Pariglasgene brecaparvovec

1. INDICATIONS AND USAGE GENGLYCOS is indicated to reduce daily cornstarch intake as an adjunct to nutritional management in adult and pediatric patients 8 years of age and older with glycogen storage disease type Ia (GSDIa). This indication is approved under accelerated approval based on reduction in daily cornstarch intake. Continued approval for this indication may be contingent upon verification of clinical benefit in a confirmatory trial(s). GENGLYCOS is an adeno-associated virus (AAV) vector-based gene therapy indicated to reduce daily cornstarch intake as an adjunct to nutritional management in adult and pediatric patients 8 years of age and older with glycogen storage disease type Ia (GSDIa). Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trial(s).

12.1. Mechanism of Action GENGLYCOS is an adeno-associated virus serotype 8 (AAV8) based gene therapy designed to deliver a copy of the glucose-6-phosphatase ( G6PC ) gene with native human G6PC promoter and enhancer elements to hepatocytes, resulting in the production of normally functioning G6Pase.

2. DOSAGE AND ADMINISTRATION For single-dose intravenous infusion only Perform baseline testing for pre-existing antibodies to AAV8. Review baseline liver function tests prior to GENGLYCOS infusion. The recommended dose of GENGLYCOS is 1.0 × 10 13 genome copies (gc) per kg body weight. Premedicate with acetaminophen and non-sedating antihistamines 30 to 60 minutes prior to infusion. Follow the recommended intervals and rates of infusion as shown in Table 2. Starting 2 weeks after GENGLYCOS administration, administer prophylactic corticosteroids for a minimum of 8 weeks. 2.1. Patient Selection Select patients without detectable anti-AAV8 antibodies for treatment with GENGLYCOS. Do not administer GENGLYCOS to patients with a detected result for antibodies to AAV8. An FDA authorized test for detection of anti-AAV8 total binding antibodies is not currently available.

4. CONTRAINDICATIONS GENGLYCOS is contraindicated in patients with known severe hepatic fibrosis or cirrhosis. Known severe hepatic fibrosis or cirrhosis.

5. WARNINGS AND PRECAUTIONS Hypersensitivity and Infusion Reactions: Monitor during and after infusion. If symptoms occur, pause the infusion. Restart at half the prior rate after the infusion reaction has resolved. Hepatotoxicity: Monitor transaminase levels and liver health for the first 6 months. Continue to monitor transaminases in all patients who develop liver enzyme elevations until liver enzymes return to baseline. Adrenal Insufficiency: Monitor patients for signs and symptoms of adrenal insufficiency and adrenal crisis after GENGLYCOS administration during and after corticosteroid therapy and tapering. AAV Vector Integration and Risk of Tumorigenicity: There is a theoretical risk of tumorigenicity due to integration of AAV vector DNA into the genome. Report cases of tumors in patients who received GENGLYCOS, to Ultragenyx Pharmaceutical. 5.1.

6. ADVERSE REACTIONS Most common adverse reactions (incidence ≥10%) are increased transaminases and nausea. 6.1. Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety data described in this section reflects exposure to GENGLYCOS in two clinical studies. Study 1 was a randomized, double-blind, placebo-controlled study in 46 patients aged 8 years and older with GSDIa. During the Primary Efficacy Analysis Period (PEAP, Weeks 1–48), 21 patients received GENGLYCOS at the recommended dose of 1.0 × 10¹³ gc/kg and 25 received placebo. After Week 48, 19 placebo-treated patients subsequently received GENGLYCOS up to Week 96.

Vaccinations Vaccine schedules may need to be adjusted for immunosuppressive therapy, and vaccines should be avoided 1 month prior to GENGLYCOS administration. A patient's vaccine schedule may need to be adjusted for immunosuppressive therapy administration, and vaccines should be avoided 1 month prior to GENGLYCOS administration.

GENGLYCOS is shipped and stored at ≤ -60ºC (-76ºF). Store upright at ≤ -60ºC (-76ºF). If necessary, an intact vial (stopper not yet punctured) that has been thawed can be stored refrigerated 2°C-8°C (36°F - 46°F) for up to 12 days, upright and protected from light (e.g., in the original carton). Store in the original carton until ready to use. After dilution If the diluted GENGLYCOS solution is not administered immediately, it may be stored: at room temperature 20 °C to 25 °C (68 °F to 77 °F) for a maximum of 24 hours, including preparation and infusion times, or under refrigeration 2 °C to 8 °C (36 °F to 46 °F) for up to 48 hours, including preparation and infusion times.