Methods to alleviate concerns about the appearance of the eye associated with pterygium

Abstract

This provides a method to reduce anxiety, such as worry or distress, about the eye disease and / or the appearance of the eye in patients with pterygium. [Solution] A method for reducing worry or anxiety about an eye disease and / or the appearance of an affected eye in a subject having an eye disease, comprising the steps of: identifying a subject having an eye disease and / or the appearance of an affected eye; and administering a therapeutically effective amount of a multikinase inhibitor to the subject's affected eye for a period of time, wherein the affected eye is suffering from an eye disease selected from the group consisting of pterygium, conjunctival hyperemia, conjunctivitis, pinguecula, pseudopterygium, and combinations thereof.

Description

Technical Field

[0001] Cross - reference to Related Applications This application claims priority based on U.S. Provisional Application No. 62 / 898,401, filed on September 10, 2019, which is hereby incorporated by reference in its entirety.

[0002] Technical Field Materials and methods for reducing concerns about eye diseases and / or the appearance of the eye, such as concerns about eye diseases and / or changes in the appearance of the eye associated with eye diseases such as pterygium, are provided herein.

Background Art

[0003] Background A pterygium is a non - malignant vascular connective tissue growth that originates from the nasal or temporal conjunctiva and then progresses onto the corneal surface. Pterygia often cause eye symptoms and psychological symptoms that significantly affect the quality of life of patients. Currently, there are no approved therapeutic drug products for treating pterygia. Surgical excision is used to remove pterygial lesions due to visual impairment and / or an unsightly eye appearance. [[ID=2,4]]

Summary of the Invention

[0004] Summary Materials and methods for reducing concerns about the appearance of the eye, such as concerns about the appearance of the eye due to eye diseases such as pterygium, are provided herein.

[0005] In one aspect, a method of reducing concern or anxiety about the appearance of an affected eye in a subject, the method comprising identifying a subject having concern or anxiety about the appearance of the eye and administering a therapeutically effective amount of a multi - kinase inhibitor to the affected eye of the subject for a period of time, wherein the affected eye is affected by pterygium, pterygial injection, injection, pinguecula, or pseudopterygium, is provided herein.

[0006] The implementation may include one or more of the following features: The score for concern or anxiety about the appearance of the eyes, as determined by a patient questionnaire depending on the subject, may decrease between (a) before the administration of a therapeutically effective dose of a multikinase inhibitor to the subject's affected eye for a period of time and (b) after the administration of a therapeutically effective dose of a multikinase inhibitor to the subject's affected eye for a period of time. The score may be on a numerical scale. The score may decrease by at least approximately 25%. The score may decrease by at least approximately 30%. The score may decrease by at least approximately 35%. The score may decrease by at least approximately 40%. The score may decrease by at least approximately 45%. The score may decrease by at least approximately 50%. The score may decrease by at least approximately 55%. The score may decrease by at least approximately 60%. The score may decrease by at least approximately 65%. The score may decrease by at least approximately 70%. The score may decrease by at least approximately 75%. The numerical scale may be a 5-point scale. The score may decrease by at least approximately 0.5. The score may decrease by at least approximately 0.7. The score may decrease by at least approximately 0.9. The score may decrease by at least approximately 1.0. The score may decrease by at least approximately 1.1. The score may decrease by at least approximately 1.3. The score of worry or anxiety about the appearance of the eyes, as determined by the patient questionnaire, may be based on a question about whether worry about the appearance of the affected eye has affected the subject's quality of life in the past week. The score of worry or anxiety about the appearance of the eyes, as determined by the patient questionnaire, may be based solely on a question about whether worry about the appearance of the affected eye has affected the subject's quality of life in the past week. The score of worry or anxiety about the appearance of the eyes, as determined by the patient questionnaire, may include the category "Has the appearance of the affected eye affected your quality of life in the past week?" and the question "Are you worried about the appearance of your eyes?". The patient questionnaire's assessment of concern or anxiety about the appearance of the eyes can only be based on the category "Has the appearance of your affected eye affected your quality of life in the past week?" and the question "Are you concerned about the appearance of your eyes?".The questionnaire may be derived at least in part from the Visual Functioning Questionnaire-25 (VFQ-25) questionnaire. The questionnaire may be derived at least in part from the Ocular Surface Disease Index (OSDI) questionnaire. Multikinase inhibitors include afatinib, amvatinib, axitinib, cabozantinib, canertinib, cejilanib, ceritinib, clenolanib, crizotinib, dabrafenib, dacomitinib, dasatinib, erlotinib, foretinib, gefitinib, golbatinib, ibrutinib, icotinib, idelalisib, imatinib, and lapatinib. The following may be selected: lenvatinib, neratinib, nilotinib, nintedanib, palbociclib, pazopanib, ponatinib, quizartinib, regorafenib, ruxolitinib, sorafenib, sunitinib, tanzutinib, tivantinib, tivozanib, trametinib, vandetanib, batalanib, vemurafenib, or combinations thereof. The multikinase inhibitor may be selected from axitinib, nintedanib, regorafenib, and pazopanib. The multikinase inhibitor may be axitinib. The multikinase inhibitor may be nintedanib. The multikinase inhibitor may be pazopanib. The multikinase inhibitor may be a free base. The multikinase inhibitor may be a pharmaceutically acceptable salt.

