FAYUVI Suspension for infusion Ref.[116937] Active ingredients: Rebisufligene etisparvovec

5.1 Hepatotoxicity

Elevated liver enzymes (ALT, AST, and GGT) were observed in clinical studies of FAYUVI [see Adverse Reactions (6.1)].

Prior to FAYUVI infusion, assess liver function by clinical examination and laboratory testing (ALT, AST, GGT and total bilirubin) and evaluate liver-related medical history. Administer corticosteroids to all patients before and after FAYUVI infusion. If abnormalities are observed, adjust the corticosteroid treatment regimen, including increasing the dose and/or prolonging the corticosteroid taper period [see Dosage and Administration (2.1)].

Closely monitor ALT, AST, GGT and total bilirubin levels after FAYUVI administration until 2 weeks after the corticosteroid taper is complete and as clinically indicated. Continue to monitor liver function in all patients who develop elevated liver enzymes until levels return to baseline [see Dosage and Administration (2.3)].

5.2 Thrombocytopenia

Decreased platelet counts were observed in clinical studies of FAYUVI [see Adverse Reactions (6.1)].

Prior to FAYUVI infusion, assess platelet counts. Monitor platelet counts weekly for the first 4 weeks, then monthly for 6 months following infusion. Continue monitoring as clinically indicated [see Dosage and Administration (2.3)].

5.3 Thrombotic Microangiopathy

Thrombotic microangiopathy (TMA) has been reported in association with AAV gene therapies. While there have been no cases of TMA associated with FAYUVI in clinical studies, laboratory and clinical monitoring for TMA following FAYUVI infusion is recommended.

Monitor platelet counts closely within the first 4 weeks following FAYUVI infusion [see Warnings and Precautions (5.2)]. Signs and symptoms of TMA may include, but are not limited to, thrombocytopenia, hemolytic anemia, easy bruising, hypertension, seizures, decreased urine output and renal dysfunction. If TMA is suspected, immediately consult a pediatric hematologist and/or nephrologist for further evaluation and management as clinically indicated.

5.4 Hypersensitivity and Infusion Reactions

Infusion reactions, including hypersensitivity reactions and anaphylaxis, may occur with infusion of FAYUVI. Symptoms may include but are not limited to hypotension, pyrexia, palpitation, nausea, vomiting, chills, or headache.

Closely monitor patients for clinical signs and symptoms of infusion reactions, including hypersensitivity reactions, and monitor vital signs during and after completion of FAYUVI infusion as clinically indicated. In the event of an infusion reaction during administration, pause the infusion and provide supportive care according to clinical practice. If the infusion is paused and continued administration is appropriate, restart at a slower rate after the infusion reaction has resolved [see Dosage and Administration (2.3)].

5.5 Risk of Malignancy

Malignancy may occur following treatment with FAYUVI due to potential integration of AAV vector DNA into the genome.

In the event of a malignancy, contact 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 of FAYUVI was evaluated in 33 pediatric patients with MPS IIIA who received a single intravenous infusion of FAYUVI in 3 clinical studies: 2 open-label, single-arm studies (Study 1 and Study 3) and 1 long-term follow-up study (Study 2) which enrolled patients who participated in one of the prior studies [see Clinical Studies (14)]. Twenty-seven patients received the recommended dose of 3.0 × 10¹³ vg/kg. The mean age at the time of treatment was 38.5 months (range: 3.0 months to 9.2 years) and the mean weight was 17.1 kg (range: 3.9 to 31.2 kg). Patients treated with the recommended dose were 96% White and 4% of multiple race; 11% were Hispanic or Latino. The median duration of follow-up following FAYUVI infusion was 4.1 years (range: 7.0 months to 7.8 years).

Adverse reactions in patients who received the recommended dose of 3.0 × 10¹³ vg/kg of FAYUVI (N=27) in clinical studies are listed in Table 3.

Table 3. Adverse Reactions Occurring in ≥5% of Patients Following Treatment with FAYUVI:

^a Includes aspartate aminotransferase (AST) increased, alanine aminotransferase (ALT) increased, and gamma-glutamyl transferase (GGT) increased.
^b All adverse reactions were of Grade 1 or Grade 2 severity.
^c Includes abnormal behavior, affect lability, aggression, agitation, irritability, nervousness, anxiety, attention deficit hyperactivity disorder, behavior disorder, insomnia, mental status changes, and related behavioral terms.
^d Includes white blood cell count decreased, leukopenia, lymphocyte count decreased, lymphopenia, and neutropenia.
^e Includes platelet count decreased and thrombocytopenia.
^f Includes seizure, epilepsy, status epilepticus, partial seizures

