EVRYSDI 0.75mg / ml powder for oral solution medication leaflet

Evrysdi 0.75 mg/mL powder for oral solution

Each bottle contains 60 mg risdiplam in 2 g powder for oral solution.

Each mL of the constituted solution contains 0.75 mg risdiplam.

Each mL contains 0.38 mg of sodium benzoate (E 211) and 2.97 mg of isomalt (E 953).

For the full list of excipients, see section 6.1.

Powder for oral solution. Light yellow, yellow, greyish yellow, greenish yellow, or light greenpowder.

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

Treatment with Evrysdi should be initiated by a physician with experience in the management of

SMA.

The recommended once daily dose of Evrysdi is determined by age and body weight (see Table 1).

Evrysdi is taken orally once a day after a meal at approximately the same time each day.

Table 1. Dosing regimen by age and body weight

Age* and body weight Recommended daily dose< 2 months of age 0.15 mg/kg2 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

Treatment with a daily dose above 5 mg has not been studied.

If a planned dose is missed, it should be administered as soon as possible if still within 6 hours of thescheduled dose. Otherwise, the missed dose should be skipped and the next dose should beadministered at the regularly scheduled time the next day.

If a dose is not fully swallowed or vomiting occurs after taking a dose of Evrysdi, another dose shouldnot be administered to make up for the incomplete dose. The next dose should be administered at theregularly scheduled time.

No dose adjustment is required in elderly patients based on limited data in subjects aged 65 years andolder (see section 5.2).

Risdiplam has not been studied in this population. No dose adjustment is expected to be required inpatients with renal impairment (see section 5.2).

No dose adjustment is required in patients with mild or moderate hepatic impairment. Patients withsevere hepatic impairment have not been studied and may have increased risdiplam exposure (seesections 5.1 and 5.2).

Use of Evrysdi for SMA in patients 2 months of age and younger is supported by pharmacokinetic andsafety data from paediatric patients 16 days and older (see sections 4.8, 5.1 and 5.2). No data onrisdiplam pharmacokinetics are available in patients less than 16 days of age.

Oral use.

Evrysdi 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 toprepare the prescribed daily dose prior to administration of the first dose.

Evrysdi is taken orally once a day after a meal at approximately the same time each day, using the re-usable oral syringe provided. In infants who are breastfed, Evrysdi should be administered afterbreastfeeding. 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 within5 minutes, it should be discarded from the oral syringe and a new dose be prepared. If Evrysdi spills orgets 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 beencompletely swallowed. If the patient is unable to swallow and has a nasogastric or gastrostomy tube insitu, Evrysdi 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 markings1 mL 0.3 mL to 1 mL 0.01 mL6 mL 1 mL to 6 mL 0.1 mL12 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 volumeshould be rounded to the nearest graduation mark on the selected oral syringe.

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

Potential embryo-foetal toxicity

Embryo-foetal toxicity has been observed in animal studies (see section 5.3). Patients of reproductivepotential should be informed of the risks and must use highly effective contraception during treatmentand until at least 1 month after the last dose in female patients, and 4 months after the last dose in malepatients. The pregnancy status of female patients of reproductive potential should be verified prior toinitiating Evrysdi therapy (see section 4.6).

Potential effects on male fertility

Based on observations from animal studies, male patients should not donate sperm while on treatmentand for 4 months after the last dose of Evrysdi. Prior to initiating treatment, fertility preservationstrategies should be discussed with male patients of reproductive potential (see sections 4.6 and 5.3).

The effects of Evrysdi on male fertility have not been investigated in humans.

Isomalt

Evrysdi contains isomalt (2.97 mg per mL). Patients with rare hereditary problems of fructoseintolerance should not take this medicine.

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’.

Risdiplam is primarily metabolized by hepatic enzymes flavin monooxygenase 1 and 3 (FMO1 and 3),and also by cytochrome P450 enzymes (CYPs) 1A1, 2J2, 3A4, and 3A7. Risdiplam is not a substrateof human multidrug resistance protein 1 (MDR1).