[0007] In another aspect, the Specified Method provides for reducing one or more patient-reported signs or symptoms in a patient having an eye affected by pterygium, pterygium conjunctivitis, hyperemia, pinguecula, or pseudopterygium, comprising the step of administering a therapeutically effective amount of a multikinase inhibitor to the affected eye of the patient.

[0008] The implementation may include one or more of the following features: The patient-reported sign or symptom may be concern or anxiety about the appearance of the eye in the patient. A reduction in one or more patient-reported signs or symptoms may include a measured reduction of at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, or at least about 70% of one or more patient-reported signs or symptoms compared to baseline in a control, an untreated patient, or a patient before administration of the multikinase inhibitor. A therapeutically effective dose of the multikinase inhibitor may be administered to the affected eye of the subject for a period of time. A reduction in one or more patient-reported signs or symptoms may include a measured reduction in one or more patient-reported signs or symptoms compared to a control. A reduction in one or more patient-reported signs or symptoms may include a measured reduction in one or more patient-reported signs or symptoms compared to an untreated patient. A reduction in one or more patient-reported signs or symptoms may include a measured reduction in one or more patient-reported signs or symptoms compared to baseline in patients before administration of the multikinase inhibitor. A reduction in one or more patient-reported signs or symptoms may include a measured reduction of at least about 25% of one or more patient-reported signs or symptoms. A reduction in one or more patient-reported signs or symptoms may include a measured reduction of at least about 30% of one or more patient-reported signs or symptoms. A reduction in one or more patient-reported signs or symptoms may include a measured reduction of at least about 35% of one or more patient-reported signs or symptoms. A reduction in one or more patient-reported signs or symptoms may include a measured reduction of at least about 40% of one or more patient-reported signs or symptoms. A reduction in one or more patient-reported signs or symptoms may include a measured reduction of at least about 45% of one or more patient-reported signs or symptoms. A reduction in one or more patient-reported signs or symptoms may include a measured reduction of at least about 50% of one or more patient-reported signs or symptoms.A reduction in one or more patient-reported signs or symptoms may include a measured reduction of at least approximately 55% of one or more patient-reported signs or symptoms. A reduction in one or more patient-reported signs or symptoms may include a measured reduction of at least approximately 60% of one or more patient-reported signs or symptoms. A reduction in one or more patient-reported signs or symptoms may include a measured reduction of at least approximately 65% ​​of one or more patient-reported signs or symptoms. A reduction in one or more patient-reported signs or symptoms may include a measured reduction of at least approximately 70% of one or more patient-reported signs or symptoms. A reduction in one or more patient-reported signs or symptoms may include a measured reduction of at least approximately 75% of one or more patient-reported signs or symptoms. A reduction in one or more patient-reported signs or symptoms may include a measured reduction of one or more patient-reported signs or symptoms on a 5-point numerical scale. A reduction in one or more patient-reported signs or symptoms may include a measured reduction of at least 0.5 of one or more patient-reported signs or symptoms on a numerical scale. A reduction in one or more patient-reported signs or symptoms may include a measured reduction of at least 0.7 in one or more patient-reported signs or symptoms on a numerical scale. A reduction in one or more patient-reported signs or symptoms may include a measured reduction of at least 0.9 in one or more patient-reported signs or symptoms on a numerical scale. A reduction in one or more patient-reported signs or symptoms may include a measured reduction of at least 1.0 in one or more patient-reported signs or symptoms on a numerical scale. A reduction in one or more patient-reported signs or symptoms may include a measured reduction of at least 1.3 in one or more patient-reported signs or symptoms on a numerical scale. Patient-reported signs or symptoms may be determined by a patient questionnaire that includes questions about whether concern about the appearance of the affected eye has affected the subject's quality of life in the past week.Patient-reported signs or symptoms may be based solely on questions regarding whether concern about the appearance of an affected eye has affected the subject's quality of life in the past week. Patient-reported signs or symptoms may be determined by a patient questionnaire that includes the category "Has the appearance of an affected eye affected your quality of life in the past week?" and the question "Are you concerned about the appearance of your eye?" Patient-reported signs or symptoms may be determined by a patient questionnaire, based solely on the category "Has the appearance of an affected eye affected your quality of life in the past week?" and the question "Are you concerned about the appearance of your eye?" Patient-reported signs or symptoms may be determined by a patient questionnaire that is at least partially derived from the Visual Functional Questionnaire-25 (VFQ-25) questionnaire. Patient-reported signs or symptoms may be determined by a patient questionnaire that is at least partially derived from the Ocular Surface Disease Index (OSDI) questionnaire. Multikinase inhibitors include afatinib, amvatinib, axitinib, cabozantinib, canertinib, cejilanib, ceritinib, clenolanib, crizotinib, dabrafenib, dacomitinib, dasatinib, erlotinib, foretinib, gefitinib, golbatinib, ibrutinib, icotinib, idelalisib, imatinib, and lapatinib. The following may be selected: lenvatinib, neratinib, nilotinib, nintedanib, palbociclib, pazopanib, ponatinib, quizartinib, regorafenib, ruxolitinib, sorafenib, sunitinib, tanzutinib, tivantinib, tivozanib, trametinib, vandetanib, batalanib, vemurafenib, or combinations thereof. The multikinase inhibitor may be selected from axitinib, nintedanib, regorafenib, and pazopanib. The multikinase inhibitor may be axitinib. The multikinase inhibitor may be nintedanib. The multikinase inhibitor may be pazopanib. The multikinase inhibitor may be a free base. The multikinase inhibitor may be a pharmaceutically acceptable salt.

