Molecular mass: 401.474 g/mol
Risdiplam is a survival of motor neuron 2 (SMN2) pre-mRNA splicing modifier designed to treat SMA caused by mutations of the SMN1 gene in chromosome 5q that lead to SMN protein deficiency. Functional SMN protein deficiency is directly linked to the SMA pathophysiology which includes progressive loss of motor neurons and muscle weakness. Risdiplam corrects the splicing of SMN2 to shift the balance from exon 7 exclusion to exon 7 inclusion into the mRNA transcript, leading to an increased production of functional and stable SMN protein. Thus, risdiplam treats SMA by increasing and sustaining functional SMN protein levels.
In clinical studies, risdiplam led to an increase in SMN protein in blood with a greater than 2-fold median change from baseline within 4 weeks of treatment initiation across all SMA types studied. The increase was sustained throughout the treatment period (of at least 24 months).
Pharmacokinetic parameters have been characterised in healthy adult subjects and in patients with SMA.
After administration of treatment as an oral solution, PK of risdiplam were approximately linear between 0.6 and 18 mg. Risdiplam’s PK was best described by a population PK model with three-transit-compartment absorption, two-compartment disposition and first-order elimination. Body weight and age were found to have significant effect on the PK.
The estimated exposure (mean AUC0-24h) for infantile-onset SMA patients (age 2-7 months at enrolment) at the therapeutic dose of 0.2 mg/kg once daily was 1930 ng.h/mL. The estimated exposure for later-onset SMA patients (2-25 years old at enrolment) in the SUNFISH (Part 2) study at the therapeutic dose (0.25 mg/kg once daily for patients with a body weight <20 kg; 5 mg once daily for patients with a body weight ≥20 kg) was 2070 ng.h/mL. The observed maximum concentration (mean Cmax) was 194 ng/mL at 0.2 mg/kg in FIREFISH and 120 ng/mL in SUNFISH Part 2.
Risdiplam was rapidly absorbed in the fasted state with a plasma tmax ranging from 1 to 4 hours after oral administration. Based on limited data (n=3), food (high-fat, high calorie breakfast) had no relevant effect on the exposure of risdiplam. In the clinical studies, risdiplam was administered with a morning meal or after breastfeeding.
Risdiplam distributes evenly to all parts of the body, including the central nervous system (CNS) by crossing the blood brain barrier, and thereby leading to SMN protein increase in the CNS and throughout the body. Concentrations of risdiplam in plasma and SMN protein in blood reflect its distribution and pharmacodynamic effects in tissues such as brain and muscle.
The population pharmacokinetic parameter estimates were 98 L for the apparent central volume of distribution, 93 L for the peripheral volume, and 0.68 L/hour for the inter-compartment clearance.
Risdiplam is predominantly bound to serum albumin, without any binding to alpha-1 acid glycoprotein, with a free fraction of 11%.
Risdiplam is primarily metabolized by FMO1 and FMO3, and also by CYPs 1A1, 2J2, 3A4 and 3A7.
Co-administration of 200 mg itraconazole twice daily, a strong CYP3A inhibitor, with a single oral dose of 6 mg risdiplam showed no clinically relevant effect on the PK of risdiplam (11% increase in AUC, 9% decrease in Cmax).
Population PK analyses estimated an apparent clearance (CL/F) of 2.6 L/h for risdiplam. The effective half-life of risdiplam was approximately 50 hours in SMA patients.
Risdiplam is not a substrate of human multidrug resistance protein 1 (MDR1).
Approximately 53% of the dose (14% unchanged risdiplam) was excreted in the feces and 28% in urine (8% unchanged risdiplam). Parent drug was the major component found in plasma, accounting for 83% of drug related material in circulation. The pharmacologically inactive metabolite M1 was identified as the major circulating metabolite.
Body weight and age were identified as covariates in the population PK analysis. The dose is therefore adjusted based on age (below and above 2 years) and body weight (up to 20 kg) to obtain similar exposure across the age and body weight range. No data are available in patients less than 2 months of age.
No dedicated studies have been conducted to investigate PK in patients with SMA above 60 years of age. Subjects without SMA up to 69 years of age were included in the clinical PK studies, which indicates that no dose adjustment is required for patients up to 69 years of age.
No studies have been conducted to investigate the PK of risdiplam in patients with renal impairment. Elimination of risdiplam as unchanged entity via renal excretion is minor (8%).
