risdiplam: prescribing information – dosing, contraindications, interactions, side effects

Evrysdi is indicated for the treatment of 5q spinal muscular atrophy (SMA) in patients with a clinical diagnosis of SMA Type 1, Type 2 or Type 3 or with one to four SMN2 copies.

Treatment with risdiplam should be initiated by a physician with experience in the management of SMA.
Posology
The recommended once daily dose of risdiplam is determined by age and body weight (see Table 1).
Table 1. Evrysdi powder for oral solution dosing regimen by age and body weight
Age* and body weight
Recommended daily dose
< 2 months of age
0.15 mg/kg
2 months to < 2 years of age
0.20 mg/kg
≥2 years of age (< 20 kg)
0.25 mg/kg
≥2 years of age (≥ 20 kg)
5 mg
* based on corrected age for preterm infants

There is an alternative film-coated tablet dosage form available for patients ≥ 2 years of age with ≥ 20 kg body weight. Refer to the Evrysdi film-coated tablet summary of product characteristics (SmPC).
The physician should prescribe the appropriate pharmaceutical form according to the dose required and the patient’s needs, including the patient’s ability to swallow. For patients with difficulty swallowing a whole tablet or who require administration via a nasogastric or gastrostomy tube, the film-coated tablet can be dispersed in water, or the powder for oral solution can be prescribed.
Treatment with a daily dose above 5 mg has not been studied.
Delayed or missed doses
If a planned dose is missed, it should be administered as soon as possible if still within 6 hours of the scheduled dose. Otherwise, the missed dose should be skipped and the next dose should be administered at the regularly scheduled time 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 incomplete dose. The next dose should be administered at the regularly scheduled time.
Elderly
No dose adjustment is required in elderly patients based on limited data in subjects aged 65 years and older (see section 5.2).
Renal impairment
Risdiplam has not been studied in this population. No dose adjustment is expected to be required in patients with renal impairment (see section 5.2).
Hepatic impairment
No dose adjustment is required in patients with mild or moderate hepatic impairment. Patients with severe hepatic impairment have not been studied and may have increased risdiplam exposure (see sections 5.1 and 5.2).
Paediatric population
No data on risdiplam pharmacokinetics are available in patients less than 16 days of age.
Method of administration
Oral use.
Evrysdi powder for oral solution must be constituted by a healthcare professional (e.g. pharmacist) prior to being dispensed. It is recommended that a healthcare professional (HCP) discuss with the patient or caregiver how to prepare the prescribed daily dose prior to administration of the first dose.
Evrysdi is taken orally once a day with or without food at approximately the same time each day, using the re-usable oral syringe provided. Evrysdi should not be mixed with milk or formula milk.
Evrysdi should be taken immediately after it is drawn up into the oral syringe. If it is not taken within 5 minutes, it should be discarded from the oral syringe and a new dose be prepared. If Evrysdi spills or gets on the skin, the area should be washed with soap and water.
The patient should drink water after taking Evrysdi to ensure the medicinal product has been completely swallowed. If the patient is unable to swallow and has a nasogastric or gastrostomy tube in situ, Evrysdi powder for oral solution can be administered via the tube. The tube should be flushed with water after delivering Evrysdi.

Selection of the oral syringe for the prescribed daily dose:
Syringe size
Dosing volume
Syringe markings
1 mL
0.3 mL to 1 mL
0.01 mL
6 mL
1 mL to 6 mL
0.1 mL
12 mL
6.2 mL to 6.6 mL
0.2 mL
For the calculation of dosing volume, the syringe markings need to be considered. The dose volume should be rounded to the nearest graduation mark on the selected oral syringe.

Treatment with risdiplam should be initiated by a physician with experience in the management of SMA.
Posology
The recommended once daily dose of risdiplam film-coated tablet for patients ≥ 2 years of age with ≥ 20 kg body weight is 5 mg.
There is an alternative oral solution available for patients of all age groups . Refer to the Evrysdi powder for oral solution SmPC.
The physician should prescribe the appropriate pharmaceutical form according to the dose required and the patient’s needs, including the patient’s ability to swallow. For patients with difficulty swallowing a whole tablet or who require administration via a nasogastric or gastrostomy tube, the film-coated tablet can be dispersed in water, or the powder for oral solution can be prescribed.
Treatment with a daily dose above 5 mg has not been studied.
Delayed or missed doses
If a planned dose is missed, it should be administered as soon as possible if still within 6 hours of the scheduled dose. Otherwise, the missed dose should be skipped and the next dose should be administered at the regularly scheduled time 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 incomplete dose. The next dose should be administered at the regularly scheduled time.