Effects of other medicinal products on risdiplam

Co-administration of 200 mg itraconazole twice daily, a strong CYP3A inhibitor, with a single oraldose 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 Evrysdi 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 risdiplamonce daily for 2 weeks slightly increased the exposure of midazolam, a sensitive CYP3A substrate(AUC 11%; Cmax 16%). The extent of the interaction is not considered clinically relevant, andtherefore no dose adjustment is required for CYP3A substrates.

In vitro studies have shown that risdiplam and its major human metabolite M1 are not significantinhibitors of human MDR1, organic anion-transporting polypeptide (OATP)1B1, OATP1B3, organicanion transporter 1 and 3 (OAT 1 and 3). However, risdiplam and its metabolite are in vitro inhibitorsof the human organic cation transporter 2 (OCT2) and the multidrug and toxin extrusion (MATE)1and MATE2-K transporters. At therapeutic drug concentrations, no interaction is expected with OCT2substrates. 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 plasmaconcentrations 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 ofthe 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 contraceptionrequirements:

● Female patients of childbearing potential should use highly effective contraception duringtreatment and for at least 1 month after the last dose.

● Male patients, and their female partners of childbearing potential, should both ensure that highlyeffective contraception is achieved during treatment and for at least 4 months after the last dose.

The pregnancy status of female patients of reproductive potential should be verified prior to initiating

Evrysdi therapy. Pregnant women should be clearly advised of the potential risk to the foetus.

There are no data from the use of Evrysdi in pregnant women. Studies in animals have shownreproductive toxicity (see section 5.3).

Evrysdi is not recommended during pregnancy and in women of childbearing potential not usingcontraception (see section 4.4).

It is not known whether risdiplam is excreted in human breast milk. Studies in rats show that risdiplamis excreted into milk (see section 5.3). As the potential for harm to the breastfed infant is unknown, itis recommended not to breastfeed during treatment.

Male patients

Male fertility may be compromised while on treatment, based on nonclinical findings. In rat andmonkey reproductive organs, sperm degeneration and reduced sperm numbers were observed (seesection 5.3). Based on observations from animal studies, the effects on sperm cells are expected to bereversible upon discontinuation of risdiplam.

Male patients may consider sperm preservation prior to treatment initiation or after a treatment-freeperiod of at least 4 months. Male patients who wish to father a child should stop treatment for aminimum 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.

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

In infantile-onset SMA patients, the most common adverse reactions observed in Evrysdi clinicalstudies were pyrexia (54.8%), rash (29.0%) and diarrhoea (19.4%).

In later-onset SMA patients, the most common adverse reactions observed in Evrysdi clinical studieswere 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 andgenerally resolved despite ongoing treatment in infantile-onset and later-onset SMA patients.

Based on the primary analysis of RAINBOWFISH, the safety profile of Evrysdi in pre-symptomaticpatients is consistent with the safety profile of symptomatic infantile-onset and later-onset SMApatients. The RAINBOWFISH study enrolled 26 patients with pre-symptomatic SMA between 16 and41 days of age at the time of the first dose (weight range 3.1 to 5.7 kg). The median exposure durationwas 20.4 months (range: 10.6 to 41.9 months). Limited post-marketing data are available in neonates<20 days of age.

See also section 5.3 for the effects of Evrysdi observed in nonclinical studies.

The corresponding frequency category for each adverse drug reaction is based on the followingconvention: 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). 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 SMAbased on Evrysdi clinical studies

System Organ Class Infantile-onset SMA Later-onset SMA(Type 1) (Type 2 and 3)

Diarrhoea Very common Very common

Nausea Not applicable Common

Mouth ulcerations andaphthous ulcers Common Common

Rash* Very common Very common

Headache Not applicable Very common

Pyrexia (including Very common Very commonhyperpyrexia)

Urinary tract infection(including cystitis) Common Common

Arthralgia Not applicable Common

*Includes dermatitis, dermatitis acneiform, dermatitis allergic, erythema, folliculitis, rash, rash erythematous, rashmaculo-papular, rash papular

Safety profile in patients previously treated with other SMA-modifying therapies

Based on the primary analysis of the JEWELFISH study, the safety profile of Evrysdi in SMAtreatment non-naive patients who received Evrysdi for up to 59 months (including those previouslytreated with nusinersen [n=76] or with onasemnogene abeparvovec [n=14]) is consistent with thesafety profile in SMA treatment-naive patients treated with Evrysdi in the FIREFISH, SUNFISH and

RAINBOWFISH studies (see section 5.1).

