Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties
Pharmacotherapeutic group: Other alimentary tract and metabolism products, Enzymes; ATC code: A16AB26

Mechanism of action

AADC deficiency is an inborn error of neurotransmitter biosynthesis with an autosomal recessive inheritance in the dopa decarboxylase (DDC) gene. The DDC gene encodes the AADC enzyme, which converts L-3,4-dihydroxyphenylalanine (L-DOPA) to dopamine. Mutations in the DDC gene result in reduction or absence of AADC enzyme activity, causing a reduction in the levels of dopamine and the failure of most patients with AADC deficiency to achieve developmental milestones.

Eladocagene exuparvovec is a gene therapy based on recombinant AAV2 vector containing the human cDNA for the DDC gene. After infusion into the putamen, the product results in the expression of the AADC enzyme and subsequent production of dopamine, and consequently, development of motor function in treated AADC-deficient patients.


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Pharmacodynamic effects
L-6-[18F] fluoro-3, 4-dihydroxyphenylalanine (18F-DOPA) uptake in central nervous system (CNS) Measurement of 18F-DOPA uptake in the putamen via positron emission tomography (PET) imaging following treatment is an objective measurement of de novo dopamine production in the brain and assesses the success and stability of the DDC gene transduction over time. Most patients demonstrated small, sustained increases in PET-specific uptake. An increase was evident as early as 6 months, was further increased by 12 months after treatment, and sustained at least for 5 years.
Table 4         Percent change from baseline in uptake of 18F-DOPA after Eladocagene Exuparvovec treatment (Studies AADC-010 and AADC-011)
Timepoint             Month 12 (n=19) Month 24 (n=17)            Month 60 (n=11)
PET specific          220.3                261.39                287.88 uptake
% Change from baseline

Clinical efficacy and safety

The efficacy of Upstaza gene therapy was assessed in 2 clinical studies (AADC-010, AADC-011).
Together, these 2 studies included 22 patients with severe AADC deficiency, diagnosed by decreased homovanillic acid and 5-hydroxyindoleacetic acid and elevated L-DOPA CSF levels, the presence of DDC gene mutation in both alleles, and the presence of clinical symptoms of AADC deficiency (including developmental delay, hypotonia, dystonia, and oculogyric crisis [OGC]). These patients had not achieved motor development milestones at baseline including the ability to sit, stand, or walk, compatible with the severe phenotype. Patients were treated with a total dose of 1.8 × 1011 vg (N = 13) or 2.4 × 1011 vg (N = 9) during a single operative session. The results for efficacy and safety parameters were similar between the 2 doses.
Data beyond the Month 60 and Month 12 timepoints in Study AADC-010 and Study AADC-011, respectively, were collected in the long-term follow-up Study AADC-1602 as indicated below, with a data cutoff date of 16 June 2023.
Study AADC-CU/1601 was conducted with treatment from an older manufacturing process. This study enrolled 8 subjects and demonstrated similar results with benefits maintained up to 126.5 months.

Motor function
Motor milestone achievement was derived from the Peabody Developmental Motor Scale, version 2 (PDMS-2). The PDMS-2 is an assessment of a child’s motor development up to the developmental age of 5, and assesses both gross and fine motor skills, and with items that specifically capture motor milestone achievement. The PDMS-2 motor skill items were chosen to determine the number of patients who achieved at least the following motor milestones (Mastery of the skill – score of 2): 1) full head control (sitting supported at his/her hips and holding his/her head aligned while rotating his/her head to follow a toy for 8 seconds), 2) sitting unassisted (sit without support and maintain balance while in a sitting position for 60 seconds), 3) standing with support (take at least 4 alternating steps, either in place or in forward motion, with the evaluator’s hands around the child’s trunk), and 4) walking assisted (walk at least 8 feet with alternating steps, with the evaluator beside the patient and holding only one of the child’s hands).

Table 5 summarizes the primary analysis, which evaluated the number of patients who demonstrated acquisition of the key motor milestones (Mastery), at 24 months, 60 months and 96 months after gene therapy.


