LUXTURNA(voretigene neparvovec-rzyl)intraocular suspension forsubretinal injection(八)
equences were not detected in the gonads.
Clinical data
LUXTURNA vector shedding and biodistribution were investigated in a study measuring LUXTURNA DNA intears from both eyes, and from serum, and whole blood of subjects in Study 2. In summary, LUXTURNAvector was shed transiently and at low levels in tears from the injected eye in 45% of the subjects in Study 2,
and occasionally (7%) from the uninjected eye until Day 3 post-injection.
In 29 subjects who received bilateral administrations, LUXTURNA vector DNA was present in tear samples of13 subjects (45%). Peak levels of vector DNA were detected in the tear samples on Day 1 post-injection, afterwhich no vector DNA was detected in a majority of the subjects (8 of 13). Three subjects (10%) had vector
DNA in tear samples until Day 3 post-injection, and two subjects (7%) had vector DNA in tear samples foraround two weeks post-injection. In another two subjects (7%), vector DNA was detected in tear samples fromthe uninjected (or previously injected) eye until Day 3 post-injection. Vector DNA was detected in serum in3/29 (10%) subjects, including two with vector DNA in tear samples up to Day 3 following each injection.
Specific Populations
No pharmacokinetic studies with LUXTURNA have been conducted.
Drug Interaction Studies
No interaction studies have been performed with LUXTURNA.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
No animal studies have been conducted to eva luate the effects of LUXTURNA on carcinogenesis, mutagenesis,and impairment of fertility.
13.2 Animal Toxicology and/or Pharmacology
Bilateral, simultaneous subretinal administration of LUXTURNA was well tolerated at dose levels up to 8.25 x1010 vg per eye in dogs with a naturally occurring RPE-65 mutation and 7.5 x 1011 vg (5 times higher than therecommended human dose level) per eye in non-human primates (NHPs) with normal-sighted eyes. In both
animal models, bilateral, sequential subretinal administrations, where the contralateral eye was injected following the first eye, were well tolerated at the recommended human dose level of 1.5 x 1011 vg per eye. Inaddition, dogs with with the RPE-65 mutation displayed improved visual behavior and pupillary responses.
Ocular histopathology showed only mild changes, which were mostly related to healing from the surgicaladministration procedure. Other findings observed following subretinal injection of LUXTURNA in dogs andNHPs included occasional and isolated inflammatory cells in the retina, with no apparent retinal degeneration.
Dogs not previously exposed to AAV2 vectors developed antibodies to the AAV2 capsid following a singleadministration of LUXTURNA, whereas NHPs did not.
14 CLINICAL STUDIES
The efficacy of LUXTURNA in pediatric and adult patients with biallelic RPE65 mutation-associated retinaldystrophy was eva luated in an open-label, two-center, randomized trial (Study 2). Of the 31 enrolled subjects,21 subjects were randomized to receive subretinal injection of LUXTURNA. One subject discontinued from the
study prior to treatment. Ten subjects were randomized to the control (non-intervention) group. One subject inthe control group withdrew consent and was discontinued from the study.
The nine subjects who werrandomized to the control group were crossed over to receive subretinal injection of LUXTURNA after oneyear of observation. The average age of the 31 randomized subjects was 15 years (range 4 to 44 years),inc |