[0009] Details of one or more embodiments of the present invention are shown in the accompanying drawings and the following description. Other features, purposes, and advantages of the present invention will become apparent from the description and drawings and the claims. [Brief explanation of the drawing]

[0010] [Figure 1] Figure 1 is a plot comparing the change in the subject's score on the Concern about the Appearance of the Eye Questionnaire between nintedanib and placebo via topical intraocular administration, as part of a Phase 2 clinical trial. [Modes for carrying out the invention]

[0011] Detailed explanation The descriptions herein are provided to illustrate details to provide an understanding of various aspects of the invention, and are made with the understanding that the disclosures provided are illustrative of the subject matter described in the claims and not intended to limit the claims to specific aspects. Accordingly, the specific aspects disclosed herein may be combined with other specific aspects disclosed herein, for example, specific aspects under various headings provided for convenience and order and which should not be construed as limiting the claims.

[0012] All published documents cited herein are incorporated herein in their entirety by reference.

[0013] As used herein, unless the context makes otherwise clear, the singular forms "(a)", "(an)", and "(the)" shall also include the plural forms.

[0014] As used herein, unless otherwise specified, the term “about” is provided to indicate that, when used with a number or range of values, that value or range of values ​​may deviate to an extent that would be considered reasonable to a person skilled in the art (e.g., a specific temperature or temperature range). For example, when used in this respect, the term “about” can, in some embodiments, indicate that a number or range of values ​​may vary by 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% from the specified value or range of values. In some embodiments, the number or range of values ​​may vary by 5%.

[0015] Pterygium is an ocular surface disease characterized by vascular connective tissue proliferation that spreads from the nasal or temporal conjunctiva across the corneal margin into the cornea. Current understanding of pterygium pathogenicity suggests that multiple processes are involved, including genetic factors, environmental triggers (UV light, viral infection), and factors that perpetuate its proliferation (cytokines, growth factors, and matrix metalloproteinases). Of these, chronic UV exposure is typically understood to be one of the most important factors in pterygium pathogenicity. Approximately 10 million people in the United States suffer from pterygium. Later stages of the disease impair vision, while early to mid-stage disease causes concern and anxiety in patients about the disease (e.g., pterygium, pterygium-related conjunctivitis, hyperemia, pinguecula, and / or pseudopterygium) and / or the appearance of the eye (e.g., altered appearance of the eye as a result of the disease). The current standard treatment is surgical removal of the lesional tissue. However, in about 10% of patients, the rapidly growing lesion may recur postoperatively.

[0016] Patients with pterygium often experience symptoms and suffer from psychological stress and anxiety due to the disease and / or altered appearance of the eye. Currently, there are no approved pharmacological treatments for pterygium. Pterygium excision with conjunctival autograft is often the procedure of choice for the curative treatment of both primary and recurrent pterygium. Many of these lesions can be easily removed, and both the surgeon and the patient are initially satisfied, but pterygium recurrence can occur. Apart from visual impairment, one of the main reasons patients choose surgical treatment is the sense of unsightly appearance caused by the disease. In a recent study of 40 pterygium patients, Pandey analyzed the most common pterygium risk factors that lead patients to decide on surgical removal of pterygium (Pandey, 2017, semanticscholar.org / 60f4 / a88614fb8b12f2dd9a0b50dde324ae50adf3.pdf). One conclusion from the study was that, for younger patients, the primary reason for choosing surgical removal was dissatisfaction with the external appearance caused by pterygium. In a review article (Kaufman et al. 2013, sciencedirect.com / science / article / pii / S0039625702004630), the authors state that "the presence of pterygium is a concern for both patients due to its unsightly appearance and surgeons due to its tendency to recur." Therefore, the distress or anxiety induced by the unsightly appearance is a significant factor in pterygium patients seeking surgery.

[0017] Pterygium is a multifactorial disease in which several growth factors, such as vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF), are possible pathological factors. However, drugs targeting these growth factors are not approved to treat this disease. Recently, the inventors of this disclosure tested nintedanib, a small molecule multikinase inhibitor, anti-angiogenic, and anti-fibrotic agent, in a phase 2 clinical trial in patients with pterygium. Nintedanib represents a class of multikinase inhibitors that confer anti-angiogenic properties primarily by targeting VEGFR1, VEGFR2, VEGFR3, PDGFR alpha (PDGFRα) and PDGFR beta (PDGFRβ), as well as / or FGFR1, FGFR2, FGFR3, and / or FGFR4.

[0018] One possible benefit of the materials and methods disclosed herein may be the cessation of pterygium progression. Another possible benefit of the materials and methods disclosed herein may be the reduction of the need for excision and the reduction of the risk of disease recurrence after surgery. Yet another possible benefit of the materials and methods disclosed herein is the reduction of symptoms and / or signs of pterygium, pterygium hyperemia, conjunctivitis, pinguecula, and / or pseudopterygium. An example of symptoms and / or signs is the patient's worry or anxiety about the disease and / or the appearance of the eye (e.g., the altered appearance of the eye as a result of the disease). Another possible benefit of the materials and methods disclosed herein is the improvement of the patient's quality of life.

