptoms assessed included burning / stinging, itching, foreign body sensation, blurred vision, dry eyes, photophobia, and pain.

[0022] Figure 2A Shows the second visit relative to the baseline Results of the VAS dryness, VAS burning / stinging, and VAS photophobia scales at the pre-assessment, third, and fourth visits. Figure 2A As shown, both the BRM421-OS and placebo groups showed improvements from baseline. The BRM421-OS group showed significant differences in mean changes from baseline in improvements in burning / stinging, dry eyes, and photophobia in the intent-to-treat (ITT) population at Visit 3 compared to the placebo group, but not at Visit 4. The lack of significant differences between the treatment and placebo groups at Visit 4 is because the vehicle also has some soothing effects that can relieve / reduce symptoms over time. The fact that a significant difference was observed between the treatment and placebo groups at Visit 3 suggests that BRM421 has a relatively rapid onset of action.

[0023] Figure 2BThe second visit as baseline is shown Pre-assessment or The results of VAS dryness and VAS burning / stinging scores at the third visit were compared after the follow-up assessment. The BRM421 group showed significant improvements in both VAS dryness and VAS burning / stinging compared with the placebo group. At baseline, the BRM421 group showed less significant improvement in VAS dryness relative to the placebo group, whereas the BRM422 group showed significant improvement in VAS burning / stinging relative to the placebo group.

[0024] Table 2 summarizes the results of the VAS dryness, burning / stinging, and photophobia assessments.

[0025] Table 2. Visual Analogue Scale (VAS) Data

[0026]

[0027]

[0028] Subjects were also asked to rate the severity of dry eye symptoms in a diary in the morning and evening before instillation of study medication. The Ora Ocular Discomfort and 4 Symptoms Questionnaire (ODS Questionnaire) was used, which included scoring the severity of 5 symptoms: ocular discomfort, burning, dryness, grittiness, and stinging. Each symptom was rated between 0 and 5, where 0 = none and 5 = worst.

[0029] Figure 3A Daily diary results of dryness and burning are shown. Compared with the placebo group, the BRM421 OS group had significantly lower nighttime dryness from day 1 to day 7 (visit 2 to visit 3) than the baseline ( The improvement was significant in the morning (before day), but no significant improvement was observed in the dryness in the morning, and from day 8 to day 15 (visit 3 to visit 4). The improvement was not significant in the morning, which may be because the dryness is not severe in the morning after a long night's sleep (closed eyes). The fact that no better improvement was observed in the BRM421 OS group compared with the placebo group from day 8 to day 15 (visit 3 to visit 4) suggests that the onset of action of BRM421 is relatively fast, and the slow soothing effect of the vehicle eventually catches up with BRM421.

[0030] In terms of ocular discomfort and burning, BRM421 OS group had significantly higher ocular discomfort and burning during the morning examination ( baseline ) from Day 1 to Day 7 ( Visit 2 to Visit 3 ) compared with the placebo group. The fact that no better improvement was observed in the BRM421 OS group compared with the placebo group from day 8 to day 15 (visit 3 to visit 4) suggests that the onset of action of BRM421 is relatively fast and the slow soothing effect of the vehicle eventually catches up with BRM421.

[0031] Figure 3B The second visit as baseline is shown Pre-assessment or The results of ODS dryness, ODS burning, and ODS stinging at the third visit were compared with those at the last visit. Qianhe There were no significant differences in the post-ODS evaluation. The post-assessment showed a significant effect compared with the placebo group, but Not in the previous assessment.

[0032] Table 3 summarizes the results of ocular discomfort and 4-symptom questionnaire (ODS) diary data.

[0033] Table 3. Ocular Discomfort and Four Symptoms Questionnaire (Diary)—ITT Population with Observational Data Only

[0034]

[0035]

[0036]

[0037] A cataract is a cloudy area in the lens of the eye. The prevalence of dry eye and cataracts increases with age. Therefore, patients often have both DED and cataracts. The above BRM421 and placebo groups were further analyzed based on whether they had cataracts. This analysis unexpectedly showed that based on Before or BRM421 treatment did not show significant improvement in VAS burning / stinging in patients with DED alone after evaluation (see Figure 4A ). However, based on Qianhe After evaluation, BRM421 treatment showed highly significant improvements in VAS burning / stinging in patients with DED and cataracts (see Figure 4B ).

