Highlights

Indications and usage

Risdiplam is indicated for the treatment of spinal muscular atrophy in pediatric and adult patients.

Dosage and administration

Dosing information

Risdiplam is administered orally once daily with or without food. The recommended dosage is determined by age and body weight (see Table 1). Risdiplam tablets are available for patients prescribed the 5 mg dose.

Table 1. Adult and Pediatric Dosing Regimen by Age and Body Weight

Important administration instructions

It is recommended that a healthcare provider discuss with the patient or caregiver how to prepare the prescribed daily dose before administration of the first dose.

Risdiplam is taken orally once daily with or without food at approximately the same time each day.

Risdiplam for oral solution. In infants who are breastfed, risdiplam for oral solution can be administered before or after breastfeeding. Risdiplam cannot be mixed with formula or milk.

Instruct patients or caregivers to administer the dose using the reusable oral syringe provided.

Risdiplam for oral solution must be taken immediately after it is drawn up into the oral syringe. If risdiplam is not taken within 5 minutes, risdiplam should be discarded from the oral syringe, and a new dose should be prepared.

Instruct patients to drink water after taking risdiplam for oral solution to ensure the drug has been completely swallowed.

If the patient is unable to swallow and has a nasogastric or gastrostomy tube in place, risdiplam for oral solution can be administered through the tube. The tube should be flushed with water after delivering risdiplam for oral solution.

Risdiplam tablets. Swallow risdiplam tablets whole with water. Do not chew, cut, or crush the tablets.

The risdiplam tablet can also be dispersed in one teaspoon (5 mL) of room-temperature non-chlorinated drinking water (eg, filtered water). Risdiplam tablets must not be dispersed in any liquid other than non-chlorinated drinking water. Do not expose the prepared dispersion to sunlight. Swirl the small cup gently for up to 3 minutes until thoroughly mixed (though some particles will remain). Administer the dispersed tablet immediately. To ensure no particles are left in the small cup, refill it with at least one tablespoon (15 mL) of non-chlorinated drinking water, swirl, and administer it again immediately.

Risdiplam must be taken immediately after it is dispersed in non-chlorinated drinking water. Discard the prepared dispersion if it is not used within 10 minutes of adding non-chlorinated drinking water.

Do not administer the prepared dispersion via a nasogastric or gastrostomy tube. If administration through a nasogastric or gastrostomy tube is required, risdiplam for oral solution should be used.

Missed dose

If a dose of risdiplam is missed, risdiplam should be administered as soon as possible if still within 6 hours of the missed dose, and the usual dosing schedule can be resumed on the next day. Otherwise, the missed dose should be skipped, and the next dose should be taken at the regularly scheduled time on the next day.

If a dose is not fully swallowed or vomiting occurs after taking a dose of risdiplam, another dose should not be administered to make up for the lost dose. The patient should wait until the next day to take the next dose at the regularly scheduled time.

Preparation of powder for oral solution by a healthcare provider

Risdiplam powder must be constituted into the oral solution by a pharmacist or other healthcare provider before dispensing to the patient.

Preparation of the risdiplam oral solution 0.75 mg/mL. The risdiplam "Instructions for Constitution" booklet contains more detailed instructions on the preparation of the oral solution.

Caution should be exercised when handling risdiplam powder for oral solution. Avoid inhalation and direct contact with skin or mucous membranes with the dry powder and the constituted solution. If such contact occurs, wash thoroughly with soap and water; rinse eyes with water. Wear disposable gloves during the preparation and cleanup procedure.

(1) Gently tap the bottom of the closed glass bottle to loosen the powder.

(2) Remove the cap. Do not throw away the cap.

(3) Carefully pour 79 mL of purified water into the risdiplam bottle to yield the 0.75 mg/mL oral solution. Do not mix risdiplam with formula or milk.

(4) Insert the press-in bottle adapter into the bottle opening by pushing it down against the bottle lip. Ensure it is completely pressed against the bottle lip.

(5) Re-cap the bottle tightly and shake well for 15 seconds. Wait for 10 minutes. You should have obtained a clear solution. If not, shake well again for another 15 seconds or until a clear solution is obtained.

(6) Write the date of expiration of the constituted oral solution (calculated as 64 days after constitution) and the lot number on the bottle label. Peel off the part of the bottle label that has the expiration date of the powder.

(7) Put the bottle back in its original carton.

(8) Select the appropriate oral syringes (1 mL, 6 mL, or 12 mL) based on the patient's dosage and remove the other oral syringes from the carton.

(9) Dispense with the "Instructions for Use" and FDA-approved patient labeling. Alert patients to read the important handling information described in the Instructions for Use.

