An oral drug may treat some forms of LCA

As already mentioned in this blog,  an oral drug is being tested to treat some forms of LCA, and preliminary results have been astounding.

 

QLT is a Canadian company focused on developing innovative ocular products. QLT091001 is an oral synthetic retinoid proposed as a potential treatment for retinal diseases caused by gene mutations that interfere with the availability of 11-cis-retinal. Specifically, it is design to treat forms of Leber Congenital Amaurosis, and of RP. The forms of LCA the drug is targeting are those caused by mutations in LRAT (lecithin: retinol acyltransferase) and RPE65 (retinal pigment epithelium protein 65).

 

At the McGill University Health Centre of Montreal Children's Hospital, an early phase clinical trial is currently underway, to test safety and efficacy of QLT091001 in subjects with LCA due to RPE65 or LRAT gene mutations. Study participants are treated with oral QLT091001 daily for 7 days, and their visual function measured at predetermined time points after treatment, along with other physical and laboratory tests. To date, 9 subjects with LCA due to LRAT or RPE65 mutations have been enrolled. Preliminary results show improvements in best-corrected visual acuity and visual fields, which in some cases have persisted for up to 11 months beyond the end of treatment. Many subjects reported meaningful improvements in their activities of daily living. No serious adverse events occurred. These findings are very encouraging and indicate that seven days of oral QLT091001, generally well-tolerated, can produce rapid and sustained vision improvements, as well as subjective improvements in activities of daily living.

More LCA subjects are currently being enrolled; the results from patients in the LCA cohort are expected in the second quarter of 2011.

 

LCA, RP and the Visual Cycle

 

As mentioned above, QLT091001 is being developed for LCA and RP due to mutations in LRAT and RPE65.  Mutations in LRAT and RPE65 result in the absence of 11-cis-retinal, an important molecule essential for vision.  11-cis-retinal is produced in the retinal pigment epithelium (RPE) and binds to the protein opsin to form rhodopsin in the rod outer segment.

Vision is initiated when a light photon is captured by 11-cis-retinal, resulting in isomerization to all-trans-retinal and dissociation from opsin. Vision is sustained by the cycling of all trans-retinal back into 11-cis-retinal, which occurs by a complex series of biochemical reactions involving multiple enzymes and proteins in the retinoid cycle.

 

How the Drug Works

 

The therapeutic strategy with QLT091001 is to facilitate recovery or restoration of visual function by acting as an analogue replacement for missing 11-cis-retinal and restoring the key biochemical component of the visual (retinoid) cycle.  QLT091001 is an orally available synthetic prodrug that is converted to 9-cis-retinal, which forms the visual pigment isorhodopsin (instead of the usual rhodopsin formed from 11-cis-retinal). Isorhodopsin is a functionally active pigment in the visual cycle that undergoes conformational changes through the same photoproducts as 11-cis-retinal-regenerated rhodopsin.

 

In humans with a deficiency in 11-cis-retinal, isorhodopsin may act as a suitable substitute for rhodopsin in the visual cycle. This strategy proved successful in animal studies, as well as in humans, according to the preliminary findings of the Phase I clinical trial.

 

As with all drugs at the Phase I stage of development, these preliminary results need to be substantiated in larger safety and efficacy studies in the future.

 

To learn more, visit

http://www.clinicaltrials.gov/ct2/show/NCT01014052?term=qlt&rank=1