Cutaneous vasculitis was reported during post-marketing experience. Symptoms recovered afterpermanent discontinuation of Evrysdi. The frequency cannot be estimated based on available data.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

There is no known antidote for overdosage of Evrysdi. In the event of an overdose, the patient shouldbe closely supervised and supportive care instituted.

Pharmacotherapeutic group: Other drugs for disorders of the musculo-skeletal system

ATC code: M09AX10

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 includesprogressive loss of motor neurons and muscle weakness. Risdiplam corrects the splicing of SMN2 toshift the balance from exon 7 exclusion to exon 7 inclusion into the mRNA transcript, leading to anincreased production of functional and stable SMN protein. Thus, risdiplam treats SMA by increasingand sustaining functional SMN protein levels.

In the studies FIREFISH (patients aged 2-7 months at enrolment), SUNFISH (patients aged 2-25 yearsat enrolment), and JEWELFISH (patients aged 1-60 years at enrolment) in infantile-onset SMA andlater-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).

The effect of risdiplam on the QTc interval was evaluated in a study in 47 healthy adult subjects. Atthe therapeutic exposure, risdiplam did not prolong the QTc interval.

The efficacy of Evrysdi for the treatment of SMA patients with infantile-onset (SMA Type 1) andlater-onset SMA (SMA type 2 and 3) was evaluated in 2 pivotal clinical studies, FIREFISH and

SUNFISH. Efficacy data of Evrysdi for the treatment of pre-symptomatic SMA patients was evaluatedin the RAINBOWFISH clinical study. Patients with a clinical diagnosis of Type 4 SMA have not beenstudied in clinical trials.

Infantile-onset SMA

Study BP39056 (FIREFISH) is an open-label, 2-part study to investigate the efficacy, safety, PK andpharmacodynamics (PD) of Evrysdi in symptomatic Type 1 SMA patients (all patients had geneticallyconfirmed 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

Evrysdi. 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) grossmotor scale, after 12 months of treatment.

FIREFISH Part 2

In FIREFISH Part 2, 41 patients with Type 1 SMA were enrolled. The median age of onset of clinicalsigns and symptoms of Type 1 SMA was 1.5 months (range: 1.0-3.0 months), 54% were female, 54%

Caucasian and 34% Asian. The median age at enrolment was 5.3 months (range: 2.2-6.9 months) andthe median time between onset of symptoms and first dose was 3.4 months (range: 1.0-6.0 months). Atbaseline, the median Children's Hospital of Philadelphia Infant Test for Neuromuscular Disease(CHOP-INTEND) score was 22.0 points (range: 8.0-37.0) and the median Hammersmith Infant

Neurological Examination Module 2 (HINE-2) score was 1.0 (range: 0.0-5.0).

The primary endpoint was the proportion of patients with the ability to sit without support for at least5 seconds after 12 months of treatment (BSID-III gross motor scale, Item 22). The key efficacyendpoints of Evrysdi treated patients are shown in Table 3.

Table 3. Summary of key efficacy results at month 12 and month 24 (FIREFISH Part 2)

Efficacy Endpoints Proportion of Patients

N=41 (90% CI)

Month 12 Month 24

Motor function and development milestones

BSID-III: sitting without support for at least 29.3% 61.0%5 seconds (17.8%, 43.1%) (46.9%, 73.8%)p <0.0001a

CHOP-INTEND: score of 40 or higher 56.1% 75.6%(42.1%, 69.4%) (62.2%, 86.1%)

CHOP-INTEND: increase of ≥4 points from 90.2% 90.2%baseline (79.1%, 96.6%) (79.1%, 96.6%)

HINE-2: motor milestone respondersb 78.0% 85.4%(64.8%, 88.0%) (73.2%, 93.4%)

