GENGLYCOS Suspension for intravenous infusion Ref.[116921] Active ingredients: Pariglasgene brecaparvovec

5.1. Hypersensitivity and Infusion Reactions

Hypersensitivity reactions including anaphylaxis and infusion reactions (IRs) have occurred with GENGLYCOS treatment. Severe reactions have been reported [see Adverse Reactions (6.1)]. Monitor for signs and symptoms of hypersensitivity and IRs, including urticaria, flushing, hypotension, bronchospasm, dyspnea, chest tightness, nausea, vomiting, headache, abdominal pain, lightheadedness, flu-like symptoms, shivering, rash, and hypertension.

Premedicate with acetaminophen and non-sedating antihistamines and administer GENGLYCOS according to recommended infusion rates. Monitor patients during and after completion of GENGLYCOS infusion as clinically indicated. If anaphylaxis or a severe IR occurs, pause GENGLYCOS infusion immediately and initiate medical treatment as clinically indicated, monitoring as needed. For mild to moderate IRs, consider slowing or temporarily interrupting the infusion, and administer symptomatic treatment as clinically indicated. The infusion may be restarted at half the prior rate upon resolution of symptoms [see Dosage and Administration (2.4)].

Medical support measures, including cardiopulmonary resuscitation equipment and medications for the treatment of anaphylaxis (e.g., epinephrine, antihistamines, corticosteroids), should be available during GENGLYCOS administration.

5.2. Hepatotoxicity

Immune-mediated hepatotoxicity, with elevated ALT and/or AST levels, has occurred with GENGLYCOS [see Adverse Reactions (6.1)]. Avoid use in patients with preexisting hepatic impairment or acute hepatic viral infection.

Prior to GENGLYCOS infusion, evaluate liver-related medical history and assess liver function by clinical examination and laboratory testing. Advise patients to immediately report signs and symptoms of hepatotoxicity, including fatigue, jaundice, dark urine, nausea, vomiting, and right upper quadrant pain. Administer corticosteroids to all patients after GENGLYCOS infusion in order to mitigate hepatic reactions. Elevated transaminases may require adjustment of the corticosteroid treatment regimen, including increased dose or prolongation of the corticosteroid taper [see Dosage and Administration (2.4)].

Monitor transaminase levels for the first 6 months after GENGLYCOS administration. Continue to monitor transaminases in all patients who develop transaminase elevations, until transaminases return to baseline or as clinically indicated [see Dosage and Administration (2.4)].

5.3. Adrenal Insufficiency

Adrenal insufficiency, including serious events, has been reported in patients receiving GENGLYCOS during corticosteroid use and tapering [see Adverse Reactions (6.1)].

Signs and symptoms of adrenal insufficiency include fatigue, weakness, anorexia, nausea, vomiting, hypotension, hyponatremia, and hypoglycemia. Adrenal crisis may present as severe hypotension, acute abdominal pain, or loss of consciousness.

Monitor patients for signs and symptoms of adrenal insufficiency and adrenal crisis after GENGLYCOS administration during and after corticosteroid therapy and tapering. [see Dosage and Administration (2.4)]. Taper corticosteroid therapy gradually. Do not abruptly discontinue corticosteroid therapy.

5.4. AAV Vector Integration and Risk of Tumorigenicity

There is a theoretical risk of tumorigenicity due to integration of AAV vector DNA into the genome. GENGLYCOS is composed of a recombinant, non-replicating AAV8 vector whose DNA persists largely in episomal form. Random integration of recombinant AAV-vector DNA into human DNA has been reported with AAV gene therapies. The clinical relevance of individual integration events is unknown, but it is acknowledged that individual integration events could potentially contribute to a risk of tumorigenicity. If a tumor develops in a patient receiving GENGLYCOS, health care providers should contact and report the tumor to Ultragenyx Pharmaceutical Inc. at 1-888-756-8657.

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.

Study 2 was a single-arm, open-label study of GENGLYCOS in 12 adults with GSDIa with follow up duration of 52 weeks.

Seven serious adverse events (SAEs) were observed in PEAP of Study 1, including anaphylaxis/infusion reaction (2), adrenal insufficiency (2), high lactate level (2), and hypoglycemia (1).

The most common adverse reactions in the PEAP (occurring in ≥10% of patients) with higher frequency in GENGLYCOS compared to placebo during PEAP in Study 1 are shown in Table 4.

Table 4. Adverse Reactions: Study 1:

Abbreviations: ALT: Alanine Aminotransferase; AST: Aspartate Aminotransferase.
¹ All events were mild to moderate (<5.0× ULN), except one severe (Grade 3) asymptomatic event (peak ALT: 253 U/L).
ALT/AST elevations peaked between 4 and 12 weeks post-GENGLYCOS administration and resolved within 15 weeks [see Warnings and Precautions (5.2)]
² All adverse events were mild to moderate.
³ Two SAEs were reported [see Warnings and Precautions (5.3)].
⁴ All adverse events were mild.
⁵ Two Serious adverse reactions with onset within minutes of GENGLYCOS administration [see Warnings and Precautions (5.1)]

Safety evaluations during the Crossover Period of Study 1 and in Study 2 did not identify any additional adverse reactions.

