QLT Announces Positive Final Results From Phase 1b Retreatment Trial With Oral Synthetic cis-Retinoid (QLT091001) in Subjects With LCA or RP Due to Mutations in RPE65 or LRAT

VANCOUVER, Canada I September 12, 2014 I QLT Inc. (QLTI) (QLT.TO) (“QLT” or the “Company”) today announced positive final results from its international, multi-center, Phase 1b clinical trial of repeated treatments of oral QLT091001 in subjects with Leber Congenital Amaurosis (LCA) or Retinitis Pigmentosa (RP) due to inherited genetic mutations in retinal pigment epithelium (RPE65) or lecithin:retinol acyltransferase (LRAT). The results, which confirm the top line efficacy and safety outcomes reported from the study in February 2014, will be presented tomorrow, September 13, 2014, at the 47^th Annual Scientific Meeting of The Retina Society in Philadelphia, PA, by Dr. Hendrik Scholl, the Dr. Frieda Derdeyn Bambas Professor of Ophthalmology and Director of the Visual Neurophysiology Service at the Wilmer Eye Institute at the Johns Hopkins Hospital, and an investigator in the trial. The presentation slides will be made available on QLT’s web site following the Retina Society Meeting.

“As a follow up study to QLT’s RET IRD 01 study, for which the LCA data were recently published in The Lancet, it is encouraging to observe clinically meaningful improvements in visual fields with repeated dosing of QLT091001 in both LCA and RP patients with RPE65 or LRAT mutations,” said Dr. Scholl. “Also, there appears to be a small, but positive effect on visual acuity in both patient groups. This is promising given the relatively long duration of this study and the fact that inherited retinal disease is characterized by a progressive loss of visual function.”

This multicenter, open-label Phase 1b retreatment trial was an extension study in which LCA or RP subjects with RPE65 or LRAT mutations who had been treated with a single course of QLT091001 in the Company’s previously completed Phase 1b study, received up to three 7-day courses of QLT091001 to assess visual outcomes and safety following retreatment. Subjects received treatment with QLT091001 at doses of 10, 40 or 60 mg/m², with the majority of subjects receiving 40 mg/m². Visual fields were assessed using Goldmann visual field (GVF) and visual acuity was assessed using best-corrected visual acuity (BCVA) at baseline and days 7, 14, 30 and 60 after each treatment course, then bimonthly until the next treatment course.

Results of the final analysis confirmed the response rates previously reported in February 2014, with 19 of 27 subjects (70%) having a visual field response (increase in retinal area of at least 20% from the study baseline at 2 consecutive visits starting within 6 months of any study treatment), and 19 of 27 subjects (70%) having a visual acuity response (increase of at least 5 letters at 2 consecutive visits starting within 6 months of any study treatment) (see primary isopter rates and visual acuity rates in Table below). Over the course of the entire study spanning multiple treatment courses, these responses were durable, with the visual field response lasting an average of 235 days (Min-Max = 7 — 742 days), and the visual acuity response lasting an average of 232 days (Min-Max = 7 — 616 days). Overall, 10 of 13 LCA subjects (77%), and 12 of 14 RP subjects (86%) were classified as responders for either visual field retinal area or visual acuity.

GVF response: >=20% change or >=40% change in retinal area from baseline at 2 consecutive visits in at least 1 eye within 6 months of any treatment.

VA response: >= 5 letter increase from baseline at 2 consecutive visits in at least 1 eye within 6 months of any treatment.

* Since an improvement in vision can result from an increase in visual field for other isopters and not just the primary isopter (one with a mid-range retinal area less prone to floor and ceiling effects and chosen for each individual subject), changes in GVFs were also assessed at a number of additional isopters.

Repeated treatment with up to three courses of QLT091001 was generally well tolerated. Adverse events were consistent with the retinoid class of medications and with the previously completed Phase 1b single course of treatment study (RET IRD 01) and were transient and/or reversible. Headache and fatigue were the most common treatment-related adverse events followed by erythema, nausea, photophobia, photopsia, flushing and vomiting. Reversible elevations in triglyceride, LDL, cholesterol, AST and ALT levels and reduction in HDL and thyroxine were recorded. Most treatment-related adverse events were either mild (78%) or moderate (18%) in intensity. One serious adverse drug reaction (pseudotumor cerebri or intracranial hypertension, a known class effect of retinoids) was reported in the study and it was resolved. The incidence of treatment-related adverse events did not increase with successive treatment courses.