[0038] Cataracts are usually treated surgically. DED may complicate cataract surgery or postoperative effects. In addition, cataract surgery may exacerbate pre-existing dry eye or induce dry eye in patients with healthy corneas. Postoperative dry eye may affect visual outcomes and time to visual recovery. Therefore, subjects with DED and cataracts were further analyzed according to whether they had undergone cataract surgery. Figure 4C and Figure 4D As shown, BRM421 treatment demonstrated significant improvements in VAS burning / stinging compared to placebo in subjects with or without cataract surgery. However, compared to subjects who did not undergo cataract surgery (see Figure 4C ), BRM421 treatment showed greater improvement in VAS burning / stinging in subjects undergoing cataract surgery (see Figure 4D ). These results suggest that BRM421 treatment is particularly effective in the treatment of DED in patients undergoing cataract surgery.

[0039] The same results were found when the VAS was analyzed for dryness. Figure 4E As shown, BRM421 treatment did not show significant improvement compared with placebo in subjects without cataracts (based on Qianhe On the other hand, BRM421 treatment showed significant improvement in subjects with cataracts compared with the placebo group (based on Qianhe Post-evaluation) (see Figure 4F In addition, BRM421 treatment showed significant improvement in subjects with cataracts regardless of surgical status (based on Qianhe Post-evaluation) (see Figure 4G and Figure 4H ).

[0040] Severe dry eye can lead to corneal damage, which can be assessed by fluorescein staining. The PDSPs of the present invention can treat DED. In addition, these PDSPs can also repair corneal damage. Figure 5A As shown, in subjects without cataracts, BRM421 treatment did not show significant improvement in corneal damage repair. Figure 5B BRM421 treatment showed significant improvement in corneal damage repair in subjects with cataracts compared to subjects who had cataract surgery ( Figure 5D ) compared with those who underwent surgery for cataract ( Figure 5C The selective efficacy of BRM421 in patients with cataracts was unexpected.

[0041] The above results clearly demonstrate the efficacy of the PDSP of the present invention in treating DED. In particular, these PDSPs were unexpectedly found to be very effective in treating or preventing DED in cataract patients before and after surgery. Embodiments of the present invention relate to pharmaceutical compositions and methods for preventing and / or treating dry eyes in subjects. The subjects of the embodiments of the present invention may be humans or animals. The method of one embodiment of the present invention may include administering a pharmaceutical composition to a subject in need of preventing or treating dry eyes, the pharmaceutical composition comprising a peptide selected from any PDSP listed in Table 1. According to an embodiment of the present invention, the pharmaceutical composition may comprise a peptide of the present invention or a salt of the peptide, and a pharmaceutically acceptable carrier or excipient, such as distilled water, saline, oil or gel.

[0042] The pharmaceutical composition of the present invention can be prepared in any suitable dosage form, such as solution, ointment, suspension, gel or emulsion, which can be prepared in any suitable concentration, such as 10-200 μ M. Those skilled in the art will be able to prepare these drugs in appropriate concentrations to provide effective doses without creative efforts. These dosage forms can be formulated for topical application to the eye or other suitable routes of administration (e.g., oral or injection).

[0043] A limited number of embodiments have been used to illustrate the implementation of the present invention. Those skilled in the art will appreciate that other modifications and variations are possible without departing from the scope of the present invention. Therefore, the scope of protection should be limited by the appended claims.

Claims

1. A pharmaceutical composition for treating dry eye, comprising: a peptide having an amino acid sequence selected from SEQ ID NO: 1-7, wherein the dry eye is accompanied by cataract.

2. The pharmaceutical composition according to claim 1, wherein the peptide has the amino acid sequence shown in SEQ ID NO:

3.

3. The pharmaceutical composition according to claim 1 or 2, wherein the cataract has been treated surgically.

4. A method for treating dry eye, comprising: A composition comprising a peptide having an amino acid sequence selected from SEQ ID NOs: 1-7 is administered to a subject in need thereof. 5 . The pharmaceutical composition according to claim 4 , wherein the peptide has the amino acid sequence shown in SEQ ID NO:

3.

6. The method of claim 4 or 5, wherein the subject suffers from cataracts.

7. The method of claim 4 or 5, wherein the subject has cataracts that have been surgically treated.

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