[0019] In some embodiments, methods are provided herein for reducing worry or anxiety about an eye disease and / or the appearance of the affected eye (e.g., altered appearance of the eye as a result of the disease), wherein the affected eye is suffering from an eye disease such as pterygium, conjunctival hyperemia, conjunctival hyperemia, pinguecula, and / or pseudopterygium. The methods may include the steps of identifying a subject who has worry or anxiety about a disease (e.g., an eye disease such as pterygium, conjunctival hyperemia, conjunctival hyperemia, pinguecula, and / or pseudopterygium) and / or the appearance of the eye (e.g., altered appearance of the eye as a result of the disease), and administering a therapeutically effective amount of a multikinase inhibitor to the affected eye of the subject. In some embodiments, methods are provided herein for reducing worry or anxiety about an eye disease and / or the appearance of the affected eye in a subject having an eye disease. The method may include the steps of identifying subjects who have concern or anxiety about an eye disease and / or the appearance of the affected eye, and administering a therapeutically effective amount of a multikinase inhibitor to the subject's affected eye for a period of time. In some embodiments, the eye disease is selected from the group consisting of pterygium, conjunctival hyperemia, conjunctival hyperemia, pinguecula, pseudopterygium, and combinations thereof. In some embodiments, the score for concern or anxiety about the disease (e.g., an eye disease such as pterygium, conjunctival hyperemia, conjunctival hyperemia, pinguecula, and / or pseudopterygium) and / or the appearance of the eye (e.g., the appearance of the eye as a result of the disease), as determined by a patient questionnaire, may decrease between two assessment time points. In some embodiments, the score for concern or anxiety about the disease (e.g., an eye disease such as pterygium, conjunctival hyperemia, conjunctival hyperemia, pinguecula, and / or pseudopterygium) and / or the appearance of the eye (e.g., the appearance of the eye as a result of the disease), as determined by a patient questionnaire, may decrease compared to a control. In some embodiments, scores of concern or anxiety about the disease (e.g., eye diseases such as pterygium, conjunctival hyperemia, conjunctivitis, pinguecula, and / or pseudopterygium), as determined by the patient questionnaire for each subject, may be reduced compared to untreated subjects.In some embodiments, scores of concern or anxiety about disease (e.g., ocular diseases such as pterygium, conjunctival hyperemia, conjunctivitis, pinguecula, and / or pseudopterygium) and / or the appearance of the eye (e.g., altered appearance of the eye as a result of the disease), as determined by a patient questionnaire for each subject, may decrease compared to the subject's baseline before administration of the multi-kinase inhibitor.

[0020] Methods for reducing one or more patient-reported signs or symptoms in patients having an eye affected by pterygium, pterygium conjunctivitis, conjunctivitis, pinguecula, and / or pseudopterygium are also provided herein. The methods may include the step of administering a therapeutically effective amount of a multikinase inhibitor to the affected eye of the patient. Methods for reducing one or more patient-reported signs or symptoms in patients having an eye affected by an eye disease are also provided herein, including the step of administering a therapeutically effective amount of a multikinase inhibitor to the affected eye of the patient. In some embodiments, the eye disease is selected from the group consisting of pterygium, pterygium conjunctivitis, conjunctivitis, pinguecula, pseudopterygium, or a combination thereof. In some embodiments, the patient-reported signs or symptoms are worry or anxiety in the patient about the disease (e.g., an eye disease such as pterygium, pterygium conjunctivitis, conjunctivitis, pinguecula, and / or pseudopterygium) and / or the appearance of the eye (e.g., the appearance of the eye as a result of the disease). In some embodiments, one or more patient-reported signs or symptoms may decrease between two evaluation time points. In some embodiments, one or more patient-reported signs or symptoms may decrease compared to a control. In some embodiments, one or more patient-reported signs or symptoms may decrease compared to an untreated subject. In some embodiments, one or more patient-reported signs or symptoms may decrease compared to a subject's baseline before administration of a multi-kinase inhibitor.

[0021] Any assessment of signs or symptoms (e.g., ocular diseases such as pterygium, conjunctival hyperemia, conjunctivitis, pinguecula, and / or pseudopterygium) and / or the appearance of the eye (e.g., altered appearance of the eye as a result of the disease)) may be reported as a score on a numerical scale. In some cases, the reduction in signs or symptoms may be at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, or at least about 70% (e.g., compared to baseline at different assessment times, controls, untreated patients, or patients before administration of multikinase inhibitors). In some cases, the reduction in signs or symptoms may be at least approximately 25%, at least approximately 30%, at least approximately 35%, at least approximately 40%, at least approximately 45%, at least approximately 50%, at least approximately 55%, at least approximately 60%, at least approximately 65%, at least approximately 70%, or at least approximately 75% (compared to baseline at different evaluation time points, controls, untreated patients, or patients before administration of multikinase inhibitors). The numerical scale may be any appropriate numerical scale. In some embodiments, the numerical scale may be a 5-point scale (e.g., 0–4 or 1–5). In some embodiments, the numerical scale may be a 10-point scale (e.g., 0–9 or 1–10). In some embodiments, the numerical scale may be normalized to a 5-point scale for comparison with evaluations using a 5-point numerical scale, for example. In some cases, a reduction in signs or symptoms may be at least 0.3, 0.5, 0.7, 0.9, 1.0, 1.1, 1.3, or 1.5 on a numerical scale (e.g., a 5-point numerical scale, or one normalized to a 5-point numerical scale) compared to baseline (e.g., at different evaluation time points, controls, untreated patients, or patients before administration of multi-kinase inhibitors).