The observed incidence of anti-AAV8 and anti-G6Pase antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-AAV8 and anti-G6Pase antibodies in the studies described below with the incidence of anti-AAV8 and anti-G6Pase antibodies in other studies, including those of GENGLYCOS or of other AAV-based gene therapy products.

Anti-AAV8 antibody titers and anti-G6Pase antibody titers after GENGLYCOS treatment were assessed by investigational total binding antibody electrochemiluminescence assays (ECLA) in Study 1.

In clinical studies, all patients receiving treatment were required to have undetectable anti-AAV8 antibodies at screening. The safety and efficacy of GENGLYCOS in patients with detected anti-AAV8 antibodies have not been formally evaluated.

All patients seroconverted to anti-AAV8 antibody positive or demonstrated an increase in titer following administration of GENGLYCOS. At the dose of 1.0 × 10¹³ gc/kg in Study 1 (N=40), individual anti-AAV8 antibody titers peaked for the GENGLYCOS group and 'placebo to GENGLYCOS' group at a mean (SD) of 180 (132) days and 166 (87) days, respectively, after administration with mean (SD) values of 20,418,582 (3,845,048) and 18,755,295 (5,628,088), respectively, and remained positive until Week 48, the last timepoint tested. Similar seroconversion rates were observed in Study 2, with follow-up in Study 3, and remained positive until Week 208, the last timepoint tested.

In Study 1, 11 of 40 patients had an increase in anti-G6Pase antibodies in serum following administration with GENGLYCOS. At the dose of 1.0 × 10¹³ gc/kg, the mean (SD) time to seroconversion was 294 (156) days and 278 (129) days for the GENGLYCOS group (N=7) and 'placebo to GENGLYCOS' group (N=4), respectively, and the maximum titer observed was 1:40. The clinical significance of anti-G6Pase antibodies is not known.

GENGLYCOS-treated patients were tested in Study 2, with follow-up in Study 3, for cellular immune responses to the AAV8 capsid by IFNγ ELISpot in blood, which is typically indicative of a T cell response. In some patients, an increase in cellular response to AAV8 preceded rises in alanine aminotransferase during the first year after GENGLYCOS administration. Transaminase elevations generally resolved or improved with corticosteroids [see Warnings and Precautions (5.2)]. Cellular immune response to the AAV8 capsid was not assessed in Study 1.

Vaccinations

Vaccine schedules may need to be adjusted for immunosuppressive therapy [see DOSAGE AND ADMINISTRATION (2.4)], and vaccines should be avoided 1 month prior to TRADENAME administration.

Risk Summary

GENGLYCOS should not be used during pregnancy. There is no data on the use of GENGLYCOS in pregnant women. It is not known whether GENGLYCOS can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity.

Pregnant C57BL/6 mice administered pariglasgene brecaparvovec-opnr intravenously (IV) at 1.3 × 10¹⁴ gc/kg of maternal body weight on gestation day 6 showed no adverse maternal effects or fetal abnormalities. While vector DNA was detected in the blood and placenta of pregnant mice, it was not detected in the liver of the fetuses [see Nonclinical Toxicology (13.1)].

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Risk Summary

There is no information regarding the presence of GENGLYCOS in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for GENGLYCOS and any potential adverse effects on the breastfed child from GENGLYCOS or from the underlying maternal condition.

Contraception

Females

Women of childbearing potential should use effective contraception for at least 12 months after administration of GENGLYCOS.

Males

While vector DNA was detected in semen of mice on Day 29 after a single intravenous administration of 1.8 × 10¹³ gc/kg of pariglasgene brecaparvovec-opnr, there was no detection of vector DNA in semen at Day 92 even though vector DNA was still detectable in the testes [see Clinical Pharmacology (12.3), Nonclinical Toxicology (13.1)]. In a germline transmission study in mice, pariglasgene brecaparvovec-opnr was not detected in the blood and liver of offspring of mice following IV administration of pariglasgene brecaparvovec-opnr at 1.3 × 10¹⁴ gc/kg to either parent 37 days prior to mating [see Nonclinical Toxicology (13.1)]. For 6 months after administration of GENGLYCOS, men must not donate semen, and men of reproductive potential and their female partners must prevent or postpone pregnancy using an effective form of contraception.

Infertility

No human data are available on the effect of GENGLYCOS on fertility. Animal studies with pariglasgene brecaparvovec-opnr showed no effects on mating fertility or fertility index in male and female mice at 1.3 × 10¹⁴ gc/kg [see Nonclinical Toxicology (13.1)].

The safety and efficacy of GENGLYCOS have been established in pediatric patients aged 8 years and older in Study 1, including 20 patients aged 8-17 years (median 13.5 years) [see Adverse Reactions (6.1), Clinical Studies (14)].

The safety and efficacy of GENGLYCOS in pediatric patients aged less than 8 years have not been established.

GENGLYCOS has not been studied in patients 65 years of age and older.