Elderly
No dose adjustment is required in elderly patients based on limited data in subjects aged 65 years and older (see section 5.2).
Renal impairment
Risdiplam has not been studied in this population. No dose adjustment is expected to be required in patients with renal impairment (see section 5.2).
Hepatic impairment
No dose adjustment is required in patients with mild or moderate hepatic impairment. Patients with severe hepatic impairment have not been studied and may have increased risdiplam exposure (see sections 5.1 and 5.2).
Paediatric population
There is no relevant use of risdiplam film-coated tablets in children < 2 years of age and < 20 kg.
Method of administration
Oral use.
It is recommended that a healthcare professional (HCP) discuss with the patient or caregiver how to prepare the prescribed daily dose prior to administration of the first dose.
Evrysdi is taken orally once a day with or without food at approximately the same time each day.
The film‑coated tablets should be swallowed whole or dispersed in a small amount of room temperature water (see Section 6.6). Do not chew, cut, or crush the tablets.
If Evrysdi is dispersed in water, take it immediately. Evrysdi must not be dispersed in any liquid other than water. Discard the prepared mixture if it is not used within 10 minutes of adding water. Do not expose the prepared mixture to sunlight.
If the prepared mixture of Evrysdi spills or gets on the skin, the area should be washed with soap and water.
If administration through a nasogastric or gastrostomy tube is required, a tube that is 8 French or higher should be used to administer the prepared Evrysdi mixture after the dispersion is complete.
After the administration of the Evrysdi mixture, the tube should be flushed with the water (at least 15 mL) used to rinse the dispersion cup.
Detailed instructions on the administration of the tablet prepared as a mixture are given in the Instructions for Use (IFU) at the end of the package insert.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Summary of the safety profile
In infantile‑onset SMA patients, the most common adverse reactions observed in risdiplam clinical studies were pyrexia (54.8%), rash (29.0%) and diarrhoea (19.4%).
In later‑onset SMA patients, the most common adverse reactions observed in risdiplam clinical studies were pyrexia (21.7%), headache (20.0%), diarrhoea (16.7%), and rash (16.7%).
The adverse reactions listed above occurred without an identifiable clinical or time pattern and generally resolved despite ongoing treatment in infantile‑onset and later‑onset SMA patients.
Tabulated list of adverse reactions
The corresponding frequency category for each adverse drug reaction is based on the following convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data). Adverse drug reactions from clinical studies (Table 2) are listed by MedDRA system organ class.

Table 2. Adverse drug reactions occurring in patients with infantile-onset and later-onset SMA based on risdiplam clinical studies and postmarketing experience System Organ Class Infantile-onset SMA (Type 1) Later-onset SMA (Type 2 and 3) Infections and infestations Urinary tract infection (including cystitis) Common Common Nervous system disorders Headache Not applicable Very common Gastrointestinal disorders Diarrhoea Very common Very common Nausea Not applicable Common Mouth ulcerations and aphthous ulcers Common Common Skin and subcutaneous tissue disorders Rash* Very common Very common Cutaneous vasculitis** Not known Musculoskeletal and connective tissue disorders Arthralgia Not applicable Common General disorders and administration site conditions Pyrexia (including hyperpyrexia) Very common Very common *Includes dermatitis, dermatitis acneiform, dermatitis allergic, erythema, folliculitis, rash, rash erythematous, rash maculo-papular, rash papular **Cutaneous vasculitis was reported during post‑marketing experience. Symptoms recovered after permanent discontinuation of risdiplam. The frequency cannot be estimated based on available data.
Safety profile in pre-symptomatic patients
Based on the primary analysis of RAINBOWFISH, the safety profile of Evrysdi in pre‑symptomatic patients is consistent with the safety profile of symptomatic infantile‑onset and later‑onset SMA patients. The RAINBOWFISH study enrolled 26 patients with pre‑symptomatic SMA between 16 and 41 days of age at the time of the first dose (weight range 3.1 to 5.7 kg). The median exposure duration was 20.4 months (range: 10.6 to 41.9 months). Limited post‑marketing data are available in neonates < 20 days of age.
Safety profile in patients previously treated with other SMA‑modifying therapies The safety profile of risdiplam in SMA treatment non‑naive patients (including those previously treated with nusinersen or with onasemnogene abeparvovec) is consistent with the safety profile in SMA treatment-naive patients treated with risdiplam in the FIREFISH, SUNFISH and RAINBOWFISH clinical studies (see section 5.1).
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Summary of the safety profile
In infantile‑onset SMA patients, the most common adverse reactions observed in risdiplam clinical studies were pyrexia (54.8%), rash (29.0%) and diarrhoea (19.4%).

