Therapeutic regimens and methods for improving visual function in visual disorders associated with an endogenous retinoid deficiency

a technology of endogenous retinoid and therapeutic regimens, applied in the field of therapeutic regimens and methods for improving visual function, can solve the problems of severe visual impairment and childhood blindness, affect the synthesis of 11-cis-retinal, so as to reduce the severity of toxic side effects, improve the effect of vision, and improve the effect of visual function

Inactive Publication Date: 2016-10-13
NOVELION THERAPEUTICS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0022]The present disclosure provides certain dosing regimens of synthetic retinal derivatives that can provide replacement for endogenously produced 11-cis-retinal, thereby producing meaningful improvement of vision in a subject having an endogenous retinoid deficiency throughout a resting interval of less than one month, such as from 7 to 28 days, while at the same time exhibiting an acceptable safety profile throughout repeat treatment cycles of dosing and resting. In certain embodiments, the acceptable safety profile may be achieved by minimizing and/or reducing the severity of the toxic side effects associat...

Problems solved by technology

Inherited retinal diseases (IRD) caused by gene mutations that disrupt or interfere with the production, conversion and/or regeneration of 11-cis-retinal result in severe visual impairment and childhood blindness.
Endogenous retinoid deficiencies, such as those caused by mutations in the genes encoding the enzymes and proteins utilized in the visual cycle, impair the synthesis of 11-cis-retinal, the result of which leads to visual disorders due to the shortage or depletion of 11-cis-retinal.
There are a variety of forms of RP all of which show various limitations of visual performance over time and the course and progression of the disease show considerable variability between individuals.
These specific mutations, as well as mutations in ABCA4 and RDH12 are linked to defects in retinoid metabolism of the visual cycle and may result in photoreceptor degeneration.
Endogenous retinoid deficiencies, such as those caused by mutations in the genes encoding the enzymes and proteins utilized in the visual cycle impair the synthesis of 11-cis-retinal, the result of which leads to visual disorders due to the shortage or depletion of 11-cis-retinal.
Preclinical and clinical information show that loss of the function of the RPE65 protein blocks retinoid pro...

Method used

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  • Therapeutic regimens and methods for improving visual function in visual disorders associated with an endogenous retinoid deficiency
  • Therapeutic regimens and methods for improving visual function in visual disorders associated with an endogenous retinoid deficiency
  • Therapeutic regimens and methods for improving visual function in visual disorders associated with an endogenous retinoid deficiency

Examples

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example 1

Safety Study

[0319]An open-label, repeat dose escalation study of an orally-delivered pharmaceutically acceptable composition of the disclosure was conducted in twenty (20) healthy human volunteers to determine the safety and tolerability of repeat daily oral doses of a composition comprising 9-cis-retinyl acetate ((2E, 4E, 6Z, 8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohex-1-en-1-yl) nona-2,4,6,8-tetraen-1-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 dose cohorts of healthy subjects received escalating daily doses of the composition orally from 1.25 mg / m2 up to 40 mg / m2, i.e., 1.25, 2.5, 5, 10, 20 and 40 mg / m2.

[0320]Eighteen subjects received all 7 days...

example 2

Study in RP Patients

[0323]Study Protocol

[0324]A study was designed to determine the efficacy of the composition of Example 1 orally administered to human RP subjects having RP caused by mutations in either LRAT or RPE65 (also known as early-onset RP). Seventeen RP subjects received a once-daily dose of the composition orally (40 mg / m2) for 7 days. Both eyes of each RP subject were evaluated separately. Protocol-defined assessments of visual function included: best-corrected visual acuity testing using Early Treatment Diabetic Retinopathy Study (ETDRS), visual field testing, full-field electroretinogram (ERG); retinal sensitivity (FST), dynamic pupillometry, nystagmus testing, OCT and FAF, and subject questionnaire.

[0325]Baseline visual function tests were performed, within 21 days of Day 0 of the study, including spectral-domain OCT in low light conditions to determine if there were viable photoreceptors in the retina. On Day 0 each RP subject received the first dose of the composit...

example 3

Safety and Efficacy Study for LCA Subjects

[0344]The study of Example 2 was also designed to determine the efficacy of the composition of Example 1 orally administered to human subjects having LCA (caused by mutations of either LRAT or RPE65). Subjects received a once-daily loading dose of the composition orally (40 mg / m2) for 7 days. Subjects were treated on an outpatient basis, but they received study treatment in the research clinic under medical supervision for each day of treatment. Both eyes of each subject were evaluated separately. Protocol-defined assessments of visual function included: best-corrected visual acuity testing using Early Treatment Diabetic Retinopathy Study (ETDRS) testing followed by low / high contrast Smith-Kettlewell Institute Low Luminance (SKILL) charts; visual field testing using Goldmann perimetry; full-field electroretinogram (ERG); and full-field stimulus threshold testing (FST). Baseline ERGs, ETDRS, and SKILL tests were repeated twice. During and aft...

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Abstract

Therapeutic regimes for improving visual function in a subject having a deficiency in endogenously produced 11-cis retinal comprising administering the synthetic retinal derivative as a divided dose over 2-7 days then providing a resting period of 7-28 days after which the second dose of the synthetic retinal derivative is administered. Preferred synthetic retinal derivatives are 9-or 11-cis-retinyl esters. Disorders associated with deficiency in endogenously produced 11-cis retinal include retinitis pigmentosa and Leber congenital amaurosis

Description

RELATED APPLICATIONS[0001]This application is a continuation of U.S. application Ser. No. 14 / 382,235, filed Aug. 29, 2014, which is a national stage application under 35 U.S.C. §371 of International Application No. PCT / CA2013 / 050155, filed Mar. 1, 2013, which claims the benefit of priority to U.S. provisional patent application No. 61 / 605,729, filed Mar. 1, 2012; U.S. provisional patent application No. 61 / 642,212, filed May 3, 2012; and U.S. provisional patent application No. 61 / 644,360, filed May 8, 2012; the disclosures of which are incorporated herein by reference in their entirety.FIELD OF THE DISCLOSURE[0002]This disclosure is directed to therapeutic regimens and methods for improving visual function in a subject with a visual disorder associated with an endogenous retinoid deficiency comprising administering a synthetic retinal derivative to the subject.BACKGROUND[0003]Inherited retinal diseases (IRD) caused by gene mutations that disrupt or interfere with the production, conv...

Claims

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Application Information

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IPC IPC(8): A61K31/11A61K9/00A61K31/22
CPCA61K31/11A61K9/0053A61K31/22A61K31/232A61P27/02A61P43/00A61K2121/00
Inventor CADDEN, SUZANNE
Owner NOVELION THERAPEUTICS INC
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