Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties
Pharmacotherapeutic group: Ophthalmologicals, other ophthalmologicals, ATC code: S01XA27.

Mechanism of action

The retinal pigment epithelium-specific 65 kilodalton protein (RPE65) is located in the retinal pigment epithelial cells and converts all-trans-retinol to 11-cis-retinol, which subsequently forms the chromophore, 11-cis-retinal, during the visual (retinoid) cycle. These steps are critical in the biological conversion of a photon of light into an electrical signal within the retina. Mutations in the RPE65 gene lead to reduced or absent RPE65 all-trans-retinyl isomerase activity, blocking the visual cycle and resulting in vision loss. Over time, accumulation of toxic precursors leads to the death of retinal pigment epithelial cells, and subsequently to progressive photoreceptor cell death. Individuals with biallelic RPE65 mutation-associated retinal dystrophy exhibit vision loss, including impaired visual function parameters such as visual acuity and visual fields often during childhood or adolescence; this loss of vision ultimately progresses to complete blindness.

Injection of voretigene neparvovec into the subretinal space results in transduction of retinal pigment epithelial cells with a cDNA encoding normal human RPE65 protein (gene augmentation therapy), providing the potential to restore the visual cycle.

Clinical efficacy and safety

The long-term safety and efficacy of Luxturna were assessed in a phase 1 safety and dose escalation study (101), in which 12 subjects received unilateral subretinal injections of voretigene neparvovec; a follow-on study (102) in which voretigene neparvovec was administered to the contralateral eye in 11 of the 12 subjects who participated in the dose escalation study; a one-year, open-label phase 3 controlled study (301) in which 31 subjects were randomised at two sites; and the continuation of the phase 3 study, in which the 9 control subjects crossed over and received the intervention. A total of 41 subjects (81 eyes injected [one phase 1 subject did not meet eligibility criteria for a second injection]) participated in the clinical programme. All participants had a clinical diagnosis of Leber congenital amaurosis, and some may have also had prior or additional clinical diagnoses, including retinitis pigmentosa. Confirmed biallelic RPE65 mutations and the presence of sufficient viable retinal cells (an area of retina within the posterior pole of >100 micron thickness, as estimated by optical coherence tomography [OCT]) were established for all participants.

Phase 3 study
Study 301 was an open-label, randomised, controlled study. 31 subjects were enrolled, 13 males and 18 females. The average age was 15 years (range 4 to 44 years), including 64% paediatric subjects (n=20, age from 4 to 17 ears a d 3 % adults = . All su je ts had a diag osis of Le er s congenital amaurosis owing to RPE65 mutations confirmed by genetic analysis in a certified laboratory.

21 subjects were randomised to receive subretinal injection of voretigene neparvovec. Visual acuity
(LogMAR) of the first eye of these subjects at baseline was 1.18 (0.14), mean (SE). One subject discontinued from the study prior to treatment. 10 subjects were randomised to the control (non-intervention) group. Visual acuity (LogMAR) of the first eye of these subjects at baseline was 1.29 (0.21), mean (SE). One subject in the control group withdrew consent and was discontinued from the study. The nine subjects who were randomised to the control group were crossed over to 
LUX API JUN24 V6                             Page 8 of 15                         EU SmPC April 2024 receive subretinal injection of voretigene neparvovec after one year of observation. Each eye was administered a single subretinal injection of 1.5 × 1011 vector genomes voretigene neparvovec in a total volume of 300 μL. The i ter al et ee i je tio to the e es for ea h su je t as fro        to 18 days.

The primary endpoint of the phase 3 study measured the mean change from baseline to one year in binocular multi-luminance mobility testing (MLMT) between the intervention and control groups.
The MLMT was designed to measure changes in functional vision, specifically the ability of a subject to navigate a course accurately and at a reasonable pace at different levels of environmental illu i atio . This a ilit depe ds o the su je t s isual a uit , isual field a d the e te t of nyctalopia (decreased ability to perceive and/or see in dim light), each of which are functions specifically affected by the retinal disease associated with RPE65 mutations. In the phase 3 study, the MLMT used seven levels of illumination ranging from 400 lux to 1 lux (corresponding to, for example, a brightly lit office down to a moonless summer night). The testing of each subject was videotaped and assessed by independent graders. A positive change score reflects passing the MLMT at a lower light level and a lux score of 6 reflects the maximum possible MLMT improvement. Three secondary endpoints were also tested: full-field light sensitivity threshold (FST) testing using white light; the change in MLMT score for the first assigned eye; and visual acuity (VA) testing.

At baseline, subjects achieved pass marks on the mobility test at between 4 and 400 ambient lux.

Table 4     Changes in MLMT score: year 1, compared to baseline (ITT population: n=21 intervention, n=10 control)

Difference
Change in MLMT score                         (95% CI)                    p-value Intervention-Control using binocular vision                             1.6 (0.72, 2.41)                0.001 using assigned first eye only                      1.7 (0.89, 2.52)                0.001 using assigned second eye only                     2.0 (1.14, 2.85)               <0.001 
The monocular MLMT change score significantly improved in the treatment group and was similar to the binocular MLMT results (see Table 4).