In later‑onset SMA patients, the most common adverse reactions observed in risdiplam clinical studies were pyrexia (21.7%), headache (20.0%), diarrhoea (16.7%), and rash (16.7%).
The adverse reactions listed above occurred without an identifiable clinical or time pattern and generally resolved despite ongoing treatment in infantile‑onset and later‑onset SMA patients.
Tabulated list of adverse reactions
The corresponding frequency category for each adverse drug reaction is based on the following convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data). Adverse drug reactions from clinical studies (Table 1) are listed by MedDRA system organ class.
Table 1. Adverse drug reactions occurring in patients with infantile-onset and later-onset SMA based on risdiplam clinical studies and postmarketing experience System Organ Class Infantile-onset SMA (Type 1) Later-onset SMA (Type 2 and 3) Infections and infestations Urinary tract infection (including cystitis) Common Common Nervous system disorders Headache Not applicable Very common Gastrointestinal disorders Diarrhoea Very common Very common Nausea Not applicable Common Mouth ulcerations and aphthous ulcers Common Common Skin and subcutaneous tissue disorders Rash* Very common Very common Cutaneous vasculitis** Not known Musculoskeletal and connective tissue disorders Arthralgia Not applicable Common General disorders and administration site conditions Pyrexia (including hyperpyrexia) Very common Very common *Includes dermatitis, dermatitis acneiform, dermatitis allergic, erythema, folliculitis, rash, rash erythematous, rash maculo-papular, rash papular **Cutaneous vasculitis was reported during post‑marketing experience. Symptoms recovered after permanent discontinuation of risdiplam. The frequency cannot be estimated based on available data.
Safety profile in pre-symptomatic patients
Based on the primary analysis of RAINBOWFISH, the safety profile of Evrysdi in pre‑symptomatic patients is consistent with the safety profile of symptomatic infantile‑onset and later‑onset SMA patients. The RAINBOWFISH study enrolled 26 patients with pre‑symptomatic SMA between 16 and 41 days of age at the time of the first dose (weight range 3.1 to 5.7 kg). The median exposure duration

was 20.4 months (range: 10.6 to 41.9 months). Limited post‑marketing data are available in neonates < 20 days of age.
Safety profile in patients previously treated with other SMA‑modifying therapies The safety profile of risdiplam in SMA treatment non-naive patients (including those previously treated with nusinersen or with onasemnogene abeparvovec) is consistent with the safety profile in SMA treatment-naive patients treated with risdiplam in the FIREFISH, SUNFISH and RAINBOWFISH clinical studies (see section 5.1).
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Potential embryo‑foetal toxicity
Embryo‑foetal toxicity has been observed in animal studies (see section 5.3). Patients of reproductive potential should be informed of the risks and must use highly effective contraception during treatment and until at least 1 month after the last dose in female patients, and 4 months after the last dose in male patients. The pregnancy status of female patients of reproductive potential should be verified prior to initiating risdiplam therapy (see section 4.6).
Potential effects on male fertility
Based on observations from animal studies, male patients should not donate sperm while on treatment and for 4 months after the last dose of risdiplam. Prior to initiating treatment, fertility preservation strategies should be discussed with male patients of reproductive potential (see sections 4.6 and 5.3).
The effects of risdiplam on male fertility have not been investigated in humans.
Excipients
Isomalt
Evrysdi contains isomalt (2.97 mg per mL). Patients with rare hereditary problems of fructose intolerance should not take this medicine.
Sodium
Evrysdi contains 0.375 mg of sodium benzoate per mL. Sodium benzoate may increase jaundice (yellowing of the skin and eyes) in newborn babies (up to 4 weeks old).
Evrysdi contains less than 1 mmol sodium (23 mg) per 5 mg dose, i.e. is essentially ‘sodium-free’.

