Narsoplimab

The available data on the use of narsoplimab during pregnancy are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. In animal reproduction studies, narsoplimab was administered subcutaneously and intravenously twice weekly to pregnant mice and rabbits during organogenesis at dose exposures up to 22 and 91-fold, respectively, the human exposure at the maximum recommended human dose (MRHD) based on area under the concentration-time curve (AUC). There were no adverse effects observed in the absence of maternal toxicity.

The 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 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 narsoplimab in human milk, the effects on the breastfed child, or the effects on milk production. Narsoplimab is present in the milk of lactating mice. When a drug is present in animal milk, it is likely that the drug will be present in human milk. Endogenous maternal IgG and monoclonal antibodies are transferred into human milk. The effects of local gastrointestinal exposure and the extent of systemic exposure in the breastfed child to narsoplimab are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for narsoplimab and any potential adverse effects on the breastfed child from narsoplimab or from the underlying maternal condition.

Genotoxicity and animal carcinogenicity studies of narsoplimab have not been conducted.

A fertility study of narsoplimab in male and female mice produced no adverse effects on reproductive parameters, although a transient decrease in mean body-weight gain in females (premating) and a slight increase in mean percentage of sperm with abnormal morphology in males were observed in the highest dose groups. These effects were noted at exposures corresponding to 21-fold the exposure expected at the MRHD (based on AUC). In the absence of any functional effects on mating, fertility, or reproductive organ weight, these effects on sperm morphology were not considered adverse.

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 reflect exposure to narsoplimab in the TA-TMA Study in which 28 adult patients received narsoplimab. In total, 24 patients received narsoplimab at a dose of 4 mg/kg intravenously once weekly for 4 or 8 weeks and 4 patients received 370 mg intravenously weekly for 8 weeks. The median duration of treatment with narsoplimab was 8 weeks (range: 2 to 16.4 weeks).

Serious adverse reactions were reported in 61% of patients receiving narsoplimab. Serious adverse reactions in >5% of patients who received narsoplimab included acute kidney injury, confusional state, acute respiratory failure, neutropenic sepsis, septic shock, pulmonary edema, and vomiting. Fatal adverse reactions occurred in 7% of patients, including neutropenic sepsis and septic shock.

Adverse reactions leading to dosage interruptions occurred in 7% of patients who received narsoplimab and included Escherichia sepsis, pyrexia, pulmonary alveolar hemorrhage, and acute myocardial infarction.

The most common adverse reactions (≥20%) were viral infections, sepsis, hemorrhage, diarrhea, vomiting, nausea, neutropenia, pyrexia, fatigue, and hypokalemia.

Table 1 summarizes the adverse reactions, without regard to causality or relatedness to narsoplimab, in the TA-TMA Study.

Table 1. Adverse Reactions (≥15%) in Patients Receiving Narsoplimab in the TA-TMA Study:

^* Grouped terms

An additional 221 adult and pediatric patients with TA-TMA were treated with narsoplimab in a global expanded access program (EAP) that included patients for whom narsoplimab was their initial treatment following diagnosis of TA-TMA as well as patients who had previously failed or stopped other treatments. The median number of narsoplimab doses received by the 221 patients in the EAP was 8 and the median duration of therapy was 5.5 weeks. No new clinically significant safety signals were identified in patients treated in the EAP.