Gildeuretinol for use for treating geographic atrophy and neovascular age-related macular degeneration

Abstract

Disclosed is a method of treating a patient with Geographic Atrophy or with wet Age-related Macular Degeneration or Choroidal Neovascularization. Also disclosed is a method of delaying the progression of vision loss in a patient with Geographic Atrophy or with wet Age-related Macular Degeneration or Choroidal Neovascularization. The methods comprise administering an effective amount of gildeuretinol acetate to the patient.

Description

[0001] Attorney Docket No. 57198-0010W01

[0002] DOSAGE REGIMENS FOR TREATING GEOGRAPHIC ATROPHY AND NEOVASCULAR AGE-RELATED MACULAR DEGENERATION

[0003] BACKGROUND OF THE INVENTION

[0004] Geographic Atrophy is a progressive condition that results in blindness and physical, psychological, and social challenges for nearly all those affected. Geographic Atrophy is a major cause of blindness in the elderly. Geographic Atrophy typically presents in the seventh decade of life, even though symptoms can appear during a person’s fifties or sixties. The disease is usually characterized by a progressive loss of central vision causing blurry vision and, occasionally, an increasing difficulty in adapting to the dark. Affected individuals may also have impaired color vision. Symptoms of vision loss due to Geographic Atrophy continue to worsen over time and cannot be corrected by glasses or contact lenses because the light sensitive part of the eye, the retina, is damaged by the disease. Symptoms are caused by patchy areas of dead retina in the eye called atrophic lesions. Because these areas resemble a map, the disease is called Geographic Atrophy.

[0005] Patients with one eye with Geographic Atrophy may have their other eye independently affected with Geographic Atrophy, Choroidal Neovascularization, or unspecified Age-related Macular Degeneration. Geographic Atrophy can be complicated by the development, worsening, or recurring of Choroidal Neovascularization, which involves the growth of abnormal blood vessels under, in or around the retina, which can leak fluid or blood, further exacerbating vision loss, and damaging the retina. Choroidal Neovascularization is the underlying cause of wet Age- related Macular degeneration. “Choroidal Neovascularization” and “wet Age-related Macular Degeneration” are used interchangeably herein, and sometimes by their respective abbreviation “CNV” or “wet AMD”. Choroidal Neovascularization is particularly devastating as it can cause rapid and severe deterioration of central vision. The co-occurrence of Choroidal Neovascularization in patients with Geographic Atrophy can significantly complicate the disease course, leading to more aggressive vision loss and additional treatment challenges.

[0006] Currently, two FDA-approved therapies are available in the United States that involve frequent injections into the eye to manage Geographic Atrophy, and several more injections into the eye to manage wet Age-related Macular Degeneration. These treatments are invasive and burdensome for patients, highlighting the need for a safe and effective oral medication that can Attorney Docket No. 57198-0010W01 slow the progression of Geographic Atrophy, or delay or reduce the likelihood of the onset, worsening or recurrence of wet Age-related Macular Degeneration. “Recurrence, re-occuring, recurring” will be used interchangeably.

[0007] SUMMARY OF THE INVENTION

[0008] It has now been found that gildeuretinol acetate (code name: ALK-001) administered over about 24 months slows the progression of retinal degeneration in patients with Geographic Atrophy (see Example 2 and Fig. 2), slows vision loss, and delays or reduces the likelihood of the onset, worsening, or re-occurrence of wet Age-related Macular Degeneration (see Examples 3 and 4 and Fig. 3). Side effects were comparable overall with placebo. Based on these results, this disclosure provides safe and effective methods for treating and slowing the progression of Geographic Atrophy through the administration of gildeuretinol acetate. This disclosure further provides safe and effective methods for treating and delaying or reducing the likelihood of the onset, worsening, or re-occurrence of wet Age-related Macular Degeneration. This disclosure further provides safe and effective methods for slowing or reducing vision loss, especially visual acuity in patients with dry Age-related Macular Degeneration, Geographic Atrophy, or wet Age- related Macular Degeneration.

[0009] One embodiment of the invention is a method of treating a patient with Geographic Atrophy. The method comprises administering an effective amount of gildeuretinol acetate to the patient.

[0010] Another embodiment of the invention is a method of delaying the progression of vision loss in a patient with Geographic Atrophy. The method comprises administering an effective amount of gildeuretinol acetate to the patient.

[0011] Another embodiment of the invention is gildeuretinol acetate for treating a patient with Geographic Atrophy. Another embodiment of the invention is gildeuretinol acetate for delaying the progression of vision loss in a patient with Geographic Atrophy. In both embodiments, an effective amount of gildeuretinol acetate is administered to the patient.

[0012] Another embodiment of the invention is the use of gildeuretinol acetate for the manufacture of a medicament for treating a patient with Geographic Atrophy. Another embodiment of the invention is the use of gildeuretinol acetate for the manufacture of a Attorney Docket No. 57198-0010W01 medicament for delaying the progression of vision loss in a patient with Geographic Atrophy. Tn both embodiments, an effective amount of gildeuretinol acetate is administered to the patient.

[0013] Another embodiment of the invention is a method of treating a patient with wet Age- related Macular Degeneration. The method comprises administering an effective amount of gildeuretinol acetate to the patient.

[0014] Another embodiment of the invention is a method of delaying the progression of vision loss in a patient with wet Age-related Macular Degeneration. The method comprises administering an effective amount of gildeuretinol acetate to the patient.

[0015] Another embodiment of the invention is a method of delaying the onset or reducing the likelihood of developing wet Age-related Macular Degeneration in a patient at risk of developing wet Age-related Macular Degeneration in one or both eyes. The method comprises administering an effective amount of gildeuretinol acetate to the patient.

[0016] Another embodiment of the invention is a method of treating a patient at risk of developing wet Age-related Macular Degeneration to delay or reduce the likelihood of developing wet Age-related Macular Degeneration; or to treat a patient with wet Age-related Macular Degeneration to reduce worsening or the likelihood of reoccurrence of wet Age-related Macular Degeneration.