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Treatment with eladocagene exuparvovec demonstrated acquisition of motor milestones observed as early as 3 months post-surgery. Key motor milestone acquisition was continued or maintained beyond 24 months and up to 96 months, corresponding to 8 years follow-up (Figure 2).
Table 5                                                  Cumulative number of subjects achieving new PDMS-2 motor milestones (Mastery) at month 24, month 60, and month 96) (Studies AADC-010,
AADC-011, and AADC-1602; N=22)
Number of Subjects (%)
Motor Milestone/ Month                                                               Month 24               Month 60              Month 96 Full head control                                                                14 (64)                16 (73)                16 (73) Sitting unassisted                                                               11 (50)                15 (68)                16 (73) Standing with support                                                            8 (36)                 11 (50)                11 (50) Walking
PTC        with assistance
Therapeutics Inc.                                                            2 (9)                  6 (27) Studies:        7 (32) AADC-010, AADC-011 and           AADC-1602


Figure 1.1.3.1 (Page 3 of 3)
Cumulative Number of Subjects Achieved Motor Milestones by Time Point Figure 2                                                 Cumulative number of subjects -All demonstrating
Doses        motor milestone (mastery skill)
Intent-To-Treat Population (N=22) up to Month 96 (Studies AADC-010, AADC-011, and AADC-1602)
Mastery

24
Number of Subjects Achieved Motor Milestones



16


8



0
BL   3    6       9     12     18      24     30      36        42    48    54     60    72      84       96 Month

Head control (Sta Q10)                     Sitting unassisted (Sta Q14) Standing with support (Loc Q28)            Walking with assistance (Loc Q34) Program: ..\AADC\AADC\ISE\ISE-202306-3studies\tlf\pgms\f_milestone_cum_M60.sas                                                                    11JAN2024 09:52 


PDMS-2 total score
PDMS-2 total score was measured as a secondary endpoint throughout the clinical studies. PDMS-2 maximal scores are 450-482, depending on age (<12 months or > 12 months). All subjects treated with eladocagene exuparvovec showed increases from baseline in mean PDMS-2 total scores over time, with some benefit observed as early as 3 months (Figure 3). At the 24-month timepoint, the least squares (LS) mean of change from baseline in PDMS-2 total score was 111.2 points. Improvement from baseline in PDMS-2 total score was as early as 12 months after treatment (77.6 points) and was maintained to 60 months (139.0 points) and 96 months (141.6 points). Patients who receive eladocagene exuparvovec at a younger age demonstrate a faster treatment response and appear to reach a higher final level.

Figure 3                                                 PDMS-2 total scores by visit – through Month 96 (Studies AADC-010, AADC- 011, and AADC-1602; N=22)


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The following data were collected as secondary endpoints in the clinical studies.

Cognitive and communication skills
Bayley-III, a standard assessment of cognition, language, and motor development for, infants and toddlers (1-42 months of age), was utilized in Studies AADC-010 and AADC-011 to assess cognitive and language development. The language subscale consists of receptive and expressive communications.

Over time, all subjects showed gradual and sustained increases in mean cognitive and total language scores, which is the combined score for receptive and expressive communication scores. The mean raw total score for cognitive subscale at baseline was 12.41 (N=22). The LS mean change from baseline in cognitive score showed an increase of 12.3 at Month 12, 16.4 at Month 24, and 23.6 at Month 60. The mean raw total score for language subscale at baseline was 18.09 (N=22). The LS mean change from baseline in total language score showed an increase of 7.6 at Month 12, 10.1 at Month 24, and 14.9 at Month 60.

Body weight
Eighteen out of 19 subjects (95%) maintained (47%, 9 subjects) or increased (47%, 9 subjects) their body weight over a 12-month period based on gender and age specific growth chart.

Floppiness (hypotonia) limb dystonia, stimulus-provoked dystonia
Following gene therapy, the percentage of subjects with symptoms of floppiness (hypotonia) decreased from 55.0% at baseline (N=22) to 23.5% at Month 12 (N = 17). No subject experienced limb dystonia 12 months post-treatment, compared with 40.0% subjects at baseline (N = 22).

OGC episodes
Following gene therapy, the duration of OGC episodes, was reduced and sustained over time and up to 12 months after treatment. The mean time in OGC was 11.90 hours/week at baseline (N=21). This time was reduced following treatment by 1.39 hours per week by Month 3 (N=19) and by 4.82 hours per week by Month 12 (N=6).

The magnitude of the effect of eladocagene exuparvovec on the autonomic symptoms of the AADC deficiency has not been systematically evaluated.


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Pharmacokinetic Properties

5.2   Pharmacokinetic properties
No pharmacokinetic studies with eladocagene exuparvovec have been conducted. Eladocagene exuparvovec is infused directly into the brain and has not been shown to distribute outside the CNS.

Distribution

The biodistribution of the AAV2-hAADC viral vector in blood and urine was measured in subjects using a validated real-time quantitative polymerase chain reaction assay. In one subject treated with eladocagene exuparvovec, very low levels, far below treatment concentrations, have been detected in urine at Month 6.