Nirogacestat

Nirogacestat increases exposure of CYP3A substrates, which may increase the risk of adverse reactions related to these substrates.

Avoid concomitant use with CYP3A substrates where minimal concentration changes may lead to serious adverse reactions.

Nirogacestat is a CYP3A substrate. Strong or moderate CYP3A inhibitors increase nirogacestat exposure, which may increase the risk of nirogacestat adverse reactions.

Avoid concomitant use of nirogacestat with strong or moderate CYP3A inhibitors including grapefruit products, Seville oranges, and starfruit.

Nirogacestat is a CYP3A substrate. Strong or moderate CYP3A inducers decrease serum nirogacestat exposure, which may reduce the effectiveness of nirogacestat.

Avoid concomitant use of nirogacestat with strong or moderate CYP3A inducers.

Nirogacestat is poorly soluble at pH ≥ 6. Gastric acid reducing agents may decrease serum nirogacestat exposure, which may reduce the effectiveness of nirogacestat.

Avoid concomitant use with proton pump inhibitors and H₂ blockers.

If concomitant use cannot be avoided, nirogacestat can be staggered with antacids (e.g., administer nirogacestat 2 hours before or 2 hours after antacid use).

Ovarian toxicity

Female reproductive function and fertility may be impaired in patients being treated with nirogacestat. Impact on fertility may depend on factors including the duration of therapy and the state of gonadal function at the time of treatment. The long-term effects of nirogacestat on fertility have not been established. Advise patients on the potential risks for ovarian toxicity before initiating treatment with nirogacestat. Monitor patients for changes in menstrual cycle regularity or the development of symptoms of estrogen deficiency, including hot flashes, night sweats, and vaginal dryness.

Impairment of fertility

Nirogacestat resulted in reduced fertility when administered to male and female rats at doses ≥5 mg/kg/day (approximately 0.16 times the recommended dose of 150 mg twice daily based on body surface area (BSA), and a lack of fertility when administered to male and female rats at doses ≥40 mg/kg/day (approximately 1.3 times the recommended dose of 150 mg twice daily based on BSA). Adverse findings in rats included ovarian atrophy, reduced testes weights, and decreased sperm concentration and motility.

Risk Summary

Based on findings from animal studies and its mechanism of action, nirogacestat can cause fetal harm or loss of pregnancy when administered to a pregnant woman. Oral administration of nirogacestat to pregnant rats during the period of organogenesis resulted in embryo-fetal toxicity and embryo-fetal death at maternal exposures below the human exposure at the recommended dose of 150 mg twice daily [see Data]. There are no available data on the use of nirogacestat in pregnant women. Advise pregnant women of the potential risk to a fetus.

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.

Data

Animal Data

Daily oral administration of nirogacestat to pregnant rats during the period of organogenesis resulted in decreased fetal body weights, pre- and post-implantation loss, and fetal subcutis edema at doses ≥ 20 mg/kg/day (approximately 0.85 times the recommended dose of 150 mg twice daily based on area under the curve).

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

Carcinogenesis

In a 6-month carcinogenicity study, transgenic rasH2 mice received up to 100 mg/kg/day of oral nirogacestat, resulting in mean exposure levels (AUC) less than those in humans at the recommended dose of 150 mg twice daily. No statistically significant neoplastic findings occurred. The carcinogenic potential of nirogacestat in rats has not been assessed.

Mutagenesis

Nirogacestat was not mutagenic in a bacterial reverse mutation (Ames) assay and was not clastogenic in an in vitro chromosome aberration assay in human lymphocytes or in vivo rat bone marrow micronucleus study.

Impairment of Fertility

Nirogacestat resulted in reduced fertility when administered to male and female rats at doses ≥5 mg/kg/day (approximately 0.16 times the recommended dose of 150 mg twice daily based on body surface area (BSA), and a lack of fertility when administered to male and female rats at doses ≥40 mg/kg/day (approximately 1.3 times the recommended dose of 150 mg twice daily based on BSA). Adverse findings in rats included ovarian atrophy, reduced testes weights, and decreased sperm concentration and motility.

• Diarrhea
• Ovarian Toxicity
• Hepatotoxicity
• Non-Melanoma Skin Cancers
• Electrolyte Abnormalities

Clinical Trials Experience

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 nirogacestat was evaluated in 69 patients enrolled in DeFi with progressing desmoid tumor. Patients received nirogacestat 150 mg orally twice daily or placebo orally twice daily until disease progression or unacceptable toxicity. The median duration of exposure to nirogacestat was 20.6 months (range: 0.3 to 33.6).

Serious adverse reactions occurred in 20% of patients who received nirogacestat. Serious adverse reactions occurring in ≥ 2% of patients were ovarian toxicity (4%).

Permanent discontinuation of nirogacestat due to an adverse reaction occurred in 20% of patients. Adverse reactions which resulted in permanent discontinuation of nirogacestat in ≥2% of patients were diarrhea, ovarian toxicity, increased ALT, and increased AST.

Dosage interruptions of nirogacestat due to an adverse reaction occurred in 51% of patients. Adverse reactions which required dosage interruption in ≥ 2% of patients included diarrhea, rash, stomatitis, hypophosphatemia, fatigue, folliculitis, nausea, and ovarian toxicity.

Dose reductions of nirogacestat due to an adverse reaction occurred in 42% of patients. Adverse reactions which required dose reductions in ≥2% of patients included diarrhea, rash, stomatitis, hypophosphatemia, folliculitis, hidradenitis, and ovarian toxicity.

The most common (≥15% with a difference between arms of ≥5% compared to placebo) adverse reactions that occurred in patients receiving nirogacestat were diarrhea, ovarian toxicity, rash, nausea, fatigue, stomatitis, headache, abdominal pain, cough, alopecia, upper respiratory tract infection and dyspnea.

Table 1 summarizes the adverse reactions that occurred in DeFi.

Table 1. Adverse Reactions (≥15%) in Patients with Desmoid Tumor Who Received nirogacestat with a Difference Between Arms of ≥5% Compared to Placebo on DeFi:

^a Includes multiple related composite terms.
^b Investigator assessment of ovarian toxicity included ovarian failure, premature menopause, amenorrhea, and menopause
^c The number of females of reproductive potential in each arm is used as the denominator (nirogacestat N = 36, Placebo N = 37)

Clinically relevant adverse reactions occurring in < 15% of patients receiving nirogacestat in DeFi included non-melanoma skin cancers, epistaxis, hidradenitis suppurativa, folliculitis, and influenza-like illness.

Table 2 summarizes laboratory abnormalities in DeFi.

Table 2. Laboratory Abnormalities (≥15%) that Worsened from Baseline in Patients with Desmoid Tumor Who Received nirogacestat in DeFi:

^a The denominator used to calculate the rate was 69 for nirogacestat and 72 for placebo based on the number of patients with a baseline value and at least one post-treatment value.
^b CTCAE Version 5.0 does not include numeric thresholds for grading of hypophosphatemia; all grades represent patients with lab value < Lower Limit of Normal (LLN).
^c The denominator used to calculate the rate was 68 for nirogacestat and 69 for placebo based on the number of patients with a baseline value and at least one post-treatment value.
^d CTCAE Version 5.0 does not include numeric thresholds for grading of increased urine glucose.