Ansuvimab

Zaire ebolavirus infection is life-threatening for both the mother and fetus and treatment should not be withheld due to pregnancy. Available data from the PALM trial in which pregnant women with Zaire ebolavirus infection were treated with ansuvimab demonstrate the high rate of maternal and fetal/neonatal morbidity consistent with published literature regarding the risk associated with underlying maternal Zaire ebolavirus infection. These data are insufficient to evaluate for a drug associated risk of major birth defects, miscarriage, or adverse maternal/fetal outcome.

Animal reproduction studies with ansuvimab have not been conducted. Monoclonal antibodies, such as ansuvimab, are transported across the placenta; therefore, ansuvimab has the potential to be transferred from the mother to the developing fetus.

The Centers for Disease Control and Prevention recommend that mothers with confirmed Zaire ebolavirus not breastfeed their infants to reduce the risk of postnatal transmission of Zaire ebolavirus infection.

There are no data on the presence of ansuvimab in human or animal milk, the effects on the breastfed infant, or the effects on milk production. Maternal IgG is known to be present in human milk. The effects of local gastrointestinal exposure and limited systemic exposure in the breastfed infant to ansuvimab are unknown.

Carcinogenicity, genotoxicity and fertility studies have not been conducted with ansuvimab.

Clinical trials experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice.

Overall, 424 adult and pediatric subjects with Zaire ebolavirus infection received ansuvimab in one clinical trial and as part of an expanded access program during the 2018 Zaire ebolavirus outbreak in the Democratic Republic of Congo (DRC).

In the PALM trial, the safety of ansuvimab was evaluated in a multi-center, open-label, randomized controlled trial, in which 173 subjects (119 adults and 54 pediatric subjects) with confirmed Zaire ebolavirus infection received ansuvimab as a single 50 mg/kg IV infusion and 168 subjects received an investigational control. All subjects received optimized standard of care treatment (oSOC). The median age of the study population that received ansuvimab was 26 years (range: 1 day to 85 years). Fifty-five percent (55%) of enrolled subjects were female and 45% were male.

During the same outbreak, 251 subjects (173 adults and 78 pediatric subjects) with laboratory-confirmed Zaire ebolavirus infection received ansuvimab under an expanded access program; 57% of whom were female and 43% of whom were male. Ages ranged from 6 days to 80 years, with a median age of 25 years.

Common Adverse Events

Table 1 summarizes the adverse events that were reported in the PALM trial from a pre-defined list of signs and symptoms that occurred during ansuvimab infusion. The evaluation of adverse events in subjects who received ansuvimab may have been confounded by the signs and symptoms of the underlying Zaire ebolavirus infection. Twenty nine percent (n=51) of subjects who received ansuvimab in the PALM Trial experienced a pre-specified infusion-related adverse event. The most common pre-specified infusion-related adverse event reported in at least 10% of subjects who received ansuvimab was fever (Table 1). The adverse event profile in adult and pediatric subjects treated with ansuvimab was similar.

Table 1. Adverse Events That Occurred During Infusion in >10% of Adult and Pediatric Subjects in the PALM Trial:

^* Adverse events in this table were reported on the day of infusion, and included signs and symptoms that occurred during or immediately after infusion
^† Investigational therapy administered as three separate infusions
^‡ Adverse events that occurred during infusion but were not pre-specified.
^§ The term chills includes other similar adverse events including rigors and tremors

The following pre-specified symptoms, which were assessed on a daily basis during admission while admitted to the treatment unit, were reported in ≥40% of subjects who received ansuvimab: diarrhea, pyrexia, abdominal pain, and vomiting. Evaluation of these symptoms may have been confounded by the underlying Zaire ebolavirus infection.

Discontinuation and Infusion Rate Adjustments

Approximately 99% of subjects who received ansuvimab in the PALM trial were able to complete their dose within one hour. Two subjects who received ansuvimab (1%) did not receive their complete infusion. In eight subjects (5%) the ansuvimab infusion rate was decreased due to an AE.

Selected Laboratory Abnormalities in the PALM Trial

Table 2 presents selected laboratory abnormalities (worsening to Grade 3 or 4 compared to baseline) in the PALM trial.

Table 2. Selected Grade 3 and 4 Laboratory Abnormalities^a, Worsened Grade from Baseline in the PALM Trial:

ULN = upper limit of normal
^* Graded per Division of AIDS (DAIDS) v2.1
^† Based on a ULN of 1.2 mg/dL.
^‡ Based on a ULN of 47U/L.
^§ Based on a ULN of 38 U/L.