Storage

Keep the constituted oral solution of risdiplam in the original amber bottle to protect from light. Store in a refrigerator at 2°C to 8°C (36°F to 46°F). Do not freeze. Discard any unused portion 64 days after constitution. Keep the bottle in an upright position with the cap tightly closed. If refrigeration is not available, risdiplam can be kept at room temperature up to 40°C (up to 104°F) for a combined total of 5 days. Risdiplam can be removed from, and returned to, a refrigerator. The total combined time out of refrigeration should not exceed 5 days.

Dosage forms and strengths

Risdiplam for oral solution: 60 mg as a light yellow, pale yellow, yellow, greyish yellow, greenish yellow, or light green powder for constitution. Following constitution, the volume of the greenish-yellow to yellow solution is 80 mL, providing 60 mg/80 mL (0.75 mg/mL) risdiplam.

Risdiplam tablet: 5 mg as a pale yellow film-coated tablet, round and curved, with EVR debossed on one side.

Contraindications

None.

Adverse reactions

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 clinical trials of another drug and may not reflect the rates observed in practice.

In clinical trials including patients with infantile-onset, later-onset, and pre-symptomatic spinal muscular atrophy, a total of 491 patients (51% female, 74% Caucasian) were exposed to risdiplam for up to a median duration of 48.1 months (range: 0.6 to 63.4 months), with 231 patients receiving treatment for more than 24 months. At the time of first risdiplam dose, 90 (18%) patients were 18 years and older, 119 (24%) were 12 years to less than 18 years, 189 (39%) were 2 years to less than 12 years, 67 (14%) 2 months to less than 2 years, and 26 (5%) were less than 2 months.

Clinical trial in later-onset spinal muscular atrophy. The safety of risdiplam for later-onset spinal muscular atrophy is based on data from a randomized, double-blinded, placebo-controlled study (Study 2 Part 2) in patients with spinal muscular atrophy Type 2 or 3 (n = 180). The patient population in Study 2 Part 2 ranged in age from 2 to 25 years at the time of the first dose.

The most common adverse reactions (reported in at least 10% of patients treated with risdiplam and at an incidence greater than on placebo) in Study 2 Part 2 were fever, diarrhea, and rash. Table 2 lists the adverse reactions that occurred in at least 5% of patients treated with risdiplam and at an incidence of 5% or greater than on placebo in Study 2 Part 2.

Table 2. Adverse Reactions Reported in 5% or More of Patients Treated with Risdiplam and with an Incidence of 5% or Greater Than on Placebo in Study 2 Part 2

Clinical trial in infantile-onset spinal muscular atrophy. The safety of risdiplam therapy for infantile-onset spinal muscular atrophy is based on data from an open-label study in 62 patients (Study 1). The patient population ranged in age from 2 to 7 months at the time of the first risdiplam dose (weight range: 4.1 to 10.6 kg).

The most frequent adverse reactions reported in patients with infantile-onset spinal muscular atrophy treated with risdiplam in Study 1 were similar to those observed in patients with later-onset spinal muscular atrophy in Study 2. Additionally, the adverse reactions reported in 10% or more of patients were upper respiratory tract infection (including nasopharyngitis, rhinitis), lower respiratory tract infection (including pneumonia, bronchitis), constipation, vomiting, and cough.

Clinical trial in pre-symptomatic spinal muscular atrophy. The safety of risdiplam therapy for pre-symptomatic spinal muscular atrophy is based on data from an open-label, single-arm study in 26 patients (Study 3). The patient population ranged in age from 16 to 41 days at the time of the first dose (weight range: 3.1 to 5.7 kg). The safety profile of risdiplam in pre-symptomatic patients in Study 3 is consistent with the safety profile for patients with symptomatic spinal muscular atrophy treated with risdiplam in clinical trials.

Drug interactions

Effect of risdiplam on substrates of multidrug and toxin extrusion (MATE) protein transporters

Based on in vitro data, risdiplam may increase plasma concentrations of drugs eliminated via MATE1 or MATE2-K, such as metformin. Avoid coadministration of risdiplam with MATE substrates. If coadministration cannot be avoided, monitor for drug-related toxicities and consider dosage reduction of the coadministered drug (based on the labeling of that drug) if needed.

Use in specific populations

Pregnancy

Pregnancy exposure registry. There is a pregnancy exposure registry that monitors pregnancy and fetal, neonatal, and infant outcomes in women exposed to risdiplam during pregnancy. Physicians are encouraged to register patients, and pregnant women are encouraged to register themselves by calling 1-833-760-1098 or visiting https://www.evrysdipregnancyregistry.com.

