Tividenofusp alfa

There are no available data on the use of tividenofusp alfa during pregnancy to evaluate for a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Animal studies to evaluate the potential for embryofetal developmental toxicity and pre- and postnatal developmental toxicity of tividenofusp alfa have not been conducted.

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defects, loss, and other adverse outcomes. 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.

There are no data on the presence of tividenofusp alfa in either human or animal 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 tividenofusp alfa and any potential adverse effects on the breastfed infant from tividenofusp alfa or from the underlying maternal condition.

Carcinogenesis

Animal studies to evaluate the carcinogenic potential of tividenofusp alfa have not been conducted.

Mutagenesis

Studies to evaluate the mutagenic potential of tividenofusp alfa have not been conducted.

Impairment of Fertility

In a fertility and embryonic development study in transgenic mice, twice weekly intravenous tividenofusp alfa doses were administered to females for two weeks prior to mating and through day 4 of gestation, and to males two weeks prior to mating. No adverse effects on fertility parameters were observed in either female or male transgenic mice at exposures approximately 12-fold greater than those observed in patients at the maintenance dosage level of 15 mg/kg (based on AUC).

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 tividenofusp alfa was evaluated in male pediatric patients with Hunter syndrome in Trial 1. A total of 47 male patients (age range: 3 months to 13 years) received intravenous tividenofusp alfa at 3 mg/kg to 30 mg/kg (0.2 to 2 times the approved recommended maintenance dose) weekly, and the majority of patients received 15 mg/kg intravenously weekly after Week 24. The median (minimum, maximum) duration of exposure was 117 (19, 219) weeks.

In Trial 1, the most common adverse reactions (≥20%) reported in tividenofusp alfa-treated patients were infusion-associated reaction (IAR), upper respiratory tract infection, ear infection, pyrexia, anemia, cough, vomiting, diarrhea, rash, COVID-19, rhinorrhea, nasal congestion, fall, headache, skin abrasion, and urticaria.

Dose interruptions of tividenofusp alfa due to an adverse reaction occurred in 91% of patients. The most frequently reported adverse reaction leading to dose interruption was IAR (31 [66%] patients). Other frequently reported adverse reactions leading to dose interruption were COVID-19 (18 [38%] patients), pyrexia (16 [34%]), upper respiratory tract infection (16 [34%]), nasal congestion (6 [13%]), and vomiting (6 [13%]). Dose interruption included skipped infusions due to an adverse reaction as well as temporary infusion pauses with subsequent completion during the same visit.

Dose reductions of tividenofusp alfa due to adverse reactions occurred in 57% of patients; the majority of these reactions were IARs.

In Trial 1, one (2%) tividenofusp alfa-treated patient experienced anaphylaxis, which occurred in the first month of treatment.

The following table summarizes adverse reactions that occurred in >15% of tividenofusp alfa-treated pediatric patients with Hunter syndrome.

Adverse Reactions That Occurred in >15% in Tividenofusp alfa-treated Pediatric Patients With Hunter Syndrome (Trial 1):

^a Infusion-associated reaction includes infusion-related reaction.
^b Ear infection includes ear infection, otitis media, otitis media acute, otitis externa.
^c Anemia includes anemia, iron deficiency anemia, and decreased hemoglobin.

Description of Selected Adverse Reactions

Infusion-Associated Reaction

Three (6%) tividenofusp alfa-treated patients experienced severe IARs. One patient permanently discontinued treatment due to an IAR.

Anemia

Two (4%) tividenofusp alfa-treated patients experienced severe anemia (defined as hemoglobin <8 g/dL) prior to Week 24. One (2%) tividenofusp alfa-treated patient, aged 0.5 years, experienced moderate anemia (hemoglobin 9.2 g/dL), which was considered serious due to the patient's age.

Membranous Nephropathy

A case of biopsy-confirmed, steroid-refractory membranous nephropathy with immune complex deposits in the kidney was reported in an tividenofusp alfa-treated patient.