[0017] Another embodiment of the invention is gildeuretinol acetate for treating a patient with wet Age-related Macular Degeneration. Another embodiment of the invention is gildeuretinol acetate for delaying the progression of vision loss in a patient with wet Age-related Macular Degeneration. Another embodiment of the invention is gildeuretinol acetate for delaying the onset or reducing the likelihood of developing wet Age-related Macular Degeneration in a patient at risk of developing wet Age-related Macular Degeneration in one or both eyes. In all three embodiments, an effective amount of gildeuretinol acetate is administered to the patient.

[0018] Another embodiment of the invention is the use of gildeuretinol acetate for the manufacture of a medicament for treating a patient with wet Age-related Macular Degeneration. Another embodiment of the invention is the use of gildeuretinol acetate for the manufacture of a medicament for delaying the progression of vision loss in a patient with wet Age-related Macular Degeneration. Another embodiment of the invention is the use of gildeuretinol acetate for the manufacture of a medicament for delaying the onset or reducing the likelihood of developing wet Age-related Macular Degeneration in a patient at risk of developing wet Age-related Macular Attorney Docket No. 57198-0010W01

[0019] Degeneration in one or both eyes. In all three embodiments, an effective amount of gildeuretinol acetate is administered to the patient.

[0020] Another embodiment of the invention is gildeuretinol acetate to delay or reduce the likelihood of developing wet Age-related Macular Degeneration in a patient at risk of developing wet Age-related Macular Degeneration; or to reduce worsening or the likelihood of reoccurrence of wet Age-related Macular Degeneration in a patient with wet Age-related Macular Degeneration. Another embodiment of the invention is the use of gildeuretinol acetate for the manufacture of a medicament to delay or reduce the likelihood of developing wet Age-related Macular Degeneration in a patient at risk of developing wet Age-related Macular Degeneration; or to reduce worsening or the likelihood of reoccurrence of wet Age-related Macular Degeneration in a patient with wet Age- related Macular Degeneration. In both embodiments, an effective amount of gildeuretinol acetate is administered to the patient.

[0021] BRIEF DESCRIPTION OF THE FIGURES

[0022] Fig- 1 is a graph showing the percent gildeuretinol (deuterated vitamin A) versus total plasma vitamin A (as gildeuretinol + retinol) over time in months in patients administered 14 mg / day gildeuretinol acetate for 24 month; in patients administered 24 mg / day gildeuretinol acetate for 12 months followed by 14 mg / day gildeuretinol acetate for 12 months; in patients administered placebo for 12 months followed by 14 mg / day gildeuretinol acetate for 12 months; and in patients administered placebo for 24 months.

[0023] Fig- 2 is a graph showing the change in size of total Geographic Atrophy lesion areas over time in patients treated with gildeuretinol acetate compared with placebo. Gray line corresponds to placebo and black line corresponds to gildeuretinol acetate arm. The observed growth rate of Geographic Atrophy area was 1.62 sqmm / year in the gildeuretinol arm (N=135 randomized patients) compared to 1.87 (N=63 randomized patients). Error bars are Standard Errors of the mean.

[0024] Fig. 3 is a graph showing the change in low luminance visual acuity over time in patients diagnosed with Age-related Macular Degeneration (including patients with Geographic Atrophy and patients with wet Age-related Macular Degeneration) treated with 14 mg / day of gildeuretinol acetate for up to 24 months. Low luminance visual acuity is measured by loss of letters on the ETDRS eyechart measured using a low luminance setting. Attorney Docket No. 57198-0010W01

[0025] DETAILED DESCRIPTION OF THE INVENTION

[0026] When gildeuretinol acetate was administered to individuals clinically diagnosed with Geographic Atrophy secondary to age-related macular degeneration, the growth of the atrophic retinal lesions was slowed by about 15% (see Example 2 and Fig. 2). Moreover, in the same trial, 13% patients receiving placebo (8 out of 63) vs 5% of patients receiving gildeuretinol acetate 14 mg (7 out of 135) developed an incidental, worsening or recurring wet Age-related Macular Degeneration (see Example 3). Additionally, in the same trial, out of the 52 patients with Choroidal Neovascularization or wet Age-related Macular Degeneration at baseline in one eye, only 11% of those treated with gildeuretinol acetate experienced worsening or recurring wet AMD compared to 44% of those receiving placebo (see Example 3). Daily doses of gildeuretinol acetate of approximately 14 mg of gildeuretinol acetate for 24 months also slowed vision loss in patients with Age-related Macular Degeneration (including measurements from eyes of patients with Geographic Atrophy and patients with wet Age-related Macular Degeneration) (see Example 4 and Fig. 3).

[0027] Disclosed herein are methods of treating a patient with Geographic Atrophy or delaying the progression of vision loss in a Geographic Atrophy patient by administering an effective amount of gildeuretinol acetate to the patient. Also disclosed are methods of treating a patient with wet Age- related Macular Degeneration, delaying the progression of vision loss in a patient with wet Age- related Macular Degeneration, delaying or reducing the likelihood of developing wet Age-related Macular degeneration in a patient at risk of developing wet Age-related Macular Degeneration, or delaying or reducing the likelihood of worsening, or recurrence of wet Age-related Macular Degeneration in a patient with wet Age-related Macular Degeneration by administering an effective amount of gildeuretinol acetate to the patient. An “effective amount” of gildeuretinol acetate is an amount which results in minimal side effects and which slows or delays the progression of symptoms associated with Geographic Atrophy. Alternatively, in asymptomatic patients, an “effective amount” is an amount which results in minimal side effects and which slows or delays the onset of symptoms associated with Geographic Atrophy. In another alternative, an “effective amount” of gildeuretinol acetate is an amount which results in minimal side effects and which slows or delays the progression of symptoms associated with wet Age-related Macular Degeneration. In another alternative, an “effective amount” of gildeuretinol acetate is an amount Attorney Docket No. 57198-0010W01 which results in minimal side effects and which delays the progression of vision loss in a patient with wet Age-related Macular Degeneration. In another alternative, an “effective amount” of gildeuretinol acetate is an amount which results in minimal side effects and delays or reduces the likelihood of developing wet Age-related Macular degeneration in a patient at risk of developing wet Age-related Macular Degeneration or reduces the likelihood of worsening, or recurrence of wet Age-related Macular Degeneration in a patient with wet Age-related Macular Degeneration. In another alternative, an “effective amount” of gildeuretinol acetate is an amount which results in replacing at least approximately 80% of vitamin A in plasma with gildeuretinol (deuterated retinol). In one embodiment, an “effective amount” is 10 mg to 20 mg per day gildeuretinol acetate. Alternatively, an “effective amount” is 14 mg per day of gildeuretinol acetate.