[0022] In some cases, any two suitable evaluation time points can be used. For example, (a) before the step of administering a therapeutically effective amount of a multi-kinase inhibitor to the affected eye of a subject for a period of time, and (b) after the step of administering a therapeutically effective amount of a multi-kinase inhibitor to the affected eye of a subject for a period of time, such evaluation time points can be used. As another example, (a) before the step of administering a multi-kinase inhibitor to the affected eye of a subject one or more times over a period of time, and (b) after the step of administering a multi-kinase inhibitor to the affected eye of a subject one or more times over a period of time, such evaluation time points can be used. As yet another example, (a) before the step of administering a multi-kinase inhibitor to the affected eye of a subject one or more times, and (b) after the step of administering a multi-kinase inhibitor to the affected eye of a subject one or more times, such evaluation time points can be used.

[0023] In some cases, the evaluation of signs or symptoms (e.g., diseases (e.g., eye diseases such as pterygium, pterygium congestion, congestion, pinguecula, and / or pseudopterygium) and / or concerns or anxieties about the appearance of the eye (e.g., the appearance of the eye changed as a result of the disease)) can be performed after one or more administrations of the multi-kinase inhibitor. One or more administrations of the multi-kinase inhibitor can include any suitable number of administrations or dosing periods (also referred to as the "period" of administration). In some cases, the period can be about 1 week, about 2 weeks, about 3 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months (about 1 year), or more. In some cases, the period can be about 3 months. In some cases, the period can be about 12 months.

[0024] The administration can be performed at any suitable frequency. For example, the administration can be performed once a day, twice a day, three times a day, four times a day, five times a day, or six times a day. In some embodiments, the multi-kinase inhibitor can be administered twice a day. In some embodiments, the multi-kinase inhibitor can be administered three times a day.

[0025] Any assessment of signs or symptoms (e.g., eye diseases such as pterygium, conjunctival hyperemia, conjunctival hyperemia, pinguecula, and / or pseudopterygium) and / or the appearance of the eye (e.g., altered appearance of the eye as a result of the disease) may be based on a questionnaire (e.g., a patient questionnaire). The questionnaire may be any appropriate questionnaire. In some cases, the questionnaire may include questions about whether concern about the disease (e.g., eye diseases such as pterygium, conjunctival hyperemia, conjunctival hyperemia, pinguecula, and / or pseudopterygium) and / or the appearance of the affected eye (e.g., altered appearance of the eye as a result of the disease) has affected the subject's quality of life in the past week. In some cases, the assessment of signs or symptoms may be based solely on questions about whether the condition (e.g., eye conditions such as pterygium, conjunctival hyperemia, conjunctivitis, pinguecula, and / or pseudopterygium) and / or concerns about the appearance of the affected eye have affected the subject's quality of life in the past week. In some cases, the questionnaire may include the category, “Has the appearance of the affected eye affected your quality of life in the past week?” and the question, “Are you concerned about the appearance of your eye?” For example, the question, “Are you concerned about the appearance of your eye?” may relate to whether the appearance of the subject's eye has affected their quality of life in the past week. Options may include: always worried (e.g., associated with a score of 5 on a 5-point scale), almost always worried (e.g., associated with a score of 4 on a 5-point scale), half the time worried (e.g., associated with a score of 3 on a 5-point scale), sometimes worried (e.g., associated with a score of 2 on a 5-point scale), never worried (e.g., associated with a score of 1 on a 5-point scale), or not applicable (e.g., "NA"). In some cases, the questionnaire may include the category, "Has the appearance of your affected eye affected your quality of life in the past week?" and the question, "Are you worried about the appearance of your eye?", and the assessment of signs or symptoms (e.g., worry or anxiety about the appearance of your eye) may be based solely on this question.In some embodiments, the questionnaire may be derived at least in part from the Visual Functional Questionnaire-25 (VFQ-25) questionnaire (National Eye Institute, 2000). In some embodiments, the questionnaire may be derived at least in part from the Ocular Surface Disease Index (OSDI) questionnaire (Schiffman RM, Christianson MD, Jacobsen G, Hirsch JD, Reis BL. Reliability and validity of Ocular Surface Disease Index. Arch Ophthalmol. 2000; 118(5): 615-621.doi:10.1001 / archopht. 118.5.615).

[0026] Any suitable multi-kinase inhibitor can be used. In some cases, the multi-kinase inhibitor is selected from afatinib, amuvatinib, axitinib, cabozantinib, canertinib, cediranib, ceritinib, clenolanib, crizotinib, dabrafenib, dacomitinib, dasatinib, erlotinib, foretinib, gefitinib, golvatinib, ibrutinib, icotinib, idelalisib, imatinib, lapatinib, lenvatinib, neratinib, nilotinib, nintedanib, palbociclib, pazopanib, ponatinib, quizartinib, regorafenib, luxitinib, sorafenib, sunitinib, tandutinib, tibantineb, tiboxanib, trametinib, vandetanib, batatinib, bemrafenib, or combinations thereof. In some cases, the multi-kinase inhibitor is selected from axitinib, nintedanib, regorafenib, and pazopanib. In some cases, the multi-kinase inhibitor is axitinib. In some cases, the multi-kinase inhibitor is nintedanib. In some cases, the multi-kinase inhibitor is regorafenib. In some cases, the multi-kinase inhibitor is pazopanib. In some cases, the multi-kinase inhibitor is the free base. In some cases, the multi-kinase inhibitor is a pharmaceutically acceptable salt.