Potential embryo‑foetal toxicity
Embryo‑foetal toxicity has been observed in animal studies (see section 5.3). Patients of reproductive potential should be informed of the risks and must use highly effective contraception during treatment and until at least 1 month after the last dose in female patients, and 4 months after the last dose in male patients. The pregnancy status of female patients of reproductive potential should be verified prior to initiating risdiplam therapy (see section 4.6).

Potential effects on male fertility
Based on observations from animal studies, male patients should not donate sperm while on treatment and for 4 months after the last dose of risdiplam. Prior to initiating treatment, fertility preservation strategies should be discussed with male patients of reproductive potential (see sections 4.6 and 5.3).
The effects of risdiplam on male fertility have not been investigated in humans.
Excipients
Sodium
Evrysdi contains less than 1 mmol sodium (23 mg) per 5 mg dose, i.e. is essentially ‘sodium-free’.

Effects of other medicinal products on risdiplam
Co‑administration of 200 mg itraconazole twice daily, a strong CYP3A inhibitor, with a single oral dose of 6 mg risdiplam did not exhibit a clinically relevant effect on the PK parameters of risdiplam (11% increase in AUC, 9% decrease in Cmax). No dose adjustments are required when risdiplam is co‑administered with a CYP3A inhibitor.
No drug‑drug interactions are expected via the FMO1 and FMO3 pathway.

Effects of risdiplam on other medicinal products
Risdiplam is a weak inhibitor of CYP3A. In healthy adult subjects, oral administration of risdiplam once daily for 2 weeks slightly increased the exposure of midazolam, a sensitive CYP3A substrate (11% increase in AUC, 16% increase in Cmax). The extent of the interaction is not considered clinically relevant, and therefore no dose adjustment is required for CYP3A substrates.
In vitro studies have shown that risdiplam and its major human metabolite M1 are not significant inhibitors of human MDR1, organic anion-transporting polypeptide (OATP)1B1, OATP1B3, organic anion transporter 1 and 3 (OAT 1 and 3). However, risdiplam and its metabolite are in vitro inhibitors of the human organic cation transporter 2 (OCT2) and the multidrug and toxin extrusion (MATE)1 and MATE2‑K transporters. At therapeutic drug concentrations, no interaction is expected with OCT2 substrates. The effect of co-administration of risdiplam on the pharmacokinetics of MATE1 and MATE2‑K substrates in humans is unknown. Based on in vitro data, risdiplam may increase plasma concentrations of medicinal products eliminated via MATE1 or MATE2‑K, such as metformin. If co- administration cannot be avoided, drug‑related toxicities should be monitored and dosage reduction of the co-administered medicinal product should be considered if needed.
There is no efficacy or safety data to support the concomitant use of risdiplam and nusinersen.