About the Retreatment Trial

This multicenter, open-label Phase 1b retreatment trial was an extension study in which 27 LCA or RP subjects with RPE65 or LRAT mutations who had been treated with a single course of QLT091001 in the Company’s previously completed Phase 1b study, received up to three 7-day courses of QLT091001 to assess visual outcomes and safety following retreatment. Subjects received treatment with QLT091001 at doses of 10, 40 or 60 mg/m², with the majority of subjects receiving 40 mg/m². Visual fields were assessed using Goldmann visual field (GVF) and visual acuity was assessed using best-corrected visual acuity (BCVA) at baseline and days 7, 14, 30 and 60 after each treatment course, then bimonthly until the next treatment course. Safety assessments included complete ophthalmic and physical examinations, electroretinograms (ERGs), optical coherence tomography (OCT) retinal architecture, electrocardiograms, laboratory testing and reported adverse events.

Duration of GVF response was calculated as the time difference between the first and last time points at which the response criteria were met for the responding eye. Duration of response was determined for the overall study period, and not for individual treatment courses. There could be 1 intervening visit at which the subject fell below the response criteria without affecting the duration of response.

After the first treatment course in this retreatment study (RET IRD 02), the timing of subsequent courses of retreatment with QLT091001 was initially determined based on prespecified GVF response criteria or was at Investigator discretion. The clinical trial protocol was later amended to allow retreatment to occur as early as 30 days but no later than 60 days after a previous treatment course to maintain dosing within a fixed time interval. For these reasons, the time between each treatment course in this trial varied between subjects and also varied between courses for each subject. The duration of follow-up after each course ranged from 30 days to 12 months for Course 1, 30 days to 8 months for Course 2, and was 6 months for Course 3. There was also a wide range in time (7-32 months) per subject that elapsed between the single course treatment in the previously completed Phase 1b trial and treatment in this trial.

Thirteen LCA and 14 RP subjects aged 7 to 57 years with mutations in RPE65 (N=15) or LRAT (N=12) were enrolled in the study. The mean age for the LCA subjects was 20 years versus 29 years for the RP subjects. All 27 subjects received the first course of treatment, 23 subjects received a second course, and 21 subjects received a third course.

About Leber Congenital Amaurosis (LCA)

LCA is an inherited degenerative retinal disease characterized by abnormalities such as roving eye movements and sensitivity to light, and manifesting in severe vision loss from birth. Both rod and cone photoreceptors are affected in LCA. Eye examinations of infants with LCA often reveal normal appearing retinas. However, a low level of retinal activity, measured by electroretinography, indicates very little visual function. According to current epidemiological estimates, LCA affects approximately one in 81,000 newborns worldwide, of which approximately 10% carry the inherited deficiencies of either RPE65 or LRAT.

About Retinitis Pigmentosa (RP) Due to RPE65 and LRAT Mutations

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. RP is currently estimated to affect at least 300,000 individuals worldwide, of which approximately 20% to 30% are autosomal recessive (arRP). It is currently estimated that less than 3% of autosomal recessive RP patients carry the inherited deficiencies of either RPE65 or LRAT.

About Synthetic Retinoid Drugs

Genetic diseases in the eye such as Leber Congenital Amaurosis (LCA) and Retinitis Pigmentosa (RP) arise from gene mutations of enzymes or proteins required in the biochemistry of vision. QLT091001 is a replacement for 11-cis-retinal, which is an essential component of the retinoid-rhodopsin cycle and visual function, and is under investigation for the treatment of LCA and RP. QLT091001 has received orphan drug designations for the treatment of LCA (due to inherited mutations in LRAT or RPE65 genes) and RP (all mutations) by the FDA, and for the treatment of LCA and RP (all mutations) by the EMA. The drug has also been granted two Fast Track designations by the FDA for the treatment of LCA and RP due to inherited mutations in the LRAT and RPE65 genes. The FDA has also formally acknowledged that the orphan drug designations granted by the FDA on QLT091001 also cover QLT091001 for the treatment of Inherited Retinal Disease caused by LRAT or RPE65 mutations, including severe early childhood onset retinal dystrophy, which disease/condition we believe subsumes both LCA and RP. The clinical characteristics and progression of disease in LCA and RP overlap as do some of their genetic causes. At least 7 of the known LCA disease genes, including LRAT and RPE65, have also been linked to the clinical appearance of RP. Despite disease heterogeneity and terminology, there is an overlap in the genetic mechanisms underlying some forms of LCA and RP such as those caused by LRAT and RPE65 mutations where 11-cis-retinal production is either severely or completely compromised. RP is the most common inherited retinal disease, and is generally the diagnosis given to patients who begin to lose vision after the first decade of life, whereas the diagnosis of LCA is given to patients who have vision loss soon after birth. There is no universally accepted diagnostic term for patients with characteristics in between; clinicians have considered such cases as being either LCA or severe RP.

About QLT

QLT is a biotechnology company dedicated to the development and commercialization of innovative ocular products that address the unmet medical needs of patients and clinicians worldwide. We are focused on developing our synthetic retinoid program for the treatment of certain inherited retinal diseases.

SOURCE: QLT