[0027] Multikinase inhibitors (e.g., nintedanib, axitinib, or pazopanib) can be administered at any appropriate concentration. In some cases, multikinase inhibitors can be administered in amounts of approximately 0.001% to approximately 10.0% (w / w). In some cases, multikinase inhibitors can be administered in amounts of approximately 0.005% to approximately 2% (w / w), approximately 0.001% to approximately 1% (w / w), approximately 0.001% to approximately 0.005% (w / w), approximately 0.005% to approximately 0.01% (w / w), approximately 0.01% to approximately 0.05% (w / w), approximately 0.05% to approximately 0.1% (w / w), approximately 0.01% to approximately 1% (w / w), approximately 0.05% to approximately 0.5%, approximately 0.01% to approximately 0.8% (w / w), and approximately 0.3%. It may be administered in amounts of approximately 0.7% (w / w), 0.4% to 0.6% (w / w), 0.1% to 10% (w / w), 0.1% to 0.5% (w / w), 0.2% to 8% (w / w), 0.4% to 5% (w / w), or 0.4% to 2% (w / w).

[0028] This disclosure includes data from a Phase 2 randomized clinical trial.

[0029] Certain aspects of the present invention are described herein. Naturally, variations of these described aspects will be apparent to those skilled in the art upon reading the above description. The inventors anticipate that those skilled in the art will appropriately utilize such variations, and they intend that the present invention may be carried out in ways other than those specifically described herein. Accordingly, the present invention includes all modifications and equivalents of the subject matter described in the claims appended herein, as permitted by applicable law. Furthermore, unless otherwise indicated herein or expressly refuted by context, any combination of the aforementioned elements in all possible variations is encompassed within the present invention.

[0030] The present invention is not limited to those shown and described herein. Specific embodiments disclosed herein may be further limited in the claims using the words “consisting of” or “essentially consisting of.” When used in the claims, whether filed or added by amendment, the transitional phrase “consisting of” excludes elements, processes, or components not specified in the claims. The transitional phrase “essentially consisting of” limits the scope of the claims to the specified materials or processes and those that do not substantially affect the fundamental novel features. Embodiments of the present invention as described herein are essentially or expressly described and enabled herein.

[0031] It should be understood that the embodiments of the present invention disclosed herein are illustrative of the principles of the present invention. Other modifications that may be used are within the scope of the invention. Accordingly, alternative configurations of the present invention may be used, in accordance with the teachings herein, as examples rather than limitations.

[0032] References TIFF2026090631000002.tif49149 [Examples]

[0033] Example 1. Phase 2a multicenter randomized solvent-controlled dose-escalation study to evaluate the safety, efficacy, and pharmacokinetics of nintedanib ophthalmic solution in patients with primary or recurrent pterygium. The objective of this study was to evaluate the ocular and systemic safety of nintedanib and its efficacy in reducing pterygium angiogenesis in patients with primary or recurrent pterygium. Several other secondary endpoints, such as symptomatic and lifestyle impacts, were also assessed using a questionnaire based on a numerical scale of 1–5. A double-blind, solvent-controlled, parallel study was conducted using solvent and 0.2% nintedanib with repeated 28-day TID intraocular infusions.

[0034] result This disclosure focuses on relevant questionnaire endpoints, including 15 questions regarding ocular symptoms, vision-related function, and their impact on quality of life in patients. The questionnaires were derived from the validated Visual Functional Questionnaire-25 (VFQ-25) (National Eye Institute, 2000) and the validated Ocular Surface Disease Index (OSDI) questionnaire (Schiffman RM, Christianson MD, Jacobsen G, Hirsch JD, Reis BL. Reliability and validity of Ocular Surface Disease Index. Arch Ophthalmol. 2000;118(5):615-621). Patients were asked to rate their severity using a 5-point scale, with 5 being the most severe.

[0035] Analysis of questionnaire data revealed surprising results. Regarding the question "Are you concerned about the appearance of your eye?" in the category "Has the appearance of your affected eye affected your quality of life in the past week?", the drug group showed significantly better improvement than the solvent group in terms of the frequency of concern about the appearance of the eye, as shown in Figure 1. Questionnaire surveys regarding symptoms and psychological assessments are often variable. It is surprising that a single question or set of questions was able to identify a difference between the drug and solvent groups in concern or anxiety about appearance. The fact that only one of the 15 questions showed a significant difference is also consistent with this unexpected result. As previously described, concern about the appearance of the eye plays a major role in the decision to undergo surgery in pterygium patients. Improving this concern with multi-kinase inhibitors such as nintedanib would address a clear unmet medical need in pterygium treatment.

Claims

1. The process of identifying individuals who have concerns or anxieties about eye diseases and / or the appearance of affected eyes; and The process of administering a therapeutically effective dose of a multi-kinase inhibitor to the affected eye for a certain period of time. A method for reducing worry or anxiety about the appearance of an eye disease and / or affected eye in a subject having an eye disease, including, A method wherein the affected eye suffers from an eye disease selected from the group consisting of pterygium, conjunctival hyperemia, conjunctival hyperemia, pinguecula, pseudopterygium, and combinations thereof.

2. The method according to claim 1, wherein, between (a) before administering a therapeutically effective amount of a multikinase inhibitor to the affected eye of a subject for a period of time, and (b) after administering a therapeutically effective amount of a multikinase inhibitor to the affected eye of a subject for a period of time, the subject's score for worry or anxiety about the appearance of the eye disease and / or the affected eye, as determined by a patient questionnaire, is reduced.

