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QLT091001 is a synthetic retinoid replacement for 11-cis-retinal. It is an investigational product under development for the treatment of retinal diseases caused by gene mutations that interfere with the availability of 11-cis-retinal. The therapeutic strategy with QLT091001 is to facilitate recovery or restoration of visual function by acting as a replacement for missing 11-cis-retinal and restoring a key biochemical component of the visual (retinoid) cycle.
QLT091001 orphan drug program for the treatment of Inherited Retinal Disease (Leber Congenital Amaurosis and Retinitis Pigmentosa)
LCA and RP are inherited, progressive, retinal degenerative diseases that arise from genetic mutations of enzymes or proteins required in the biochemistry of vision. LCA is characterized by abnormalities such as roving eye movements and sensitivity to light, and manifests in severe vision loss from birth. Both rod and cone photoreceptors are affected in LCA. Eye examinations of infants with LCA reveal normal appearing retinas; however, low level of retinal activity, measured by electroretinography, indicates very little visual function. RP is a set of hereditary retinal diseases demonstrating clinical features similar to LCA. RP is also characterized by degeneration of rod and cone photoreceptors, but it presents with a more variable loss of vision in late childhood to adulthood. Deficits in dark adaptation and peripheral vision are particular hallmarks of RP. LCA and RP diseases result from genetic mutations, including retinal pigment epithelium protein 65 (RPE65) or lecithin retinol acyltransferase (LRAT), which result in an inadequate production of 11-cis-retinal, an essential component of the visual retinoid cycle. QLT091001 is a replacement therapy for 11-cis-retinal.
We are currently developing QLT091001 for the treatment of Leber Congenital Amaurosis (LCA) and Retinitis Pigmentosa (RP). QLT091001 has received orphan drug designations from the FDA and the EMA for the treatment of LCA and RP.
Results from our initial Phase Ib clinical proof-of-concept study in patients with LCA and RP due to inherited deficiencies of RPE65 or LRAT were reported for the 14 LCA patients in 2011 and for the 18 early-onset RP patients in March 2012.
Our Phase 1b retreatment study in these patients was completed and we reported positive results from the retreatment study on September 12, 2014.
We have also conducted a Phase 1b study in five RP patients with autosomal dominant mutations in RPE65 and results of this study were reported.
QLT091001 for the treatment of Impaired Dark Adaptation (IDA)
Impaired Dark Adaptation (IDA) is a condition that results in decreased ability of the eye to recover visual sensitivity in the dark following exposure to bright lights (photobleaching) that gets worse with age. Profoundly impaired dark adaptation is commonly associated with inherited retinal degenerations. More recently, mild to moderate impaired dark adaptation has been associated with age-related macular degeneration (AMD) and is proportionate to the severity of the disease. IDA (and/or impaired low luminance vision) may occur due to age-related inefficiencies in the retinoid cycle which results in slower regeneration of the light sensing pigment 11-cis-retinal in the eye and increased levels of free unbound opsin that lead to delayed dark adaptation and reduced retinal sensitivity. Ultimately, these factors impair vision in low light or dark environments. The kinetics of the rod function have also been reported to be age-related, with the rod-mediated portion of the dark adaptation function significantly slower in older patients with normal retinal function than in younger adults. This rod-mediated dark adaptation time is further slowed down in patients with early signs of AMD but with good visual acuity.
IDA in this population causes symptomatic difficulties for functioning in dim light, especially after exposure to bright ambient light, and can hamper daily living activities such as driving, mobility and workplace tasks. Impaired mobility, in the form of falling, is one of the most common problems of old age. IDA is not a disease but a condition that can arise as a result of a number of pathologic or physiologic factors. Improving this condition has the potential to not only improve a patient’s quality of life but also delay the development of degenerative retinal conditions with more severe visual outcomes.
In late 2013, we initiated a Phase IIa proof-of-concept randomized, multi-center, parallel-group, placebo-controlled trial of QLT091001 in adult patients with Impaired Dark Adaptation (IDA). The trial evaluated the safety profile and effects of QLT091001 on impaired dark adaptation time, glare recovery time and low luminance low contrast best corrected visual acuity in 43 patients.
The study has been completed and results were reported on December 5, 2014.
Background
In 2009, a Phase 1a study of oral QLT091001 was completed in healthy volunteers to evaluate safety and estimate an appropriate dose for studies in subjects with LCA or RP. Results of this study are described in a press release issued March 12, 2009.
Preclinical studies have investigated QLT091001 in mouse and dog models of LCA. Results of these studies are available here: 2009 ASRS poster; 2009 ARVO poster.
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