Figure 2 shows the effect of the medicinal product over the three-year period in the voretigene neparvovec treatment group, as well as the effect in the control group after crossing over to receive subretinal injection of voretigene neparvovec. Significant differences in binocular MLMT performance were observed for the voretigene neparvovec treatment group at day 30 and were maintained over the remaining follow-up visits throughout the three-year period, compared to no change in the control group. However, after crossing-over to receive subretinal injection of voretigene neparvovec, the subjects in the control group showed a similar response to the voretigene neparvovec as compared to the subjects in the voretigene neparvovec treatment group.


LUX API JUN24 V6                             Page 9 of 15                        EU SmPC April 2024 Figure 2     Change in MLMT score using binocular vision versus time before / after exposure to voretigene neparvovec



BL D30 D90   D180           Y1                          Y2                         Y3 XBLXD30 XD90 XD180         XY1                         XY2



Each box represents the middle 50% of distribution of MLMT score change. Vertical dotted lines represent additional 25% above and below the box. The horizontal bar within each box represents the median. The dot within each box represents the mean. The solid line connects the mean MLMT score changes over visits for the treatment group. The dotted line connects the mean MLMT score change over visits for the control group, including five visits during the first year without receiving voretigene neparvovec. The control group was administered voretigene neparvovec after 1 year of observation.
BL: baseline;
D30, D90, D180: 30, 90 and 180 days after start of study;
Y1, Y2, Y3: one, two and three years after start of study;
XBL; XD30; XD90; XD180: baseline, 30, 90 and 180 days after start of study for control crossover group; XY1; XY2: one and two years after start of study for control crossover group.


LUX API JUN24 V6                               Page 10 of 15                         EU SmPC April 2024 Results of full-field light sensitivity testing at the first study year: white light [Log10(cd.s/m2)] are shown in Table 5 below.

Table 5      Full-field light sensitivity testing

Full-field light sensitivity testing – First assigned eye (ITT)
Intervention, N = 21
Baseline                   Year 1                     Change
N                           20                         20                         19 Mean (SE)                   -1.23 (0.10)               -3.44 (0.30)               -2.21 (0.30) 
Control, N = 10
N                            9                          9                         9 Mean (SE)                    -1.65 (0.14)               -1.54 (0.44)              0.12 (0.45) Difference (95% CI) (Intervention-Control)
-2.33 (-3.44, -1.22), p<0.001
Full-field light sensitivity testing – Second assigned eye (ITT)
Intervention, N = 21
Baseline                 Year 1                       Change
N                           20                       20                           19 Mean (SE)                   -1.35 (0.09)             -3.28 (0.29)                 -1.93 (0.31) 
Control, N = 10
N                            9                          9                         9 Mean (SE)                    -1.64 (0.14)               -1.69 (0.44)              0.04 (0.46) Difference (95% CI) (Intervention-Control)
-1.89 (-3.03, -0.75), p=0.002
Full-field light sensitivity testing - Averaged across both eyes (ITT) Difference (95% CI) (Intervention-Control): -2.11 (-3.19, -1.04), p<0.001 
Improvement in full-field light sensitivity was maintained for up to 3 years after exposure to voretigene neparvovec.

At one year after exposure to voretigene neparvovec, improvement in visual acuity of at least 0.3 LogMAR occurred in 11/20 (55%) of the first-treated eyes and 4/20 (20%) of the second-treated eyes in the intervention group; no one in the control group displayed such an improvement of visual acuity in either the first or second eye.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

Voretigene neparvovec is expected to be taken up by cells through heparin sulphate proteoglycan receptors and be degraded by endogenous proteins and DNA catabolic pathways.

Nonclinical biodistribution

Biodistribution of voretigene neparvovec was evaluated at three months following subretinal administration in non-human primates. The highest levels of vector DNA sequences were detected in intraocular fluids (anterior chamber fluid and vitreous) of vector-injected eyes. Low levels of vector DNA sequences were detected in the optic nerve of the vector-injected eye, optic chiasm, spleen and liver, and sporadically in the stomach and lymph nodes. In one animal administered with voretigene neparvovec at 7.5 × 1011 vector genomes (5 times the recommended per eye dose), vector DNA sequences were detected in colon, duodenum and trachea. Vector DNA sequences were not detected in gonads.


LUX API JUN24 V6                               Page 11 of 15                           EU SmPC April 2024 Clinical pharmacokinetics and shedding

The vector shedding and biodistribution were evaluated in tears from both eyes, serum and whole blood of subjects in the phase 3 clinical study. In 13/29 (45%) subjects receiving bilateral administrations, voretigene neparvovec vector DNA sequences were detected in tear samples; most of these subjects were negative after the day 1 post-injection visit, however, four of these subjects had positive tear samples beyond the first day, one subject up to day 14 post-second eye injection.
Vector DNA sequences were detected in serum in 3/29 (10%) subjects, including two with positive tear samples, and only up to day 3 following each injection. Overall, transient and low levels of vector DNA were detected in tear and occasional serum samples from 14/29 (48%) of subjects in the phase 3 study.

Pharmacokinetics in special populations

No pharmacokinetic studies with voretigene neparvovec have been conducted in special populations.
Hepatic and renal impairment
Luxturna is injected directly into the eye. Liver and kidney function, cytochrome P450 polymorphisms and ageing are not expected to influence the clinical efficacy or safety of the product. Therefore, no adjustment in dose is necessary for patients with hepatic or renal impairment.