Risk summary. There are no adequate data on the developmental risk associated with the use of risdiplam in pregnant women. In animal studies, administration of risdiplam during pregnancy or throughout pregnancy and lactation resulted in adverse effects on development (embryofetal mortality, malformations, decreased fetal body weights, and reproductive impairment in offspring) at or above clinically relevant drug exposures (see Data).

The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. In the U.S. general population, the estimated background risk of major birth defect and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Based on animal data, advise pregnant women of the potential risk to the fetus.

Data.

Animal data. Oral administration of risdiplam (0, 1, 3, or 7.5 mg/kg/day) to pregnant rats throughout organogenesis resulted in decreased fetal body weights and increased incidences of fetal structural variations at the highest dose tested, which was not associated with maternal toxicity. The no-effect level for adverse effects on embryofetal development (3 mg/kg/day) was associated with maternal plasma exposure (AUC) approximately two times that in humans at the maximum recommended human dose of 5 mg.

Oral administration of risdiplam (0, 1, 4, or 12 mg/kg/day) to pregnant rabbits throughout organogenesis resulted in embryofetal mortality, fetal malformations (hydrocephaly), and structural variations at the highest dose tested, which was associated with maternal toxicity. The no-effect dose for adverse effects on embryofetal development (4 mg/kg/day) was associated with maternal plasma exposure (AUC) approximately four times that in humans at the maximum recommended human dose.

When risdiplam (0, 0.75, 1.5, or 3 mg/kg/day) was orally administered to rats throughout pregnancy and lactation, gestation was prolonged in the dams, and delayed sexual maturation (vaginal opening) and impaired reproductive function (decreased numbers of corpora lutea, implantation sites, and live embryos) were observed in female offspring at the highest dose. The no-effect dose for adverse effects on pre- and postnatal development in rats (1.5 mg/kg/day) was associated with maternal plasma exposure (AUC) similar to that in humans at the maximum recommended human dose.

Lactation

Risk summary. There are no data on the presence of risdiplam in human milk, the effects on the breastfed infant, or the effects on milk production. Risdiplam was excreted in the milk of lactating rats orally administered risdiplam.

The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for risdiplam and any potential adverse effects on the breastfed infant from risdiplam or the underlying maternal condition.

Females and males of reproductive potential

Studies of risdiplam in juvenile and adult rats and in monkeys demonstrated adverse effects on the reproductive organs, including germ cells, in males at clinically relevant plasma exposures.

Pregnancy testing. Pregnancy testing is recommended for females of reproductive potential before initiating risdiplam.

Contraception. Risdiplam may cause embryofetal harm when administered to a pregnant woman.

Female patients. Advise female patients of reproductive potential to use effective contraception during treatment with risdiplam and for at least 1 month after her last dose.

Infertility.

Male patients. Male fertility may be compromised by treatment with risdiplam.

Counsel male patients of reproductive potential receiving risdiplam about the potential effects on fertility. Male patients may consider sperm preservation before treatment.

Pediatric use

The safety and effectiveness of risdiplam in pediatric patients (neonates and older) have been established. Use of risdiplam for spinal muscular atrophy is supported by evidence from adequate and well-controlled studies of risdiplam in patients 2 months of age and older with spinal muscular atrophy. Use of risdiplam for spinal muscular atrophy in patients 2 months of age and younger is supported by pharmacokinetic and safety data from pediatric patients 16 days and older, and pharmacokinetic modeling and simulation to identify the dosing regimen.

Juvenile animal toxicity data. Oral administration of risdiplam (0, 0.75, 1.5, 2.5 mg/kg/day) to young rats from postnatal day 4 through 31 resulted in decreased growth (body weight, tibia length) and delayed sexual maturation in males at the mid and high dose. The skeletal and body weight deficits persisted after cessation of dosing. Ophthalmic changes consisting of vacuoles in the anterior vitreous were seen at the high dose. Decreases in absolute B lymphocyte counts were observed at all doses after cessation of dosing. Decreases in testis and epididymis weights, which correlated with degeneration of the seminiferous epithelium in the testis, occurred at the mid and high doses; the histopathology findings were reversible, but organ weight persisted after cessation of dosing. Impaired female reproductive performance (decreased mating index, fertility index, and conception rate) was observed at the high dose. A no-effect dose for adverse developmental effects on preweaning rats was not identified. The lowest dose tested (0.75 mg/kg/day) was associated with plasma exposures (AUC) lower than that in humans at the maximum recommended human dose of 5 mg/day.