HINE-2: sitting without supportc 24.4% 53.7%(13.9%, 37.9%) (39.8%, 67.1%)

Survival and event-free survival

Event-free survivald 85.4% 82.9%(73.4%, 92.2%) (70.5%, 90.4%)

Alive 92.7% 92.7%(82.2%, 97.1%) (82.2%, 97.1%)

Feeding

Ability to feed orallye 82.9% 85.4%(70.3%, 91.7%) (73.2%, 93.4%)

Abbreviations: CHOP-INTEND=Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders; HINE-2=Module 2 of the Hammersmith Infant Neurological Examination.a p-value is based on a one-sided exact binomial test. The result is compared to a threshold of 5%.b According to HINE-2: ≥2 point increase [or maximal score] in ability to kick, OR ≥1 point increase in the motormilestones of head control, rolling, sitting, crawling, standing or walking, AND improvement in more categories of motormilestones than worsening is defined as a responder for this analysis.

c Sitting without support includes patients that achieved “stable sit” (24%, 10/41) and “pivots (rotates)” (29%, 12/41) asassessed by the HINE-2 at Month 24.

d An event is meeting the endpoint of permanent ventilation defined as tracheostomy or ≥16 hours of non-invasiveventilation per day or intubation for > 21 consecutive days in the absence of, or following the resolution of, an acutereversible event. Three patients died within the first 3 months following study enrolment and 4 patients met the endpointof permanent ventilation before Month 24. These 4 patients achieved an increase of at least 4 points in their CHOP-

INTEND score from baseline.

e Includes patients who were fed exclusively orally (29 patients overall) and those who were fed orally in combination witha feeding tube (6 patients overall) at Month 24.

At Month 24, 44% of patients achieved sitting without support for 30 seconds (BSID-III, Item 26).

Patients continued to achieve additional motor milestones as measured by the HINE-2: 80.5% wereable to roll, and 27% of patients achieved a standing measure (12% supporting weight and 15%standing with support).

Untreated patients with infantile-onset SMA would never be able to sit without support and only 25%would be expected to survive without permanent ventilation beyond 14 months of age.

Figure 1. Kaplan-Meier plot of event-free survival (FIREFISH Part 1 and Part 2)+ Censored: two patients in Part 2 were censored because the patients attended the Month 24 visit early, onepatient in Part 1 was censored after discontinuing treatment and died 3.5 months later

Figure 2. Mean change from baseline in CHOP-INTEND total score (FIREFISH Part 2)

FIREFISH Part 1

The efficacy of Evrysdi in Type 1 SMA patients is also supported by results from FIREFISH Part 1.

For the 21 patients from Part 1, the baseline characteristics were consistent with symptomatic patientswith Type 1 SMA. The median age at enrolment was 6.7 months (range: 3.3-6.9 months) and themedian time between onset of symptoms and first dose was 4.0 months (range: 2.0-5.8 months).

A total of 17 patients received the therapeutic dose of Evrysdi (dose selected for Part 2). After12 months of treatment, 41% (7/17) of these patients were able to sit independently for at least5 seconds (BSID-III, Item 22). After 24 months of treatment, 3 more patients receiving the therapeuticdose were able to sit independently for at least 5 seconds, leading to a total of 10 patients (59%)achieving this motor milestone.

After 12 months of treatment, 90% (19/21) of patients were alive and event-free (without permanentventilation) and reached 15 months of age or older. After a minimum of 33 months of treatment, 81%(17/21) of patients were alive and event-free and reached an age of 37 months or older (median 41months; range 37 to 53 months), see Figure 1. Three patients died during treatment and one patientdied 3.5 months after discontinuing treatment.

Later Onset SMA

Study BP39055 (SUNFISH), is a 2-part, multicentre study to investigate the efficacy, safety, PK and

PD of Evrysdi in SMA Type 2 or Type 3 patients between 2-25 years of age. Part 1 was theexploratory dose-finding portion and Part 2 was the randomized, double-blind, placebo-controlledconfirmatory portion. Patients from Part 1 did not take part in Part 2.