Effects of other medicinal products on risdiplam
Omeprazole had no impact on the pharmacokinetics of risdiplam administered as a tablet. The risdiplam tablet may therefore be administered concomitantly with medication that increases the gastric pH (proton pump inhibitors, H2 antagonists, and antacids).
Co‑administration of 200 mg itraconazole twice daily, a strong CYP3A inhibitor, with a single oral dose of 6 mg risdiplam did not exhibit a clinically relevant effect on the PK parameters of risdiplam (11% increase in AUC, 9% decrease in Cmax). No dose adjustments are required when risdiplam is co‑administered with a CYP3A inhibitor.
No drug‑drug interactions are expected via the FMO1 and FMO3 pathway.
Effects of risdiplam on other medicinal products
Risdiplam is a weak inhibitor of CYP3A. In healthy adult subjects, oral administration of risdiplam once daily for 2 weeks slightly increased the exposure of midazolam, a sensitive CYP3A substrate (11% increase in AUC, 16% increase in Cmax). The extent of the interaction is not considered clinically relevant, and therefore no dose adjustment is required for CYP3A substrates.
In vitro studies have shown that risdiplam and its major human metabolite M1 are not significant inhibitors of human MDR1, organic anion-transporting polypeptide (OATP)1B1, OATP1B3, organic anion transporter 1 and 3 (OAT 1 and 3). However, risdiplam and its metabolite are in vitro inhibitors of the human organic cation transporter 2 (OCT2) and the multidrug and toxin extrusion (MATE)1 and MATE2‑K transporters. At therapeutic drug concentrations, no interaction is expected with OCT2 substrates. The effect of co-administration of risdiplam on the pharmacokinetics of MATE1 and MATE2‑K substrates in humans is unknown. Based on in vitro data, risdiplam may increase plasma concentrations of medicinal products eliminated via MATE1 or MATE2‑K, such as metformin. If co- administration cannot be avoided, drug‑related toxicities should be monitored and dosage reduction of the co-administered medicinal product should be considered if needed.
There is no efficacy or safety data to support the concomitant use of risdiplam and nusinersen.

Patients of reproductive potential
Contraception in male and female patients
Male and female patients of reproductive potential should adhere to the following contraception requirements:
●
Female patients of childbearing potential should use highly effective contraception during treatment and for at least 1 month after the last dose.
●
Male patients, and their female partners of childbearing potential, should both ensure that highly effective contraception is achieved during treatment and for at least 4 months after the last dose.
Pregnancy testing
The pregnancy status of female patients of reproductive potential should be verified prior to initiating risdiplam therapy. Pregnant women should be clearly advised of the potential risk to the foetus.
Pregnancy
There are no data from the use of risdiplam in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3).
Risdiplam is not recommended during pregnancy and in women of childbearing potential not using contraception (see section 4.4).
Breast‑feeding
It is not known whether risdiplam is excreted in human breast milk. Studies in rats show that risdiplam is excreted into milk (see section 5.3). As the potential for harm to the breastfed infant is unknown, it is recommended not to breastfeed during treatment.

Fertility
Male patients
Male fertility may be compromised while on treatment, based on nonclinical findings. In rat and monkey reproductive organs, sperm degeneration and reduced sperm numbers were observed (see section 5.3). Based on observations from animal studies, the effects on sperm cells are expected to be reversible upon discontinuation of risdiplam.
Male patients may consider sperm preservation prior to treatment initiation or after a treatment-free period of at least 4 months. Male patients who wish to father a child should stop treatment for a minimum of 4 months. Treatment may be re-started after conception.
Female patients
Based on nonclinical data (see section 5.3), an impact of risdiplam on female fertility is not expected.

Risdiplam has no or negligible influence on the ability to drive and use machines.

There is no known antidote for overdosage of risdiplam. In the event of an overdose, the patient should be closely supervised and supportive care instituted.
5.
PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Other drugs for disorders of the musculo‑skeletal system ATC code: M09AX10 Mechanism of action 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.
Pharmacodynamic effects
In the studies FIREFISH (patients aged 2‑7 months at enrolment), SUNFISH (patients aged 2‑25 years at enrolment), and JEWELFISH (patients aged 1‑60 years at enrolment) in infantile‑onset SMA and later‑onset SMA patients, 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).
Cardiac electrophysiology
The effect of risdiplam on the QTc interval was evaluated in a study in 47 healthy adult subjects. At the therapeutic exposure, risdiplam did not prolong the QTc interval.
Clinical efficacy and safety
The efficacy of risdiplam for the treatment of SMA patients with infantile‑onset (SMA Type 1) and later‑onset SMA (SMA type 2 and 3) was evaluated in 2 pivotal clinical studies, FIREFISH and SUNFISH. Efficacy data of risdiplam for the treatment of pre-symptomatic SMA patients was evaluated in the RAINBOWFISH clinical study. Patients with a clinical diagnosis of Type 4 SMA have not been studied in clinical trials.
Infantile-onset SMA
Study BP39056 (FIREFISH) is an open-label, 2-part study to investigate the efficacy, safety, PK and pharmacodynamics (PD) of risdiplam in symptomatic Type 1 SMA patients (all patients had genetically confirmed disease with 2 copies of the SMN2 gene). Part 1 of FIREFISH was designed as a dose-finding part of the study. The confirmatory Part 2 of the FIREFISH study assessed the efficacy of risdiplam. Patients from Part 1 did not take part in Part 2.
The key efficacy endpoint was 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, after 12 months of treatment.

