THERAPEUTIC REGIMENS AND METHODS FOR IMPROVING VISUAL FUNCTION IN VISUAL DISORDERS ASSOCIATED WITH IMPAIRED DARK ADAPTATION AND/OR IMPAIRED LOW LUMINANCE VISION

Related Applications

This application claims the benefit of priority from U.S. provisional patent application No. 61/865,837, filed August 14, 2013. The disclosure of the foregoing application is incorporated herein by reference in their entirety.

Field of the Disclosure

This disclosure is directed to therapeutic regimens and methods for improving visual function in a subject with impaired dark adaptation.

Background

The term dark adaptation refers to the recovery of the visual system in darkness following exposure of the eye to intense or prolonged illumination (Leibrock et al. 1998; Lamb and Pugh 2004). The classical dark adaptation function is biphasic, consisting of an initial rapid recovery which is cone-mediated (6 to 8 minutes) and a second slower component which is rod-mediated (20 to 25 minutes). Dark adaptation reflects recovery of scotopic sensitivity over a dynamic range, going from little or no sensitivity immediately following photobleaching to full recovery in approximately 40 minutes. The rod-mediated portion of dark adaptation is thought to represent the regeneration of the rhodopsin photopigment and other aspects of recovery during the retinoid cycle (Leibrock et al. 1998; Lamb 1981; Lamb et al. 1998). The retinoid cycle involves a cascade of enzymatic reactions in which 11-cis-retinal is regenerated or recycled by enzymatic isomerization of all-trans retinol within the RPE cell. The ability of the visual system to regenerate 11-cis-retinal in order to return to pre-illumination conditions is one of the necessities for sustained vision. Leibrock (1998) also suggests that for normal recycling of rhodopsin to occur, a sufficient quantity of 11-cis-retinal must be available. The complex protocol of the retinoid cycle involves multiple interconnected events and its proper functioning is dependent on the presence of key enzymes as well as a robust infrastructure to ensure homeostasis.

It is well accepted that aging is a risk factor for pathological changes seen in age- related macular degeneration (AMD). Age-related changes include progressive thickening of Bruch's membrane, accumulation of extracellular material between the RPE and Bruch's membrane, reduced hydraulic conductivity of Bruch's membrane, and changes in the structure of RPE cells. These observations have led to the consideration that sub-RPE deposits in the aged retina may cause a diffusion barrier that disrupts metabolic exchange between the choroid and photoreceptors.

Photoreceptor loss is also characteristic of both aging and AMD pathogenesis

(Pauleikhoff et al. 1990). Rods are more vulnerable in the aging process than are cones and show earlier signs of pathogenesis. While the number of cones in the fovea remains relatively stable throughout adulthood, the number of rods in the same eyes decreases by 30% as a normal degenerative change with age. The greatest loss occurs in the parafovea (1 to 3 mm from fixation) (Jackson et al. 2002; Curcio et al. 1993). The location of age- related rod loss differs from the region where rod density is maximal (4 to 6 mm from fixation) and from the region where the cell loss associated with inherited retinal

degenerations typically begin (8 to 10 mm from fixation) (Curcio, Owsley et al. 2000).

By the seventh decade of life, the density of rod photoreceptors decreases

dramatically in the peri-macula as indicated by donor retinas (Curcio et al. 1993).

Psychophysical studies of photopic and scotopic sensitivity have identified functional correlates to the histopathologic findings that rods are more vulnerable than cones to the aging process (Owsley et al. 2000). This decline in scotopic sensitivity is twice the rate of photopic sensitivity decline (Jackson et al. 2000). This is consistent with findings that spatial contrast sensitivity impairments in older adults are accentuated at low luminance (Owsley et al. 2001; Sloane, Owsley and Jackson 1988; Sloane, Owsley and Alvarex 1988) despite good acuity. This magnitude of scotopic sensitivity decline appears to be uniform throughout the parafoveal region in areas where there is negligible rod loss, suggesting that rod loss cannot solely account for older adults' sensitivity impairment in the dark (Jackson et al. 2000).

In addition to the reduced sensitivity of the rod system, the kinetics of the rod function have also been reported to change with aging (Brown et al. 1986; Jackson et al. 1999;

Steinmetz et al. 1993). In older patients with good retinal health, the rod-mediated portion of the dark adaptation function has been reported to be significantly slower than in younger adults. For adults in their seventies, it has been reported that the transition point in the dark at which the rod system takes over is delayed almost 2 1/2 minutes, as compared to adults in their twenties. The time taken for 70 year olds to reach prebleach rod light sensitivity in the dark has been reported to be over 10 minutes longer than for 20 year olds. It has been reported that in patients with normal acuity but signs of early AMD, rod-mediated dark adaptation is hampered even further, on average 17 minutes slower. As this impairment parallels the earlier and greater loss of rod photoreceptors, it can manifest itself before visual acuity (VA) changes. Indeed, psychophysical studies have shown up to a 30 dB loss in scotopic sensitivity and prolongation of dark adaptation before any compromise in acuity can be measured (Steinmetz et al. 1993).

According to the theoretical model of dark adaptation, slowed rod-mediated recovery implies limited availability to the rods of 11-cis-retinal, resulting in the accumulation of intermediates that actively desensitize the retina. Delayed dark adaptation is a hallmark of systemic vitamin A deficiency (Haig et al. 1938) and genetic disorders affecting visual cycle components or the retinoid transport system. Vitamin A deficiency has been observed to cause preferential rod dysfunction and eventual photoreceptor death (Kemp et al. 1988; Dowling and Wald 1958). A scarcity of available vitamin A to combine with the protein opsin to form the visual pigment rhodopsin may also lead to a specific change in the rate of rhodopsin regeneration and recovery of light sensitivity after light exposure.

Slowing of the ability to dark adapt can hamper older adults performance of visual activities in daily living which rely on time-critical decisions and actions such as driving, mobility, and workplace tasks. Oncoming headlights repeatedly bleach the visual system. Following the initial daze, on return to dim lighting conditions, there is a period of considerable visual handicap resulting from impaired dark adaptation. Indeed, patients, with AMD, despite good acuity in one or both eyes report night driving as the most seriously hampered task (Scilley et al. 2002).

Impaired mobility, in the form of falling, is one of the most common problems of old age (McMurdo and Gaskell 1991). McMurdo was able to demonstrate a relationship between falls and reduced dark adaptation, despite failing to show a similar relationship between falls and VA.

Spatial contrast sensitivity impairments have also been observed in older adults, and are accentuated at low luminance. These older adults report difficulties in accomplishing daily tasks, including difficulty reading under dim light and avoiding night driving. Poor vision under reduced light levels and at night in the elderly has been linked to their involvement in motor vehicle collisions as well as falls. Relative to younger subjects, under scotopic conditions, older adults require on average three times the contrast of younger adults in order to detect a target. The use of low luminance low contrast visual acuity testing allows for an evaluation of the degree of dysfunction in the visual system of the aging

eye. Therapeutic interventions which can improve the sensitivity of the aging eye under these conditions provide an opportunity for the aging adults to improve their quality of life in low light conditions, and preserve a high-level of visual function into the advanced years of adulthood (Owsley, Vision Research, 51 : 1610-1622 (2011)).

The use of synthetic retinal derivatives and compositions thereof in methods of restoring or stabilizing photoreceptor function in a vertebrate visual system is disclosed in International Published Patent Application Nos. WO 2004/082622, WO 2006/002097, WO 2009/102418, and WO 2011/034551, WO 2011/132084, and Published U.S. Application Nos. 2004/0242704, 2008/0221208 (issued as US Patent No. 7,951,841), and 2010/0035986 (issued as US Patent No. 8,324,270). A study to evaluate the effects of daily and intermittent dosing of 9-cis-retinyl acetate, a synthetic retinal derivative, in aging mice is disclosed in Maeda, T. et al, Investigative Ophthalmology & Visual Science (2009), Vol. 50, No. 9, pp. 4368-4378).

Animal models have shown that synthetic retinoids which are highly-light sensitive compounds are photoisomerized or "bleached" by light from the retina within just a few hours unless the eyes are covered. These studies were conducted with the animals kept in the dark for specified periods during treatment with synthetic retinoids until the evaluation period in order to minimize photoisomerization/bleaching of the synthetic retinoid, defeating the entire purpose of the treatment. Batten ML et al. "Pharmacological and rAAV Gene Therapy Rescue of Visual Functions in a Blind Mouse Model of Leber Congenital Amaurosis" PLo-S Medicine vol. 2, p. 333 (2005); Margaron, P., Castaner, L., and Narfstrom, K. "Evaluation of Intravitreal cis-Retinoid Replacement Therapy in a Canine Model Of Leber's Congenital

Amaurosis" Invest Ophthalmol Vis Sci 2009; 50:E-Abstract 6280; Gearhart PM, Gearhart C, Thompson DA, Petersen- Jones SM. "Improvement of visual performance with intravitreal administration of 9-cis-retinal in Rpe65-mutant dogs" Arch Ophthalmol 2010; 128(11) 1442- 8.

Frequent administration of any retinoid to compensate for the bleaching effect implicates the well-known toxicity of the retinoid class of the compounds. See, Teelmann, K "Retinoids: Toxicity and Teratogenicity to Date," Pharmac. Ther., Vol. 40, pp 29-43 (1989); Gerber, LE et al "Changes in Lipid Metabolism During Retinoid Administration" J. Amer. Acad. Derm., Vol. 6, pp 664-74 (1982); Allen LH "Estimating the Potential for Vit A Toxicity in Women and Young Children" J. Nutr., Vol. 132, pp. 2907-19 (2002); Silverman, AK "Hypervitaminosis A Syndrome: A Paradigm of Retinoid Side Effects", J. Am. Acad. Derm., Vol. 16, pp 1027-39 (1987); Zech LA et al. "Changes in Plasma Cholesterol and Triglyceride Levels After Treatment with Oral Isotretinoin" Arch. Dermatol., Vol. 119, pp 987-93 (1983). Toxicity caused by chronic administration of retinoids can cause changes in lipid metabolism, damage to the liver, nausea, vomiting, blurred vision, damage to bones, interference with bone development and several other serious undesirable effects.

In the context of improving visual function in an aging subject with impaired dark adaptation and/or impaired low luminance vision, which is a chronic condition that may require years of treatments, management of these toxic effects can be very important.

Likewise, improving visual function in an aging subject with impaired dark adaptation may require chronic, repeat treatments. However, in subjects with impaired dark adaptation, excessive competitive inhibition of the normal rhodopsin cycle via supplementation of the visual cycle with a synthetic retinal derivative, for example 9-cis-retinal to form

isorhodopsin, has been implicated with worsened vision due to a decreased sensitivity of isorhodopsin to light. In addition, it has been reported that supplementation of the visual cycle in preclinical models of AMD showed increased accumulation of retinotoxic compounds, such as A2E and lipofuscin in and around the retinal pigment epithelium, with potential side effects including impaired night or low-light vision and night blindness (WO 2005/079774).

Oral 9-cis retinyl acetate has previously been shown to objectively improve dark adaptation in aging mice (see Maeda et al, Invest Ophthalmol Vis Sci 2009; see US Patent No. 8,324,270, the entire contents of which is herein incorporated by reference).

This combination of a need for repeated administration in response to bleaching, and the undesirable serious side effects of repeated administration, along with potential implication in accumulation of retinotoxic byproducts poses a problem for the use of synthetic retinoids to improve visual function in a subject having impaired dark adaptation and/or impaired low luminance vision. What is needed are dosing regimens of suitable doses in suitable dosing intervals of synthetic retinal derivatives that may provide meaningful improvement of dark adaptation and/or impaired low luminance vision in an aging subject. Summary of Invention

The present disclosure provides certain dosing regimens of suitable doses in suitable dosing intervals of synthetic retinal derivatives that may provide meaningful improvement of dark adaptation and/or impaired low luminance vision in a subject having impaired dark adaptation and/or impaired low luminance vision, while at the same time minimizing undesired competitive inhibition of the visual cycle and accumulation of retinotoxic byproducts, and while exhibiting an acceptable safety profile, optionally throughout repeat treatment cycles. In certain embodiments, the acceptable safety profile may be achieved by minimizing and/or reducing the severity of the toxic side effects associated with frequent and subsequent administration of synthetic retinal derivatives through subsequent dosing cycles.

In certain embodiments, the present disclosure provides a method of improving visual function in a subject having impaired dark adaptation and/or impaired low luminance vision comprising administering a therapeutic dose of a composition comprising a synthetic retinal derivative to a subject in need thereof once daily on days 0, 7, 14 and 15. In certain such embodiments, the synthetic retinal derivative is a 9- or 11-cis-retinyl ester, such as 9-cis- retinyl acetate or 11-cis-retinyl acetate.

In certain embodiments, the present disclosure provides a kit for improving visual function in a subject having impaired dark adaptation and/or impaired low luminance vision, the kit comprising a) at least four therapeutic doses of a composition comprising a synthetic retinal derivative, and b) instructions for use that specify one therapeutic dose is administered daily on days 0, 7, 14 and 15.

In certain embodiments, the present disclosure provides a dosing regimen for improving visual function in a subject having impaired dark adaptation and/or impaired low luminance vision, the dosing regimen comprising at least four therapeutic doses of a composition comprising a synthetic retinal derivative, the regimen comprising administering one therapeutic dose daily on days 0, 7, 14 and 15. In certain embodiments, the present disclosure provides a dosing regimen for improving visual function in a subject having impaired dark adaptation and/or impaired low luminance vision, the dosing regimen comprising at least three therapeutic doses of a composition comprising a synthetic retinal derivative, the regimen comprising administering one therapeutic dose daily on days 0, 7, and 14. In certain embodiments, the subject is deficient in endogenous ly produced 11-cis- retinal. In some embodiments, the 9- or 11-cis-retinyl ester provides replacement of endogenously produced 11-cis-retinal.

In certain embodiments, the subject is a human subject with impaired dark adaptation and/or impaired low luminance vision, such as a human subject having age-related macular degeneration (AMD). AMD can be wet or exudative or dry or non-exudative forms (early forms). In some embodiment, the subject is an aging subject with impaired dark adaptation and/or impaired low luminance vision. In some embodiment, the aging subject is at least 45, 50, 55, 60, 65, or 70 years of age.

In certain embodiments, the subject having impaired dark adaptation has early AMD.

In some embodiments, early AMD is defined as non-exudative AMD without geographic atrophy.

In certain embodiments, the subject has impaired low luminance vision. In some embodiments, the subject with low luminance vision has wet AMD, or non-exudative AMD, or early AMD.

In certain embodiments, the subject has impaired glare recovery (also known as photostress recovery). In certain embodiments, the subject with impaired glare recovery has early AMD. In general, when a subject with a normal, healthy macula is exposed to an intense light source for a specified period of time, it will recover a defined level of function in a normal time. Any deviation from normal retinal function will manifest itself as a prolonged glare recovery time (Lovie-Kitchin and Feigl 2005).

In certain embodiments, each therapeutic dose, in milligrams per square metre of body surface area of subject, is from about 10 mg/m ² to about 40 mg/m ² . In some

embodiments, each therapeutic dose is about 10 mg/m ² . In some embodiments, each therapeutic dose is about 40 mg/m ² . In certain embodiments, each therapeutic dose, in milligrams per square metre of body surface area of subject, is from about 1.25 mg/m ² to about 40 mg/m ² . In other embodiments, each therapeutic dose, in milligrams per square metre of body surface area of subject, is from about 40 mg/m ² to about 60 mg/m ² . In other embodiments, each therapeutic dose, in milligrams per square metre of body surface area of subject, is about 1.25 or 2.5 or 5 or 20 or 40 or 60 mg/m ² of body surface area of subject.

In certain embodiments, the therapeutic doses are administered orally. In certain embodiments, the synthetic retinyl derivative is a retinyl ester. In some embodiments, the retinyl ester is a 9-cis-retinyl ester. In some embodiments, the retinyl ester is 9-cis-retinyl acetate. In some embodiments, the retinyl ester is 11-cis-retinyl acetate.

In certain embodiments the composition comprising a synthetic retinal derivative further comprises soybean oil (e.g., soybean oil USP grade). In certain embodiments the composition comprising a synthetic retinal derivative further comprises butylated

hydroxyanisole (BHA). In certain embodiments the composition comprising a synthetic retinal derivative further comprises soybean oil (e.g., soybean oil USP grade) and BHA.

In certain embodiments, the cycle of dosing is repeated. In certain embodiments, improving visual function comprises improving impaired dark adaptation and/or improving the subject's impaired low luminance vision, such as improving the rate of dark adaptation in an eye relative to the subject's baseline dark adaptation rate.