The primary endpoint was the change from baseline score at Month 12 on the Motor Function

Measure-32 (MFM32). The MFM32 has the ability to assess a wide range of motor function across abroad range of SMA patients. The total MFM32 score is expressed as a percentage (range: 0-100) ofthe maximum possible score, with higher scores indicating greater motor function.

SUNFISH Part 2

SUNFISH Part 2 is the randomized, double-blinded, placebo-controlled portion of the SUNFISH studyin 180 non-ambulant patients with Type 2 (71%) or Type 3 (29%) SMA. Patients were randomizedwith 2:1 ratio to receive either Evrysdi at the therapeutic dose (see section 4.2) or placebo.

Randomization was stratified by age group (2 to 5, 6 to 11, 12 to 17, 18 to 25 years old).

The median age of patients at the start of treatment was 9.0 years old (range 2-25 years old), themedian time between onset of initial SMA symptoms to first treatment was 102.6 (1-275) months.

Overall, 30% were 2 to 5 years of age, 32% were 6 to 11 years of age, 26% were 12-17 years of age,and 12% were 18 to 25 years of age at study enrolment. Of the 180 patients included in the study, 51%were female, 67% Caucasian and 19% Asian. At baseline, 67% of patients had scoliosis (32% ofpatients with severe scoliosis). Patients had a mean baseline MFM32 score of 46.1 and Revised Upper

Limb Module (RULM) score of 20.1. The baseline demographic characteristics were balancedbetween Evrysdi and placebo arms with the exception of scoliosis (63% of patients in the Evrysdi armand 73% of patients in the placebo control).

The primary analysis for SUNFISH Part 2, the change from baseline in MFM32 total score at Month12, showed a clinically meaningful and statistically significant difference between patients treatedwith Evrysdi and placebo. The results of the primary analysis and key secondary endpoints are shownin Table 4, Figure 3, and Figure 4.

Table 4. Summary of efficacy in patients with later-onset SMA at month 12 of treatment(SUNFISH Part 2)

Endpoint Evrysdi Placebo(N = 120) (N = 60)

Primary Endpoint:

Change from baseline in MFM32 total score1 at Month 12 1.36 -0.19

LS mean (95%, CI) (0.61, 2.11) (-1.22, 0.84)

Difference from placebo 1.55

Estimate (95% CI) (0.30, 2.81)p-value2 0.0156

Secondary Endpoints:

Proportion of patients with a change from baseline in MFM32 total 38.3% 23.7%score1 of 3 or more at Month 12 (95% CI)1 (28.9, 47.6) (12.0, 35.4)

Odds ratio for overall response (95% CI) 2.35 (1.01, 5.44)

Adjusted(unadjusted) p-value3,4 0.0469 (0.0469)

Change from baseline in RULM total score5 at Month 12 1.61 0.02

LS mean (95% CI) (1.00, 2.22) (-0.83, 0.87)

Difference from placebo estimate (95% CI) 1.59 (0.55, 2.62)

Adjusted (unadjusted) p-value2,4 0.0469 (0.0028)

LS=least squares1. Based on the missing data rule for MFM32, 6 patients were excluded from the analysis (Evrysdi n=115; placebocontrol n=59).2. Data analysed using a mixed model repeated measure with baseline total score, treatment, visit, age group, treatment-by-visit and baseline-by-visit.3. Data analysed using logistic regression with baseline total score, treatment and age group.4. The adjusted p-value was obtained for the endpoints included in the hierarchical testing and was derived based on allthe p-values from endpoints in order of the hierarchy up to the current endpoint5. Based on the missing data rule for RULM, 3 patients were excluded from the analysis (Evrysdi n=119; placebocontrol n=58).

Upon completion of 12 months of treatment, 117 patients continued to receive Evrysdi. At the time ofthe 24 month analysis, these patients who were treated with Evrysdi for 24 months overall experiencedmaintenance of improvement in motor function between month 12 and month 24. The mean changefrom baseline for MFM32 was 1.83 (95% CI: 0.74, 2.92) and for RULM was 2.79 (95% CI: 1.94,3.64).