[0028] In another alternative, an “effective amount” is 10 mg to 20 mg of gildeuretinol acetate administered to the patient once daily. In another alternative, an “effective amount” is 14 mg of gildeuretinol acetate administered to the patient once daily.

[0029] Preferably, the gildeuretinol acetate is administered orally according to one of the dosage regimens recited in the previous two paragraphs.

[0030] Gildeuretinol acetate is a retinol acetate form of vitamin A (retinol), in which the three hydrogen atoms at carbon twenty have been replaced or enriched with deuterium. The structure of gildeuretinol acetate is shown below:

[0031] Gildeuretinol acetate is also referred to as “C2o-Ds-retinol acetate”. Gildeuretinol acetate is administered to a patient to replace vitamin A (retinol) in the body with gildeuretinol. An 80% approximately or greater replacement of retinol with gildeuretinol in plasma is expected to result in the clinical benefit presented in examples herein. The deuterium enrichment in gildeuretinol acetate is at least 90.0%; at least 95.0%; at least 97.0%; or at least 98.0%. For example, the deuterium enrichment is from 90.0% to 99.8%; 95.0% to 99.8%; 97.0% to 99.8%; 98.0% to 99.8%; 90.0% to 99.5%; 94.0% to 96.0%; 94.0% to 96.0%; 95.0% to 99.5%; 97.0% to 99.5%; or 98.0% to 99.5%. The deuterium enrichment in the gildeuretinol acetate used in Example 1 and 2 was from 95.0% to 99.5%. “Deuterium enrichment” is a mole percent and is determined by Attorney Docket No. 57198-0010W01 dividing the number of deuterium atoms D at the C20 position by the total number of hydrogen H (as protium) + deuterium atoms at the C20 position. Deuterium enrichment for gildeuretinol acetate can be determined for example by mass spectrometry from the intensities of the 269.2 molecular ion peak (C20H3 vitamin A corresponding to non-deuterated vitamin A), the 270.2 molecular ion peak (C20H2D vitamin A), the 271.2 molecular ion peak (C2oHD2vitamin A) and the 272.2 (C20D3 vitamin A) molecular ion peak. Alternatively, deuterium enrichment for gildeuretinol acetate can be determined by proton nuclear magnetic resonance from the residual area under the C20 methyl (CH3) group.

[0032] “Treating” a Geographic Atrophy patient or a wet Age-related Macular Degeneration patient according to a disclosed dosing regimen includes slowing or delaying the progression of symptoms associated with Geographic Atrophy or wet Age-related Macular Degeneration. “Treating” also includes delaying the progression of Asymptomatic Geographic Atrophy Patients to Symptomatic Geographic Atrophy Patients. “Treating” also includes slowing the onset of wet Age-related Macular Degeneration in patients who are at risk of developing wet Age-related Macular Degeneration. “Treating” also includes preventing (or reducing the likelihood of) the recurrence or worsening of wet Age-related Macular Degeneration in patients who already have wet Age-related Macular Degeneration in at least one eye.

[0033] Suitable formulations for gildeuretinol acetate are as described in U.S. RE47,045, the entire teachings of which are incorporated herein by reference. Gildeuretinol acetate can be administered by any suitable means, including orally, subcutaneously, parenterally, intravenously or by injection, topically (including for example as an eyedrop, implant, drug-eluting or other device, intravitreal, suprachoroidal or other injections directly into the eye), but is typically administered orally, as a pill, for example a tablet, a capsule or a softgel. In one aspect, the gildeuretinol acetate is administered orally as a pill. In one aspect, the pill is taken daily. In one aspect, the pill comprises gildeuretinol acetate dissolved in soybean oil and stabilized with an antioxidant. In one example, the antioxidant is butylated hydroxytoluene comprising about 0.1% to 0.2% by weight of the oil. In another aspect, about 10 to 20 mg (e.g., 14 mg) of gildeuretinol acetate is dissolved into about 400 mg of the oil.

[0034] Because the acetate (or ester) group of gildeuretinol acetate is cleaved during absorption and gildeuretinol acetate is absorbed as retinol and stored as the palmitate ester of gildeuretinol, gildeuretinol acetate can be replaced by other esters, such as C1-C20 alkyl esters (e.g., formate, Attorney Docket No. 57198-0010W01 propionate, butyrate, pentanoate, hexanoate, heptanoate, octanoate, nonoate, decanoate, dodecanoate, palmitate and the like) and benzoate esters and by other prodrugs of gildeuretinol (including deuterated beta-carotene or other pro-vitamin A carotenoids), or by the active moiety itself gildeuretinol. Because gildeuretinol acetate chain is long and conjugated, a variety of cis / trans stereoisomers of gildeuretinol acetate may form spontaneously in vitro or in the body. Just like vitamin A, these cis / trans stereoisomers have the biological activity of vitamin A and therefore, could be used alone or as a combination with gildeuretinol acetate.

