Aficamten

There are no available data on the use of lisocabtagene maraleucel during pregnancy to evaluate for a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. The underlying maternal condition during pregnancy poses a risk to the mother and fetus. In embryo-fetal and pre- and postnatal development studies, when pregnant rats were administered aficamten during the period of organogenesis, aficamten increased the incidence of structural malformations at exposures ≥4-times the maximum recommended human dose (MRHD) of 20 mg based on free area under the concentration curve (AUC). No adverse effects on development were seen at 3-times the MRHD exposure.

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 aficamten in human milk, the effects on the breastfed infant, or the effects on milk production. Aficamten was detected in the plasma of rat pups when dams were dosed with the drug orally during the lactation period. When a drug is present in animal milk, it is likely that the drug will be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for lisocabtagene maraleucel and any potential adverse effects on the breastfed infant from lisocabtagene maraleucel or from the underlying maternal condition.

Carcinogenesis

The carcinogenic potential of aficamten was assessed in a 26-week study in transgenic rasH2 mice and a 2-year study in Sprague Dawley rats. There was no evidence of carcinogenicity with oral administration of aficamten at dose levels up to 2.0 mg/kg/day in the mouse or 3 mg/kg/day in the rat (corresponding to 4-fold the MRHD based on free AUC).

Mutagenesis

Aficamten was not genotoxic in the in vitro bacterial (Ames) mutagenicity assay or the combined in vivo micronucleus assay and comet assay in rat.

Impairment of Fertility

In a fertility and early embryonic development toxicology study in the rat, aficamten was administered at doses up to 6 mg/kg/day in females and 3 mg/kg/day in males, with no drug-related effects on mating, fertility, estrous cycling, male reproductive assessments, or early embryonic survival.

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 lisocabtagene maraleucel was evaluated in SEQUOIA-HCM, a phase 3, randomized, double-blind, placebo-controlled study. Of the 282 adults with oHCM, 142 patients received daily doses of lisocabtagene maraleucel (initiated at 5 mg and titrated up to a maximum dose of 20 mg) and 140 patients received placebo. The median treatment duration for patients receiving lisocabtagene maraleucel was ~24 weeks (range 4 to 29 weeks).

Hypertension (8% vs. 2%) was the only adverse reaction occurring in >5% of patients and more commonly on lisocabtagene maraleucel than on placebo.

Eligible oHCM patients were able to participate in an ongoing, open-label, single-arm, long-term safety study (FOREST-HCM). Based on available data, the safety profile of lisocabtagene maraleucel in FOREST-HCM was similar to that observed in SEQUOIA-HCM.

Effects on Systolic Function

In SEQUOIA-HCM, the mean (SD) resting LVEF at baseline was 75% (6) in both treatment groups. Consistent with the mechanism of action of lisocabtagene maraleucel, LS mean (SE) change from baseline in LVEF was -7% (0.6) in the lisocabtagene maraleucel group and -2% (0.6) in the placebo group at the end of the 24-week treatment period. Four weeks after the end of treatment, mean LVEF was similar between the lisocabtagene maraleucel and placebo groups. During the 24-week treatment period, 5 (4%) patients in the lisocabtagene maraleucel group and 1 (1%) patient in the placebo group experienced a reversible reduction in LVEF to <50% (median LVEF: 47%; range 34% - 49% for these 5 patients in the lisocabtagene maraleucel group). Reductions in LVEF to <50% did not require treatment interruption and were not associated with clinical heart failure.

Effects on Blood Pressure

In SEQUOIA-HCM, the mean (SD) systolic/diastolic blood pressure (SBP/DBP) at baseline was 125(16)/75(11) mmHg for patients in the lisocabtagene maraleucel group and 126(16)/74(11) mmHg in the placebo group. There was a greater mean change from baseline in SBP/DBP (SD) in the lisocabtagene maraleucel group compared to the placebo group at the end of the 24-week treatment period [2(13)/3(8) mmHg and -3(14)/-1(9) mmHg, respectively]. Four weeks after the end of treatment, the mean SBP/DBP was similar between the lisocabtagene maraleucel and placebo groups. In SEQUOIA-HCM, SBP ≥160 mmHg was observed in approximately 16% of patients in the lisocabtagene maraleucel group and 8% of patients in the placebo group. lisocabtagene maraleucel-associated increases in blood pressure are consistent with relief of LVOT obstruction and improved cardiac output.