Figure 3. Mean change from baseline in MFM32 total score over 12 months in SUNFISH Part 211The least squares (LS) mean difference for change from baseline in MFM32 score [95% CI]

Figure 4. Mean change from baseline in RULM total score over 12 months in SUNFISH Part 211The least squares (LS) mean difference for change from baseline in RULM score [95% CI]

SUNFISH Part 1

Efficacy in later-onset SMA patients was also supported by results from Part 1, the dose-finding partof SUNFISH. In Part 1, 51 patients with Type 2 and 3 SMA (including 7 ambulatory patients) between2 to 25 years of age were enrolled. After 1 year of treatment there was a clinically meaningfulimprovement in motor function as measured by MFM32, with a mean change from baseline of 2.7points (95% CI: 1.5, 3.8). The improvement in MFM32 was maintained up to 2 years on treatment(mean change of 2.7 points [95% CI: 1.2, 4.2]).

Use in patients previously treated with other SMA-modifying therapies (JEWELFISH)

Study BP39054 (JEWELFISH, n = 174) is a single arm, open-label study to investigate the safety,tolerability, PK and PD of Evrysdi in patients with infantile-onset and later-onset SMA (median age14 years [range 1 - 60 years]), who had previously received treatment with other approved (nusinersenn = 76, onasemnogene abeparvovec n = 14) or investigational SMA modifying therapies. At baseline,out of the 168 patients aged 2 - 60 years, 83% of patients had scoliosis and 63% had a Hammersmith

Functional Motor Scale Expanded (HFMSE) score < 10 points.

At the analysis at month 24 of treatment, patients 2 - 60 years of age showed overall stabilization inmotor function in MFM-32 and RULM (n = 137 and n = 133, respectively). Patients less than 2 years(n = 6) maintained or gained motor milestones such as head control, rolling and sitting independently.

All ambulatory patients (aged 5 - 46 years, n = 15) retained their ability to walk.

Pre-symptomatic SMA (RAINBOWFISH)

Study BN40703 (RAINBOWFISH) is an open-label, single-arm, multicenter clinical study toinvestigate the efficacy, safety, pharmacokinetics, and pharmacodynamics of Evrysdi in infants frombirth to 6 weeks of age (at first dose) who have been genetically diagnosed with SMA but do not yetpresent with symptoms.

The efficacy in pre-symptomatic SMA patients was evaluated at Month 12 in 26 patients [intent-to-treat (ITT) population] treated with Evrysdi: eight patients, 13 patients, and 5 patients had 2, 3, and ≥4copies of the SMN2 gene, respectively. The median age of these patients at first dose was 25 days(range: 16 to 41 days), 62% were female, and 85% were Caucasian. At baseline, the median CHOP-

INTEND score was 51.5 (range: 35.0 to 62.0), the median HINE-2 score was 2.5 (range: 0 to 6.0), andthe median ulnar nerve compound muscle action potential (CMAP) amplitude was 3.6 mV (range: 0.5to 6.7 mV).

The primary efficacy population (N=5) included patients with 2 SMN2 copies and a baseline CMAPamplitude ≥ 1.5 mV. In these patients, the median CHOP-INTEND score was 48.0 (range: 36.0 to52.0), the median HINE-2 score was 2.0 (range 1.0 to 3.0), and the median CMAP amplitude was2.6 mV (range: 1.6 to 3.8 mV) at baseline.

The primary endpoint was the proportion of patients in the primary efficacy population with the abilityto sit without support for at least 5 seconds (BSID-III gross motor scale, Item 22) at Month 12; astatistically significant and clinically meaningful proportion of patients achieved this milestonecompared to the predefined performance criterion of 5%.

The key efficacy endpoints of Evrysdi treated patients are shown in Table 5 and 6, and in Figure 5.