[0035] “Geographic Atrophy” as used herein, refers to the diagnosis made by a physician of a patient. Synonyms of Geographic Atrophy include, without limitation, atrophic macular degeneration, advanced atrophic macular degeneration, atrophic senile macular retinal degeneration, dry macular degeneration atrophic, atrophic Age-related Macular Degeneration, nonexudative age-related macular degeneration advanced atrophic, as can be diagnosed within the 10th revision of the International Statistical Classification of Diseases and Related Health Problems (ICD-10) as H35.3113 Nonexudative age-related macular degeneration, right eye, advanced atrophic without subfoveal involvement, H35.3114 Nonexudative age-related macular degeneration, right eye, advanced atrophic with subfoveal involvement, H35.3123 Nonexudative age-related macular degeneration, left eye, advanced atrophic without subfoveal involvement, H35.3124 Nonexudative age-related macular degeneration, left eye, advanced atrophic with subfoveal involvement, H35.3133 Nonexudative age-related macular degeneration, bilateral, advanced atrophic without subfoveal involvement, H35.3134 Nonexudative age-related macular degeneration, bilateral, advanced atrophic with subfoveal involvement, H35.3193 Nonexudative age-related macular degeneration, unspecified eye, advanced atrophic without subfoveal involvement, H35.3194 Nonexudative age-related macular degeneration, unspecified eye, advanced atrophic with subfoveal involvement. This Geographic Atrophy can be either with or without subfoveal involvement, and can affect one or both eyes.

[0036] The current clinical classification of Age-related Macular Degeneration defines three stages according to the severity of fundus lesions (drusen size and pigmentary abnormalities) assessed within 2 disc diameters of the fovea: Early Age-related Macular Degeneration, Intermediate Age- related Macular Degeneration and Advanced or Late Stage Age-related Macular Degeneration. Early Stage Macular Degeneration is characterized by one or more drusen between 63 and 125 pm and generally little or no vision impairment. Intermediate Stage Age-related Macular Stage Attorney Docket No. 57198-0010W01

[0037] Degeneration is characterized by one or more large drusen (>125 gm in the smallest diameter) crossing the optic disc margin. Intermediate Age-related Macular Degeneration transitions to Late Stage Age-related Macular Degeneration (or Geographic Atrophy) when patients begin to experience definitive central vision loss. In addition to the presence of large drusen that may fuse with other drusen, enough photoreceptors have died to cause vision loss. “Dry” Macular Degeneration is Age-related Macular Degeneration that is not wet Age-related Macular Degeneration and includes Early Age-related Macular Degeneration, Intermediated Age-related Macular Degeneration and Geographic Atrophy.

[0038] A “Geographic Atrophy symptom”, or “symptom” as used herein, refers to a characteristic or feature of Geographic Atrophy that can be perceived or identified by the patient. In one example, a Geographic Atrophy symptom is some measurable degree of vision loss. The vision loss associated with Geographic Atrophy is characterized by loss of central visual acuity, blind spots centrally or on the periphery, flashes of light, halos, hallucinations, involuntary eye movements, loss of color vision, poor night vision and / or night blindness. One patient with no symptoms is referred as “asymptomatic”.

[0039] The term “symptom”, as it is used herein, does not include those characteristics or features of Geographic Atrophy that can be measured or identified by a physician or other medical professional, but cannot be perceived or identified by the patient. Such characteristics and features of Geographic Atrophy that are measurable or identifiable only by a physician or other medical professional but not by the patient are referred to herein as “Diagnostic Indicators” of Geographic Atrophy. Often times, Diagnostic Indicators precede the appearance of symptoms. Therefore, a person who is asymptomatic with respect to Geographic Atrophy can be diagnosed with Geographic Atrophy if one or more of these Diagnostic Indicators are present. The presence of these Diagnostic Indicators is in one aspect identified by visually examining the eye with the aid of a slit lamp or similar imaging device. Imaging devices that image the retina, such as fluorescein angiography (FA), fundus autofluorescence (FAF), color fundus photography (CFP), and optical coherence tomography (OCT) can also identify Diagnostic Indicators of Geographic Atrophy. Examples of Diagnostic Indicators include retinal atrophic lesions, retinal flecks, pigment migration, retinal thinning, ellipsoid zone loss, abnormal or thickened external limiting membrane, retinal atrophy, areas of hypo and hyper-autofluorescence and maculopathy on fundus autofluorescence imaging. Often times, Diagnostic Indicators first appear in the parafoveal region. Attorney Docket No. 57198-0010W01

[0040] Retinal atrophic regions and other Diagnostic Indicators are also present when Geographic Atrophy becomes symptomatic and vision loss occurs. The size and / or growth of retinal atrophic regions and flecks can be used as a measure of disease progression.

[0041] Asymptomatic Geographic Atrophy patients can be identified through routine screening of patients for a Diagnostic Indicator as is commonly done in standard clinical practice in patients over 50 years old. Treatment with gildeuretinol acetate, as described herein, can be initiated once a patient is identified as having one or more Diagnostic Indicators.

[0042] “Wet” Age-related Macular Degeneration is characterized by abnormal blood vessels (known as Choroidal Neovascularization) which grow under the retina in the choroid region, or sometimes inside the retina. These new blood vessels may then bleed and leak fluid, causing the macula to bulge or lift up from its normally flat position, thus distorting or destroying central vision. Under these circumstances, vision loss may be rapid and severe.

