Monday, December 5, 2016

Drugs in Clinical Pipeline: Emixustat | Modulator of Retinal Pigment Epithelium 65 (RPE65) | Treatment of Age-related Macular Degeneration (AMD)

Emixustat ((1R)-3-Amino-1-(3-(cyclohexylmethoxy)phenyl)propan-1-ol hydrochloride) is an orally available, small, non-retinoid molecule that modulates retinal pigment epithelium 65 (RPE65), an enzyme required to convert trans-retinol to cis-retinol within the retinal pigment epithelium (RPE) [1, 2].

Structure of Emixustat
Emixustat : 2D and 3D Structure

In a first of its kind study, the researchers measured the inhibitory effects of Emixustat and an in vitro retinoid isomerase activity assay using bovine RPE microsomes as the enzyme source. Emixustat strongly inhibited bovine 11-cis-retinol production with IC50 values of 232 ± 3 nM; whereas the IC50 values were 4.4 ± 0.59 nM in the assay using human 11-cis-retinol.

Medicinally, it falls in the category of Visual cycle modulators (VCMs). Visual cycle modulators are pharmacologic compounds intended to modulate the visual cycle in patients with age-related macular degeneration (AMD). Visual cycle modulators essentially “slow down” the activity of the photoreceptors and reduce the metabolic load on these cells. So, these compounds may slow the deterioration by reducing the accumulation of toxic fluorophores (mainly A2-E) and lipofuscin, thereby preventing the loss of photoreceptors and RPE cells.

Retinal degenerative conditions are associated with accumulation of waste material and by-products of the chromophore recycling pathway that are toxic to the retinal pigment epithelium (RPE), resulting in RPE failure and photoreceptor dysfunction. By inhibiting the visual cycle and slowing the accumulation of these toxic by-products, preservation of photoreceptors and visual function may be achieved.
Emixustat has been shown to prevent the accumulation of A2-E in the mouse retina, thereby slowing down the visual cycle. Emixustat is given orally and acts selectively on the rod photoreceptors, the major source of A2-E in the retina [2].

Visual Cycle, N-retinylidene-N-retinylethanolamine (A2E) and Emixustat

A phototansduction process is a key step in the vertebrate retina where photoreceptors convert photons into electrical current. When visual chromophores coupled to rhodopsin absorb light energy, photoisomerization occurs and 11- cis -retinal undergoes a conformational change to all trans -retinal.
The steps involving conversion of dietary vitamin A (all-trans-retinol) into the light-sensitive visual chromophore (11-cis-retinal), and its regeneration following photobleaching, is accomplished through a series of enzymatic reactions known as the visual cycle. Processes of the visual cycle occur within the retinal pigment epithelium (RPE) and in outer segments of rod and cone photoreceptors. The 65-kDa RPE protein RPE65 plays an instrumental role in regenerating 11-cis-retinal.
In the normal state, the rate of regeneration of this critical photosensitive compound (11-cis-retinal), rapidly adapts to the demands of the photoreceptors. Retinal degenerative conditions are associated with accumulation of waste material and by-products of the chromophore recycling pathway that are toxic to the retinal pigment epithelium (RPE), resulting in RPE failure and photoreceptor dysfunction. Photobleaching of the visual pigments liberates opsin apo-proteins and all-trans-retinal. Under normal physiological conditions, all-trans-retinal is reduced to all-trans-retinol and returned to the RPE for recycling. However, under conditions which allow all-trans-retinal to transiently accumulate in photoreceptor outer segments (e.g., during intense light exposure or due to a genetic defect), the retina becomes extremely susceptible to oxidative damage. All-trans-retinal is a toxic aldehyde and a potent photosensitizer. It can induce lipid peroxidation through the generation of reactive oxygen species (ROS), such as singlet oxygen, and cause damage to outer segment proteins. Primarily of its toxic properties, all-trans-retinal is believed to be a key mediator of retinal light damage.
N-retinylidene-N-retinylethanolamine (A2E) is a well-characterized bis-retinoid that has been shown to have several deleterious effects on RPE cells, including generation of ROS, impairment of lysosomal function, induction of pro-apoptotic proteins, complement activation, and upregulation of vascular endothelial growth factor (VEGF). In animal models of excessive A2E accumulation, compounds that either inhibit visual cycle activity or reduce vitamin A delivery to the RPE are effective to halt the accumulation of A2E and attenuate retinal pathology. 
Following light exposure, 11-cis-retinal and all trans-retinal levels accumulate in the outer segments and lead to the formation of retinal-lipid complexes. These lipid complexes, which are precursors of A2E, lead to an increase in the concentration of A2E inside the cell. By blocking RPE65, Emixustat reduces the levels of 11-cis- and all trans- retinal and thereby also reduces the concentration of A2E within the cell [1, 2].