3. The method according to claim 2, wherein the score is based on a numerical scale.

4. The method according to claim 3, wherein the score is reduced by at least about 25%.

5. The method according to claim 3, wherein the score is reduced by at least about 30%.

6. The method according to claim 3, wherein the score is reduced by at least about 35%.

7. The method according to claim 3, wherein the score is reduced by at least about 40%.

8. The method according to claim 3, wherein the score is reduced by at least about 45%.

9. The method according to claim 3, wherein the score is reduced by at least about 50%.

10. The method according to claim 3, wherein the score is reduced by at least about 55%.

11. The method according to claim 3, wherein the score is reduced by at least about 60%.

12. The method according to claim 3, wherein the score is reduced by at least about 65%.

13. The method according to claim 3, wherein the score is reduced by at least about 70%.

14. The method according to claim 3, wherein the score is reduced by at least about 75%.

15. The method according to any one of claims 3 to 14, wherein the numerical scale is a 5-point scale.

16. The method according to any one of claims 3 to 15, wherein the score is reduced by at least about 0.

5.

17. The method according to any one of claims 3 to 15, wherein the score is reduced by at least about 0.

7.

18. The method according to any one of claims 3 to 15, wherein the score is reduced by at least about 0.

9.

19. The method according to any one of claims 3 to 15, wherein the score is reduced by at least about 1.

0.

20. The method according to any one of claims 3 to 15, wherein the score is reduced by at least about 1.

1.

21. The method according to any one of claims 3 to 15, wherein the score is reduced by at least about 1.

3.

22. The method according to any one of claims 2 to 21, wherein the score for concern or anxiety about the appearance of an eye disease and / or affected eye, determined by a patient questionnaire, is based on a question regarding whether concern about the appearance of an eye disease and / or affected eye has affected the subject's quality of life in the past week.

23. The method according to any one of claims 2 to 21, wherein the score for worry or anxiety about eye disease and / or the appearance of the affected eye, determined by a patient questionnaire, is based solely on questions regarding whether worry about eye disease and / or the appearance of the affected eye has affected the subject's quality of life in the past week.

24. Multikinase inhibitors include afatinib, amvatinib, axitinib, cabozantinib, canertinib, cejiranib, ceritinib, clenolanib, crizotinib, dabrafenib, dacomitinib, dasatinib, erlotinib, foretinib, gefitinib, golbatinib, ibrutinib, icotinib, idelalisib, imatinib, lapatinib, lenvatinib, and nerachi. The method according to any one of claims 1 to 23, selected from the group consisting of nib, nilotinib, nintedanib, palbociclib, pazopanib, ponatinib, quizartinib, regorafenib, ruxolitinib, sorafenib, sunitinib, tanzutinib, tivantinib, tivozanib, trametinib, vandetanib, batalanib, vemurafenib, and combinations thereof.

25. The method according to any one of claims 1 to 24, wherein the multikinase inhibitor is selected from the group consisting of axitinib, nintedanib, regorafenib, pazopanib, and combinations thereof.

26. The method according to any one of claims 1 to 24, wherein the multikinase inhibitor is axitinib.

27. The method according to any one of claims 1 to 24, wherein the multikinase inhibitor is nintedanib.

28. The method according to any one of claims 1 to 24, wherein the multikinase inhibitor is regorafenib.

29. The method according to any one of claims 1 to 24, wherein the multikinase inhibitor is pazopanib.

30. The method according to any one of claims 1 to 29, wherein the multi-kinase inhibitor is a free base.

31. The method according to any one of claims 1 to 29, wherein the multikinase inhibitor is a pharmaceutically acceptable salt.

32. A method for reducing one or more patient-reported signs or symptoms in a patient having an eye affected by an eye disease, comprising the step of administering a therapeutically effective amount of a multikinase inhibitor to the affected eye of the patient, wherein the eye disease is selected from the group consisting of pterygium, conjunctival hyperemia, conjunctivitis, pinguecula, pseudopterygium, and combinations thereof.

33. The method according to claim 32, wherein the patient-reported sign or symptom is concern or anxiety about the appearance of an eye disease and / or affected eye in the patient.

34. The method according to any one of claims 32 to 33, wherein the reduction in one or more patient-reported signs or symptoms includes a measured reduction of at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, or at least about 70% of one or more patient-reported signs or symptoms compared to baseline in a control, an untreated patient, or a patient before administration of a multikinase inhibitor.

35. The method according to any one of claims 32 to 34, wherein a therapeutically effective amount of a multikinase inhibitor is administered to the affected eye for a period of time.

36. The method according to any one of claims 32 to 35, wherein a reduction in one or more patient-reported signs or symptoms includes a measured reduction in one or more patient-reported signs or symptoms compared to a control.

37. The method according to any one of claims 32 to 35, wherein the reduction of one or more patient-reported signs or symptoms includes a measured reduction of one or more patient-reported signs or symptoms compared to an untreated patient.

38. The method according to any one of claims 32 to 35, wherein the reduction of one or more patient-reported signs or symptoms includes a measured reduction of one or more patient-reported signs or symptoms compared to baseline in the patient before administration of the multikinase inhibitor.