In certain embodiments, the rate of dark adaptation in at least one eye of a subject is improved by at least about 20% relative to the subject's earlier measured rate of dark adaptation, for example, at baseline prior to any therapeutic intervention using the compositions and regimens of the present invention. In certain embodiments, the

improvement in rate of dark adaptation is determined by way of comparing the rates of dark adaptation in a subject between earlier, for example, the rates of dark adaptation at baseline before treatment with a synthetic retinoid derivative, and later time points in a dosing schedule. In certain embodiments, the improvement in impaired dark adaptation is measured by determining dark adaptation parameters including rod-cone break or the rod-intercept using a dark adaptometer or equivalent relative to a subject's baseline dark adaptation parameters. In certain embodiments, the improvement in dark adaptation time is measured by the time to the rod-cone break after light exposure, the dark adaptation rate after light exposure, or the dark adaptation duration after light exposure.

In certain embodiments, impaired dark adaptation may be defined as a rod-cone break time of about 11.0 to 17.3 minutes. In other embodiments, impaired dark adaptation may be defined as a rod-cone break time of 9 minutes or more.

Improvements in the rate of dark adaptation, defined as the subject's rod-cone break time, rod threshold time, or rod adaptation slope, may be determined based on a comparison of a subject's rate of dark adaptation after treatment as compared to the subject's baseline rate. In some embodiments, the improvement in the subject's dark adaptation time is at least 30%, or at least 25%, or at least 20% or at least 15% from baseline. In some embodiments, the improvement in the dark adaptation time is an improvement by about 5 minutes to about 10 minutes (e.g., by 5, 6, 7, 8, 9 or 10 minutes), or by about 5 minute to 8 minutes (e.g., by 5, 6, 7, or 8 minutes), or by about 1 minute to 5 minutes (e.g., by 1, 2, 3, 4, or 5 minutes). In some embodiments, such improvement in the subject's dark adaptation time may be demonstrated by a decrease in the time to the rod-cone break (i.e., rod-cone break time) by about 5 minutes to about 10 minutes, or by about 5 minutes to about 8 minutes, or by about 1 minute to 5 minutes as compared to baseline (e.g,. before treatment). For example, the rod- cone break time at baseline (e.g., before treatment) is 9 minutes. After treatment, the rod- cone break time is decreased from 9 minutes to 8 minutes, to 7 minutes, to 6 minutes, to 5 minutes, or to 4 minutes (i.e., the decrease in rod-cone break time is by 1 minute to 5 minutes, which corresponds to an improvement in dark adaptation time/rod-cone break time of 1 minute to 5 minutes). Such decrease demonstrates an improvement in the subject's dark adaptation time. In one embodiment, the improvement in the subject's dark adaptation time comprises decreasing the time to the rod-cone break by about 5 to about 8 minutes, or by about 1 to about 5 minutes. In some embodiments, the improvement in the subject's dark adaptation time may be demonstrated by comparing the subject's dark adaptation rate with a comparable human visual system not receiving the therapeutic regimen.

In certain embodiments, improving visual function associated with improved dark adaptation or impaired low luminance vision comprises improving low luminance low contrast best corrected visual acuity (LLLC BCVA), such as improving LLLC BCVA in an eye by greater than or equal to 5 letters from baseline. In some embodiments, the

improvement in the subject's LLLC BCVA comprises increasing the LLLC BCVA in one or more eyes of the subject by greater than or equal to 10 letters (2 lines) from baseline. In some embodiments, the improvement in the subject's LLLC BCVA comprises increasing the LLLC BCVA in one or more eyes of the subject by greater than or equal to 15 letters (3 lines) from baseline. In certain such embodiments, the improvement in LLLC BCVA is measured using tinted goggles to provide low luminance, and a Low Contrast Early Treatment Diabetic Retinopathy Study (ETDRS) eye chart. In certain embodiments, the Low Contrast ETDRS eye chart is a 2.5%, 5%, or 10% contrast chart.

In certain embodiments, the therapeutic doses are administered orally. In certain embodiments, improving visual function comprises improving glare recovery time, such as improving glare recovery time in an eye by at least 30%, 25%, 20%>, or 15% from the subject's baseline glare recovery time. In certain such embodiments, the improvement in glare recovery time is measured by assessing the subject's recovery time after light exposure to achieve a comparable LLLC BCVA score as achieved before light exposure. In some embodiments, the glare recovery time is improved by at least 5 seconds from baseline, or at least 10 seconds from baseline, or at least 15 seconds, or at least 20 seconds from baseline. In some embodiments, the glare recovery time is improved by at least 1 minute. In some embodiments, such improvement in the glare recovery time may be demonstrated by a decrease in the glare recovery time by at least 5 seconds from baseline, or at least 10 seconds from baseline, or at least 15 seconds, at least 20 seconds from baseline. For example, the glare recovery time at baseline (e.g., before treatment) is 40 seconds. After the treatment, the glare recovery time is decreased from 40 seconds to 20 seconds, or to 25 seconds, or to 30 seconds, or to 35 seconds. Such decrease demonstrates an improvement in the glare recovery time.

In certain embodiments, improving visual function comprises an improvement in activities of daily living relating to dark adaptation. In some embodiments, the improvements in activities of daily living are measured using visual function questionnaires or patient reported outcomes.

In certain embodiments of any of the foregoing methods, dosing regimens and kits, the subject is a human subject.

Specific embodiments of these aspects of the disclosure are described in more detail below. Detailed Description of the Drawings

Figure 1 provides a schematic drawing of the retinoid cycle.

Figure 2 provides a schematic diagram of the study design for Study RET IDA 02 of Example 4.

Figure 3 provides a table summarizing the demographics of the subjects enrolled in Study RET IDA 02 of Example 4.

Figure 4 shows the median low luminance low contrast BCVA change from baseline versus dose and time points (day 7, day 14, day 15, day 17, day 28 and day 42) in the per protocol subset of patients with impaired low luminance low contrast visual acuity at baseline.

Figure 5 show the median glare recovery change from baseline in seconds versus dose in the per protocol subset of patients at the various times points (day 7, day 14, day 15, day 17, day 28 and day 42).

Figure 6 shows the median glare recovery change from baseline in seconds versus dose for the per protocol subset of patients having a baseline (BL) glare recovery time of greater than 40 seconds.

Figure 7 shows the median glare recovery change from baseline in seconds versus dose at the various times points (day 7, day 14, day 15, day 17, day 28 and day 42) for the per protocol subset of patients having a baseline (BL) glare recovery time of greater than 30 seconds.

Figure 8 shows a theoretical dark adaptation graph that plots the threshold intensity vs. time for the rods and cones and showing the rod-cone break time.

Figure 9 shows the median change in rod-cone break time versus dose at the various times points (day 7, day 14, day 15, day 17, day 28 and day 42) for the per protocol subset of subjects having a baseline (BL) rod-cone break (RCB) time of 9 minutes or more.

Detailed Description of the Invention

The present disclosure provides methods, dosing regimens, and kits for improving visual function in a subject with impaired dark adaptation and/or impaired low luminance vision. The dosing regimens, kits and subsequent methods of improving visual function may be used to provide for efficacy while a clinically relevant safety profile is maintained.

Herein, the present disclosure provides a dosing regimen comprising a) at least four therapeutic doses of a composition comprising a synthetic retinal derivative that provides replacement for deficient endogenously produced 11-cis-retinal, such as a 9- or 11-cis-retinyl ester, wherein one therapeutic dose is administered daily on days 0, 7, 14 and 15. This dosing regimen can provide for clinically efficacious improvement of visual function in a subject with impaired dark adaptation and/or impaired low luminance vision, while not providing the synthetic retinal derivative to the patient for a dosage and/or period of time longer than is necessary. In certain embodiments, this dosing regimen avoids the known class-effect safety concerns (e.g. chronic retinoid toxicity) associated with synthetic retinal derivatives.

Herein, the present disclosure also provides a dosing regimen comprising a) at least once weekly doses of a composition for at least three weeks comprising a synthetic retinal derivative that provides replacement for deficient endogenously produced 11-cis-retinal, such as a 9- or 11-cis-retinyl ester, wherein one therapeutic dose is administered daily on days 0, 7, and 14. This dosing regimen can provide for clinically efficacious improvement of visual function in a subject with impaired dark adaptation and/or impaired low luminance vision, while not providing the synthetic retinal derivative to the patient for a dosage and/or period of time longer than is necessary. In certain embodiments, this dosing regimen avoids the known class-effect safety concerns (e.g. chronic retinoid toxicity) associated with synthetic retinal derivatives.

The amount of the therapeutic dose can be designated either as the total amount administered for a particular dose on each day or as an amount administered over the dosing cycle. For example, the therapeutic dose may be designated as a dose of 160 mg/m ² for the dosing cycle or as 40 mg/m ² administered each day on days 0, 7, 14 and 15. Thus, in one aspect the therapeutic dose is about 40 mg/m ² to about 160 mg/m ² . In another aspect the therapeutic dose is about 10 mg/m ² to about 40 mg/m ² when administered each day on days 0, 7, 14 and 15.

In some embodiments, the therapeutic dose is about, 5-10 mg/m ² each day for days 0, 7, 14 and 15, 10-15 mg/m ² each day for days 0, 7, 14 and 15, 15-20 mg/ m ² each day for days 0, 7, 14 and 15, 20-25 mg/m ² each day for days 0, 7, 14 and 15, 25-30 mg/m ² each day for days 0, 7, 14 and 15, 30-35 mg/m ² each day for days 0, 7, 14 and 15, 30-40 mg/m ² each day for days 0, 7, 14 and 15, or about 40-45 mg/ m ² each day for days 0, 7, 14 and 15.

In some embodiments, the therapeutic dose is about 10, 15, 20, 25, 30, 35 or 40 mg/m ² each day for days 0, 7, 14 and 15.

In some embodiments, the therapeutic dose is about 5-10 mg/m ² each day for days 0, 7, and 14, 10-15 mg/m ² each day for days 0, 7, and 14, 15-20 mg/m ² each day for days 0, 7, and 14, 20-25 mg/m ² each day for days 0, 7, and 14, 25-30 mg/m ² each day for days 0, 7, and 14, 30-35 mg/m ² each day for days 0, 7, and 14, 30-40 mg/m ² each day for days 0, 7, and 14, or about 40-45 mg/ m ² each day for days 0, 7, and 14, or about 10-40 mg/m ² each day for days 0, 7, and 14. In some embodiments, the therapeutic dose is about 10, 15, 20, 25, 30, 35 or 40 mg/m ² each day for days 0, 7, and 14.

In one aspect, the synthetic retinal derivative, such as 9- or 11-cis-retinyl ester, being administered to the subject having impaired dark adaptation is 9-cis retinyl acetate, as used in the composition of Example 2, or 11-cis retinyl acetate.

In one embodiment, the present disclosure provides a method of improving visual function in a subject having impaired dark adaptation comprising administering a therapeutic dose of a composition comprising a synthetic retinal derivative to a subject in need thereof once daily on days 0, 7, 14 and 15, or, in another embodiment, once daily on days 0, 7, and 14. In certain such embodiments, the synthetic retinal derivative is a 9- or 11-cis-retinyl ester, such as 9-cis-retinyl acetate or 11-cis-retinyl acetate.

In certain embodiments, impaired dark adaptation may be detected by measurement of impaired low luminance vision, defined as having an low luminance low contras (LLLC) best-corrected visual acuity (BCVA) that is more than 25 letters (about 5 lines) below their high luminance high contrast (HLHC) BCVA (Haegerstrom-Portnoy et al., 1999) as determined using the Early Treatment Diabetic Retinopathy Study (ETDRS) chart.

In certain other embodiments, impaired dark adaptation may be detected by determination of a rod-cone break dark adaptation time, such as a rod-cone break dark adaptation time of about 11-17 minutes at baseline in a subject (Jackson 2006) or about 8 or 9 minutes at baseline in a subject depending on the conditions of the dark adaptation test.

In one aspect, the improvement in a subject's visual function is measured as a function of baseline. A baseline may be determined for each subject or it may be determined for a group of subjects. In another aspect, a baseline may not be individually determined for a subject but a baseline from a similar group of subjects may be applied to an individual subject.

In one embodiment, the baseline of the subject's visual function is established prior to the administration of the first therapeutic effective dose of the composition comprising a synthetic retinal derivative, such as a 9-cis-retinyl ester or an 11-cis-retinyl ester, or a pharmaceutically acceptable composition thereof by evaluating one or more of the subject's dark adaptation, glare recovery, or low luminance low contrast best corrected visual acuity. In another embodiment, establishing the subject's baseline of visual function comprises establishing a baseline of one or more of the subject's dark adaptation, glare recovery, or low luminance low contrast best corrected visual acuity.

In one embodiment, the subject's visual function rapidly improves within the dosing period from the baseline of the subject's visual function established prior to administration of the first therapeutic effective amount of the composition comprising a synthetic retinal derivative, for example a 9-cis-retinyl ester or an 11-cis-retinyl ester, to the subject. For purposes of this disclosure, "rapidly improves" refers to a clinically meaningful improvement in a subject's visual functions as compared to the baseline of the subject's visual functions in a period shorter than the first dosing period. Preferably, in one embodiment, the subject's visual functions are significantly improved within one week of the commencement of the dosing period. In another embodiment, the subject's visual functions improve during the dosing period, for example as compared to baseline, and remain above baseline after the completion of the first dosing period and into a resting period. In a further embodiment, the improvement in the subject's visual function in the first dosing period comprises improving dark adaptation time as compared to the baseline of dark adaptation time, improving glare recovery time as compared to the baseline of glare recovery time, or improving low luminance low contrast best corrected visual acuity (LLLC BCVA) as compared to baseline LLLC BCVA..

In one embodiment, the improvement in the subject's visual function comprises an improvement in dark adaptation time in one or more eyes as compared to the baseline. In some embodiments, the improvement in the subject's dark adaptation time during or following the dosing cycle comprises improving dark adaptation time in one or more eyes of the subject by at least 30%, 25%, 20% or 15% from baseline. In certain such embodiments, the improvement in dark adaptation time is measured by the time to the rod-cone break after light exposure. In some embodiments, the improvement in dark adaptation time is measured by the dark adaptation rate of recovery after light exposure. In some embodiments, the improvement in dark adaptation time is measured by the dark adaptation duration after light exposure. In some embodiments, the improvement in the subject's dark adaptation time comprises decreasing dark adaptation time in an eye of the subject by at least 20% from baseline. In some embodiments, the improvement in the subject's dark adaptation time comprises decreasing the time to the rod-cone break by about 5 minutes, or about 4 minutes or about 3 minutes or about 2 minutes or about 1 minute. In some embodiments, the improvement in the subject's dark adaptation time comprises decreasing the time to the rod- cone break by about 5 to about 10 minutes.

In another embodiment, the improvement in the subject's visual function in one or more eyes comprises an improvement in the subject's low luminance low contrast best corrected visual acuity (LLLC BCVA) as compared to the baseline. In some embodiments, the improvement in the subject's LLLC BCVA comprises increasing LLLC BCVA in one or more eyes of the subject by greater than or equal to 5 letters (1 line) from baseline. In some embodiments, the improvement in the subject's LLLC BCVA comprises increasing the LLLC BCVA in one or more eyes of the subject by greater than or equal to 10 letters (2 lines) from baseline. In some embodiments, the improvement in the subject's LLLC BCVA comprises increasing the LLLC BCVA in one or more eyes of the subject by greater than or equal to 15 letters (3 lines) from baseline. In certain such embodiments, the improvement in LLLC BCVA is measured using tinted goggles to provide low luminance, and a Low

Contrast Early Treatment Diabetic Retinopathy Study (ETDRS) eye chart. In certain embodiments, the Low Contrast ETDRS eye chart is a 2.5%, 5%, or 10% contrast chart.

In one embodiment, the improvement in the subject's visual function comprises an improvement in glare recovery time in one or more eyes as compared to the baseline. In some embodiments, the improvement in the subject's glare recovery time during or following the dosing cycle comprises improving glare recovery time in one or more eyes of the subject by at least 30%, 25%, 20% or 15% from baseline. In certain such embodiments, the

improvement in glare recovery time is measured by an improvement in the time to recover to a fixed amount (about 5 letters) above the subject's LLLC BCVA before light/glare exposure. In some embodiments, the improvement in the subject's glare recovery time comprises decreasing glare recovery time in an eye of the subject by at least 20% from baseline. In some embodiments, the improvement in the subject's glare recovery time comprises decreasing glare recovery time in an eye of the subject by at least about 5 seconds, or at least about 10 seconds, or at least about 15 seconds, or at least about 20 seconds. In other embodiments, improvement in the subject's glare recovery time comprises decreasing glare recovery time in an eye of the subject by up to and including about 20 seconds, or about up to and including 15 seconds, or about up to and including 10 seconds, or about up to and including 5 seconds, relative to the subject's baseline glare recovery time. In some embodiments, the improvement in the subject's glare recovery time comprises decreasing glare recovery time in an eye of the subject by at least about 1 minute from baseline.