Oral administration of risdiplam (0, 1, 3, or 7.5 mg/kg/day) to young rats from postnatal day 22 through 112 produced a marked increase in micronuclei in the bone marrow, male reproductive organ histopathology (degeneration/necrosis of the seminiferous tubule epithelium, oligo/aspermia in the epididymis, spermatic granulomas), and adverse effects on sperm parameters (decreased sperm concentration and motility, increased sperm morphology abnormalities) at the highest dose tested. Increases in T lymphocytes (total, helper, and cytotoxic) were observed at the mid and high doses. The reproductive and immune effects persisted after cessation of dosing. The no-effect dose (1 mg/kg/day) for adverse effects on postweaning juvenile rats was associated with plasma exposures (AUC) lower than that in humans at the maximum recommended human dose.

Geriatric use

Clinical studies of risdiplam did not include patients aged 65 years and older to determine whether they respond differently from younger adult patients.

Clinical pharmacology

Mechanism of action

Risdiplam is a survival of motor neuron 2 (SMN2) splicing modifier designed to treat patients with spinal muscular atrophy caused by mutations in chromosome 5q that lead to SMN protein deficiency. Using in vitro assays and studies in transgenic animal models of spinal muscular atrophy, risdiplam was shown to increase exon 7 inclusion in SMN2 messenger ribonucleic acid (mRNA) transcripts and production of full-length SMN protein in the brain.

In vitro and in vivo data indicate that risdiplam may cause alternative splicing of additional genes, including FOXM1 and MADD. FOXM1 and MADD are thought to be involved in cell cycle regulation and apoptosis, respectively, and have been identified as possible contributors to adverse effects seen in animals.

Pharmacodynamics

In clinical trials for infantile-onset and later-onset spinal muscular atrophy patients, risdiplam led to an increase in SMN protein with a greater than two-fold median change from baseline within 4 weeks of treatment initiation across all spinal muscular atrophy types studied. The increase was sustained throughout the treatment period (of at least 24 months).

Cardiac electrophysiology. At the maximum recommended dose, clinically significant QTc interval prolongation was not observed.

Pharmacokinetics

The pharmacokinetics of risdiplam have been characterized in healthy adult subjects and in patients with spinal muscular atrophy.

After administration of risdiplam as an oral solution, the pharmacokinetics of risdiplam were approximately linear between 0.6 and 18 mg in a single-ascending-dose study in healthy adult subjects and between 0.02 and 0.25 mg/kg once daily in a multiple-ascending-dose study in patients with spinal muscular atrophy. Following once-daily oral administration of risdiplam in healthy subjects, approximately 3-fold accumulation of peak plasma concentrations (C_max) and area under the plasma concentration-time curve (AUC_0-24h) was observed. Risdiplam exposures reach steady state 7 to 14 days after once daily administration. Risdiplam tablet (swallowed whole or dispersed in water) demonstrated comparable bioavailability to risdiplam for oral solution in adult healthy volunteers under fasted and fed states.

Absorption. Following oral administration of risdiplam in a fasted state, the median time to reach maximum plasma concentration (T_max) was 3.26 to 4 hours. The T_max was delayed by up to1 hour in a fed state compared to that under the fasted state.

Effect of food. Food (high-fat, high-calorie breakfast) had no relevant effect on the exposure to risdiplam. In the clinical efficacy studies (Study 1 and Study 2), risdiplam was administered with a morning meal or after breastfeeding.

Distribution. The apparent volume of distribution at steady state is 190.4 L for a 31.3 kg patient.

Risdiplam is predominantly bound to serum albumin, without any binding to alpha-1 acid glycoprotein, with a free fraction of 11%.

Elimination. The apparent clearance (CL/F) of risdiplam is 2.45 L/h for a 31.3 kg patient.

The terminal elimination half-life of risdiplam was approximately 50 hours in healthy adults.

Metabolism. Risdiplam is primarily metabolized by flavin monooxygenase 1 and 3 (FMO1 and FMO3) and also by CYPs 1A1, 2J2, 3A4, and 3A7.

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.

Excretion. Following a dose of 18 mg, approximately 53% of the dose (14% unchanged risdiplam) was excreted in the feces and 28% in urine (8% unchanged risdiplam).

Specific populations. There were no clinically significant differences in the pharmacokinetics of risdiplam based on race or gender. Renal impairment is not expected to alter the exposures to risdiplam.

The impact of geriatric age on the pharmacokinetics of risdiplam has not been studied.