[0043] Synonyms of wet Age-related Macular Degeneration include, without limitation, neovascular late-stage age-related macular degeneration, advanced exudative age-related macular degeneration, advanced exudative AMD - [age-related macular degeneration], advanced neovascular age related macular degeneration, neovascular age-related macular degeneration, subretinal neovascularization of macula, exudative macular degeneration, EMD - [exudative macular degeneration], exudative age-related macular degeneration, exudative senile macular retinal degeneration, wet senile macular degeneration, advanced wet AMD - [age-related macular degeneration], choroidal neovascular membrane, Subfoveal - CNV under the foveal centre, Juxtafoveal - CNV between 1 and 199 microns from the foveal centre, Extrafoveal - CNV 200 microns or more from the foveal centre, serous pigment epithelial detachment and Haemorrhagic pigment epithelial detachment. The following ICD codes are used to diagnose wet Age-related Macular Degeneration: ICD10 (current terminology): exudative macular degeneration (wet), with active choroidal neovascularization, H35.3211, H35.3221 and H35.3231; exudative macular degeneration (wet), with inactive choroidal neovascularization, H35.3212, H35.3222 and H35.3232; exudative macular degeneration (wet), inactive scar, H35.3213, H35.3223 and H35.3233; exudative macular degeneration (wet), stage unspecified, H35.3210, H35.3220 and H35.3230. ICD11 (future terminology): 9B75.04 Neovascular late-stage age-related macular degeneration. Terminology may continue to be updated over the years. Attorney Docket No. 57198-0010W01

[0044] Patients who are “at risk” of developing wet Age-related Macular Degeneration are those who: i) have wet macular degeneration in one eye and are therefore at risk of developing wet Age- related Macular Degeneration in the other eye; ii) have dry macular degeneration (e.g., Early and Intermediate Stage Age-related Macular Degeneration); iii) have Geographic Atrophy; iv) or have a history of wet macular degeneration and is therefore at risk of recurring wet macular degeneration. Gildeuretinol acetate can be administered to patients who are “at risk” of developing wet Age-related Macular Degeneration to delay onset of wet Age-Related Macular Degeneration.

[0045] Gildeuretinol acetate can be prepared according to methods described in U.S. RE47,045; in Pardoen et al., Can. J. Chem. 63: 1431 (1985) and Bonrath et al., Org. Process Res. Dev.. 2 A557 (2023; and in Bergen et al., Journal of Labelled Compounds XXV: 11 (1987).

[0046] “Patient” refers to a human patient.

[0047] EXEMPLIFICATION

[0048] The following examples are offered to illustrate exemplary embodiments of the invention and do not define or limit its scope.

[0049] EXAMPLE 1: Administering daily doses ranging from approximately 7 to 14 mg of gildeuretinol acetate resulted in an average replacement percentage of deuterated plasma retinol with gildeuretinol of about 75% and 85%, respectively, after about 4 weeks of treatment.

[0050] METHODS

[0051] Study Design: This was an open-label, non-randomized, multiple dose study in healthy volunteers aged 21 to 70 years of age (inclusion criteria). Subjects who met all entrance criteria at screening were invited to receive the study medication. There were six treatment arms: 2 mg / day, 3.5 mg / day, 5 mg / day, 7 mg / day, 10 mg / day and 14 mg / day gildeuretinol acetate. For the four lower dose groups, the dose regimen was one capsule per day, orally, to be taken at home, preferably in the evening unless a different time was preferred by the subject. For the two highest doses, the dose regimen was two capsules per day, one in the morning and one in the evening, although subjects with a preference to take both capsules at once were offered to do so. After taking the 1stdose at the study site, subjects were invited to return two and four weeks after starting the treatment. Each visit had an authorized window of ± 1 day. Attorney Docket No. 57198-0010W01

[0052] The clinical staff made periodic calls to monitor adverse events and ensure subject compliance. In addition, a text message was sent daily to remind subjects to take their medication. Subjects were instructed to avoid foods that contain large amounts of vitamin A (such as liver-based products), including supplements containing vitamin A, and to report their vitamin A intake by answering a daily text message diary. Fruits and vegetables were permitted without restriction.

[0053] Pharmacokinetic Evaluations:

[0054] Deuterated retinol (gildeuretinol) (“D3”) and non-deuterated retinol (“Do”) and other vitamin A metabolites were measured to calculate the percentage of deuterated vitamin A in plasma. For all treatment groups, plasma samples were collected at baseline, 14 ± 1 days (“2 weeks”) and 28 ± 1 days (“4 weeks”) after initiation of treatment. Blood samples were usually collected following at least 10 hours of fasting (including last gildeuretinol acetate intake), preferably in the morning. For the 7 mg / day and the 14 mg / day groups only, after the first and last dose, blood samples were collected every 4 hours for 24 hours. A liquid chromatography / mass spectrometry assay was used to measure the metabolite levels.

[0055] RESULTS

[0056] Subject Disposition: Forty-five subjects were enrolled. Thirty-seven subjects were assigned to one of the six treatment groups; the remaining eight subjects, enrolled as back-ups, were withdrawn prior to receiving a dose. The 37 treated subjects completed the treatment part of the study. No subject discontinued the treatment. Disposition of the 37 subjects is shown in Table 1.

[0057] Table 1. Subject Disposition

[0058] 2 3.5 5 7 10 14

[0059] Number of subjects Total mg / day mg / day mg / day mg / day mg / day mg / day

[0060] Screened 45

[0061] Withdrawn before treatment 8

[0062] Total assigned to treatment 37

[0063] Assigned to treatment group 37 7 6 6 6 6 6

[0064] Treated 37 7 6 6 6 6 6

[0065] Completed the treatment 37 7 6 6 6 6 6 Attorney Docket No. 57198-0010W01

[0066] Still on treatment 0 0 0 0 0 0 0

[0067] Discontinued during 0 0 0 0 0 0 0 treatment

[0068] Note: All subjects completed the treatment.

[0069] Pharmacokinetic Results:

[0070] Table 2 provides %Ds Retinol (gildeuretinol), i.e. the percentage of deuterated retinol (gildeuretinol) over total retinol (as deuterated + non-deuterated), in plasma measured 12-24 hours following gildeuretinol acetate intake.