In some embodiments, the methods of the present invention provide dosing regimens that combine a clinically relevant safety profile in combination with a plurality of therapeutic dosing periods and resting periods is established. In some embodiments, up to 6, up to 5, up to 4, or up to 3 dosing cycles are administered in up to 6 months, up to 5 months, up to 4 months or up to 3 months. In some embodiments, up to 12, up to 11, up to 10, up to 9, up to 8, up to 7, up to 6, up to 5, up to 4, or up to 3 dosing cycles are administered to a subject in up to 12 months, up to 11 months, up to 10 months, up to 9 months, up to 8 months, up to 7 months, up to 6 months, up to 5 months, up to 4 months, or up to 3 months. In another embodiment, up to 3 dosing cycles are administered in about 3 months. In another embodiment, up to 6 dosing cycles are administered in about 6 months. In certain instances of the foregoing, no more than one dosing cycle is administered per month. In each of the foregoing embodiments, a dosing cycle may comprise administration of one therapeutic dose daily on days 0, 7, 14 and 15, or may comprise administration of one therapeutic dose daily on days 0, 7, and 14, i.e. one therapeutic dose weekly for at least three consecutive weeks.

In one embodiment, the present disclosure is directed to a dosing regimen for improving visual function of a subject having impaired dark adaptation and/or improving low luminance vision, wherein the dosing regimen comprises at least four therapeutic doses of a synthetic retinyl derivative, such as a 9- or 11-cis-retinyl ester, the regimen comprising administering one therapeutic dose daily on days 0, 7, 14 and 15, or comprising

administration of one therapeutic dose daily on days 0, 7, and 14, i.e., one therapeutic dose weekly for at least three consecutive weeks.

In one embodiment, the 9- or 11-cis-retinyl ester provides replacement of

endogenously produced 11-cis retinal. In another embodiment, the 9- or 11-cis-retinyl ester is administered orally to the subject. In yet another embodiment, the dosing regimen further comprises repeating the dosing cycle one or more times as needed.

In yet another aspect, the present disclosure provides a kit for improving visual function in a subject having impaired dark adaptation and/or impaired low luminance vision, wherein the kit comprises at least a) four therapeutic doses of a composition comprising a synthetic retinal derivative, for example a 9- or 11-cis-retinyl ester; and b) instructions for use that specify one therapeutic dose is administered daily on days 0, 7, 14 and 15. In yet another aspect, the present disclosure provides a kit for improving visual function in a subject having impaired dark adaptation and/or impaired low luminance vision, wherein the kit comprises at least a) three therapeutic doses of a composition comprising a synthetic retinal derivative, for example a 9- or 11-cis-retinyl ester; and b) instructions for use that specify one therapeutic dose is administered daily on days 0, 7, and 14, i.e., one therapeutic dose weekly for at least three consecutive weeks.

In an embodiment, the combined therapeutic doses provided in the kit are from about 40 mg/m ² to about 160 mg/m ² . In one aspect, the instructions direct that the therapeutic dose is administered at about 10 mg/m ² per day to about 40 mg/m ² per day on each of days 0, 7, 14 and 15, or on each of days 0, 7 and 14. In certain such embodiments, the instructions direct that the therapeutic dose is administered at about 10 mg/m ² on each of days 0, 7, 14 and 15, or on each of days 0, 7 and 14. In other embodiments, the instructions direct that the therapeutic dose is administered at about 40 mg/m ² on each of days 0, 7, 14 and 15 or on each of days 0, 7 and 14. In certain embodiments, the instructions direct that a therapeutic dose is administered at either 10 or 40 mg/m ² once per week for three consecutive weeks with one additional dose the day after the third dose. In another aspect, the therapeutic dose comprises 9- or 11-cis retinyl acetate, such as 9-cis-retinyl acetate.

The synthetic retinal derivative, for example a 9- or 11-cis-retinyl ester, can be delivered by any pharmacologic vehicle in which it is stably delivered to the subject having impaired dark adaptation, and effectively released upon administration. The pharmaceutical vehicle art is well familiar with the chemistry of retinoids and the formulations of

pharmacologic vehicles for them. These known delivery vehicles include those which have physical properties, chemical properties and release rates that are suited to delivery synthetic retinal derivatives. Liquid delivery vehicles, such as vegetable oils (including soybean, olive, and rapeseed or canola oils) can be used.

In one embodiment, the synthetic retinal derivative is an 11-cis-retinyl ester and is selected from 11-cis-retinyl acetate, 11-cis-retinyl succinate, 11-cis-retinyl citrate, 11-cis- retinyl ketoglutarate, 11-cis-retinyl fumarate, 11-cis-retinyl malate or 11-cis-retinyl oxaloacetate. Preferably the synthetic retinal derivation is 11-cis retinyl acetate.

In another embodiment, the 9-cis-retinyl ester is selected from 9-cis-retinyl acetate or

9-cis-retinyl succinate. In one embodiment, the 9-cis-retinyl ester is 9-cis-retinyl acetate. In other embodiments, the synthetic retinal derivative is 9-cis retinal, 11-cis-retinal, 9- cis-retinol, or 11-cis-retinol.

In certain embodiments, the pharmaceutically acceptable composition further comprises a lipid vehicle.

In certain embodiments, the pharmaceutically acceptable composition comprises the synthetic retinal derivative, such as a 9-cis-retinyl ester, and soybean oil. Another

embodiment of this aspect is wherein the pharmaceutically acceptable composition comprises a 9-cis-retinyl acetate and soybean oil. Yet another embodiment of this aspect is wherein the pharmaceutically acceptable composition comprises a 9-cis-retinyl acetate and soybean oil (USP grade).

In certain embodiments, the pharmaceutical composition further comprises an antioxidant. Another embodiment of this aspect is wherein the pharmaceutically acceptable composition comprises 9-cis-retinyl acetate, soybean oil, and butylated hydroxyanisole (BHA). Yet another embodiment of this aspect is wherein the pharmaceutically acceptable composition comprises 9-cis-retinyl acetate, soybean oil (USP grade), and butylated hydroxyanisole (BHA).

Unless defined otherwise in the specification, the following terms and phrases shall have the following meanings:

As used herein, "visual disorders" refers broadly to disorders in the photoreceptors, tissue or structures of the eye. Visual disorders include, but are not limited to, retinal degeneration, retinal dystrophy, retinal dysfunction, loss of photoreceptor function, photoreceptor cell death and structural abnormalities. Visual disorders of the disclosure are typically characterized by impaired or less than normal (including complete loss of) visual functions in a subject, which include, for example, impaired dark adaptation, impaired low luminance vision, impaired night vision, impaired contrast sensitivity, impaired glare recovery, and the like. Visual disorders of this disclosure may be associated with, for example, normal aging, age-related macular degeneration, age-related retinal dysfunction (AMD including wet AMD and early AMD), nyctalopia, and the like.

"Therapeutically effective amount" refers to that amount of a compound which, when administered to a subject having impaired dark adaptation and/or impaired low luminance vision, preferably a human, is sufficient to cause a clinically meaningful therapeutic effect. The term "therapeutic effect" as used herein refers to the improvement of the vision of a subject, in one or both eyes of the subject, wherein an improvement in the subject's visual function in one or both eyes during a therapeutic regimen of the disclosure can be

demonstrated by comparing the subject's visual functions of one or both eyes with a baseline measure of the subject's visual functions of one or both eyes prior to administration of a therapeutic regimen of the disclosure or by comparing the subject's visual functions of one or both eyes with a comparable human visual system not receiving the therapeutic regimen.

Clinically meaningful improvements can be documented by any of several known clinical measures discussed in this application. These measures and others are all well known to the clinicians and are routinely used in clinical practice. Clinicians are easily able to identify and observe these changes as part of routine clinical evaluations of subject with visual disorders associated with an endogenous retinoid deficiency, including impaired dark adaptation subjects. Consequently, clinicians are also easily able to observe the identify improvements in vision that are meaningful in the context of a given subject.

The synthetic retinal derivative can be administered prophylactically or

therapeutically to a subject. As used herein, "prophylactic" and "prophylactically" refer to the administration of a synthetic retinal derivative to prevent deterioration or further deterioration of the visual system, as compared with a comparable visual system not receiving the therapeutic regimen and methods of the present invention.

Suitable subjects include vertebrates, for example, human and non- human

vertebrates. Suitable non-human vertebrates include, for example, mammals, such as dogs (canine), cats (feline), horses (equine) and other domesticated animals.

Visual disorders associated with Retinoid Deficiency

The therapeutic regimens and methods of the disclosure are for the improvement of visual function in a subject, having loss of visual functions characterized by impaired dark adaptation and/or impaired low luminance vision.

Endogenous retinoid deficiency can be caused by one or more defects in the visual cycle which includes a slowing of the visual cycle, including impaired transport processes between the photoreceptors and retinal pigment epithelial cells (RPE). Figure 1

schematically shows a vertebrate, preferably the human, visual cycle (or retinoid cycle), which operates between the RPE and the outer segments of photoreceptors. 11-cis-retinal is regenerated through a series of enzymatic reactions and transport processes to and from the RPE after which it binds to opsin to form rhodopsin in the photoreceptor. Rhodopsin is then activated by light to form meta-rhodopsin which activates the phototransduction cascade while the bound cis-retinoid is isomerized to all-trans-retinal (von Lintig, J. et al., Trends Biochem Sci Feb 24 (2010)).

Subject Populations

Impaired dark adaptation is characteristic of normal aging and is associated with early stages of AMD. Localized endogenous retinoid deficiency in the eye of the aging or early AMD subject may therefore result in the slowing of the rod-mediated component of dark adaptation and low luminance vision by slowing rhodopsin regeneration rates. Age related macular degeneration (AMD) is one of the specific diseases associated with the posterior portion of the eyeball and is the leading cause of legal blindness among older people. AMD results in damage to the macula, a small circular area in the center of the retina. Because the macula is the area which enables one to discern small details and to read or drive, its deterioration may bring about diminished visual acuity and even legal blindness. The retina contains two forms of light receiving cells, rods and cones, that change light into electrical signals. The brain then converts these signals into the images. The macula is rich in cone cells, which provides central vision. People with AMD suffer deterioration of central vision but usually retain peripheral sight. Therefore, in certain embodiments, the subject is a human subject characterized as having age-related macular degeneration. AMD can be wet or exudative or dry or non-exudative forms (early forms). In certain embodiments, the subject is characterized as having non-exudative AMD without geographic atrophy. In AMD, vision loss occurs when complications late in the disease either cause new blood vessels to grow under the retina or the retina atrophies. Without intending to be bound by any particular theory, excessive production of waste products from the photoreceptors may overload the RPE due to a shortfall of 11-cis-retinal available to bind opsin. Free opsin is not a stable compound and can spontaneously cause firing of the biochemical reactions of the visual cascade without the addition of light. Excess unbound opsin randomly excites the visual transduction system. This creates noise in the system and thus more light and more contrast are necessary to see well. Quenching these free opsin molecules with a synthetic retinal may reduce spontaneous misfiring and increase the signal to noise ratio, thereby also improving night vision and contrast sensitivity.

In certain other embodiments, the synthetic retinal derivative is administered to an aging subject. As used herein, the term "subject" or "patient" refers to a vertebrate, for example a mammal such as a human. In one embodiment, the subject has an aging eye, which is characterized as having age-related impairment in dark adaptation, and/or impaired low luminance vision. In yet other aspects, a synthetic retinal derivative is administered to an aging subject, such as a human. As used herein, an aging human subject is typically at least 45, or at least 50, or at least 55, or at least 60, or at least 65 years old.

In certain other embodiments, the subject is characterized as an aging subject with

AMD. In certain embodiments, the subject is characterized as an aging subject with wet or dry AMD. In certain embodiments, the subject is characterized as an aging subject with dry AMD without geographic atrophy. In certain embodiments, the subject is characterized as an aging subject with AMD being least 45 years or age, or at least 50 years of age, or at least 55 years of age, or at least 60 years or age, or at least 65 years of age. In certain other embodiments, the subject is characterized as an aging subject of at least 60 years of age and as having non-exudative AMD without geographic atrophy.

In certain embodiments, the subject having impaired dark adaptation can be a subject categorized as having impaired dark adaptation associated with Night Blindness as defined by the World Health Organization (WHO), ICD-9-CM, which in turn is defined as a failure or imperfection of vision at night or in dim light, or an inability to see clearly in dim light.

In certain other embodiments, the subject having impaired dark adaptation can be further characterized as having an abnormal dark adaptation curve, abnormal threshold of cones or rods, delayed rod-cone break time, or delayed adaptation of cones or rods.

In certain other embodiments, the subject is characterized as a subject having impaired low luminance low contrast best corrected visual acuity (LLLC BCVA). In some embodiments, a subject is defined as having impaired low luminance vision when their LLLC BCVA score is more than 25 letters below their screening HLHC BCVA. In other embodiments, a subject is defined as having impaired low luminance vision when their LLLC BCVA score is more than 15 letters below their screening HLHC BCVA. Spatial contrast sensitivity impairments have been observed in older adults, and are accentuated at low luminance. These older adults report difficulties in accomplishing daily tasks, including difficulty reading under dim light and avoiding night driving. Poor vision under reduced light levels and at night in the elderly has been linked to their involvement in motor vehicle collisions as well as falls. Relative to younger subjects, under scotopic conditions, older adults require on average three times the contrast of younger adults in order to detect a target. The use of low contrast low luminance visual acuity testing allows for an evaluation of the degree of dysfunction in the visual system of the aging eye. Therapeutic interventions which can improve the sensitivity of the aging eye under these conditions provide an opportunity for the aging adults to improve their quality of life in low light conditions, and preserve a high-level of visual function into the advanced years of adulthood (Owsley, Vision Research, 51 : 1610-1622 (2011)).

Impaired dark adaptation may be due to an age-related inefficient retinoid cycle that leads to an excessive build-up of unbound opsin within the outer segments of the

photoreceptors and in the RPE. Excess unbound opsin may lead to a dynamic equilibrium with rhodopsin that can lead to phototransduction in the absence of photon capture. This may create a lower signal-to-noise ratio at the level of the visual cortex, which reduces low light and night vision, and impairs dark adaptation rates. Accumulation of extracellular material and deposits in the RPE and Bruch's membrane, such as cholesterol, may be due to excessive production and/or impaired clearance to the choroid, resulting in a localized retinoid deficiency in the aging and early AMD eye.

In certain other embodiments, the subject is characterized as an aging subject with impaired glare recovery, also known as photostress recovery. Glare recovery is defined as the time to recover high or low contrast visual acuity or other visual functions (e.g., contrast sensitivity) after exposure to a glare source of known illuminance, for a set exposure time. Glare recovery is therefore considered a method of measuring the rate of recovery of visual functions (e.g., visual acuity and/or contrast discrimination) in a subject after light exposure. The effect of the exposure to the glare source is to bleach the retinal pigments of the eye. Visual function returns as the retinal pigments are resynthesized in the outer segments of the photoreceptor. Longer glare recovery time is therefore associated with delayed rhodopsin regeneration rates, slow visual cycle, and local deficiencies of endogenous retinoid, such as 11-cis-retinal.

Without wishing to be bound by a particular theory, it is believed that the present disclosure may provide methods of improving visual function by competitively binding excess free opsin with a synthetic retinal derivative, for example 9-cis-retinyl acetate capable of providing 9-cis retinal, thereby forming a relatively stable isorhodopsin that may improve the signal-to-noise ratio leading to improved dark adaptation. It is hypothesized that the sequestration of excess opsin as isorhodopsin in the outer segment may lead to a lower background noise of spontaneous phototransduction from excess unbound opsin.

Synthetic Retinal Derivatives

The present disclosure provides methods of improving in a subject having impaired dark adaptation. Synthetic retinal derivatives can be administered to improve visual function, and/or to ameliorate the effects of a deficiency in retinoid levels. Visual function can be improved, for example, by providing a synthetic retinoid that can act as an 11-cis-retinoid replacement and/or an opsin agonist. The synthetic retinoid also can ameliorate the effects of a retinoid deficiency on a subject's visual system. A synthetic retinoid can be administered prophylactically (e.g., to a subject diagnosed with impaired dark adaptation, to prevent, slow, or delay deterioration or further deterioration of the subject's visual function, as compared to a comparable subject not receiving the synthetic retinoid) or therapeutically to a subject.

The synthetic retinal derivatives are retinoids derived from 11-cis-retinal or 9-cis- retinal. In certain embodiments, the synthetic retinal derivative is a synthetic 9- or 11-cis retinoid. In other embodiments, the synthetic retinoid is a derivative of 11-cis-retinal or 9-cis- retinal. In some embodiments, a synthetic retinal derivative can, for example, be a retinoid replacement, supplementing the levels of endogenous retinoid. In other embodiments, the synthetic retinal derivatives are 9- or 11-cis retinyl esters. In other embodiments, the synthetic retinal derivative is 9-cis-retinol or 11-cis-retinol. In other embodiments, the synthetic retinal derivative is 9-cis-retinal or 11-cis-retinal.

Without intending to be bound by any particular theory, in certain embodiments of the present invention, the synthetic retinal derivatives used in the therapeutic regimens of the disclosure provide replacements for endogenously produced 11-cis-retinal, thereby restoring the key biochemical component of the visual cycle. A synthetic retinal derivative suitable for the therapeutic regimens of the disclosure can be a derivative of 9-cis-retinal or 11-cis-retinal. Like 11-cis-retinal, 9-cis-retinal can bind to opsin to form photoactive isorhodopsin which, when bleached, undergoes conformational changes via the same photoproducts as 11-cis- retinal regenerated rhodopsin (Yoshizawa, T. et al, Nature 214, 566-571 (1967) and Filipek S. et al, Annu Rev Physiol 65:851-79 (2003)). 9-cis-retinal and its derivatives are generally more thermodynamically stable than their 11-cis retinal counterparts.