39. The method according to any one of claims 32 to 38, wherein a reduction in one or more patient-reported signs or symptoms comprises a measured reduction of at least about 25% of one or more patient-reported signs or symptoms.

40. The method according to any one of claims 32 to 38, wherein a reduction in one or more patient-reported signs or symptoms comprises a measured reduction of at least about 30% of one or more patient-reported signs or symptoms.

41. The method according to any one of claims 32 to 38, wherein a reduction in one or more patient-reported signs or symptoms comprises a measured reduction of at least about 35% of one or more patient-reported signs or symptoms.

42. The method according to any one of claims 32 to 38, wherein a reduction in one or more patient-reported signs or symptoms comprises a measured reduction of at least about 40% of one or more patient-reported signs or symptoms.

43. The method according to any one of claims 32 to 38, wherein a reduction in one or more patient-reported signs or symptoms comprises a measured reduction of at least about 45% of one or more patient-reported signs or symptoms.

44. The method according to any one of claims 32 to 38, wherein a reduction in one or more patient-reported signs or symptoms comprises a measured reduction of at least about 50% of one or more patient-reported signs or symptoms.

45. The method according to any one of claims 32 to 38, wherein a reduction in one or more patient-reported signs or symptoms comprises a measured reduction of at least about 55% of one or more patient-reported signs or symptoms.

46. The method according to any one of claims 32 to 38, wherein a reduction in one or more patient-reported signs or symptoms comprises a measured reduction of at least about 60% of one or more patient-reported signs or symptoms.

47. The method according to any one of claims 32 to 38, wherein a reduction in one or more patient-reported signs or symptoms comprises a measured reduction of at least about 65% of one or more patient-reported signs or symptoms.

48. The method according to any one of claims 32 to 38, wherein a reduction in one or more patient-reported signs or symptoms comprises a measured reduction of at least about 70% of one or more patient-reported signs or symptoms.

49. The method according to any one of claims 32 to 38, wherein a reduction in one or more patient-reported signs or symptoms comprises a measured reduction of at least about 75% of one or more patient-reported signs or symptoms.

50. The method according to any one of claims 32 to 49, wherein a reduction in one or more patient-reported signs or symptoms includes a measured reduction in one or more patient-reported signs or symptoms on a 5-point numerical scale.

51. The method according to any one of claims 32 to 50, wherein a reduction in one or more patient-reported signs or symptoms includes a measured reduction of at least 0.5 in one or more patient-reported signs or symptoms on a numerical scale.

52. The method according to any one of claims 32 to 50, wherein a reduction in one or more patient-reported signs or symptoms includes a measured reduction of at least 0.7 in one or more patient-reported signs or symptoms on a numerical scale.

53. The method according to any one of claims 32 to 50, wherein a reduction in one or more patient-reported signs or symptoms includes a measured reduction of at least 0.9 of one or more patient-reported signs or symptoms on a numerical scale.

54. The method according to any one of claims 32 to 50, wherein a reduction in one or more patient-reported signs or symptoms includes a measured reduction of at least 1.0 on a numerical scale of one or more patient-reported signs or symptoms.

55. The method according to any one of claims 32 to 50, wherein a reduction in one or more patient-reported signs or symptoms includes a measured reduction of at least 1.1 of one or more patient-reported signs or symptoms on a numerical scale.

56. The method according to any one of claims 32 to 50, wherein a reduction in one or more patient-reported signs or symptoms includes a measured reduction of at least 1.3 of one or more patient-reported signs or symptoms on a numerical scale.

57. The method according to any one of claims 32 to 56, wherein patient-reported signs or symptoms are determined by a patient questionnaire including questions about whether concerns about the appearance of an eye disease and / or affected eye have affected the subject's quality of life in the past week.

58. The method according to any one of claims 32 to 56, wherein the patient-reported signs or symptoms are determined by a patient questionnaire and are based solely on questions regarding whether concern about the appearance of an eye disease and / or affected eye has affected the subject's quality of life in the past week.

59. Multikinase inhibitors include afatinib, amvatinib, axitinib, cabozantinib, canertinib, cejiranib, ceritinib, clenolanib, crizotinib, dabrafenib, dacomitinib, dasatinib, erlotinib, foretinib, gefitinib, golbatinib, ibrutinib, icotinib, idelalisib, imatinib, lapatinib, lenvatinib, and nerachi. The method according to any one of claims 32 to 58, selected from the group consisting of nib, nilotinib, nintedanib, palbociclib, pazopanib, ponatinib, quizartinib, regorafenib, ruxolitinib, sorafenib, sunitinib, tanzutinib, tivantinib, tivozanib, trametinib, vandetanib, batalanib, vemurafenib, and combinations thereof.

60. The method according to any one of claims 32 to 59, wherein the multikinase inhibitor is selected from the group consisting of axitinib, nintedanib, regorafenib, pazopanib, and combinations thereof.

61. The method according to any one of claims 32 to 60, wherein the multikinase inhibitor is axitinib.

62. The method according to any one of claims 32 to 60, wherein the multikinase inhibitor is nintedanib.

63. The method according to any one of claims 32 to 60, wherein the multikinase inhibitor is regorafenib.

64. The method according to any one of claims 32 to 60, wherein the multikinase inhibitor is pazopanib.

65. The method according to any one of claims 32 to 64, wherein the multikinase inhibitor is a free base.

66. The method according to any one of claims 32 to 64, wherein the multikinase inhibitor is a pharmaceutically acceptable salt.

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