What is Upstaza used for?

Upstaza is indicated for the treatment of patients aged 18 months and older with a clinical, molecular, and genetically confirmed diagnosis of aromatic L-amino acid decarboxylase (AADC) deficiency with a severe phenotype (see section 5.1).

What is the active ingredient in Upstaza?

Eladocagenum exuparvovecum (Eladocagenum exuparvovecum)

What pharmaceutical form is Upstaza available in?

Upstaza: Roztwór do infuzji 5,6x10^11 vg/ml (Podanie do skorupy mózgu)

What are the side effects of Upstaza?

Summary of the safety profile The safety information was observed in 3 open-‑label clinical studies in which eladocagene exuparvovec was administered to 30 AADC-deficient patients aged 19 months to 8.5 years at the time of dosing. Patients were followed for a median duration of 59.3 months (minimum of 11.8 months to a maximum of 5.7 years). Twenty-six patients treated in the clinical studies enrolled in a long-term follow-up study. The duration of follow-up from the time of gen

Who should NOT take Upstaza?

Hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.1.

Does Upstaza interact with other medications?

No interaction studies have been performed. No interaction is expected due to very limited systemic distribution of eladocagene exuparvovec. Vaccinations There has been no reported interaction between general vaccinations and gene therapy administration. The health care provider should determine if adjustments to the patient's vaccination schedule are necessary.

Can Upstaza be used during pregnancy?

Based on the lack of systemic exposure and negligible biodistribution to the gonads, the risk for germline transmission is low. Pregnancy There are no data from the use of eladocagene exuparvovec in pregnant women. Animal reproductive studies have not been conducted with eladocagene exuparvovec (see section 5.3). Breast‑feeding It is unknown whether eladocagene exuparvovec is excreted in human milk. Eladocagene exuparvovec is not absorbed systemically following intraputaminal a

Who manufactures Upstaza?

PTC Therapeutics International Ltd. (Irlandia)

What ATC class does Upstaza belong to?

Upstaza: ATC A16AB26. ATC is the WHO Anatomical Therapeutic Chemical classification — it groups drugs by organ system and pharmacological mechanism.

Upstaza

This information is for educational purposes only. It is not intended as medical advice. Always consult a qualified healthcare professional.

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. Pharmacodynamic effects L‑6‑[ 18 F] fluoro‑3, 4‑dihydroxyphenylalanine ( 18 F ‑ DOPA) uptake in central nervous system (CNS) Measurement of 18 F‑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 18 F-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 uptake % Change from baseline 220.3 261.39 287.88 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 × 10 11 vg (N = 13) or 2.4 × 10 11 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 summarises 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. 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 PDMS-2 motor milestones (Mastery) at month 24, month 60, and month 96) (Studies AADC-010, AADC-011, and AADC-1602; N=22) Motor Milestone/ Month Number of Subjects (%) 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 with assistance 2 (9) 6 (27) 7 (32) Figure 2 Cumulative number of subjects demonstrating motor milestone (mastery skill) up to Month 96 (Studies AADC-010, AADC-011, and AADC-1602) 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). 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) 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 80.0% at baseline (N=20) to 41.2% at Month 12 (N = 17). No subject experienced limb dystonia 12 months post-treatment, compared with 70.0% subjects at baseline (N = 20), respectively. 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. Exceptional circumstances This medicinal product has been authorised under 'exceptional circumstances'. This means that due to the rarity of the disease it has not been possible to obtain complete information on this medicinal product. The Medicines and Healthcare products Regulatory Agency will review any new information which may become available every year and this SmPC will be updated as necessary.

⚠️ Warnings

Each vial is for single use only.‍‍‍‍‍‍‍‍‍‍‍‍‍ This medicinal product should only be infused with the SmartFlow ventricular cannula. Precautions to be taken before handling or administering the medicinal product This medicinal product contains genetically modified virus. During preparation, administration, and disposal, personal protective equipment (including gown, safety glasses, mask, and gloves) should be worn when handling eladocagene exuparvovec and materials that have been in contact with the solution (solid and liquid waste). Thawing in the hospital pharmacy • Upstaza is delivered to the pharmacy frozen and must be maintained in the outer carton at ≤ ‑65 °C until prepared for use. • Upstaza should be handled aseptically under sterile conditions. • Allow the frozen vial of Upstaza to thaw upright at room temperature until the content is completely thawed. Gently invert the vial approximately 3 times, do NOT shake. • Inspect Upstaza after mixing. If particulates, cloudiness, or discolouration are visible, do not use the product. Preparation prior to administration • Transfer the vial, syringe, needle, syringe cap, sterile bags, or sterile wrappings compliant with hospital procedure for transfer and use of the filled syringe in the planned surgical suite, and label into the Biological Safety Cabinet (BSC). Wear sterile gloves and other personal protective equipment (including gown, safety glasses and mask) as per normal procedure for BSC work. • Open the 1 mL or 5‑mL syringe [1 mL or 5 mL, polypropylene syringes with latex-free‑ elastomer plunger, lubricated with -medical grade- silicone oil] and label as the product-filled syringe per pharmacy procedure and local regulations. • Attach the 18‑ or 19‑gauge filter needle [18‑ or 19‑gauge, 1.5‑inch, stainless steel, 5‑µm filter needles] to the syringe. • Draw the full volume of the vial of Upstaza into the syringe. Invert the vial and syringe and partially withdraw or angle the needle as necessary to maximise recovery of product. • Draw air in the syringe so that the needle is emptied of product. Carefully remove the needle from 1 mL or 5‑mL syringe containing Upstaza. Purge the air from the syringe until there is no air bubble and then cap with a syringe cap. • Wrap the syringe in one sterile plastic bag (or several bags based on standard hospital procedure) and place in an appropriate secondary container (eg, hard plastic cooler) for delivery to the surgical suite at room temperature. Use of the syringe (ie, connecting the syringe to the syringe pump and starting priming of the cannula) should begin within 6 hours of starting product thaw. Administration in the surgical suite • Tightly connect the syringe containing Upstaza to the SmartFlow ventricular cannula. • Install the Upstaza syringe into a syringe infusion pump compatible with 1 mL or 5‑mL syringe. Pump Upstaza with the infusion pump at 0.003 mL/min until the first drop of Upstaza can be seen from the tip of the needle. Stop and wait until ready for infusion. Precautions to be taken for the disposal of the medicinal product and accidental exposure • Accidental exposure to eladocagene exuparvovec, including contact with skin, eyes, and mucous membranes, is to be avoided. • In the event of exposure to skin, the affected area must be thoroughly cleaned with soap and water for at least 5 minutes. In the event of exposure to eyes, the affected area must be thoroughly flushed with water for at least 5 minutes. • In the event of needlestick injury, the affected area must be cleaned thoroughly with soap and water and/or a disinfectant. • Any unused eladocagene exuparvovec or waste material should be disposed of in compliance with local guidance for pharmaceutical waste. Potential spills should be wiped with absorbent gauze and disinfected using a bleach solution followed by alcohol wipes. • After administration, the risk of shedding is considered to be low. It is recommended that caregivers and patient families are advised on and follow proper handling precautions of patient bodily fluids and waste for 14 days after administration of eladocagene exuparvovec (see section 4.4).

Upstaza

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