Mechanism of Action in Emixustat: 

Emixustat is a non-retinoid, small molecule compounds that target key proteins of the visual cycle.  Emixustat acts an inhibitor of the visual cycle isomerase (RPE65). It modulated visual cycle function and preserves retinal integrity in animal models. Emixustat potently inhibited isomerase activity in vitro (IC50 = 4.4 nM) and was found to reduce the production of visual chromophore (11-cis retinal) in wild-type mice following a single oral dose (ED50 = 0.18 mg/kg). Measure of drug effect on the retina by electroretinography revealed a dose-dependent slowing of rod photoreceptor recovery (ED50 = 0.21 mg/kg) that was consistent with the pattern of visual chromophore reduction.

Moreover, researchers have observed an anti-angiogenic effect of Emixustat which has not been previously demonstrated with other RPE65 inhibitors, but is explainable based upon the VEGF modulating mechanism of Emixustat action.

Dosages and Approvals:

Emixustat (Tradename: -) is being developed by Acucela in collaboration with Otsuka Pharmaceutical Co., Ltd. Acucela and Otsuka share commercial rights for Emixustat in the USA. Otsuka has exclusive rights in Japan, Asia and other countries, while Acucela has exclusive rights in Europe and other countries. This deal was terminated in June 2016.

Geographic atrophy (GA) is a severe and advanced form of age-related macular degeneration (AMD), affecting more than 9 million people worldwide. In GA, the center of the retina (the macula) responsible for high acuity and color vision becomes atrophic; the atrophic lesion grows over time, eventually leading to irreversible blindness. GA is typically present in both eyes and patients frequently report problems with every day activities such as reading and recognizing faces. GA represents a significant unmet medical need as there are currently no approved treatments for this condition.

Emixustat is under clinical trials for treatment of dry, age-related macular degeneration (AMD) including GA. The compound is also being investigated as a potential therapy for proliferative diabetic retinopathy, diabetic macular edema and Stargardt disease.

Reported Activities for Emixustat:

Emixustat potently inhibited human RPE65 isomerase activity in vitro (IC50 = 4.4 ± 0.59 nM); whereas IC50 was 232 ± 3 nM for bovine isomerase . In albino mice, Emixustat was shown to be effective in preventing photoreceptor cell death caused by intense light exposure. Pre-treatment with a single dose of Emixustat (0.3 mg/kg) provided a ~50% protective effect against light-induced photoreceptor cell loss, while higher doses (1 - 3 mg/kg) were nearly 100% effective.

Moreover, Emixustat is not a retinoid and, therefore, neither bind nor activate retinoic acid receptors, and does not affect retinoid levels in the visual cycle. Treatment with Emixustat specifically reduces visual chromophore levels without affecting levels of the opsin protein.

IC50 (Inhibition of (h) RPE65 isomerase activity) = 4.4 ± 0.59 nM

IC50 (Inhibition of (bov) RPE65 isomerase activity) = 232 ± 3 nM


Common name: ACU-02; ACU 02; ACU02; ACU-4429; ACU 4429; ACU4429; Emixustat hydrochloride; Emixustat
Trademarks: -
Molecular Formula: C16H25NO2
CAS Registry Number: 1141777-14-1; 1141934-97-5 (hydrochloride)
CAS Name: (R)-3-amino-1-(3-(cyclohexylmethoxy)phenyl)propan-1-ol
Molecular Weight: 263.38
InChI: InChI=1S/C16H25NO2/c17-10-9-16(18)14-7-4-8-15(11-14)19-12-13-5-2-1-3-6-13/h4,7-8,11,13,16,18H,1-3,5-6,9-10,12,17H2/t16-/m1/s1
Mechanism of Action: Retinoid Isomerohydrolase Inhibitors; Visual Cycle Isomerase Inhibitor; Retinal Pigment Epithelium (RPE) Inhibitor
Activity: Treatment for Dry Age-related Macular Degeneration (AMD); Diabetic Retinopathy; Eye Disorder Therapies
Status: Under Phase Trials
Chemical Class: Small molecules; Aliphatic amine containing; Ether containing; Hydroxyl containing; Benzene containing; Cyclohexane containing
Originator: Acucela/Otsuka Pharmaceutical
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