The synthetic retinal derivatives can be converted directly or indirectly into a retinal or a synthetic retinal analog. Thus, in some aspects, the compounds according to the present disclosure can be described as pro-drugs, which upon metabolic transformation are converted into 9-cis-retinal, 11-cis-retinal or a synthetic retinal derivative thereof. Metabolic transformation can occur, for example, by acid hydrolysis, esterase activity, acetyltransferase activity, dehydrogenase activity, or the like. For example, without wishing to be bound by theory, it is thought that a synthetic 9-cis-retinal derivative (e.g., a 9-cis-retinyl ester, such as 9-cis-retinyl acetate), is converted to 9-cis-retinol in the alimentary pathway, transported to the retina through the bloodstream and converted to 9-cis-retinal in the RPE.

In one embodiment, 9- and 11-cis-retinyl esters suitable for the methods of the present disclosure can be the 9-cis-retinyl esters or 11-cis-retinyl esters described in International Published Patent Application No. and WO 2006/002097 and Published U.S. Application No. 2010/0035986, which applications are incorporated herein by reference in their entireties. In certain embodiments of the present invention, the synthetic retinal derivatives can directly, or via a metabolite thereof, bind to opsin and function as an opsin agonist. As used herein, the term "agonist" refers to a synthetic retinal derivative that binds to opsin and facilitates the ability of the opsin/synthetic retinal derivative complex to respond to light. As an opsin agonist, a synthetic retinal derivative can create a pharmacological bypass of a blocked retinoid cycle, thus sparing the requirement for endogenous retinoid (e.g., 11-cis-retinal).

In certain embodiments, the 9- or 11-cis-retinyl ester for use in the present invention is not a naturally occurring retinyl ester normally found in the eye. In some embodiments, the 9- or 11-cis-retinyl ester is an isolated retinyl ester. As used herein, "isolated" refers to a molecule that exists apart from its native environment and is therefore not a product of nature. An isolated molecule may exist in a purified form or may exist in a non-native environment. In additional embodiments, the synthetic retinal derivative is 9-cis-retinol, 9- cis-retinal, 11-cis-retinol or 11-cis-retinal.

In one aspect, the 9- or 11-cis-retinyl ester can be a 9-cis-retinyl ester of formula I:

wherein A is -OC(0)R, and

R is an optionally substituted alkyl group or alkenyl group.

In certain embodiments, R is a CI to C24 straight chain or branched alkyl group, such as a Cl to C14 or Cl to C12 straight chain or branched alkyl group. In other embodiments, R can be a CI to CIO straight chain or branched alkyl group, such as a CI to C8 or a CI to C6 straight chain or branched alkyl group. Exemplary alkyl groups include methyl, ethyl, n- propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecanyl.

In certain embodiments, R is methyl.

In certain embodiments, R is a C15 alkyl group. In certain such embodiments, the compound of formula I is 9-cis-retinyl palmitate.

In certain embodiments, R is a C17 alkyl group. In certain such embodiments, the compound of formula I is 9-cis-retinyl stearate.

In certain embodiments, R is a C17 alkenyl group. In certain such embodiments, the compound of formula I is 9-cis-retinyl oleate.

In certain embodiments, R is a substituted alkyl or alkenyl group, such as an alkyl or alkenyl group substituted with one or more carboxylic acids. In certain embodiments, the alkyl or alkenyl group substituted with one or more carboxylic acids is further substituted with one or more hydroxyl groups. In certain embodiments of the foregoing, A is a polycarboxylic acid group, such as a di-, tri- or higher order carboxylic acid. For example, in some embodiments, A is a C2-C22, C3-C22, C2-C10, C3-C10, C4-C10, C4-C8, C4-C6 or C4 polycarboxylic acid group. Certain exemplary embodiments of the foregoing include embodiments wherein A is an oxalic acid (ethanedioic acid), malonic acid (propanedioic acid), succinic acid (butadedioic), fumaric acid (butenedioic acid), malic acid (2- hydroxybutenedioic acid), glutaric acid (pentanedioic acid), adipic acid (hexanedioic acid), pimelic acid (heptanedioic), suberic acid (octanedioic), azelaic acid (nonanedioic acid), sebacic acid (decanedioic acid), citric acid, oxaloacetic acid or ketoglutaratic acid group, or the like. In some embodiments, the polycarboxylic acid group is not tartaric acid. (In this context, the term "group" refers to a radical which may be covalently linked to the terminal carbon of the polyene chain of formula I.)

Examples of suitable synthetic 9-cis retinyl esters include, for example, 9-cis-retinyl acetate, 9-cis-retinyl succinate, 9-cis-retinyl citrate, 9-cis-retinyl ketoglutarate, 9-cis-retinyl fumarate, 9-cis-retinyl malate or 9-cis-retinyl oxaloacetate. In certain embodiments, the 9-

-retinyl ester is 9-ci

In a related aspect, the 11-cis-retinyl ester may be an 11-cis-retinyl ester of formula II

wherein A is -OC(0)R, and

R is an optionally substituted alkyl group or alkenyl group.

In certain embodiments, R is a CI to C24 straight chain or branched alkyl group, such as a Cl to C14 or Cl to C12 straight chain or branched alkyl group. In other embodiments, R can be a CI to CIO straight chain or branched alkyl group, such as a CI to C8 or a CI to C6 straight chain or branched alkyl group. Exemplary alkyl groups include methyl, ethyl, n- propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecanyl.

In certain embodiments, R is methyl.

In certain embodiments, R is a C15 alkyl group. In certain such embodiments, the compound of formula II is 11-cis-retinyl palmitate.

In certain embodiments, R is a C17 alkyl group. In certain such embodiments, the compound of formula II is 11-cis-retinyl stearate.

In certain embodiments, R is a C17 alkenyl group. In certain such embodiments, the compound of formula II is 11-cis-retinyl oleate. In certain embodiments, R is a substituted alkyl or alkenyl group, such as an alkyl or alkenyl group substituted with one or more carboxylic acids. In certain embodiments, the alkyl or alkenyl group substituted with one or more carboxylic acids is further substituted with one or more hydroxyl groups. In certain embodiments of the foregoing, A is a polycarboxylic acid group, such as a di-, tri- or higher order carboxylic acid. For example, in some embodiments, A is a C2-C22, C3-C22, C2-C10, C3-C10, C4-C10, C4-C8, C4-C6 or C4 polycarboxylic acid group. Certain exemplary embodiments of the foregoing include embodiments wherein A is an oxalic acid (ethanedioic acid), malonic acid (propanedioic acid), succinic acid (butadedioic), fumaric acid (butenedioic acid), malic acid (2- hydroxybutenedioic acid), glutaric acid (pentanedioic acid), adipic acid (hexanedioic acid), pimelic acid (heptanedioic), suberic acid (octanedioic), azelaic acid (nonanedioic acid), sebacic acid (decanedioic acid), citric acid, oxaloacetic acid or ketoglutaratic acid group, or the like. In some embodiments, the polycarboxylic acid group is not tartaric acid. (In this context, the term "group" refers to a radical which may be covalently linked to the terminal carbon of the polyene chain of formula II.).

Examples of suitable synthetic 11-cis retinyl esters include, for example, 11-cis- retinyl acetate, 11-cis-retinyl succinate, 11-cis-retinyl citrate, 11-cis-retinyl ketoglutarate, 11- cis-retinyl fumarate, 11-cis-retinyl malate or 11-cis-oxaloacetate. In certain preferred embodiments, the 11-cis-retinyl ester is 11-cis-retinyl acetate,

The term "acyl" is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)-, preferably alkylC(O)-.

The term "acylamino" is art-recognized and refers to an amino group substituted with an acyl group and may be represented, for example, by the formula hydrocarbylC(0)NH-, preferably alkylC(0)NH-.

The term "acyloxy" is art-recognized and refers to a group represented by the general formula hydrocarbylC(0)0-, preferably alkylC(0)0-. The term "aliphatic", as used herein, includes straight, chained, branched or cyclic hydrocarbons which are completely saturated or contain one or more units of unsaturation. Aliphatic groups may be substituted or unsubstituted.

The term "alkoxy" refers to an oxygen having an alkyl group attached thereto.

Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy and the like.

"Alkenyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing at least one unsaturation (i.e., C=C), having from two to up to twenty carbon atoms. In various embodiments, R is CI 2- 17 alkenyl, CI -8 alkenyl, CI -6 alkenyl or CI -4 alkenyl. Unless stated otherwise specifically in the specification, an alkyl group may be optionally substituted with one or more substituents. Such substituents may occur on one or more carbons that are included or not included in one or more double bonds. Exemplary substituents include halo (including -F, -Br, -CI and -I), cyano (-CN), nitro (-N02), oxo (=0), and hydroxyl (-OH).

In certain embodiments, "alkyl" refers to the radical of saturated aliphatic groups, including straight-chain alkyl groups and branched-chain alkyl groups. In certain

embodiments, an alkyl may comprise twelve to seventeen carbon atoms (also referred to as "C12-17 alkyl"). In certain embodiments, an alkyl may comprise twelve to fifteen carbon atoms (also referred to as "C12-15 alkyl"). In certain embodiments, an alkyl may comprise one to eight carbon atoms (also referred to as "CI -8 alkyl"). In other embodiments, an alkyl may comprise one to six carbon atoms (also referred to as "CI -6 alkyl"). In further embodiments, an alkyl may comprise one to four carbon atoms (also referred to as "CI -4 alkyl"). The alkyl is, for example, methyl, ethyl, n-propyl, 1-methylethyl (iso-propyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl, and the like.

Moreover, the term "alkyl" (or "lower alkyl") as used throughout the specification, examples, and claims is intended to include both "unsubstituted alkyls" and "substituted alkyls", the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents can include, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, an alkylthio, an acyloxy, a phosphoryl, a phosphate, a phosphonate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aryl or heteroaryl moiety. In certain embodiments, an alkyl group may be optionally substituted by one or more of the following substituents: halo (including -F, -Br, -CI and -I), cyano (-CN), nitro (-N02), oxo (=0), and hydroxyl (-OH).

The term "C _x _ _y " when used in conjunction with a chemical moiety, such as, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant to include groups that contain from x to y carbons in the chain. For example, the term "C _x _ _y alkyl" refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched-chain alkyl groups that contain from x to y carbons in the chain, including haloalkyl groups such as

trifluoromethyl and 2,2,2-tirfluoroethyl, etc. Co alkyl indicates a hydrogen where the group is in a terminal position, a bond if internal. The terms "C2- _y alkenyl" and "C2- _y alkynyl" refer to substituted or unsubstituted unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.

The term "alkylamino", as used herein, refers to an amino group substituted with at least one alkyl group.

The term "alkylthio", as used herein, refers to a thiol group substituted with an alkyl group and may be represented by the general formula alkylS-.

The term "alkynyl", as used herein, refers to an aliphatic group containing at least one triple bond and is intended to include both "unsubstituted alkynyls" and "substituted alkynyls", the latter of which refers to alkynyl moieties having substituents replacing a hydrogen on one or more carbons of the alkynyl group. Such substituents may occur on one or more carbons that are included or not included in one or more triple bonds. Moreover, such substituents include all those contemplated for alkyl groups, as discussed above, except where stability is prohibitive. For example, substitution of alkynyl groups by one or more alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups is contemplated. In preferred embodiments, an alkynyl has 1-12 carbons in its backbone, preferably 1-8 carbons in its backbone, and more preferably 1-6 carbons in its backbone. Exemplary alkynyl groups include propynyl, butynyl, 3-methylpent-l-ynyl, and the like.

The term "amide", as used herein, refers to a group wherein R ⁹ and R ¹⁰ each independently represent a hydrogen or hydrocarbyl group, or R ⁹ and

R ¹⁰ taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure.

The terms "amine" and "amino" are art-recognized and refer to both unsubstituted and substituted amines and salts thereof, e.g. , a moiety that can be represented by

wherein R ⁹ , R ¹⁰ , and R ¹⁰ each independently represent a hydrogen or a hydrocarbyl group, or R ⁹ and R ¹⁰ taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure.

The term "aminoalkyl", as used herein, refers to an alkyl group substituted with an amino group.

The term "aralkyl", as used herein, refers to an alkyl group substituted with one or more aryl groups.

The term "aryl", as used herein, include substituted or unsubstituted single-ring aromatic groups in which each atom of the ring is carbon. Preferably the ring is a 5- to 7- membered ring, more preferably a 6-membered ring. Aryl groups include phenyl, phenol, aniline, and the like.

The term "carbamate" is art-reco nized and refers to a group

wherein R ⁹ and R ¹⁰ independently represent hydrogen or a hydrocarbyl group, such as an alkyl group.

The terms "carbocycle", "carbocyclyl", and "carbocyclic", as used herein, refers to a non-aromatic saturated or unsaturated ring in which each atom of the ring is carbon.

Preferably a carbocycle ring contains from 3 to 10 atoms, more preferably from 5 to 7 atoms.

The term "carbocyclylalkyl", as used herein, refers to an alkyl group substituted with a carbocycle group.

The term "carbonate" is art-recognized and refers to a group -OC0 ₂ -R ⁹ , wherein R ⁹ represents a hydrocarbyl group, such as an alkyl group. The term "carboxy", as used herein, refers to a group represented by the formula -

C0 ₂ H.

The term "cycloalkyl", as used herein, refers to the radical of a saturated aliphatic ring. In preferred embodiments, cycloalkyls have from 3-10 carbon atoms in their ring structure, and more preferably from 5-7 carbon atoms in the ring structure. Suitable cycloalkyls include cycloheptyl, cyclohexyl, cyclopentyl, cyclobutyl and cyclopropyl.

The term "ether", as used herein, refers to a hydrocarbyl group linked through an oxygen to another hydrocarbyl group. Accordingly, an ether substituent of a hydrocarbyl group may be hydrocarbyl-O-. Ethers may be either symmetrical or unsymmetrical.

Examples of ethers include, but are not limited to, heterocycle-O-heterocycle and aryl-O- heterocycle. Ethers include "alkoxyalkyl" groups, which may be represented by the general formula alkyl-O-alkyl.

The terms "halo" and "halogen", as used herein, means halogen and includes chloro, fluoro, bromo, and iodo.

The term "heteroalkyl", as used herein, refers to a saturated or unsaturated chain of carbon atoms including at least one heteroatom (e.g., O, S, or NR ⁵⁰ , such as where R ⁵⁰ is H or lower alkyl), wherein no two heteroatoms are adjacent.

The terms "hetaralkyl" and "heteroaralkyl", as used herein, refers to an alkyl group substituted with a hetaryl group.

The terms "heteroaryl" and "hetaryl" include substituted or unsubstituted aromatic single ring structures, preferably 5- to 7-membered rings, more preferably 5- to 6-membered rings, whose ring structures include at least one heteroatom (e.g., O, N, or S), preferably one to four or one to 3 heteroatoms, more preferably one or two heteroatoms. When two or more heteroatoms are present in a heteroaryl ring, they may be the same or different. The terms "heteroaryl" and "hetaryl" also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heteroaromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls. Preferred polycyclic ring systems have two cyclic rings in which both of the rings are aromatic. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, quinoline, and pyrimidine, and the like. The term "heteroatom", as used herein, means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, and sulfur.

The terms "heterocyclyl", "heterocycle", and "heterocyclic" refer to substituted or unsubstituted non-aromatic ring structures, preferably 3- to 10-membered rings, more preferably 3- to 7-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. Heterocyclyl groups include, for example, piperidine, piperazine, pyrrolidine, morpholine, lactones, lactams, and the like.

The term "heterocyclylalkyl", as used herein, refers to an alkyl group substituted with a heterocycle group.

The term "hydrocarbyl", as used herein, refers to a group that is bonded through a carbon atom that does not have a =0 or =S substituent, and typically has at least one carbon- hydrogen bond and a primarily carbon backbone, but may optionally include heteroatoms. Thus, groups like methyl, ethoxyethyl, 2-pyridyl, and trifluoromethyl are considered to be hydrocarbyl for the purposes of this application, but substituents such as acetyl (which has a =0 substituent on the linking carbon) and ethoxy (which is linked through oxygen, not carbon) are not. Hydrocarbyl groups include, but are not limited to aryl, heteroaryl, carbocycle, heterocycle, alkyl, alkenyl, alkynyl, and combinations thereof.

The term "lower" when used in conjunction with a chemical moiety, such as, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant to include groups where there are ten or fewer non-hydrogen atoms in the substituent, preferably six or fewer. A "lower alkyl", for example, refers to an alkyl group that contains ten or fewer carbon atoms, preferably six or fewer. Examples of straight chain or branched chain lower alkyl include methyl, ethyl, isopropyl, propyl, butyl, tertiary-butyl, and the like. In certain embodiments, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy substituents defined herein are respectively lower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl, or lower alkoxy, whether they appear alone or in combination with other substituents, such as in the recitation aralkyl (in which case, for example, the atoms within the aryl group are not counted when counting the carbon atoms in the alkyl substituent).