Hepatic impairment. The pharmacokinetics and safety of risdiplam have been studied in subjects with mild or moderate hepatic impairment (as defined by Child-Pugh class A and B, respectively, n = eight each) compared to subjects with normal hepatic function (n = 10). Following the administration of 5 mg risdiplam, the AUC_inf and C_max of risdiplam were approximately 20% and 5% lower, respectively, in subjects with mild hepatic impairment and were approximately 8% and 20% higher, respectively, in subjects with moderate hepatic impairment, versus matched healthy control subjects. The magnitude of these changes is not considered to be clinically meaningful. The pharmacokinetics and safety in patients with severe hepatic impairment (Child-Pugh class C) have not been studied.

Pediatric patients. Body weight and age were found to have a significant effect on the pharmacokinetics of risdiplam. The estimated exposure (mean AUC_0-24h) in pre-symptomatic infants at the age of 1 to 2 months was 2090 ng.h/mL at the recommended dose of 0.15 mg/kg once daily. The estimated exposure for patients with infantile-onset spinal muscular atrophy (age 2 to 7 months at enrollment) at the recommended dose of 0.2 mg/kg once daily was 1930 ng.h/mL. The estimated exposure for patients with later-onset spinal muscular atrophy (2 to 25 years old at enrollment) at the recommended dose was 2070 ng.h/mL (0.25 mg/kg once daily for patients with a body weight lower than 20 kg and 5 mg once daily for patients with a body weight of 20 kg or more).

No data on risdiplam pharmacokinetics are available in patients less than 16 days of age.

Drug interaction studies.

Effect of other drugs on risdiplam. Coadministration of 200 mg itraconazole (a strong CYP3A inhibitor) twice daily with a single 6 mg oral dose of risdiplam did not have a clinically relevant effect on the pharmacokinetics of risdiplam (11% increase in AUC and 9% decrease in C_max).

Risdiplam is a weak substrate of human MDR-1 and breast cancer resistant protein (BCRP) transporters in vitro. Human MDR-1 or BCRP inhibitors are not expected to result in a clinically significant increase of risdiplam concentrations.

Effect of risdiplam on other drugs. Risdiplam and its major circulating metabolite M1 did not induce CYP1A2, 2B6, 2C8, 2C9, 2C19, or 3A4 in vitro. Risdiplam and M1 did not inhibit (reversible or time-dependent inhibition) any of the CYP enzymes tested (CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6), with the exception of CYP3A in vitro.

Risdiplam is a weak inhibitor of CYP3A. In healthy adult subjects, administration of risdiplam once daily for 2 weeks slightly increased the exposure of midazolam, a sensitive CYP3A substrate (AUC 11%; C_max 16%); this increase is not considered clinically relevant. Based on physiologically-based pharmacokinetic (PBPK) modeling, a similar increase is expected in children and infants as young as 2 months of age.

In vitro studies have shown that risdiplam and its major metabolite are not significant inhibitors of human MDR1, organic anion-transporting polypeptide (OATP) 1B1, OATP1B3, organic anion transporter 1 and 3 (OAT 1 and 3) transporters, and human organic cation transporter 2 (OCT2), at clinically relevant concentrations. Risdiplam and its metabolite are, however, in vitro inhibitors of the multidrug and toxin extrusion (MATE) 1 and MATE2-K transporters.

Nonclinical toxicology

Carcinogenesis, mutagenesis, impairment of fertility

Carcinogenesis. Risdiplam was not carcinogenic in Tg.rasH2 mice when administered at oral doses of up to 9 mg/kg/day for 26 weeks.

In a 2-year carcinogenicity study in rats, oral administration of risdiplam (0, 0.3, 1, or 3 mg/kg/day) resulted in increased incidences of preputial gland squamous cell carcinomas in males and combined thyroid follicular cell adenomas and carcinomas in females at the highest dose tested. The higher dose, not associated with an increase in tumors (1 mg/kg/day), was associated with plasma drug exposures (AUC) similar to that in humans at the maximum recommended human dose of 5 mg/day.

Mutagenesis. Risdiplam was negative in an in vitro Ames assay. In an in vivo combined bone marrow micronucleus and comet assay in rat, risdiplam was clastogenic, as evidenced by an increase in micronuclei in bone marrow, but was negative in the comet assay. A pronounced increase in bone marrow micronuclei was also observed in toxicity studies in adult and juvenile rats.

Impairment of fertility. Oral administration of risdiplam to rats for four (0, 1, 3, or 9 mg/kg/day) or 26 (0, 1, 3, or 7.5 mg/kg/day) weeks resulted in histopathological effects in the testis (degenerated spermatocytes, degeneration/atrophy of the seminiferous tubules) and epididymis (degeneration/necrosis of ductular epithelium) at the mid and/or high doses. At the high dose in the 26-week study, the testicular lesions persisted to the end of the recovery period, which corresponds, in rat, to approximately one spermatogenic cycle. The no-effect dose for adverse reproductive system effects in adult male rats (1 mg/kg/day) was associated with plasma drug exposures (AUC) similar to that in humans at the maximum recommended human dose of 5 mg/day.