[0071] Table 2. Percentage of deuterated retinol over total retinol in plasma of fasting subjects % gildeuretinol over retinol + gildeuretinol

[0072] 3.5 5 7 10 14

[0073] Visit 2 mg / day mg / day mg / day mg / day mg / day mg / day

[0074] Baseline 0% 0% 0% 0% 0% 0%

[0075] 24 hours post 1st dose NM NM NM 27% NM 41%

[0076] After 2 weeks of treatment 27% 39% 53% 55% 66% 64%

[0077] After 4 weeks of treatment 31% 46% 51% 63% 72% 79%

[0078] NM: not measured

[0079] Pharmacokinetic Results (integrated levels over 24 hours post dosing): total vitamin A in plasma, both deuterated (gildeuretinol) and non-deuterated (retinol), was measured every 4 hours following administration of 7 mg or 14 mg at the first dose, and following administration of the 28thdose (4 weeks of daily treatment). The area under the curve (AUC) was calculated and the % deuterated %Ds of total vitamin A (as retinol and gildeuretinol) was computed as an average over 24 hours. Results are presented below in Table 3.

[0080] Table 3. Area under the curve (ng / mL.hr) for vitamin A (primarily retinol) and deuterated vitamin A (primarily gildeuretinol) analytes following initial (day 1) and final (day 28) 7 mg dose of gildeuretinol acetate. Percentages of deuterated vitamin A over a 24-hour period are showed in the last column (%D3 Vitamin A)

[0081] AUC Vitamin A AUC D3 Vitamin A Group Dose (ng / mL.hr) (ng / mL.hr) %D3 Vitamin A

[0082] 7 mg / day 1st dose 9,621 6,022 38% Attorney Docket No. 57198-0010W01

[0083] 28th dose 4,689 13,824 75%

[0084] 14 mg / day 1st dose 8,355 9,407 52%

[0085] 28th dose 2,976 18,093 85%

[0086] AUC: Area under the curve

[0087] EXAMPLE 2; Administering daily doses of gildeuretinol acetate of approximately 14 mg of gildeuretinol acetate for 24 months slows retinal degeneration.

[0088] METHODS

[0089] Study Design

[0090] The Study of gildeuretinol acetate in Geographic Atrophy (known as “SAGA”) was a 24-month, multicenter, double-masked, placebo-controlled trial designed to evaluate the efficacy and safety of daily oral gildeuretinol acetate in slowing the growth of Geographic Atrophy lesions in Geographic Atrophy patients. The trial was conducted at multiple sites in the United States (NCT03845582).

[0091] The study protocol was approved by independent institutional review boards. The trial was conducted in accordance with the principles of the Declaration of Helsinki, International Conference on Harmonization E6 Good Clinical Practice Consolidated Guideline, and other relevant regulations. All participants provided written informed consent prior to screening or initiation of any study-related procedures and received visit-based reimbursement as approved by the independent institutional review boards. No additional stipends or incentives were provided.

[0092] Patients

[0093] Patients were 60 years or older, clinically diagnosed with Geographic Atrophy and with at least one eye presenting with Geographic Atrophy secondary to dry age-related macular degeneration were eligible.

[0094] Randomization, Masking, and Treatments

[0095] Patients were randomized to gildeuretinol acetate 14 mg capsules or placebo capsules, to be taken once daily for one year. Attorney Docket No. 57198-0010W01

[0096] Gildeuretinol acetate and placebo capsules were identical appearing capsules. Patients were advised to avoid vitamin A-containing supplements and liver-based products. Fruits and vegetables contain beta-carotene, not preformed vitamin A, and could be consumed without limitation. Trial visits occurred every 6 months approximately following screening and randomization periods.

[0097] Primary Efficacy Endpoint

[0098] The prespecified primary efficacy endpoint was the growth rate (slope) of areas of geographic atrophic lesions measured by fundus autofluorescence retinal imaging comparing patients treated with gildeuretinol acetate versus placebo. Only eyes without neovascular Age-related Macular Degeneration as confirmed by a reading center were included in the primary analysis. The primary efficacy endpoint is the mean rate of growth (slope) in the Geographic Atrophy area as measured by FAF from baseline to Month 24. Sensitivity analysis includes the mean rate of growth in the Geographic Atrophy area as measured by FAF from Month 6 to Month 24.

[0099] Statistical Analysis

[0100] The mean rates of change (slope) in the Geographic Atrophy area were computed for the gildeuretinol acetate and the placebo arms, by use of a linear mixed-effects model applied to the GA area measured on FAF images at time points (baseline, Month 6, Month 12, Month 18 and Month 24) assuming time as continuous and linear (“slope model”). In the sensitivity analysis a piece-wise linear linear-mixed effects model with a knot time at 6 months was used.

[0101] The analysis model used the change from baseline in the Geographic Atrophy area measured by FAF as the response variable, and included treatment arm (gildeuretinol acetate, placebo) and pattern of FAF at the junctional zone of GA (focal, other) as fixed effects, baseline Geographic Atrophy lesion area and time (year, continuous assuming linearity) as covariates, time x treatment interaction, and baseline GA lesion area (< 7.5 mm2, >=7.5 mm2) * time interaction. Random effects included subject and subject’s eye (OD or OS). A common unstructured covariance matrix was used to model the within subject errors, and the Ken ward-Roger’s (Kenward and Roger 1997) method used to estimate denominator degrees of freedom. Attorney Docket No. 57198-0010W01

[0102] The mean rate of change (sqmm / year), standard error, and 95% confidence interval (CI) were estimated from baseline to Month 24 for each treatment arm. The estimated difference in slopes among the treatment groups along with the 95% Cis and p-value were provided to test the statistical significance of the treatment effect. The observed values for the Geographic Atrophy area (sqmm) of eligible eyes was summarized by treatment group and visit and plotted over time.