The terms "polycyclyl", "polycycle", and "polycyclic" refer to two or more rings

(e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls) in which two or more atoms are common to two adjoining rings, e.g., the rings are "fused rings". Preferred polycycles have 2-3 rings. Each of the rings of the polycycle can be substituted or unsubstituted. In certain embodiments, each ring of the polycycle contains from 3 to 10 atoms in the ring, preferably from 5 to 7.

The term "substituted" refers to moieties having substituents replacing a hydrogen on one or more carbons of the backbone. It will be understood that "substitution" or "substituted with" includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by

rearrangement, cyclization, elimination, etc. As used herein, the term "substituted" is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of the disclosure, the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. Substituents can include any substituents described herein, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, an alkylthio, an acyloxy, a phosphoryl, a phosphate, a phosphonate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety.

Unless specifically stated as "unsubstituted," references to chemical moieties herein are understood to include substituted variants. For example, reference to an "aryl" group or moiety implicitly includes both substituted and unsubstituted variants.

The term "sulfate" is art-recognized and refers to the group -OSO ₃ H, or a

pharmaceutically acceptable salt or ester thereof.

The term "sulfonamide" is art-recognized and refers to the group represented by the general formulae wherein R ⁹ and R ¹⁰ independently represents hydrogen or hydrocarbyl, such

The term "sulfoxide" is art-recognized and refers to the group -S(0)-R ⁹ , wherein R ⁹ represents a hydrocarbyl, such as alkyl, aryl, or heteroaryl.

The term "sulfonate" is art-recognized and refers to the group -SO ₃ H, or a

pharmaceutically acceptable salt or ester thereof.

The term "sulfone" is art-recognized and refers to the group -S(0) ₂ -R ⁹ , wherein R ⁹ represents a hydrocarbyl, such as alkyl, aryl, or heteroaryl.

The term "thioester", as used herein, refers to a group -C(0)SR ⁹ or -SC(0)R ⁹ wherein R ⁹ represents a hydrocarbyl, such as alkyl.

The term "thioether", as used herein, is equivalent to an ether, wherein the oxygen is replaced with a sulfur.

The term "urea" is art-recognized and may be represented by the general formula

wherein R ⁹ and R ¹⁰ independently represent hydrogen or a hydrocarbyl, such

At various places in the present specification substituents of compounds of the disclosure are disclosed in groups or in ranges. It is specifically intended that the disclosure include each and every individual subcombination of the members of such groups and ranges. For example, the term "Ci-C ₆ alkyl" is specifically intended to individually disclose methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, etc.

In certain embodiments, the 9-cis-retinyl esters can be converted by the liver to a metabolic pro-drug form, namely fatty acid 9-cis-retinyl esters, which are stored in the liver in hepatic lipid droplets. Fatty acid 9-cis-retinyl esters and retinol are mobilized from the liver and enter the circulation where they travel to the eye and RPE. There, they are converted to 9-cis-retinal which ultimately combines with photoreceptor opsins to form active visual pigments.

A preferred 9-cis-retinyl ester is 9-cis-retinyl acetate. Also referred to as "9-cis-R- Ac", 9-cis-retinyl acetate is which is metabolized by the liver to fatty acid 9-cis-retinyl esters, such as 9-cis-retinyl palmitate. Fatty acid 9-cis-retinyl esters and retinol are then converted to 9-cis-retinal in the eye and RPE as replacement of deficient chromophores such as 11-cis- retinal. In one embodiment, 9-cis-R-Ac can be prepared by initially converting all-trans- retinyl acetate (Sigma-Aldrich) to a mixture of 9-cis-retinyl acetate and all-trans-retinyl acetate in the presence of a palladium catalyst (e.g., palladium salts, palladium oxides). The mixture of 9-cis-retinyl acetate and all-trans-retinyl acetate are then hydrolyzed to produce a mixture of 9-cis-retinol and all-trans-retinol. The pure 9-cis-retinol can be isolated by selective recrystallization and further esterified to pure 9-cis-R-Ac. A detailed description of the processes for preparing and purifying 9-cis-R-Ac can be found, for example, in GB Patent No. 1452012.

In certain embodiments, the 9-cis-retinyl esters described herein can be prepared from 9-cis-retinol using appropriate esterifying agents in a manner similar to the preparation of 9- cis-R-Ac, the methods of which are within the knowledge of one skilled in the art.

In certain embodiments, 9- and 11-cis-retinyl esters can be formed by methods known in the art such as, for example, by acid-catalyzed esterification of a retinol with a carboxylic acid, by reaction of an acyl halide with a retinol, by transesterification of a retinyl ester with a carboxylic acid, by reaction of a primary halide with a carboxylate salt of a retinoic acid, by acid-catalyzed reaction of an anhydride with a retinol, or the like. In an exemplary embodiment, 9- and 11-cis-retinyl esters can be formed by acid-catalyzed esterification of a retinol with a carboxylic acid, such as, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, caprylic acid, pelargonic acid, capric acid, lauric acid, oleic acid, stearatic acid, palmitic acid, myristic acid, linoleic acid, succinic acid, fumaric acid or the like. In another exemplary embodiment, retinyl esters can be formed by reaction of an acyl halide with a retinol (see, e.g., Van Hooser et al, Proc. Natl. Acad. Sci. USA, 97:8623-28 (2000)).

Suitable acyl halides include, for example, acetyl chloride, palmitoyl chloride, or the like.

In certain embodiments, trans-retinoids can be isomerized to cis-retinoids by exposure to UV light. For example, all-trans-retinal, all-trans-retinol, all-trans-retinyl ester or all-trans- retinoic acid can be isomerized to 9-cis -retinal, 9-cis-retinol, 9-cis-retinyl ester or 9-cis - retinoic acid, respectively. Trans-Retinoids can be isomerized to 9-cis-retinoids by, for example, exposure to a UV light having a wavelength of about 365 nm, and substantially free of shorter wavelengths that cause degradation of cis-retinoids, as further described herein.

In another embodiment of the disclosure, trans-retinoids can be isomerized to cis- retinoids by exposure to UV light. For example, all-trans-retinal, all-trans-retinol, all-trans- retinyl ester or all-trans-retinoic acid can be isomerized to 9-cis-retinal, 9-cis-retinol, 9-cis- retinyl ester or 9-cis-retinoic acid, respectively, by exposure to a UV light having a wavelength of about 365 nm, and substantially free of shorter wavelengths that cause degradation of cis-retinoids, as further described herein.

The synthetic retinal derivative of the disclosure can be substantially pure in that it contains less than about 5% or less than about 1%, or less than about 0.1%, of other retinoids. One or more synthetic retinal derivatives may be used in the therapeutic regimens of the disclosure.

Pharmaceutically Acceptable Compositions of the Disclosure

Synthetic retinal derivatives, including 9- and 11-cis-retinyl esters, of the disclosure can be formulated for oral administration using pharmaceutically acceptable vehicles as well as techniques routinely used in the art. In certain embodiments, the synthetic retinal derivative is formulated into a formulation suitable for oral administration. Most of the synthetic retinal derivatives are oily substances and lipophilic and are therefore easily miscible with one or more lipid vehicles.

Synthetic retinal derivatives, including 9- and 11-cis-retinyl esters, of the disclosure (e.g., 9-cis-retinyl esters) are light- and oxygen-sensitive. It is therefore desirable to maintain the stability and maximize the efficacy and shelf-life of the formulation. A suitable lipid vehicle may be selected based on its ability to stabilize the synthetic retinal derivatives suspended or solubilized therein. As used herein, "lipid" or "lipid vehicle" refers to one or a blend of fatty acid esters. In various embodiments, the lipid vehicle comprises one or more triglycerides, which are formed when a single glycerol is esterified by three fatty acids.

Triglycerides include both vegetable oils and animal fats. In various embodiments, the lipid vehicle comprises more than 50 w/w% polyunsaturated fatty acids, the polyunsaturated fatty acids including an omega-6 fatty acid and an omega-3 fatty acid in a ratio (by weight) of less than 15.

In a preferred embodiment, the synthetic retinal derivatives, for example 9- or 11-cis- retinyl esters, are formulated into an oral formulation comprising a retinal derivative, such as a 9- or 11-cis-retinyl ester, and a lipid vehicle. In a further embodiment, the 9- or 11-cis- retinyl ester is 9-cis-retinyl acetate, and the lipid vehicle is soy bean oil. In a further embodiment, the formulation further comprises an antioxidant. In certain such embodiments, the antioxidant is butylated hydroxyanisole (BHA). The description of additional lipid vehicles and formulations suitable for use with the present invention can be found in, for example, International Patent Application No. PCT/US2009/059126 in the name of QLT Inc., the relevant disclosure of which is incorporated herein in its entirety.

Additional suitable oral dosage forms include, for example, tablets, pills, sachets, or capsules of hard or soft gelatin, methylcellulose or of another suitable material easily dissolved in the digestive tract. Suitable nontoxic solid carriers can be used which include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like. (See, e.g., Remington "Pharmaceutical Sciences'", 17 Ed., Gennaro (ed.), Mack Publishing Co., Easton, Pennsylvania (1985).)

The present disclosure also provides kits that contain a synthetic retinal derivative, preferably a 9- or 11-cis-retinyl ester or a pharmaceutically acceptable composition thereof. The kit also includes instructions for the use of the synthetic retinal derivative in the therapeutic regimens and methods of the disclosure. Preferably, a commercial package will contain one or more unit doses of the synthetic retinal derivative, for example, one or more unit doses of a 9- or 11-cis-retinyl ester or the pharmaceutically acceptable composition for use in a therapeutic regimen or method of the disclosure. It will be evident to those of ordinary skill in the art that the synthetic retinal derivative, for example a 9- or 11-cis-retinyl ester or pharmaceutically acceptable compositions thereof which are light and/or air sensitive may require special packaging and/or formulation. For example, packaging may be used for the kit which is opaque to light, and/or sealed from contact with ambient air, and/or formulated with suitable excipients.

Dosage, Dosage Frequency and Modes of Administration

The synthetic retinal derivatives and pharmaceutically acceptable pharmaceutical compositions comprising the synthetic retinal derivatives used in the therapeutic regimens of the disclosure may be in the form of an oral dose. In one embodiment, a pharmaceutically acceptable composition of the disclosure comprising a 9- or 11-cis-retinyl ester and a lipid vehicle is administered orally to the subject in the therapeutic regimen of the disclosure. In another embodiment of the disclosure, the orally-administered pharmaceutically acceptable composition of the disclosure comprises a 9-cis-retinyl ester and soybean oil. In another embodiment of the disclosure, the orally-administered pharmaceutically acceptable composition comprises 9-cis-retinyl acetate or 9-cis-retinyl succinate and soybean oil (USP grade).

Oral administration of the synthetic retinal derivative, for example a 9- or 11-cis- retinyl ester, of the disclosure has several potential advantages, including exposure of all photoreceptors in both eyes of the subject undergoing the therapeutic regimen of the disclosure to therapy, lack of surgical intervention, and cessation of administration at any time.

The therapeutic regimens of the present disclosure produce meaningful improvement of visual function, while exhibiting an acceptable safety profile, in, and thus in one embodiment, the therapeutic regimens of the present disclosure may be suitable as a long- term (chronic) therapeutic regimen.

The length of time between the first therapeutic dosing cycle and a second or subsequent therapeutic dosing cycle may be selected based on the persistence or increase in one or more of the subject's visual function parameters, as defined herein during the time between dosing cycles. Dosing-dependent effects or improvement in the subject's visual functions may be observed and assessed on an individual basis to allow for customization of the subject's dosing requirements during the time following the dosing cycle. Alternatively, administration of a second dosing cycle may be based on a decrease in one or more of the subject's visual function parameters relative to previous efficacy assessments during a first dosing cycle and any subsequent time without dosing. At any point of the assessment, a subsequent therapeutic dosing cycle may be administered based on a regression of one or more of the subject's visual function parameters during the time following the dosing cycle.

Following oral administration of the composition, without wishing to be bound by any particular theory, it is believed that the drug is incorporated into lipid droplets in the liver and in the RPE (called retinosomes) from which it is mobilized. Imanishi Y. et al. J Cell Biol

166:447-53 (2004). It is secreted by the liver bound to retinol binding-protein 4 (RBP4) and delivered to peripheral tissues, whereas in the eye it is oxidized to its aldehyde form which feeds back into the retinoid cycle (Figure 1). Moise A.R. et al. Biochemistry 46:4449-58 (2007). Retinols, regardless of their isomeric form, are also stored in adipocytes and mobilized as needed into the circulation. O'Byrne S.M. et al. J Biol Chem 280:35647-

57(2005). Thus, the long-term effects of this chromophore analog may derive from the fact that active drug is slowly released from adipocytes in the periphery. Evaluation of Therapeutic Effect

The effectiveness of the therapeutic regimens of the disclosure in improving visual function in a subject with impaired dark adaptation and/or impaired low luminance vision can be evaluated based on several measures of vision function, including those as described below.

Improvements in the subject's visual functions in one or both eyes may be evaluated based on measures of rates of dark adaptation, low luminance low contrast best corrected visual acuity (LLLC BCVA), or glare recovery time. Improvements in the subject's visual functions in one or both eyes during a therapeutic regimen of the disclosure can be demonstrated by comparing the subject's visual functions of each eye with a baseline measure of the subject's visual functions of each eye prior to administration of a therapeutic regimen of the disclosure or by comparing the subject's visual functions of each eye with a

comparable human visual system not receiving the therapeutic regimen.

I. Dark Adaptation

Dark adaptation is defined as the recovery of light sensitivity by the retina in the dark after exposure to a bright light. Impairment in dark adaptation rates is associated with a range of visual disease states, and is often associated with aging and early AMD. Dark adaptation parameters include, but are not limited to, the time constant of the cone-mediated sensitivity recovery, the time constant of rod-mediated sensitivity recovery, the cone plateau, the rod plateau, the rod-cone break, the rod intercept, the slope and/or time constant of the first component of the rod-mediated recovery, the slope and/or time constant of the second component of the rod-mediated recovery, the transition time between the first and second rod-mediated components, and the duration from the bleaching to the final threshold measurement.

Methods to measure dark adaptation are known in the art, including those methods defined in US 7,494,222 and US 7,798,646, the contents of which are herein incorporated by reference, and as defined in Jackson et al. 2006.

In one embodiment, dark adaptation testing may be performed using a Diagnosys

LLC, Espion E3 Electroretinography system with Colordome and button box, or equivalent. The study eye may be dilated prior to the test and the fellow eye patched. After the study eye has fully dilated, subjects are exposed to a bleaching light source (for example a one second or less flash from a strobe light) while looking into the Colordome. Alternatively, once the study eye has fully dilated, the subject may be placed in a completely dark room with their head in the full-field Diagnosys Colordome Ganzfeld. Bleaching light may then be emitted in the Colordome (for example, white light, produced by all four LEDs, which is ramped up from 0 to 2000 cd/m ² over 30 seconds and then maintained at 2000 cd/m ² for an additional 150 seconds). Once the bleach process is complete, the Colordome may be darkened and the subjects respond when they see a full-field stimulus in the Colordome that measures their return to specific threshold sensitivities. An ascending method of limits procedure of increasing brightness of flashes may be used to estimate detection thresholds over a period of 30 minutes. The dark adaptation analysis of the threshold data may be derived from a nonlinear regression technique for modeling the kinetics of dark adaptation (McGwin et al., Behavior Research Methods, Instruments and Computers, 31(4), 712-717 (1999)), and may be performed using appropriate modeling software, such as the SAS JMP software. The threshold level of the asymptote of the exponential portion of the equation may be identified as the Cone Threshold Plateau. The linear portion of the equation threshold may be fit to the values from rod responses to full-field stimulus threshold levels less than the asymptote derived from the fit to the exponential portion of the equation but more than a value which is 2 log units below this level. The time corresponding with the intercept of these two curves may then be calculated in order to arrive at the rod-cone break time. The rod-cone break time is defined as the time at which the rods first become more sensitive than the cones. The rod threshold time is defined as the time at which visual sensitivity recovers to two log units below the rod-cone break sensitivity. The slope of the linear portion of the equation may be calculated to define the rod adaptation slope. In certain embodiments, impaired dark adaptation may be defined as a rod-cone break time of about 11.0 to 17.3 minutes. In other embodiments, impaired dark adaptation may be defined as a rod-cone break time of 9 minutes or more.