Adverse effects of risdiplam on the testis could not be fully evaluated in the monkey because the majority of monkeys tested were sexually immature. However, oral administration of risdiplam (0, 2, 4, or 6 mg/kg/day) for 2 weeks resulted in histopathological changes in the testis (increases in multinucleate cells, germ cell degeneration) at the highest dose. At the no-effect dose for testicular toxicity in monkeys, plasma exposures were approximately three times that in humans at the maximum recommended human dose.

Oral administration of risdiplam to postweaning juvenile rats resulted in male reproductive toxicity (degeneration/necrosis of the testis seminiferous epithelium with associated oligo/aspermia in the epididymis and abnormal sperm parameters). The no-effect dose for adverse reproductive effects in postweaning male juvenile rats was associated with plasma exposures approximately four times that in humans at the maximum recommended human dose.

Animal toxicology or pharmacology

Retinal toxicity. Risdiplam-induced functional and structural retinal abnormalities were seen in animal studies. In a 39-week toxicity study in monkeys, oral administration of risdiplam (0, 1.5, 3, or 7.5/5 mg/kg/day; high dose lowered after 4 weeks) produced functional abnormalities on the electroretinogram in all mid- and high-dose animals at the earliest examination time (Week 20). These findings were associated with retinal degeneration, detected by optical coherence tomography, at week 22, the first examination time. The retinal degeneration, with peripheral photoreceptor loss, was irreversible. A no-effect dose for the retinal findings (1.5 mg/kg/day) was associated with plasma exposures (AUC) similar to that in humans at the maximum recommended human dose of 5 mg.

Effect on epithelial tissues. Oral administration of risdiplam to rats and monkeys resulted in histopathological changes in epithelium of the gastrointestinal tract (apoptosis or single cell necrosis), lamina propria (vacuolation), the exocrine pancreas (single cell necrosis), the skin, tongue, and larynx (parakeratosis, hyperplasia, or degeneration) with associated inflammation. The skin and gastrointestinal epithelial effects were reversible. The no-effect doses for effects on epithelial tissues in rats and monkeys were associated with plasma exposures (AUC) similar to that in humans at the maximum recommended human dose.

Clinical studies

The efficacy of risdiplam for the treatment of patients with infantile-onset, later-onset, and pre-symptomatic spinal muscular atrophy was evaluated in three clinical studies, Study 1 (NCT02913482) and Study 2 (NCT02908685), and Study 3 (NCT03779334), respectively.

The overall findings of these studies support the effectiveness of risdiplam in pediatric and adult patients with spinal muscular atrophy and appear to support the early initiation of treatment with risdiplam.

Infantile-onset spinal muscular atrophy

Study 1 was an open-label, 2-part study to investigate the efficacy, safety, pharmacokinetics, and pharmacodynamics of risdiplam for oral solution in patients with Type 1 spinal muscular atrophy (symptom onset between 28 days and 3 months of age). All patients had genetic confirmation of homozygous deletion or compound heterozygosity predictive of loss of function of the SMN1 gene, and two SMN2 gene copies.

Part 1 of Study 1 was designed as a dose-finding study. Part 2 of Study 1 assessed the safety and efficacy of risdiplam at 0.20 mg/kg, the recommended dose determined in Part 1. Patients from Part 1 did not take part in Part 2.

A total of 62 patients with symptomatic Type 1 spinal muscular atrophy were enrolled in FIREFISH Part 1 (n = 21) and Part 2 (n = 41), of which 58 patients received the recommended dosage. The median age of onset of clinical signs and symptoms was 1.5 months (range: 0.9 to 3.0 months). The median age at enrollment was 5.6 months (range: 2.2 to 6.9 months), and the median time between onset of symptoms and the first dose was 3.7 months (range 1.0 to 6.0 months). Of these patients, 60% were female, 57% were Caucasian, and 29% were Asian. The demographics and baseline disease characteristics were comparable between Part 1 and Part 2 of the study.

Effectiveness was established based on the ability to sit without support for at least 5 seconds (as measured by Item 22 of the Bayley Scales of Infant and Toddler Development – Third Edition [BSID-III] gross motor scale) and based on survival without permanent ventilation. Permanent ventilation was defined as requiring a tracheostomy or more than 21 consecutive days of either non-invasive ventilation (16 or more hours per day) or intubation, in the absence of an acute reversible event.