Mild and moderate hepatic impairment had no significant impact on the PK of risdiplam. After a single oral administration of 5 mg risdiplam, the mean ratios for Cmax and AUC were 0.95 and 0.80 in mild (n=8) and 1.20 and 1.08 in moderate hepatic impaired subjects (n=8) versus matched healthy controls (n=10). The safety and PK in patients with severe hepatic impairment have not been studied.
The PK of risdiplam do not differ in Japanese and Caucasian subjects.
Treatment with risdiplam was associated with male germ cell arrest in rats and monkeys without safety margins based on systemic exposures at the no observed adverse effect level (NOAEL). These effects led to degenerated spermatocytes, degeneration/necrosis of the seminiferous epithelium, and oligo/aspermia in the epididymis. Sperm cell effects of risdiplam are likely related to an interference of risdiplam with the cell cycle of dividing cells, which is stage specific and expected to be reversible. No effects were seen on female reproductive organs in rats and monkeys after treatment with risdiplam.
No fertility and early embryonic development studies were conducted with concomitant administration of risdiplam, as sperm cell arrest and embryotoxic potential under treatment was already identified with treatment of rats and monkeys in other toxicity studies. No impairment on male fertility or female fertility was observed in two studies in which rats were mated, either following completion of a 13-week treatment period starting at weaning, or 8 weeks after completion of a 4-week treatment period starting at 4 days of age.
Chronic treatment of monkeys with risdiplam yielded evidence for an effect on the retina in terms of photoreceptor degeneration starting in the periphery of the retina. Upon cessation of treatment, the effects on the retinogram were partially reversible but the photoreceptor degeneration did not reverse. The effects were monitored by optical coherence tomography (OCT) and by electroretinography (ERG). Effects were seen with exposures in excess of 2-fold the exposure in humans at the therapeutic dose without safety margin based on systemic exposures at the NOAEL. No such findings were observed in albino or pigmented rats when dosed chronically with risdiplam at exposures exceeding those in the monkey.
Effects on skin, larynx and eyelid histology and the gastro intestinal tract were evident in rats and monkeys treated with risdiplam. Changes started to be seen at high doses with treatment of 2 weeks and longer. With chronic treatment for 39 weeks in monkeys, the NOAEL was at an exposure in excess of 2-fold the average exposure in humans at the therapeutic dose.
In the acute bone marrow micronucleus test in rats, a reduction of more than 50% in the ratio of polychromatic (young) to normochromatic (adult) erythrocytes, indicative of substantial bone marrow toxicity, was observed at the high dose level with exposure in excess of 15-times the average exposure in humans at the therapeutic dose. With longer treatment of rats for 26 weeks, the exposure margins to the NOAEL were approximately 4-foldthe average exposure in humans at the therapeutic dose.
Risdiplam is not mutagenic in a bacterial reverse mutation assay. In mammalian cells in vitro and in bone marrow of rats, risdiplam increases the frequency of micronucleated cells. Micronucleus induction in bone marrow was observed in several toxicity studies in rats (adult and juvenile animals). The NOAEL across the studies is associated with an exposure of approximately 1.5-fold the exposure in humans at the therapeutic dose. Data indicated that this effect is indirect and secondary to an interference of risdiplam with the cell cycle of dividing cells. Risdiplam does not possess a potential to damage DNA directly.
In studies in pregnant rats treated with risdiplam, embryofoetal toxicity with lower fetal weight and delayed development was evident. The NOAEL for this effect was approximately 2-fold above the exposure levels reached at the therapeutic dose of risdiplam in patients. In studies with pregnant rabbits, dysmorphogenic effects were observed at exposures also associated with maternal toxicity. These consisted of four fetuses (4%) from 4 litters (22%) with hydrocephaly. The NOAEL was approximately 4-fold the exposure levels reached at the therapeutic dose of risdiplam in patients. In a pre- and post-natal development study in rats treated daily with risdiplam, risdiplam caused a slight delay in gestation length. Studies in pregnant and lactating rats showed that risdiplam crosses the placental barrier and is excreted into milk.
A 2-year carcinogenicity study in rat is ongoing. A study using rasH2 transgenic mice with 6 months duration of treatment did not generate any evidence for a tumorigenic potential.
Juvenile animal data reveal no special hazard for humans.
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