Improvements in the rate of dark adaptation, defined as the subject's rod-cone break time, rod threshold time, or rod adaptation slope, may be determined based on a comparison of a subject's rate of dark adaptation after treatment as compared to the subject's baseline rate. In one embodiment, the improvement in the subject's dark adaptation time is at least 30%, or at least 25%, or at least 20% or at least 15% from baseline. In one embodiment, the improvement in the subject's dark adaptation time comprises decreasing the time to the rod- cone break by about 5 to about 10 minutes (e.g., by 5, 6, 7, 8, 9 or 10 minutes), by 5 to about 8 minutes (e.g., by 5, 6, 7, or 8 minutes), or by about 1 to about 5 minutes (e.g., by 1, 2, 3, 4, or 5 minutes). In some embodiments, the improvement in the subject's dark adaptation time may be demonstrated by comparing the subject's dark adaptation rate with a comparable human visual system not receiving the therapeutic regimen.

In one embodiment of the therapeutic regimens of the invention, the subject's rate of dark adaptation improves during the initial dosing period as compared to the subject's rate of dark adaptation at baseline before dosing. In certain embodiments, the subject's rate of dark adaptation continues to improve during the resting period between dosing periods as compared to the subject's rate of dark adaptation at the end of the initial dosing period. In certain embodiments, the improvement in the subject's rate of dark adaptation is sustained during the resting period at about the subject's rate of dark adaptation at the end of the initial dosing period. In certain embodiments, the improvement in the subject's rate of dark adaptation is sustained at a level above the subject's baseline rate of dark adaptation during the resting period.

2. Low Luminance Low Contrast Visual Acuity

High luminance high contrast best corrected visual acuity (HLHC BCVA) has been noted to be maintained on average until age 65 to 70 (Haegerstrom-Portnoy et al., 1999). In certain embodiments, analysis of HLHC BCVA can therefore be used as a baseline to identify subjects with impairment of low luminance low contrast LLLC BCVA, based on a LLLC BCVA score which is below their HLHC BCVA score.

LogMAR charts, particularly the Early Treatment Diabetic Retinopathy Study (ETDRS) charts have become the gold-standard for measuring VA in clinical trials. This method measures vision under high contrast and standard room lighting conditions.

Impairment in low luminance vision may be evaluated using low-luminance, low- contrast visual acuity tests. The Smith-Kettlewell Institute Low Luminance (SKILL) Chart was designed to assess vision under conditions of low contrast that simulates low lighting, through a test performed with standard indoor lighting. The SKILL Chart has a high-contrast near-acuity chart on one side (black letter on white), and a low-luminance, low-contrast chart on the other (gray letters on a dark background). The low reflectance of the dark side of the card simulates testing in a dim environment. Alternatively, low-luminance may be achieved through use of tinted goggles worn by the subject.

Testing parameters used in the HLHC BCVA testing may be employed, with the application of low contrast ETDRS charts. Low contrast ETDRS charts include, for example, the Precision Vision Standard LC 4 Meter ETDRS charts at 2.5%, 5%, and 10% contrast. Subjects may be identified as having impaired low luminance vision when their LLLC BCVA scores fewer letters than their screening HLHC BCVA. In certain embodiments, the LLLC BCVA score is more than 25 letters below their screening HLHC BCVA.

In certain embodiments of the present invention, the degree of improvement in LLLC visual acuity over baseline may be dependent on the subject's baseline visual acuity. For patients with very low visual acuity (light perception or hand waving, zero letters), clinically meaningful improvement may be associated with an improvement of 1-5 ETDRS letters. In certain embodiments, the subject may have a LLLC VA improvement of >5 ETDRS letters upon administration of a first therapeutic dose. In certain embodiments, the subject may have a LLLC VA improvement of >5 to <10 upon administration of a first therapeutic dose. In certain embodiments, the subject may have a LLLC VA improvement of >10 to <15 letters upon administration of a first therapeutic dose. In certain embodiments, the subject may have LLLC VA improvements of >15 to <20 letters upon administration of a first therapeutic dose. In certain embodiments, the subject may have LLLC VA improvements of >20 letters upon administration of a first therapeutic dose. Thus, in one embodiment of the therapeutic regimens of the invention, the subject's LLLC visual acuity improves during the initial dosing period as compared to the subject's visual acuity level prior to the treatment during the initial dosing period, i.e, the subject's visual acuity baseline. In certain embodiments, the subject's visual acuity continues to improve during the resting period as compared to the improvement in the subject's visual acuity level observed at the end of the initial dosing period. In certain embodiments, the improvement in the subject's visual acuity is sustained above the subject's baseline level during the resting period.

3. Glare Recovery

Glare recovery, also known as photostress recovery, has been noted to be impaired in aging subjects and subjects with early AMD (Lovie-Kitchin and Feigl, 2005). Glare recovery is defined as the time to recover visual function (e.g., high or low contrast visual acuity) after exposure to a glare source of known illuminance, for a set exposure time. Glare recovery is therefore considered a method of measuring the rate of recovery of contrast detection in a subject after light exposure. The effect of the exposure to the glare source is to bleach the retinal pigments of the eye. Visual function returns as the retinal pigments are resynthesized in the outer segments of the photoreceptor. Longer glare recovery time is therefore associated with delayed rhodopsin regeneration rates, slow visual cycle, and local

deficiencies of endogenous retinoid, such as 11-cis-retinal.

Methods to measure glare recovery are known in the art, including those methods defined in Elliot and Whitaker, 1991. Glare recovery may be measured by first adapting the subject's study eye to a low luminance environment through use of tinted 4% transmission goggles for 10 minutes. The subject may then remove the goggles and position their head within a full-field Diagnosys Colordome Ganzfeld to receive a glare of 5000 cd/m ² for 10 seconds in their study eye. After 7 seconds but before 10 seconds of the glare process, a xenon light may be triggered to deliver two 2 millisecond 3000 cd*s/m ² flashes at an interval of 2 milliseconds apart. The timer may be started at the end of the 10 second glare process. Trial lens frames with correct refraction may be placed on the subject and the tinted 4% transmission goggles paced over the trial lens frames. The subject may then begin reading letters from the scrambled version of the LC chart used in their LLLC BCVA test (i.e., 2.5%, 5% or 10% contrast) performed at screening, starting three lines above the best line from their LLLC BCVA baseline result. The timer may be stopped as soon as the subject has read the third correct letter on the line above their best line from the LLLC BCVA test at baseline. Alternatively, glare recovery may be measured using low contrast visual acuity charts, including the Precision Vision Scrambled LC ETDRS chart. Glare recovery may be measured after the LLLC BCVA has been established for the subject. After exposure to a glare source (for example, a one second or less flash from a strobe light), a subject wearing tinted goggles attempts to read a scrambled version of the LC chart used in their LLLC BCVA test. Timing begins immediately following the flash of light, and ends when the subject has read within 5 letters of their LLLC BCVA score.

In one embodiment of the therapeutic regimens of the invention, the subject's glare recovery time improves during the initial dosing period as compared to the subject's glare recovery time prior to the treatment during the initial dosing period, i.e, the subject's baseline. In certain embodiments, the subject's glare recovery time continues to improve during the resting period between dosing periods as compared to the subject's glare recovery time at the end of the initial dosing period. In certain embodiments, the improvement in the subject's glare recovery time is sustained during the resting period at about the subject's glare recovery time at the end of the initial dosing period. In certain embodiments, the improvement in the subject's glare recovery time is sustained at a level above the subject's baseline glare recovery time during the resting period.

In some embodiments, improvements in the subject's glare recovery time is at least 5 seconds to at least 65 seconds from baseline, such as 1 minute from baseline. In some embodiments, improvements in the subject's glare recovery time is at least 5 seconds to at least 20 seconds from baseline (e.g., at least 5 seconds, 10 seconds, 15 seconds, or 20 seconds). In one embodiment, the improvement in the subject's glare recovery time may be demonstrated by comparing the subject's glare recovery rate with a comparable human visual system not receiving the therapeutic regimen.

4. Visual Function Questionnaires and Patient Reported Outcomes

Visual function questionnaires may be administered to subjects at certain study visits to assess visual function and its effects on activities of daily living. There are a number of known Visual Function Questionnaires (VFQ's) which may be used to assess improvement in a subject's visual function. The Low Luminance Questionnaire (LLQ) is a questionnaire that has been developed specifically to assess visual performance of adults in low lighting conditions, such as night-time or darkened rooms (see, e.g., Owsley, C, McGwin G, Scilley K, et al, Invest Ophthalmol Vis Sci 47:528-535 (2006). This questionnaire has been used in assessing self-reported visual problems under low luminance and at night in studies on AMD.

Treatment effects on dark adaptation may also be monitored using subjective, patient reported outcomes, which document improvements in activities of daily living related to the rate of a subject's vision to dark-adapt when transitioning from light to dark environments. Patient-reported outcomes and questionnaires assist in identifying subjective improvements in visual function following administration of a compound of the invention by the therapeutic regimens described herein through comparison of the subject's questionnaire results after treatment and during the resting period as compared to the subject's questionnaire results at baseline, or by evaluating patient-reported outcomes relating to the effect of treatment on activities of daily living requiring rod-mediated vision, including mobility tasks under low lighting.

Examples

Example 1 : Impaired Dark Adaptation

The following study will be performed to evaluate the safety of 9-cis-retinyl acetate in adults with impaired dark adaptation or impaired low luminance low contrast best corrected visual acuity (LLLC BCVA). In addition, the study will determine if oral doses of 9-cis- retinyl acetate at either 10 or 40 mg/m ² dosed once per week for three consecutive weeks with one additional dose the day after the third dose improve impaired dark adaptation time, improve glare recovery time, or improve low luminance low contrast best corrected visual acuity (LLLC BCVA).

Overall Study Design

This will be a randomized, single-masked, parallel-design, safety/proof-of-concept study. The study will include approximately 40 subjects with impaired dark adaptation or impaired LLLC BCVA in at least 1 eye and no known ophthalmic pathologies to explain their condition other than early age-related macular degeneration (AMD). The Investigator will select one eye from each subject to be assessed as the study eye. Subjects who meet the eligibility criteria will be randomized to receive one of the following oral doses of 9-cis- retinyl acetate at Day 0, Day 7, Day 14 and Day 15: 0 (placebo), 10, or 40 mg/m ² in a 2:3:3 randomization ratio. Those randomized to placebo will receive the same formulation without the active pharmaceutical ingredient. Dark adaptation time, LLLC BCVA, and glare recovery will be assessed at screening and repeated on Day 0, Day 7, Day 14, and Day 15 prior to dosing and on Day 17, Day 28 and Day 42 to evaluate efficacy. Safety assessments (HLHC BCVA, biomicroscopic examinations, vital signs, adverse events, concomitant medications) will be conducted before the initial dose and at all study visits. IOP measurement and dilated fundus examination will be performed at screening and Day 42. Clinical chemistry, hematology, and urinalysis samples will be collected at screening, prior to dosing on Day 7 and at follow-up visits on Day 17 and Day 42.

Approximately 40 subjects will be enrolled in this study. To be eligible for the study, subjects must fulfill all of the following criteria:

1. Male or female subjects >60 years old. 2. Subjects with early AMD in the study eye (defined as non-exudative AMD without geographic atrophy), who have:

- LLLC BCVA that is more than 25 letters (about 5 lines) below their HLHC BCVA (Haegerstrom-Portnoy 1999), or, evidence of impaired dark adaptation, defined as a rod-cone break dark adaptation time of 11.0-17.3 minutes (Jackson 2006)

3. Subjects who have ETDRS HLHC BCVA score in the study eye of 0.3 logMAR (Snellen equivalent of 20/40) or better.

Subjects excluded from the study will include those meeting any of the following criteria:

1. Women of child-bearing potential.

2. Subjects with late AMD, including any atrophy or neovascularization in the study eye.

3. Subjects who have ETDRS HLHC BCVA score in the study eye of worse than 0.3 logMAR (Snellen equivalent of worse than 20/40).

4. Subjects who are actively participating in an experimental therapy study or who have received experimental therapy within 60 days of Day 0.

5. Subjects who, in the study eye, have glaucoma, optic neuropathy, AMD that is exudative or shows geographic atrophy, or any ocular conditions other than early AMD, or refractive error (spherical equivalent) having an absolute value >6 diopters.

6. Subjects with posterior subcapsular cataract or a multifocal intra-ocular lens (such as ReStor™, ReZoom® or Tecnis®) in the study eye (subjects with non- visually significant cataracts or standard or accommodating intra-ocular lens [such as

Crystalens®] in the study eye are eligible to participate).

7. Subjects with severe osteoporosis (determined at the discretion of the Investigator).

8. Subjects who have neurological diseases such as Alzheimer's disease, Parkinson's disease, history of stroke or multiple sclerosis, and/or diabetes, or conditions which in the Investigator's opinion will not allow the subject to perform the psychophysical task used to measure dark adaptation or LLLC BCVA.

9. Subjects who, in the Investigator's opinion, have any severe acute or chronic medical condition, psychiatric condition, or laboratory abnormality that may increase the risk associated with study participation or administration of study drug, or interfere with the interpretation of study results. 10. Subjects who have taken any prescription or investigational oral retinoid medication (e.g., Accutane®, Soriatane®) within 6 months of Day 0 and subjects who did not tolerate their previous oral retinoid medication, regardless of the time of last exposure.

11. Subjects who have used a daily mega-dose of vitamin A (> 10,000 IU/day) within 1 month of Day 0.

12. Subjects with a history of hepatitis, pancreatitis, or cirrhosis of the liver.

13. Subjects with an allergy to soy.

14. Subjects with a marked baseline prolongation of QT/QTc intervals (e.g., repeated [3 times within 1 hour] demonstration of a QTc interval >450 milliseconds [ms]) verified manually by a qualified physician or qualified technologist.

15. Subjects with a history of additional risk factors for torsade de pointes (e.g., heart failure, hypokalemia, history or family history of Long QT Syndrome), or those with Wolff-Parkinson- White syndrome.

16. Subjects who are receiving tetracyclines, or concomitant medication(s) that are either metabolized by cytochrome P4502C8 (CYP2C8) or that may prolong the QT/QTc interval. Examples of medications under the latter two categories include the fluoroquinolones, gemfibrozil, trimethoprim, paclitaxel, repaglinide, rosiglitazone, cerivastatin, amodiaquine, torsemide, and sorafenib.

Drug Specifications

9-cis-retinyl acetate Oral Solution will be supplied in 5-mL vials containing 5 mL of 20 mg/mL solution. The vials will be labeled with investigational drug statements, in accordance with applicable regulations. Inactive ingredients are soybean oil and 0.1% butylated hydroxyanisole.

Placebo Oral Solution is supplied in 5-mL vials and is composed of soybean oil and 0.1% butylated hydroxyanisole.

9-cis-retinyl acetate is light and air sensitive. Vials are provided in a pouch and must be stored in the dark and refrigerated between 2°C and 8°C. Each vial is for a single-use only.

Drug Dosage and Administration Dosing will be based on each subject's body surface area (BSA). Each subject's BSA will be calculated using the following formula; however, it is a requirement to use the online calculator as the primary tool for calculating BSA for treatment:

http://www.letscalculate.com/calculators/Medical-Calculators /Body-Surface-Area-

Mosteller-Formula-Calculator/body surface area mosteller formula calculator.php

BSA (m2) = ( [Height(cm) x Weight(kg) ] / 3600 )½

e.g., BSA = SQRT( [cm*kg] / 3600 )

Note: BSA values greater than 0.05 graduation will be rounded up.

The following calculation will be used for determining the dosing solution volume of 9-cis-retinyl acetate:

[Total Drug dose (mg/m ² ) x BSA (m2)]/[Concentration of 9-cis-retinyl acetate Oral Solution (mg/mL)] = volume to dispense in mL

An example is provided below for each dose at an example BSA of 1.8 ml.

Drug Dose

Clinical Study RET IRD 01 proof-of-concept study with 9-cis-retinyl acetate (Clinicaltrials.gov identifier NCT01014052,) previously showed that daily oral dosing of 40 mg/m ² for 7 days improved vision in children and adults with LCA and RP, two endogenous retinoid deficiency -related vision disorders. This dose was chosen in part to ensure that sufficient substrate was available to produce enough chromophore to detect an effect.

However, in subjects with impaired dark adaptation or impaired low luminance vision, it is hypothesized that excessive competitive inhibition of the normal rhodopsin cycle may lead to worsened vision, through formation of less sensitive opsin complexes or through accumulation of retinotoxic compounds such as A2E or lipofuscin.

Additionally, in a separate, randomized, open-label, 4 arm parallel study to investigate the safety, tolerability and PK of repeated 7-day oral dosing cycles of 9-cis-retinyl acetate (dosed at 20, 40 and 60 mg/m ² ) and placebo, oral doses of up to 60 mg/m ² /day over 7 days for 6 monthly cycles were demonstrated to be tolerable in normal healthy volunteers (Clinical Study ID RET HV 04)In the present study, the lower doses are selected to provide sufficient substrate to improve functional vision while avoiding the deleterious competitive inhibition.

As with other retinoids and vitamin A derivatives, 9-cis-retinyl acetate toxicology studies suggest that the manifestation of observable adverse events (AEs) is a function of repeated dosing rather than acute dose magnitude. Accordingly, in the present study, 9-cis- retinyl acetate is dosed once weekly for three weeks.