The primary endpoint was the proportion of patients with the ability to sit without support for at least 5 seconds (BSID-III gross motor scale, Item 22) after 12 months of treatment in Part 2; 29% of patients (n = 12/41) achieved this milestone.

Other efficacy endpoints of risdiplam-treated patients in Study 1 (pooled Part 1 and Part 2) are shown in Table 3.

Table 3. Key Efficacy Results at Month 12 and Month 24 (Study 1, Parts 1 and Part 2)

At month 24, 40% (23/58) of patients who received the recommended dose achieved sitting without support for 30 seconds (BSID-III, Item 26). In addition at month 24, patients continued to achieve additional motor milestones; 28% (16/58) of patients achieved a standing measure (16% [9/58] supporting weight and 12% [7/58] standing with support), as measured by Section 2 of the Hammersmith Infant Neurological Examination (HINE-2), which assesses motor milestones.

The proportion of patients alive without permanent ventilation (event-free survival) was 84% for all patients at month 24 (Table 3). Out of 62 patients, six infants died (four within the first 3 months following study enrollment), and one additional patient withdrew from treatment and died 3.5 months later. Four patients required permanent ventilation by month 24. These results indicate a clinically meaningful deviation from the natural history of untreated infantile-onset spinal muscular atrophy. As described in the natural history of untreated infantile-onset spinal muscular atrophy, patients would not be expected to attain the ability to sit independently, and no more than 25% of these patients would be expected to survive without permanent ventilation beyond 14 months of age.

Later-onset spinal muscular atrophy

Study 2 was a 2-part, multicenter trial to investigate the efficacy, safety, pharmacokinetics, and pharmacodynamics of risdiplam for oral solution in patients diagnosed with spinal muscular atrophy Type 2 or Type 3. Part 1 of Study 2 was dose-finding and exploratory in 51 patients (14% ambulatory). Part 2 was randomized, double-blind, placebo-controlled, and is described below.

The primary endpoint in Study 2 Part 2 was the change from baseline to month 12 in the Motor Function Measure 32 (MFM32) score. A key secondary endpoint was the proportion of patients with a 3-point or greater change from baseline to month 12 in the MFM32 total score. The MFM32 measures motor function abilities that relate to daily functions. The total MFM32 score is expressed as a percentage (range: 0 to 100) of the maximum possible score, with higher scores indicating greater motor function. Another key secondary endpoint was the Revised Upper Limb Module (RULM). The RULM is a tool used to assess the upper limb motor performance in patients with spinal muscular atrophy. It tests proximal and distal motor functions of the arm. The total score ranges from 0 (all the items cannot be performed) to 37 (all the activities are achieved fully without any compensatory maneuvers).

Study 2 Part 2 enrolled 180 non-ambulatory patients with Type 2 (71%) or Type 3 (29%) spinal muscular atrophy. Patients were randomized 2:1 to receive risdiplam at the recommended dosage or placebo. Randomization was stratified by age group (2 to 5, 6 to 11, 12 to 17, or 18 to 25 years of age).

The median age of patients at the start of treatment was 9.0 years (range: 2 to 25), and the median time between onset of initial spinal muscular atrophy symptoms and first treatment was 102.6 months (range: 1 to 275). Of the 180 patients included in the trial, 51% were female, 67% were Caucasian, and 19% were Asian. At baseline, 67% of patients had scoliosis (32% of them with severe scoliosis). Patients had a mean baseline MFM32 score of 46.1 and RULM score of 20.1. Overall baseline demographic characteristics were reasonably balanced between the treatment groups (risdiplam and placebo), with the exception of scoliosis (63% in the risdiplam arm vs. 73% in the placebo group).

The primary analysis on the change from baseline in MFM32 total score at month 12 showed a clinically meaningful and statistically significant difference between patients treated with risdiplam and placebo. For the results of the primary analysis and key secondary endpoints, see the Clinical Studies section of the DAILYMED drug label information.

Presymptomatic spinal muscular atrophy

Study 3 was an open-label, single-arm, multicenter clinical study to investigate the efficacy, safety, pharmacokinetics, and pharmacodynamics of risdiplam in infants up to 6 weeks of age (at first dose) who have been genetically diagnosed with spinal muscular atrophy but do not yet present with symptoms.

The efficacy in patients with pre-symptomatic spinal muscular atrophy was evaluated at month 12 in 26 patients treated with risdiplam in Study 3: eight patients had two copies of the SMN2 gene, 13 patients had three copies, and five patients had four or more copies. The median age of these patients at first dose was 25 days (range: 16 to 41), 62% were female, and 85% were Caucasian. The primary efficacy population (N = 5) included patients with two SMN2 copies and a baseline CMAP amplitude 1.5 mV or greater.