Hepatotoxicity

In clinical trials, 85% (23/27) of patients receiving the recommended dose of FAYUVI experienced adverse reactions associated with liver enzyme elevations (AST, ALT, and/or GGT). Most liver enzyme elevations were less than Grade 3 in severity, and none were associated with elevations of total bilirubin. A single Grade 3 ALT elevation in one patient occurred in the setting of gastroenteritis 62 days following FAYUVI infusion and resolved spontaneously within 8 days. The time to first onset was most frequently within the first 14 days and ranged from 2 days to 30.3 months following FAYUVI infusion. All liver enzyme elevations resolved within 6 days to 40.6 months of onset, except in 2 patients where slight elevations persisted.

Neutropenia

In clinical trials, 22% (6/27) of patients receiving the recommended dose of FAYUVI experienced neutropenia. One patient experienced Grade 3 neutropenia, and the remaining events were of Grade 1 or 2 severity.

The observed incidence of anti-AAV9 and anti-SGSH antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-AAV9 and anti-SGSH antibodies in the studies described below with the incidence of anti-AAV9 and anti-SGSH antibodies in other studies.

Anti-AAV9 antibody titers and anti-SGSH antibody titers were assessed by investigational total binding antibody enzyme-linked immunosorbent assays (ELISA) in clinical trials.

Anti-AAV9 antibodies

Baseline anti-AAV9 total antibody titers were <1:100. The safety and efficacy of FAYUVI in patients with anti-AAV9 antibodies ≥1:100 have not been evaluated [see Clinical Studies (14)].

All patients seroconverted to anti-AAV9 antibody positive following administration of FAYUVI. At the dose of 3.0 × 10¹³ vg/kg in Study 1 (N=22), individual anti-AAV9 antibody titers peaked at a mean (SD) of 15.50 (19.36) months after administration, with mean (SD) values of 2,376,590.9 (3,097,657.4) and remained stable at Month 24 onwards. Similar seroconversion rates were observed in Study 3.

Anti-SGSH antibodies

All patients had an increase in anti-SGSH antibodies in serum following administration of FAYUVI. At the dose of 3.0 × 10¹³ vg/kg in Study 1 (N=22), individual serum anti-SGSH antibody titers peaked at a mean (SD) of 13.88 (12.02) months after administration, with mean (SD) values of 182,552.7 (659,299.6). Individual serum anti-SGSH antibody titers varied over time.

In Study 1, among patients with available CSF samples, anti-SGSH antibodies were also detected in CSF; anti-SGSH antibody titers were generally lower in CSF than in serum. At the dose of 3.0 × 10¹³ vg/kg, at Month 24, mean (SD) anti-SGSH titers in the CSF was 670.7 (1850.7) (N=15) and the mean (SD) anti-SGSH titers in serum was 162,947.3 (662,526.3) (N=22). The clinical significance of CSF anti-SGSH antibodies is not clear.

In Study 3, CSF samples for anti-SGSH antibody evaluation were not collected. Anti-SGSH antibody titers in serum were below the assay limit (1:40) at Screening for all evaluated patients. All patients developed detectable anti-SGSH antibodies by Month 12 (range: Day 14 to Month 12).

Vaccinations

Prior to FAYUVI administration, consider the patient's vaccination status. Vaccines should be avoided 30 days prior to treatment with FAYUVI (and use of corticosteroids) and while on corticosteroid therapy [see Dosage and Administration (2.1)].

Risk Summary

There are no data on the use of FAYUVI in pregnant women. No animal reproductive and developmental toxicity studies have been conducted to assess whether FAYUVI can cause fetal harm when administered to a pregnant woman. Women who are pregnant or desire to become pregnant should not be treated with FAYUVI.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Risk Summary

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

Pregnancy Testing

A negative serum pregnancy test must be confirmed before administration of FAYUVI in females of childbearing potential.

Contraception

There are insufficient exposure data to provide a recommendation on duration of contraception following treatment with FAYUVI.

Infertility

There are no data on the effects of FAYUVI on fertility. No fertility studies with FAYUVI have been conducted in animals or humans.

The safety and efficacy of FAYUVI have been established in pediatric patients with MPS IIIA. The use of FAYUVI in pediatric patients is supported by three open-label, single-arm studies (Studies 1, 2, and 3) which enrolled 33 pediatric patients with a mean age of 41.5 months (range: 3.0 months to 9.2 years) at treatment [see Adverse Reactions (6.1), Clinical Studies (14)].

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