A placebo is included in one-quarter of subjects since there is currently no approved treatment for impaired dark adaptation.

Instructions for administration of study treatment include the following:

Study drug must be administered at room temperature. Administer the oral dose of the drug to the subject within 30 minutes of study drug being drawn up into the syringe and no later than 10 minutes after a meal.

Subjects will receive one oral dose each week for 3 weeks with an additional dose administered the day after the third dose; each dose will be administered within 10 minutes after a meal.

Procedures by Visit

Screening and Baseline Procedures. Study-specific Screening/Baseline procedures will include the following procedures:

• HLHC BCVA (ETDRS charts) in both eyes

• Selection of study eye by Investigator

• LLLC BCVA (ETDRS charts) in study eye. If, after assessing dark adaptation time

• and/or LLLC BCVA, the selected study eye is found not to be eligible for the study based on inclusion criteria #2 and #3, the other eye may be tested and, if eligible, become the study eye.

• Glare recovery test in study eye

• Dark adaptation test in study eye (to be performed in all subjects enrolled at selected

• sites with the required equipment); If, after assessing dark adaptation time and/or LLLC BCVA, the selected study eye is found not to be eligible for the study based on inclusion criteria #2 and #3, the other eye may be tested and, if eligible, become the study eye.IOP

• Biomicroscopy

• Dilated fundus exam

• Color fundus photography

Day 0 Procedures. Procedures to be performed at Day 0 (efficacy and safety assessments are to be performed prior to dosing) include:

• HLHC BCVA (ETDRS charts) in both eyes

• LLLC BCVA (ETDRS charts) in study eye only

• Glare recovery test in study eye only

• Dark adaptation test in study eye only (in all subjects enrolled at selected sites with the required equipment)

Day 7 Procedures. Procedures to be performed at Day 7 include (efficacy and safety assessments are to be performed prior to dosing):

• HLHC BCVA (ETDRS charts) in both eyes

• LLLC BCVA (ETDRS charts) in study eye only

• Glare recovery test in study eye only

• Dark adaptation test in study eye only (in all subjects enrolled at selected sites with the required equipment)

Day 14 and Day 15 Procedures, (efficacy and safety assessments are to be performed prior to dosing):

• HLHC BCVA (ETDRS charts) in both eyes

• LLLC BCVA (ETDRS charts) in study eye only

• Glare recovery test in study eye only

• Dark adaptation test in study eye only (in all subjects enrolled at selected sites with the required equipment)

Day 17 Procedures: Procedures to be performed at Day 17 include:

• HLHC BCVA (ETDRS charts) in both eyes

• LLLC BCVA (ETDRS charts) in study eye only

• Glare recovery test in study eye only

• Dark adaptation test in study eye only

Day 28 Procedures. Procedures to be performed at Day 28 include:

• HLHC BCVA (ETDRS charts) in both eyes

• LLLC BCVA (ETDRS charts) in study eye only

• Glare recovery test in study eye only • Dark adaptation test in study eye only

Day 42 Procedures (Final Study Visit). Procedures are to be performed at Day 42 (final study visit) include:

• Physical examination

· Chemistry, hematology, thyroid, serum retinol and coagulation tests (samples

collected after a 12-hour overnight fast)

• Urinalysis

• Vital signs (resting heart rate, blood pressure, respiratory rate and temperature

collected after a 3 -minute resting period)

· ECG (performed in triplicate with 3 readings in succession approximately 1 minute

• apart)

• HLHC BCVA (ETDRS charts) in both eyes

• LLLC BCVA (ETDRS charts) in study eye only

• Glare recovery test in study eye only

· Dark adaptation test in study eye only (in all subjects enrolled at selected sites with the required equipment)

• IOP

• Biomicroscopy

• Dilated fundus exam

· Concomitant medications

• Adverse events

Efficacy Assessments

Efficacy will be assessed based on the following tests:

Dark Adaptation Time. Dark adaptation will be performed using a Diagnosys LLC, Espion E3 Electroretinography system with Colordome and button box. The study eye will be dilated prior to the test and the fellow eye patched. After the study eye has fully dilated, subjects will be exposed to a bleaching light source for less than one second (flash from a strobe light) prior to looking into the Colordome. The subjects will then respond when they see a full-field stimulus in the Colordome that measures their return to specific threshold sensitivities. The rod-cone break time is defined as the time at which the rods first become more sensitive than the cones. The rod intercept time is defined as the time at which visual sensitivity recovers to two log units below the rod-cone break sensitivity.

Low Luminance Low Contrast Visual Acuity. LLLC BCVA will be measured using the 2.5%, 5%, or 10%> contrast ETDRS chart at the visits scheduled. Low-luminance is achieved through use of tinted goggles worn by the subject. Standard testing parameters used in the HLHC BCVA testing may be employed, with the application of low contrast ETDRS charts. Precision Vision Standard LC 4 Meter ETDRS charts at 2.5%, 5%, and 10% contrast will be used to assess LLLC BCVA. Subjects will initially be tested using the 5% contrast chart. If 21 to 40 letters are read on the 5% chart, the 5% chart will be selected for use at all subsequent visits. If 20 letters or less are read on the 5% chart, the testing will be repeated with the 10% contrast chart and the 10% chart selected for use at all subsequent. If 41 letters or more are read on the 5% chart, testing is repeated using the 2.5% chart and the 2.5% chart is selected for use at all subsequent visits. Subjects will be identified as having impaired low luminance vision when their LLLC BCVA score is more than 25 letters below their screening HLHC BCVA..

Glare Recovery Time. Glare recovery time will be measured using the same ETDRS contrast chart as used for the LLLC visual acuity test at the visits scheduled. Glare recovery will be measured after the LLLC BCVA has been established for the subject. Glare recovery will be measured using Precision Vision Scrambled LC ETDRS charts at 2.5%, 5% and 10% contrast, equivalent to the chart selected for LLLC BCVA testing. After exposure to a glare source (for example, a one second or less flash from a strobe light), a subject wearing tinted goggles would attempt to read a scrambled version of the LC chart used in their LLLC BCVA test. Timing begins immediately following the flash of light, and ends when the subject has read within 5 letters of their LLLC BCVA score.

Study Eye

The Investigator will select one eye from each subject to act as the study eye. Efficacy assessments (dark adaptation time, glare recovery and LLLC BCVA) will only be performed on the study eye. Ocular safety assessments (including HLHC BCVA) will be performed on both the study eye and the fellow eye. Example 2: Safety Study

Study IRD HV 01 of an orally-delivered pharmaceutically acceptable composition of the present invention was conducted in twenty (20) healthy human volunteers to determine the safety of a composition comprising QLT091001 (9-cis-retinyl acetate ((2E, 4E, 6Z, 8E)- 3,7-dimethyl-9-(2,6,6-trimethylcyclohex-l-en-l-yl) nona-2,4,6,8-tetraen-l-yl acetate)) and butylated hydroxyanisole (BHA) dissolved in soybean oil (USP). The concentration of 9-cis- retinyl acetate in the composition was adjusted such that the volume to be administered was convenient. For the dosing range of the study, compositions of 1.25 mg/mL, 5.0 mg/mL and 20 mg/mL 9-cis-retinyl acetate were prepared, containing 0.10% w/w BHA in Soybean oil (USP). Six cohorts of subjects received escalating doses of the Composition orally from 1.25 mg/m ² up to 40 mg/m ² . The composition was found to be well tolerated and there were no serious adverse events after 7 days of monitored therapy in a Phase I testing center. The most frequently reported side effects were headache (6 subjects, 12 events), facial flushing (2 subjects, 7 events), and a facial burning sensation (2 subjects, 6 events), which were primarily reported from the 40 mg/m ² dose group and collectively accounted for 25 of the 43 (58%) adverse events (AE) reported. In total, 41 of 43 AEs were of mild intensity. In some subjects, there was a modest and reversible elevation in triglycerides across all doses and a modest and reversible decline in high density lipoproteins (HDL) at the 10 - 40 mg/m ² doses. Example 3 : Safety Study of Repeated Multiple-Dose Administration

A randomized, open-label, placebo-controlled, parallel-design, multiple-dose study (RET HV 04) was designed to investigate the safety, tolerability and pharmacokinetics of multiple-dose oral administration of the composition of Example 2 in healthy human volunteers. 35 subjects were enrolled. The study consisted of subjects receiving 4 (placebo and 20 mg/m ² groups) or 6 (40 and 60 mg/m ² groups) consecutive 28-day dosing/washout cycles (7-day dosing and 21 -day washout). After the final cycle, subjects were followed up for 2 months. During each cycle, subjects received either a therapeutic dose comprising a once-daily dose of the compositions of Example 2 orally (9-cis-retinyl acetate and 0.1% butylated hydroxyanisole (BHA) in soybean oil (USP) administered at 20 mg/m ² , 40 mg/m ² , or 60 mg/m ² ) or placebo for 7 days, followed by a 21 day resting period during which the subjects did not receive treatment. Subjects were periodically monitored during the cycle for various adverse events, such as headaches, facial flushing and facial burning sensation. Subjects were also monitored for toxicity associated with treatment such as an elevation in triglycerides and decline in high density lipoproteins (HDL). Adverse events observed included headache, photophobia, nausea, ALT increase, elevated triglycerides, and elevated AST.

No new or unexpected adverse events were observed in the study. Up to six repeated treatment cycles with the compositions of Example 2 (9-cis-retinyl acetate and 0.1% butylated hydroxyanisole (BHA) in soybean oil (USP)) at doses of 20 mg/m ² /day, 40 mg/m ² /day, and 60 mg/m ² /day for seven days followed by a 21 day washout period was generally safe and well tolerated. The safety profile of repeated treatment cycles was similar to that of one treatment cycle, with an overall trend toward reduction in the severity of the Adverse Events with each subsequent dosing cycle.

Interim Pharmacokinetic results of the study were derived from plasma concentrations of 9-cis-retinyl acetate and its metabolites, measured throughout the study period at prescribed time points. The scope of this interim PK analysis encompasses samples from Cohort 1 including the placebo (n=2), 40 mg/m ² (n=6) and 60 mg/m ² (n=2) dose groups obtained in treatment cycles 1, 2 and 3.

The plasma samples were analyzed by liquid chromatography-mass spectrometry- mass spectrometry (LC/MS/MS) for parent drug and potential metabolites.

Noncompartmental (NCA) pharmacokinetic (PK) parameters such as AUC were obtained using the WinNonlin software with observational determination of C _max , t _max , and duration of concentrations above baseline (TD).

9-cis-retinyl acetate plasma concentrations were low and transient, indicative of rapid first-pass metabolism, with further metabolism to non-polar and polar metabolites. At 40 mg/m ² , administered in repeated seven day cycles, the 9-cis-retinol and retinyl ester metabolites showed slight to modest accumulation on multiple-dosing with higher AUC values on Day 7 in accordance with expectations from Day 1. The longer persisting metabolites had rising daily C _m i _n values consistent with modest accumulation and these patterns and concentrations were similar for Cycles 1, 2, and 3 with no accumulation being observed from cycle to cycle.

Example 4: Efficacy Study for Subjects with Impaired Dark Adaptation or Impaired low luminance vision Study RET IDA 02 was performed to evaluate the safety of QLT091001 (9-cis-retinyl acetate) in adults with impaired dark adaptation or impaired low luminance low contrast best corrected visual acuity (LLLC BCVA). In addition, the study evaluated if oral doses of QLT091001 (9-cis-retinyl acetate) at either 10 or 40 mg/m2 dosed once per week for three consecutive weeks with one additional dose the day after the third dose improved impaired dark adaptation time, improve glare recovery time, or improved low luminance low contrast best corrected visual acuity (LLLC BCVA).

Overall Study Design

The study was a randomized, single -masked, parallel-design, safety/proof-of-concept study. The study enrolled 43 subjects with impaired dark adaptation or impaired LLLC BCVA in at least 1 eye and no known ophthalmic pathologies to explain their condition other than early age-related macular degeneration (AMD). The Investigator selected one eye from each subject to be assessed as the study eye. Subjects who meet the eligibility criteria were randomized to receive one of the following oral doses of 9-cis-retinyl acetate at Day 0, Day 7, Day 14 and Day 15: 0 (placebo), 10, or 40 mg/m ² in a 2:3:3 randomization ratio. Those randomized to placebo received the same formulation without the active pharmaceutical ingredient. Dark adaptation time, LLLC BCVA, and glare recovery were assessed at screening and repeated on Day 0, Day 7, Day 14, and Day 15 prior to dosing and on Day 17, Day 28 and Day 42 to evaluate efficacy. Safety assessments (HLHC BCVA, biomicroscopic examinations, vital signs, adverse events, concomitant medications) were conducted before the initial dose and at all study visits. IOP measurement and dilated fundus examination were performed at screening and Day 42. Clinical chemistry, hematology, and urinalysis samples were collected at screening, prior to dosing on Day 7 and at follow-up visits on Day 17 and Day 42. Figure 2 sets forth a schematic of the RET IDA 02 study design. To be eligible for the study, subjects must have fulfilled all of the following criteria:

Criteria #1. Male or female subjects >60 years old.

Criteria #2. Subjects with early AMD in the study eye (defined as non-exudative AMD without

geographic atrophy), who have:

- LLLC BCVA that is > 25 letters (about 5 lines) below their HLHC BCVA

(Haegerstrom-Portnoy 1999), or, - evidence of impaired dark adaptation, defined as a rod-cone break dark adaptation time of > 9 minutes with a rod-threshold of < 30 minutes (Jackson 2006).

Criteria #3. Subjects who have ETDRS HLHC BCVA score in the study eye of 40 letters, (Snellen equivalent of 20/40) or better.

Drug Specifications

9-cis-retinyl acetate oral solution of Example 2 (QLT 091001) was supplied in 5-mL vials containing 5 mL of 20 mg/mL solution. Inactive ingredients were soybean oil and 0.1% butylated hydroxyanisole as set out in Example 2 above.

Placebo Oral Solution was supplied in 5-mL vials and was composed of soybean oil and0.1%) butylated hydroxyanisole.

Drug Dosage and Administration

Dosing was based on each subject's body surface area (BSA). Each subject's BSA was calculated. An example is provided below for each dose at an example BSA of 1.8 m2.

A placebo was included since there was no approved treatment for impaired dark adaptation as of the study period.

Subjects received one oral dose each week for 3 weeks with an additional dose administered the day after the third dose; each dose was administered within 10 minutes after a meal. Procedures by Visit

Screening and Baseline Procedures. Study-specific Screening/Baseline procedures included the following procedures:

• HLHC BCVA (ETDRS charts) in both eyes

• Selection of study eye by Investigator

• LLLC BCVA (ETDRS charts) in study eye. If, after assessing dark adaptation time and/or LLLC BCVA, the selected study eye was found not to be eligible for the study based on inclusion criteria #2 and #3, the other eye was tested and, if eligible, became the study eye.

• Glare recovery test in study eye

• Dark adaptation test in study eye (performed in all subjects enrolled at selected sites with the required equipment); If, after assessing dark adaptation time and/or LLLC BCVA, the selected study eye was found not to be eligible for the study based on inclusion criteria #2 and #3, the other eye was tested and, if eligible, become the study eye.

• IOP

• Biomicroscopy

• Dilated fundus exam

• Color fundus photography

Day 0 Procedures. Procedures to be performed at Day 0 (efficacy and safety assessments are to be performed prior to dosing) included:

• HLHC BCVA (ETDRS charts) in both eyes

• LLLC BCVA (ETDRS charts) in study eye only

• Glare recovery test in study eye only

• Dark adaptation test in study eye only (in all subjects enrolled at selected sites with the required equipment)

Day 7 Procedures. Procedures to be performed at Day 7 include (efficacy and safety assessments are to be performed prior to dosing):

• HLHC BCVA (ETDRS charts) in both eyes

• LLLC BCVA (ETDRS charts) in study eye only

• Glare recovery test in study eye only • Dark adaptation test in study eye only (in all subjects enrolled at selected sites with the required equipment)

Day 14 and Day 15 Procedures, (efficacy and safety assessments are to be performed prior to dosing):

• HLHC BCVA (ETDRS charts) in both eyes

• LLLC BCVA (ETDRS charts) in study eye only

• Glare recovery test in study eye only

• Dark adaptation test in study eye only (in all subjects enrolled at selected sites with the required equipment)

Day 17 Procedures: Procedures to be performed at Day 17 include:

• HLHC BCVA (ETDRS charts) in both eyes

• LLLC BCVA (ETDRS charts) in study eye only

• Glare recovery test in study eye only

• Dark adaptation test in study eye only

Day 28 Procedures. Procedures to be performed at Day 28 include:

• HLHC BCVA (ETDRS charts) in both eyes

• LLLC BCVA (ETDRS charts) in study eye only

• Glare recovery test in study eye only

• Dark adaptation test in study eye only

Day 42 Procedures (Final Study Visit). Procedures performed at Day 42 (final study visit) include:

• Physical examination

• Chemistry, hematology, thyroid, serum retinol and coagulation tests (samples

collected after a 12-hour overnight fast)

• Urinalysis

• Vital signs (resting heart rate, blood pressure, respiratory rate and temperature

collected after a 3 -minute resting period)

• ECG (performed in triplicate with 3 readings in succession approximately 1 minute

• apart)

• HLHC BCVA (ETDRS charts) in both eyes

• LLLC BCVA (ETDRS charts) in study eye only Glare recovery test in study eye only

Dark adaptation test in study eye only (in all subjects enrolled at selected sites with the required equipment)

IOP

Biomicroscopy

Dilated fundus exam

Concomitant medications

Adverse events

Results

Forty-three subjects were enrolled in Study RET IDA 02 following the inclusion criteria above. Demographics of the subjects enrolled are set out in Figure 3. The ages of the subjects in the study ranged from 60-90, with a mean for each of the placebo arm, 10 mg/m ² arm and 40 mg/m ² arm, of 71.0, 75.6, and 74.4, respectively. The mean age of all subjects was 74.0. Results from the efficacy assessments conducted in the study are set out below.