FIREFISH Part 2

Pharmacotherapeutic group: Other drugs for disorders of the musculo‑skeletal system ATC code: M09AX10 Mechanism of action 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.
Pharmacodynamic effects
In the studies FIREFISH (patients aged 2‑7 months at enrolment), SUNFISH (patients aged 2‑25 years at enrolment), and JEWELFISH (patients aged 1‑60 years at enrolment) in infantile‑onset SMA and later‑onset SMA patients, 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).
Cardiac electrophysiology
The effect of risdiplam on the QTc interval was evaluated in a study in 47 healthy adult subjects. At the therapeutic exposure, risdiplam did not prolong the QTc interval.

Clinical efficacy and safety
The efficacy of risdiplam for the treatment of SMA patients with infantile‑onset (SMA Type 1) and later‑onset SMA (SMA type 2 and 3) was evaluated in 2 pivotal clinical studies, FIREFISH and SUNFISH. Efficacy data of risdiplam for the treatment of pre-symptomatic SMA patients was evaluated in the RAINBOWFISH clinical study. Patients with a clinical diagnosis of Type 4 SMA have not been studied in clinical trials.
Infantile-onset SMA
Study BP39056 (FIREFISH) is an open-label, 2-part study to investigate the efficacy, safety, PK and pharmacodynamics (PD) of risdiplam in symptomatic Type 1 SMA patients (all patients had genetically confirmed disease with 2 copies of the SMN2 gene). Part 1 of FIREFISH was designed as a dose-finding part of the study. The confirmatory Part 2 of the FIREFISH study assessed the efficacy of risdiplam. Patients from Part 1 did not take part in Part 2.
The key efficacy endpoint was 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, after 12 months of treatment.
FIREFISH Part 2

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 mean exposure in pre-symptomatic infants (16 days to <2 months of age) in the RAINBOWFISH study was 2020 ng.h/mL at 0.15 mg/kg after 2 weeks once daily administration. 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 after 1 year of treatment and 1940 ng.h/mL after 5 years of treatment. The estimated exposure (mean AUC0-24h) for SMA treatment non-naïve patients (age 1-60 years at enrolment) was 1700 ng.h/mL at the therapeutic dose of 0.25 mg/kg or 5 mg. The observed maximum concentration (mean Cmax) was 194 ng/mL at 0.2 mg/kg in FIREFISH, 140 ng/mL in SUNFISH Part 2, 129 ng/mL in JEWELFISH, and the estimated maximum concentration at 0.15 mg/kg in RAINBOWFISH is 111 ng/mL.
Absorption
Risdiplam was rapidly absorbed in the fasted state with a plasma tmax ranging from 1 to 5 hours after administration of the constituted powder for oral solution. Based on data in 47 healthy subjects, 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.
Distribution

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 mean exposure in pre-symptomatic infants (16 days to <2 months of age) in the RAINBOWFISH study was 2020 ng.h/mL at 0.15 mg/kg after 2 weeks once daily administration. 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 after 1 year of treatment and 1940 ng.h/mL after 5 years of treatment. The estimated exposure (mean AUC0-24h) for SMA treatment non-naïve patients (age 1-60 years at enrolment) was 1700 ng.h/mL at the therapeutic dose of 0.25 mg/kg or 5 mg. The observed maximum concentration (mean Cmax) was 194 ng/mL at 0.2 mg/kg in FIREFISH, 140 ng/mL in SUNFISH Part 2, 129 ng/mL in JEWELFISH, and the estimated maximum concentration at 0.15 mg/kg in RAINBOWFISH is 111 ng/mL.
Absorption