[0103] RESULTS

[0104] The trial was conducted between May 2019 and July 2023. One hundred and ninety-eight patients (198 patients) were in the intent-to-treat arm including in the primary efficacy analysis, of which 135 were randomized to gildeuretinol acetate 14 mg and 63 were randomized to placebo. Patients had a mix of subfoveal or non-subfoveal (foveal sparing), multifocal or unifocal. The mean age was 78 years old and approximately two-third were female. All collected data with follow-ups were utilized for the computation of the primary endpoint. Overall, demographic and clinical characteristics at baseline were similar in the two groups.

[0105] Primary Endpoint

[0106] The growth rate of atrophic retinal lesions was 1.62 sqmm / year with gildeuretinol acetate and 1.87 sqmm / year with placebo control, a difference of 0.25 sqmm / year (95% confidence interval [CI], -0.53 to 0.03), corresponding to an approximate 15% slower growth rate in patients treated with gildeuretinol acetate (Fig. 2). Using a linear piecewise model with a knot time of 6 months, the growth rate of atrophic retinal lesions was 1.61 sqmm / year in the gildeuretinol acetate arm and 1.90 sqmm / year in the placebo control arm, a difference of 0.29 sqmm / year (95% CI, -0.58 to 0.00).

[0107] DISCUSSION

[0108] In this SAGA study, gildeuretinol acetate showed a slowing of approximately 15% on the growth rate of Geographic Atrophy lesions in patients with Geographic Atrophy. This slope change indicates that gildeuretinol acted as a disease-modifying drug. The observed effect over a 2-year period underscores gildeuretinol acetate's capacity to alter the clinical trajectory of Geographic Atrophy. Result obtained with a once-a-day oral treatment indicates that oral administration is a convenient mode of administration compared to injections in the eye (intravitreal injections). In Attorney Docket No. 57198-0010W01 conclusion, oral gildeuretinol acetate, taken once daily for up to 24 months, slowed the expansion of retinal atrophic lesions in individuals with Geographic Atrophy.

[0109] SAFETY

[0110] Safety results are provided below in Table 4:

[0111] Table 4. Safety Results Atorney Docket No. 57198-0010W01 Atorney Docket No. 57198-0010W01 Atorney Docket No. 57198-0010W01 Atorney Docket No. 57198-0010W01 Atorney Docket No. 57198-0010W01 Atorney Docket No. 57198-0010W01 Atorney Docket No. 57198-0010W01 Atorney Docket No. 57198-0010W01 Attorney Docket No. 57198-0010W01

[0112] TEAE refers to treatment-emergent adverse event. SAE refers to serious adverse event.

[0113] As can be seen from Table 4, adverse events in patients treated with gildeuretinal acetate were comparable overall with adverse events in the placebo group.

[0114] EXAMPLE 3: Administering daily doses of gildeuretinol acetate of approximately 14 mg of gildeuretinol acetate for 24 months slows the onset, worsening or recurrence of neovascular (wet) Age-related Macular Degeneration and choroidal neovascularization.

[0115] Findings: In the SAGA age-related macular degeneration trial described in Example 2, a secondary objective was to evaluate the effects of gildeuretinol acetate in wet Age-related macular degeneration. It was found that 26% (52 of 198) patients with wet Age-related Macular Degeneration or Choroidal Neovascularization in at least one eye at baseline / screening. Because of this wet Age-related Macular Degeneration or Choroidal Neovascularization in at least one eye, these patients were at higher risk of new onset (in the Geographic Atrophy eye), worsening, or recurring of wet Age-related Macular Degeneration or CNV (Choroidal Neovascularization). At the end of two years, patients who received gildeuretinol acetate 14 mg for two years had an approximately 4-fold lower chance (corresponding to 75% lower chance) of incidental, worsening or recurring wet Age-related Macular Degeneration or Choroidal Neovascularization (11% vs. 44%). Attorney Docket No. 57198-0010W01

[0116] Specifically, 52 patients had one eye marked by the reading center as having Choroidal Neovascularization or wet Age-related Macular Degeneration (16 receiving placebo for 2 years plus 36 receiving gildeuretinol acetate for 2 years). After two years of treatment, 44% of these patients receiving placebo (7 out of 16) reported or were diagnosed by retinal specialists with an adverse experience of Choroidal Neovascularization or wet Age-related Macular Degeneration indicating that their Choroidal Neovascularization or wet Age-related Macular Degeneration had worsened or recurred, or that they had developed an incidental Choroidal Neovascularization or wet Age-related Macular Degeneration in the Geographic Atrophy eye. Only 11% of patients receiving gildeuretinol acetate (4 out of 36, Fisher’s exact test p-value = 0.02) reported or were diagnosed with an adverse event of Choroidal Neovascularization or wet Age-related Macular Degeneration. Results indicate significantly lower odds of developing incidental, worsening or recurring wet Age-related Macular Degeneration or Choroidal Neovascularization for those patients receiving gildeuretinol acetate vs. those receiving placebo in the trial.

[0117] Table 5. Report of new onset, worsening, or recurring wet AMD or CNV in any eye of patients with wet AMD or CNV in at least one eye at baseline for patients receiving gildeuretinol acetate 14 mg / day or placebo for 2 years

[0118] Additionally, of these 52 patients, 19% of these patients receiving placebo (3 out of 16) developed CNV or wet AMD in the eye that had GA at baseline, vs 0% of patients receiving gildeuretinol acetate (0 out of 36, fisher’s exact test p-value = 0.03). These results indicate significantly lower odds of developing incidental wet AMD or CNV for those patients with GA who only have one eye with CNV. Attorney Docket No. 57198-0010W01

[0119] Table 6. Incidence of CNV in the GA eye (the “study eye”) of patients with CNV at baseline in the other eye (“fellow eye”) for patients receiving gildeuretinol acetate 14 mg / day or placebo for 2 years

[0120] Furthermore, when including all 198 randomized Age-related Macular Degeneration patients of the SAGA trial, 13% patients receiving placebo (8 out of 63) vs 5% of patients receiving gildeuretinol acetate 14 mg (7 out of 135) developed an incidental, worsening or recurring wet Age-related Macular Degeneration or Choroidal Neovascularization as seen in the Adverse Events table of Example 2.