Efficacy Assessments

1. Dark Adaptation Time. Dark adaptation was performed using a Diagnosys LLC, Espion E3 Electroretinography system with Colordome and button box (full-field Diagnosys Colordome Ganzfeld). The study eye was dilated prior to the test and the fellow eye patched. After the study eye was fully dilated, the subjects were placed in a completely dark room with their head in the full-field Diagnosys Colordome Ganzfeld. White light, produced by all four LEDs, was ramped from 0 to 2000 cd/m2 over 30 seconds and then maintained at 2000 cd/m2 for an additional 150 seconds to provide a bleach of the study eye. Once the bleach process was finished, the Colordome was darkened and the patient responded to full-field flashes within the Colordome with a button push. An ascending method of limits procedure of increasing brightness of flashes was used to estimate detection thresholds over a period of 30 minutes. The dark adaptation analysis of the threshold data was derived from a nonlinear regression technique for modeling the kinetics of dark adaptation (McGwin et al., Behavior Research Methods, Instruments and Computers, 31(4), 712-717 (1999)). Modeling was performed using the SAS JMP version 10.0 software. Threshold values from cone responses up to and including the 15 minute mark were fit to the exponential portion (first component) of the equation. The threshold level of the asymptote was identified as the Cone Threshold Plateau. The linear portion (second component) of the equation threshold was fit to the values from rod responses that were at threshold levels less than the asymptote derived from the fit to the exponential portion of the equation but more than a value which was 2 log units below this level. The time corresponding with the intercept of these two curves was then calculated in order to give the Rod-Cone Break time. The time at which the first linear portion of the equation coincided with a threshold value which was 2 log units less than the asymptote threshold level was calculated to be the Rod Threshold Time and the slope of the first linear portion of the equation was calculated to be the Rod Adaptation Slope. A theoretical dark adaptation measurement that plots the time vs threshold intensity for the rods and cones and the rod-cone break time is included in Figure 8.

Of the 43 total subjects enrolled in the study, 4 of the 11 subjects enrolled in the placebo arm were found to be baseline dark adaptation impaired in accordance with the defined protocol, 7 out of 16 subjects in the 10 mg/m ² arm of the study were baseline dark adaptation impaired, and 3 out of 16 subjects in the 40 mg/m ² arm of the study were baseline dark adaptation impaired, i.e., where an impaired subject was defined as one with a baseline rod-cone break time of greater than or equal to 9 minutes.

Baseline values for each subject were either the readings from the Day 0 time point in the study, or the reading taken at screening, if the Day 0 reading was not done per protocol, or not evaluable.

Results of the Per Protocol analysis of the study showing the median change in impaired dark adaptation rod-cone break time from baseline versus dose and visit (Day 7, 14, 15, 17, 28 and 42 of the Protocol of Figure 2) in subjects who were baseline impaired are set out in Figure 9. The n value for each subset is also provided in Figure 9.

In the Per Protocol analysis, both the 10 mg/m ² and the 40 mg/m ² treatment groups showed a trend towards improved median rod-cone break time compared to placebo, with median improvements at various noted time points for both the both the 10 mg/m ² and the 40 mg/m ² treatment groups between about 1 minute to up to about 5 minutes. In the Per Protocol analysis, individual subjects in the two treatment arms were observed to have a range of baseline rod-cone break times that varied from 9.4 minutes to 18.2 minutes. The placebo arm subjects showed a range of between 11.1-15.4 minutes as their baseline rod-cone break times. For those subjects in the treatment arms demonstrating an improvement in rod-cone break time, a range of about 1 to about 88% improvement in rod cone break time for individual time points was observed for the 10 mg/m ² treatment group (representing 29/41, or 71%, per protocol measurements), and a range of about 7 to about 50% improvement in rod cone break time for individual time points was observed for the 40 mg/m ² treatment group (representing 10/12, or 83%, per protocol measurements). Individual subjects in the two treatment arms at individual efficacy time point measurements showed an improvement in rod-cone break time of at least about 30%, at least about 25%, at least about 20%, at least about 10%, at least about 5% or at least about 1%. In other individual efficacy time point measurements, subjects in the two treatment arms showed an improvement in rod-cone break time of at least 35% up to about 85%. In the placebo group, about 4% to about a 45% range of improvement in rod cone break time for individual time points was observed (representing 6 of 20, or 30%>, of per protocol measurements).

In the two treatment arms and the placebo arm, increases in rod-cone break time were also observed relative to the individual baseline measurements for individual subjects. In 15 out of 20 per protocol measurements for subjects in the placebo arm, either no improvement or increases in rod-cone break time was observed, while subjects in the two treatment arms demonstrated either no improvement or increasing rod-cone break time in only 15/54 per protocol measurements. In some subjects in either the 10 or 40 mg/m ² treatment arm, improvements in rod-cone break time were noted at all efficacy measurement time points from day 7 to day 28 (i.e., at day 7, 14, 15 and 28) which is almost two weeks after the last of the four treatments was received. Other subjects in the two treatment arms showed both scattered increases and decreases in rod-cone break time at various efficacy measurement time points (individual data not shown). 2. Low Luminance Low Contrast Best Corrected Visual Acuity (LLLC BCVA). LLLC

BCVA was measured using the 2.5%, 5%, or 10%> contrast ETDRS chart at the visits scheduled. Low- luminance was achieved through use of tinted goggles worn by the subject. Standard testing parameters used in the HLHC BCVA testing were employed, with the application of low contrast ETDRS charts. Precision Vision Standard LC 4 Meter ETDRS charts at 2.5%, 5%, and 10% contrast were used to assess LLLC BCVA. Subjects were initially tested using the 5% contrast chart. If 21 to 35 letters were read on the 5% chart, the 5% chart was selected for use at all subsequent visits. If 20 letters or less were read on the 5% chart, the testing was repeated with the 10% contrast chart and the 10% chart selected for use at all subsequent. If 36 letters or more were read on the 5% chart, testing was repeated using the 2.5% chart and the 2.5% chart was selected for use at all subsequent visits. Only the study eye was tested; the non-study eye was patched.

Subjects were identified as having impaired low luminance vision when their LLLC

BCVA score is more than 25 letters below their screening HLHC BCVA.

Of the 43 total subjects enrolled in the study, for the Intend to Treat (ITT) population, 9 of the 11 subjects enrolled in the placebo arm were found to be baseline impaired, 14 out of 16 subjects in the 10 mg/m ² arm of the study were baseline impaired, and 14 out of 16 subjects in the 40 mg/m ² arm of the study were baseline impaired, i.e., defined as where the change in the baseline of the subject's measured HLHC BCVA minus the subject's LLLC BCVA was greater than or equal to 25 letters. Baseline values for each subject were either the readings from the Day 0 time point in the study, or the reading taken at screening, if the Day 0 reading was not done per protocol, or not evaluable.

Results of the Per Protocol analysis of the study showing the median impaired LLLC

BCVA change from baseline versus dose and time of measurement (Day 7, 14, 15, 17, 28 and 42 of the Protocol of Figure 2) in subjects found to be baseline impaired are set out in Figure 4. Twenty-two out of 32 subjects in the two treatment arms qualified for analysis in the Per Protocol Subset, while 9 out of 11 qualified in the placebo arm. In both the 10 mg/m ² and the 40 mg/m ² arms of the study, some individual subjects were noted to have shown a positive improvement in LLLC BCVA from their respective baselines at one or more of the visits at Day 7, 14, 15, 17, 28 and 42. In some subjects in either the 10 mg/m ² or 40 mg/m ² treatment arm, positive improvements in LLLC BVCA at the time points tested were observed, while in other subjects both scattered increases and decreases in LLC A BCVA from baseline were observed, while in others a decrease in LLLC BCVA was observed (data not shown). As shown in Figure 4, modest positive median measureable improvements in LLLC BCVA from baseline at certain time points in the protocol was observed, for example at Day 7 after a single dose of oral retinoid solution QLT091001, and after day 17 (two days after the last of the final four doses of QLT091001 was received) in the per protocol analysis. A positive median measureable improvement in LLLC BCVA from baseline was unexpectedly also noted for the placebo group for various time points in the per protocol as shown in Figure 4. These results, along with the observation that there was a large variation (> 10 letters) in some patients in their LLLC BCVA between measurement at screening and at Day 0, suggest there was a higher degree of variability in the measurement of LLLC BCVA under these testing conditions than was expected as based upon observed rates of lower variability in measurement of HLHC BCVA known in the literature.

3. Glare Recovery Time. Glare recovery time was measured using an ETDRS contrast chart as used for the LLLC visual acuity test at the visits scheduled. Glare recovery was measured after the LLLC BCVA was established for the subject. Glare recovery was measured using Precision Vision Scrambled LC ETDRS charts at 2.5%, 5% and 10% contrast, equivalent to the chart selected for LLLC BCVA testing. The fellow eye of the subject was patched and the subject was adapted to a low luminance environment by wearing tinted 4% transmission goggles for 10 minutes. The subject removed the goggles and was positioned with their head in the full-field Diagnosys Colordome Ganzfeld where they received a glare of 5000 cd/m2 for 10 seconds in their study eye. After 7 seconds but before 10 seconds into the glare process, a xenon light was triggered that delivered two 2

millisecond 3000 cd*s/m2 flashes at an interval of 2 milliseconds apart. The timer was started at the end of the 10 second glare process. The trial lens frames with the correct refraction were placed on the subject and the tinted 4% transmission goggles were placed over the trial lens frames. The subject was turned to face the scrambled version of the Precision Vision Standard LC ETDRS Chart previously selected (i.e. 2.5%, 5% or 10% contrast) as described above, and instructed to begin reading letters three lines above the best line from their LLLC BCVA test at screening or Day 0, whichever was better BCVA. The timer was stopped as soon as the subject had read the third correct letter on the line above their best line from the LLLC BCVA test at Screening or Day 0. Of the 43 total subjects enrolled in the study, 7 of the 11 subjects enrolled in the placebo arm were included in the per protocol analysis, 11 of the 16 subjects enrolled in the 10 mg/m ² arm of the study were included in the per protocol analysis, and 9 of the 16 subjects enrolled in the 40 mg/m ² arm of the study were included in the per protocol analysis.

Changes in the median glare recovery change from baseline (in seconds) versus dose in the per protocol analysis in shown in Figure 5. The median glare recovery time change from baseline for both the 10 mg/m ² treatment arm and the 40 mg/m ² treatment arm showed a trend towards improvement at most visits compared to placebo. At day 17 (two days after all four doses), 7 out of 11 subjects in the 10 mg/m ² treatment arm and 4 out of 9 subjects in the 40 mg/m ² treatment arm showed improvement in glare recovery time compared to only 1 subject within the placebo group. At Day 28 (about 2 weeks after all 4 doses were received by the subjects in the treatment arms), 8 out of 11 subjects in the 10 mg/m ² treatment arm and 6 out of 9 subjects in the 40 mg/m ² treatment arm showed improvement in glare recovery time compared to 3 subjects within the placebo group. At Day 42 (about 4 weeks after all 4 doses were received by the subjects in the treatment arms), 7 out of 10 subjects in the 10 mg/m ² treatment arm and 6 out of 9 subjects in the 40 mg/m ² treatment arm showed improvement in glare recovery time compared to 2 subjects within the placebo group.

Sub-analyses of the per protocol analysis in patients with a baseline glare recovery time of greater than 40 seconds, or greater than 30 seconds were also conducted as shown in Figure 6 and Figure 7, respectively. These baseline times for glare recovery were selected based upon Figure 6 in Haegerstrom-Portnoy G et al, Opt. Vis. Sci., 76: 141-158 (1999), the contents of which are incorporated herein by reference. Figure 6 of Haegerstrom-Portnoy G et al, Opt. Vis. Sci., 76: 141-158 (1999) provides median glare recovery time (in seconds) measured for individuals tested between the ages of 19-78, plotted in 5 and 10 year increments. Median values for ages 60-95 are also provided with vertical bars and shaded areas extending to the 25 ^th and 75 ^th percentiles. The results of their study showed the median recovery rate increases by 0.7 log units over the age range tested in the study. The variability was shown to increase with age. Based upon mean ages of between 71 and 76 in each of the arms of the present study and an overall mean age of 74 (see Figure 2), and based upon the 25 ^th through to 75 ^th percentile values for glare recovery as provided in Figure 6B of

Haegerstrom-Portnoy G et al, Opt. Vis. Sci., 76: 141-158 (1999), glare recovery timed of 40 seconds and 30 seconds were selected as baseline glare recovery times for the sub-analyses of the per protocol population. As shown in Figure 6 and Figure 7, the median glare recovery time change from baseline for both the 10 mg/m ² treatment arms and the 40 mg/m ² treatment arms in the two sub-analyses showed a trend towards improvement at most visits compared to placebo. 4. Safety Analysis. Overall, the drug was well tolerated in this study and no new or unexpected adverse events were observed. Two SAEs (severe adverse events), unrelated to the study drug, were reported in the same patient. The safety results of this study supported the use of repeated dosing of pharmaceutical compositions or 9- and 11-cis retinyl derivatives, including 9- and 1 1-cis retinyl esters, including the oral compositions of the present examples, in subjects with impaired dark adaptation and/or impaired low luminance vision.

The previous examples are provided to illustrate but not to limit the scope of the claims. Other variants of the inventions will be readily apparent to those of ordinary skill in the art and are encompassed by the claims. All publications, patents, patent applications and other references cited herein are hereby incorporated by reference.

REFERENCES

Brown B et al, Ophthalmol Physiol Optics. 6(l):81-84 (1986)

Curcio CA et al, Invest Ophthalmol Vis Sci. 34(12):3278-3296 (1993).

Curcio CA, Owsley C, et al, Invest Ophthalmol Vis Sci. 41(8):2015-2018 (2000).

Dowling JE and Wald G., Proc Natl Acad Sci USA 44(7):648-661 (1958).

Elliot DB and Whitaker D. Documenta Ophthalmol, 76: 251-259 (1991).

Haegerstrom-Portnoy G et al, Opt. Vis. Sci., 76: 141-158 (1999).

Haig C et al, Science 87(2267):534-536 (1938).

Jackson GR et al, Vision Res. 39(23):3975-3982 (1999).

Jackson GR, Owsley C. Vision Res. 40:2467-2473 (2000).

Jackson GR et al, Aging Res Rev. l(3):381-386 (2002).

Jackson GR et al, Ophthal. Physiol. Opt., 26: 431-437 (2006).

Kemp CM, et al, Exp Eye Res. 46: 185-197 (1988).

Lamb TD and Pugh EN, Jr., Prog Retin Eye Res. 23(3):307-380 (2004).

Lamb TD. Vision Res. 21 : 1773-1782 (1981).

Lamb TD, et al, J Physiol. 506:88-100 (1998).

Leibrock, CS, et al, Eye 12:511-520 (1998).

Lovie-Kitchin J and Feigl B, Clin. Exp Opt., 88: 292-303 (2005).

McMurdo MET and Gaskell A., Gerontology 37:221-224 (1991).

Maeda T, Maeda A, Leahy P, Saperstein DA, Palczewski K. Effects of long-term

administration of 9-cis-retinyl acetate on visual function in mice. Invest Ophthalmol Vis Sci.

50:322-333 (2009). Owsley C, et al, Invest Ophthalmol Vis Sci. 41(l):267-273 (2000).

Owsley C, et al, Ophthalmol. 108(7): 1196-1202 (2001).

Owsley C, McGwin G, Jackson GR et al, Invest Ophthalmol Vis Sci. 47(4): 1310-1318 (2006).

Owsley, C, McGwin G, SciUey K, et al, Invest Ophthalmol Vis Sci 47:528-535 (2006). Pauleikhoff D et al, Ophthalmol. 97(2):171-178 (1990).

SciUey K et al, Ophthalmol. 109(7): 1235-1242 (2002).

Sloane ME, Owsley C, Jackson CA., J Opt Soc Am A. 5(12):2181-2188 (1988).

Sloane ME, Owsley C, Alvarex SL., Vision Res. 28(11): 1235-1246 (1988).

Steinmetz RL et al, Br J Ophthalmol. 77(9):549-554 (1993).