Pivekimab sunirine

Based on its mechanism of action, pivekimab sunirine can cause embryo-fetal harm when administered to a pregnant woman because it contains a genotoxic compound (FGN849) and affects actively dividing cells. There are no available data on the use of pivekimab sunirine in pregnant women to inform a drug-associated risk. Advise patients of the potential risks to a fetus.

There are no data on the presence of pivekimab sunirine-pvzy or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with pivekimab sunirine and for 1 month after the last dose.

Carcinogenesis

Carcinogenicity studies have not been conducted with pivekimab sunirine-pvzy or the small molecule FGN849.

Mutagenesis

FGN849 was mutagenic in the bacterial reverse mutation (Ames) assay and clastogenic in the in vitro and in vivo (rat) micronucleus assays. These results are consistent with the pharmacological mechanism of action of DNA alkylation that induces G2-M phase arrest of dividing cells resulting in cell death.

Impairment of Fertility

Fertility studies have not been conducted with pivekimab sunirine-pvzy or FGN849.

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 pivekimab sunirine was evaluated in CADENZA, a single-arm, open-label study that included 116 adults with newly diagnosed or relapsed/refractory myeloid malignancies, including 84 with BPDCN, treated with pivekimab sunirine 0.045 mg/kg once every three weeks.

The median number of cycles administered was 3 (range: 1 to 34) in the overall population, and 3.5 (range: 1 to 34) in patients with BPDCN.

Serious adverse reactions occurred in 55% of patients treated with pivekimab sunirine. The most common (≥2%) serious adverse reactions were febrile neutropenia, pneumonia, edema, sepsis, hemorrhage, thrombosis, infusion-related reactions, viral infection, pneumonitis, infections without specified pathogens, pyrexia, and musculoskeletal pain. Fatal adverse reactions occurred in 4.3% of patients who received pivekimab sunirine, including cardiac arrest (0.9%), clostridium difficile infection (0.9%), failure to thrive (0.9%), depressed level of consciousness (0.9%), and respiratory failure (0.9%).

Permanent discontinuation due to adverse reactions occurred in 10% of patients who received pivekimab sunirine. Adverse reactions which resulted in permanent discontinuation of pivekimab sunirine in ≥1% of patients included veno-occlusive disease and pneumonitis.

Dosage interruptions of pivekimab sunirine due to adverse reactions occurred in 37% of patients. Adverse reactions which resulted in dosage interruptions in ≥2% of patients included edema, pneumonia, infusion-related reaction, bacterial infections, fatigue, hemorrhage, neutropenia, pneumonitis, and pyrexia.

Dose reductions of pivekimab sunirine due to an adverse reaction occurred in 6% of patients. Adverse reactions which required dose reductions in ≥2% of patients included edema.

The most common adverse reactions (≥20%) were edema, fatigue, musculoskeletal pain, hemorrhage, infusion-related reactions, nausea, and diarrhea. The most common Grade 3 to 4 laboratory abnormalities (≥10%) were neutrophils decreased, platelets decreased, lymphocyte count decreased, white blood cells decreased, hemoglobin decreased, and glucose increased.

Table 1 summarizes the common adverse reactions (≥10%) in patients treated with pivekimab sunirine in CADENZA.

Table 1. Adverse Reactions (≥10%) in Patients Who Received Pivekimab sunirine in CADENZA:

^§ Adverse reactions were graded based on CTCAE Version 4.03
^a Edema includes acute pulmonary edema, face edema, generalized edema, hypervolemia, edema, edema genital, edema peripheral, pericardial effusion, peripheral swelling, pleural effusion, pulmonary edema, swelling face, weight increased, ascites.
^b Consists of multiple related terms.
^c Rash includes erythema, erythema nodosum, guttate psoriasis, photosensitivity reaction, psoriasis, rash, rash erythematous, rash macular, rash maculo-papular, rash pruritic, skin lesion, skin lesion inflammation, stasis dermatitis.
^d Neuropathy peripheral includes burning sensation, dysesthesia, facial nerve disorder, hypoesthesia, IIIrd nerve disorder, neuralgia, neuropathy peripheral, paresthesia, sciatica.
^e Viral infections includes COVID-19, cytomegalovirus infection, HCoV-229E infection, herpes simplex, herpes zoster, herpes zoster disseminated, influenza, ophthalmic herpes simplex, oral herpes.
^f Bacterial infections includes cellulitis, clostridium difficile infection, erysipelas, folliculitis, vulval abscess.
^g Pneumonia includes pneumocystis jirovecii pneumonia, pneumonia, pneumonia viral.

Clinically relevant adverse reactions occurring in <10% of patients who received pivekimab sunirine in CADENZA included:

Vascular disorders: capillary leak syndrome (9%)^a, hypotension^b (7%)

Gastrointestinal disorders: stomatitis^b (6%)

Infections and infestations: sepsis^c (7%), fungal infections^d (5%)

Respiratory, thoracic and mediastinal disorders: pneumonitis (5%)

Cardiac disorders: arrhythmia^e (6%)

Renal and urinary disorders: acute kidney injury^b (6%)

Hepatobiliary disorders: veno-occlusive disease (1.7%)

^a At least 2 of the following new onset signs and symptoms within 7 days of each other: hypoalbuminemia (including albumin <3.0 g/dL), edema (including weight increase >5 kg), hypotension (including systolic blood pressure <90 mmHg).
^b Consists of multiple related terms.
^c Includes bacteremia, klebsiella bacteremia, pulmonary sepsis, sepsis, and streptococcal bacteremia.
^d Includes candida infection, fungal balanitis, fungal foot infection, fungal skin infection.
^e Includes arrhythmia, atrial fibrillation, atrioventricular block, bradycardia, cardiac arrest, tachyarrhythmia.

Table 2 summarizes laboratory abnormalities in CADENZA.

Table 2. Select Laboratory Abnormalities (≥10%) That Worsened from Baseline in Patients Who Received Pivekimab sunirine in CADENZA:

^* Laboratory abnormalities were graded based on CTCAE Version 4.03.
^a The denominator used to calculate the rate varied from 78 to 114 based on the number of patients with at least one post-baseline value.