[0121] These results indicate that gildeuretinol acetate could be used for the treatment of wet Age- related Macular Degeneration or Choroidal Neovascularization, to delay or the likelihood of the onset, the worsening, or the recurring of wet Age-related Macular Degeneration or Choroidal Neovascularization.

[0122] EXAMPLE 4: Administering daily doses of gildeuretinol acetate of approximately 14 mg of gildeuretinol acetate for 24 months slows vision loss in patients with Age-related Macular Degeneration (including patients with geographic atrophy and patients with Choroidal Neovascularization or wet Age-related Macular Degeneration).

[0123] Findings: In the SAGA clinical trial described in Example 2, 198 patients diagnosed with Age- related Macular Degeneration with geographic atrophy, also including some patients with one eye with wet Age-related Macular Degeneration or Choroidal Neovascularization. Of these Attorney Docket No. 57198-0010W01 patients, patients treated with placebo for two years showed a loss of approximately 8.3 letters on the ETDRS eyechart measured using a low luminance setting (a measurement called low luminance visual acuity). Age-related Macular Degeneration patients treated with gildeuretinol acetate showed a loss of -3.9 letters on the same scale, corresponding to a difference of +4.4 letters (approximately 1 line of vision on the eye chart) for patients receiving gildeuretinol acetate than placebo. The results are shown in tabular form in Table 5 and graphically in Fig. 3.

[0124] Table 7. Loss of Low Luminance Visual Acuity in Patients with GA in at least one eye Receiving Gildeuretinol Acetate or Placebo for 24 months

Claims

Attorney Docket No. 57198-0010W01CLAIMSWhat is claimed is:

1. A method of treating a patient with Geographic Atrophy, comprising administering an effective amount of gildeuretinol acetate to the patient.

2. A method of delaying the progression of vision loss in a patient with Geographic Atrophy, comprising administering an effective amount of gildeuretinol acetate to the patient.

3. The method of claim 1 or 2, wherein the patient is experiencing symptoms of Geographic Atrophy.

4. The method of any one of claims 1-3, wherein the patient is experiencing loss of central vision, flashes of light, blurred vision, difficulty in seeing in dim lighting or at night, difficulty in distinguishing colors, difficultly in adjusting to the dark, difficulty in adjusting to bright light exposure difficulty tracking moving objects, difficulty in reading, writing, or recognizing faces due to vision loss, blind spots in the field of vision and / or involuntary eye movements.

5. The method of any one of claims 1-3, wherein the patient is experiencing partial vision loss from the Geographic Atrophy.

6. The method of claim 1 or 2, wherein the patient is not yet experiencing vision loss from the Geographic Atrophy.

7. The method of claim 1 or 2, wherein the patient is asymptomatic for Geographic Atrophy.

8. The method of any one of claims 1, 2, 6, and 7, wherein the patient is not yet experiencing loss of central vision, flashes of light, blurred vision, difficulty in seeing in dim lighting or at night, difficulty in distinguishing colors, difficulty in adjusting to the dark, difficulty in adjusting to bright light exposure difficulty tracking moving objects, difficulty in reading, writing, or recognizing faces due to vision loss, blind spots in the field of vision and / or involuntary eye movements.Attorney Docket No. 57198-0010W019. The method of any one of claims 1-8, wherein the effective amount is 10 mg to 20 mg per day of gildeuretinol acetate.

10. The method of any one of claims 1-8, wherein the effective amount is 14 mg per day of gildeuretinol acetate.

11. The method of any one of claims 1-10, wherein gildeuretinol acetate is administered once daily.

12. The method of any one of claims 1-11, wherein gildeuretinol acetate is administered orally.

13. A method of treating a patient with wet Age-related Macular Degeneration, comprising administering an effective amount of gildeuretinol acetate to the patient.

14. A method of delaying the progression of vision loss in a patient with wet Age-related Macular Degeneration, comprising administering an effective amount of gildeuretinol acetate to the patient.

15. A method of delaying the onset or reducing the likelihood of developing wet Age-related Macular Degeneration in a patient at risk of developing wet Age-related Macular Degeneration in one or both eyes, comprising administering an effective amount of gildeuretinol acetate to the patient.

16. The method of claim 15, wherein the at risk patient: i) has wet Age-related Macular Degeneration in one eye; ii) has dry Macular Degeneration (e.g., Early Stage or Intermediate Stage Age-related Macular Degeneration); iii) has Geographic Atrophy; or iv) has a history of wet Age-related Macular Degeneration placing the patient at risk of recurring wet Age-related Macular Degeneration.

17. The method of claim 16, wherein the at risk patient has intermediate macular degeneration in at least one eye.

18. The method of claim 16, wherein the at risk patient has Geographic Atrophy in at least one eye.Attorney Docket No. 57198-0010W0119. The method of claim 16, wherein the at risk patient has wet Age-related Macular Degeneration in only one eye.

20. The method of claim 16, wherein the at risk patient has a history of wet Age-related Macular Degeneration and is at risk of recurring wet Age-related Macular Degeneration.

21. The method of claim 16, wherein the at risk patient has Choroidal Neovascularization in one or both eyes.

22. The method of any one of claims 13-21, wherein the effective amount is 10 mg to 20 mg per day of gildeuretinol acetate.

23. The method of any one of claims 13-21, wherein the effective amount is 14 mg per day of gildeuretinol acetate.

24. The method of any one of claims 13-21, wherein gildeuretinol acetate is administered once daily.

25. The method of any one of claims 13-21, wherein gildeuretinol acetate is administered orally.

Images