ects, similar siponimod exposure is expected for both genotypes.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
Oral carcinogenicity studies of spinomod were conducted in mice and rats. In mice administered siponimod (0, 2, 8, or25 mg/kg/day) for up to 104 weeks, there was an increase in malignant lymphoma in females at all doses and inhemangiosarcoma and combined hemangioma and hemangiosarcoma at all doses in males and females. The lowest dosetested is approximately 5 times the recommended human dose (RHD) of 2 mg/day, on a body surface area (mg/m2) basis.
In rats, administration of siponimod (0, 10, 30, or 90 mg/kg/day in males; 0, 3, 10, or 30 mg/kg/day in females) for up to104 weeks, there was an increase in thyroid follicular cell adenoma and combined thyroid follicular cell adenoma andcarcinoma in males at the highest dose tested. These findings are considered secondary to liver enzyme induction in rats and are not considered relevant to humans. Plasma siponimod exposure (AUC) at the highest dose tested is approximately200 times that in humans at the RHD.
Mutagenesis
Siponimod was negative in a battery of in vitro (Ames, chromosomal aberration in mammalian cells) and in vivo(micronucleus in mouse and rat) assays.
Impairment of Fertility
When siponimod was administered orally (0, 2, 20, or 200 mg/kg) to male rats (mated with untreated females) prior to andthroughout the mating period, there was a dose-related increase in precoital interval at all doses. A decrease inimplantation sites, an increase in preimplantation loss, and a decrease in the number of viable fetuses were observed at thehighest dose tested. The higher no-effect dose for adverse effects on fertility (20 mg/kg) is approximately 100 times theRHD on a mg/m2 basis.
When siponimod was administered orally (0, 0.1, 0.3, or 1 mg/kg) to female rats (mated with untreated males) prior to andduring mating, and continuing to Day 6 of gestation, no effects on fertility were observed up to the highest dose tested(1 mg/kg). Plasma siponimod exposure (AUC) at the highest dose tested is approximately 16 times that in humans at theRHD.
14 CLINICAL STUDIES
The efficacy of MAYZENT was demonstrated in Study 1, a randomized, double-blind, parallel-group, placebo-controlled,time-to-event study in patients with secondary progressive multiple sclerosis (SPMS) who had evidence of disabilityprogression in the prior 2 years, no evidence of relapse in 3 months prior to study enrollment, and an Expanded DisabilityStatus Scale (EDSS) score of 3.0-6.5 at study entry (NCT 01665144).
Patients were randomized to receive either once daily MAYZENT 2 mg or placebo, beginning with a dose titration [seeDosage and Administration (2.2)]. eva luations were performed at screening, every 3 months during the study, and at thetime of a suspected relapse. MRI eva luations were performed at screening and every 12 months.
The primary endpoint of the study was the time to 3-month confirmed disability progression (CDP), defined as at least a1-point increase from baseline in EDSS (0.5-point increase for patients with baseline EDSS of 5.5 or higher) sustained for3 months. A prespecified hierarchical analysis consisted of the primary endpoint and 2 secondary endpoints, the time to 3-month confirmed worsening of at least 20% from baseline on the timed 25-foot walk test and the change from baseline inT2 lesion volume. Additional endpoints included annualized relapse |