The primary efficacy endpoint was the proportion of patients with the ability to sit without support for at least 5 seconds (BSID-III gross motor scale, Item 22) at month 12. This milestone was achieved by 80% (4/5) of patients in the primary efficacy population. This milestone was also achieved by 87.5% (7/8) of all patients with two copies of SMN2 and 96.2% (25/26) of patients in the full treated population.

At month 12, 80.8% (21/26) of patients in the full treated population achieved sitting without support for 30 seconds (BSID-III, Item 26). Of the 26 patients treated with risdiplam, 25 patients had motor milestones measured by the HINE-2 at month 12. Of these, 24 (96%) achieved sitting (23 patients could pivot or rotate and one achieved stable sit); 21 (84%) could stand (13 patients could stand unaided, and eight could stand with support); and 12 (48%) could walk independently. Seven patients were not tested for walking at month 12. All 26 patients were alive at 12 months without permanent ventilation.

How supplied/storage and handling

Risdiplam for oral solution

How supplied. Each amber glass bottle of risdiplam for oral solution is packaged with a bottle adapter, two 1 mL reusable oral syringes, two 6 mL reusable oral syringes, and one 12 mL reusable oral syringe. Risdiplam for oral solution is a light yellow, pale yellow, yellow, greyish yellow, greenish yellow, or light green powder. Each bottle contains 60 mg of risdiplam (NDC 50242-175-07).

Storage and handling. Store the dry powder at 20°C to 25°C (68°F to 77°F), excursions permitted between 15°C to 30°C (59°F to 86°F). Keep in the original carton.

Keep the constituted oral solution of risdiplam in the original amber bottle to protect from light. Store in a refrigerator at 2°C to 8°C (36°F to 46°F).

Risdiplam tablets

How supplied. Pale yellow film-coated tablet, round and curved, with EVR debossed on one side; available in HDPE bottles of 30 tablets with a child-resistant cap (NDC 50242-202-01).

Storage and handling. Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F). Keep the bottle tightly closed to protect the solution from moisture.

Patient counseling information

Advise the patient to read the FDA-approved patient labeling.

Pregnancy and fetal risk. Inform pregnant women and women of reproductive potential that, based on animal studies, risdiplam may cause fetal harm.

Discuss with women of childbearing age whether they are pregnant, might be pregnant, or are trying to become pregnant.

Advise women of childbearing potential to use effective contraception during treatment with risdiplam and for at least 1 month after stopping risdiplam.

Advise a female patient to immediately inform the prescriber if she is pregnant or planning to become pregnant.

Pregnancy registry. Encourage patients to enroll in the EVRYSDI Pregnancy Registry if they become pregnant while taking risdiplam.

Potential effects on male fertility. Advise male patients that their fertility may be compromised while on treatment with risdiplam.

Instructions for preparation of oral solution. Advise patients and caregivers to ensure that the oral solution is in liquid form when received from the pharmacy.

Instruct patients and caregivers to take the oral solution with or without food or before or after breastfeeding at approximately the same time each day. However, instruct caregivers not to mix risdiplam with formula or milk.

Instruct patients and caregivers to take risdiplam oral solution immediately after it is drawn up into the reusable oral syringe.

Instructions for risdiplam tablets. Advise patients and caregivers to swallow risdiplam tablets whole with water. Do not chew, cut, or crush the tablets.

Alternatively, the tablet can be dispersed in one teaspoon (5 mL) of room-temperature non-chlorinated drinking water (eg, filtered water) and taken immediately. Risdiplam tablets must not be dispersed in any liquid other than non-chlorinated drinking water. Instruct the patient and caregivers that the dispersion must be administered within 10 minutes of adding non-chlorinated drinking water, or it must be discarded.

Advise patients and caregivers that the risdiplam tablet dispersion is for oral administration only. If administration through a nasogastric or gastrostomy tube is required, risdiplam for oral solution should be used.

Advise patients and caregivers to wash their hands before and after preparing or taking risdiplam tablets.

Advise patients and caregivers to avoid getting the dispersed tablet on their skin or in their eyes. Advise them to wash the area with soap and water if the dispersed tablet comes into contact with the skin and to rinse their eyes with water if the dispersed tablet gets in the eyes.

Advise patients and caregivers to use a dry paper towel to dry the area if the dispersion is spilled and then clean with soap and water. Advise them to throw the paper towel away in the trash and wash their hands with soap and water.

For more detailed instructions for use, see the DAILYMED drug label information.

Evrysdi is a registered trademark of Genentech, Inc.