Table 5. Sitting ability as defined by BSID-III Item 22 for pre-symptomatic patients at Month 12

Efficacy Endpoint Population

Primary Efficacy Patients with 2 ITT(N=5) SMN2 copiesa (N=26)(N=8)

Proportion of patients sitting 80% 87.5% 96.2%without support for at least 5 (34.3%, 99.0%) (52.9%, 99.4%) (83.0%, 99.8%)seconds (BSID-III, Item 22);(90% CI) p < 0.0001b

Abbreviations: BSID-III = Bayley Scales of Infant and Toddler Development - Third Edition; CI=Confidence Interval;

ITT=Intent-to-treat.a Patients with 2 SMN2 copies had a median CMAP amplitude of 2.0 (range 0.5 - 3.8) at baseline.b p-value is based on a one-sided exact binomial test. The result is compared to a threshold of 5%.

Additionally, 80% (4/5) of the primary efficacy population, 87.5% (7/8) of patients with 2 SMN2copies, and 80.8% (21/26) of patients in the ITT population achieved sitting without support for 30seconds (BSID-III, Item 26).

Patients in the ITT population also achieved motor milestones as measured by the HINE-2 at Month12 (N=25). In this population 96.0% of patients could sit [1 patient (1/8 patients with 2 SMN2 copies)achieved stable sit and 23 patients (6/8, 13/13, 4/4 of patients with 2, 3, and ≥4 SMN2 copies,respectively) could pivot/rotate]. In addition, 84% of patients could stand; 32% (N=8) patients couldstand with support (3/8, 3/13 and 2/4 patients with 2, 3, and ≥4 SMN2 copies, respectively) and 52%(N=13) patients could stand unaided (1/8, 10/13 and 2/4 of patients with 2, 3, and ≥4 SMN2 copies,respectively). Furthermore, 72% of patients could bounce, cruise or walk; 8% (N=2) patients couldbounce (2/8 patients with 2 SMN2 copies), 16% (N=4) could cruise (3/13 and 1/4 patients with 3 and≥4 SMN2 copies, respectively) and 48% (N=12) could walk independently (1/8, 9/13 and 2/4 patientswith 2, 3, and ≥4 SMN2 copies, respectively). Seven patients were not tested for walking at Month 12.

Table 6. Summary of key efficacy endpoints for pre-symptomatic patients at Month 12

Efficacy Endpoints ITT population (N=26)

Motor Function

Proportion of patients who achieve a Total score of 50 or higher 92%ain the CHOP-INTEND (90 CI%) (76.9%, 98.6%)

Proportion of patients who achieve a Total score of 60 or higher 80%ain the CHOP-INTEND (90 CI%) (62.5%, 91.8%)

Feeding

Proportion of patients with the ability to feed orally (90 CI%) 96.2%b(83.0%, 99.8%)

Healthcare Utilization

Proportion of patients with no hospitalisationsc (90 CI%) 92.3%(77.7%, 98.6%)

Event-Free Survivald

Proportion of patients with Event-Free Survival (90 CI%) 100%(100%, 100%)

Abbreviations: CHOP-INTEND=Children’s Hospital of Philadelphia Infant Test of

Neuromuscular Disorders; CI=Confidence Intervala Based on N=25b One patient was not assessed.c Hospitalisations include all hospital admissions which spanned at least two days, and which are not due to studyrequirements.d An event refers to death or permanent ventilation; permanent ventilation is defined as tracheostomy or ≥16hours of non-invasive ventilation per day or intubation for > 21 consecutive days in the absence of, or followingthe resolution of, an acute reversible event.

Figure 5. Median Total CHOP-INTEND Scores by Visit and SMN2 copy number (ITTpopulation)

Abbreviations: IQR = Interquartile range; SMN2 = Survival of Motor Neuron 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 linearbetween 0.6 and 18 mg. Risdiplam’s PK was best described by a population PK model withthree-transit-compartment absorption, two-compartment disposition and first-order elimination. Bodyweight 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 atenrolment) at the therapeutic dose of 0.2 mg/kg once daily was 1930 ng.h/mL. The estimated meanexposure in pre-symptomatic infants (16 days to <2 months of age) in the RAINBOWFISH study was2020 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 therapeuticdose (0.25 mg/kg once daily for patients with a body weight <20 kg; 5 mg once daily for patients witha body weight ≥20 kg) was 2070 ng.h/mL after 1 year of treatment and 1940 ng.h/mL after 5 years oftreatment. The estimated exposure (mean AUC0-24h) for SMA treatment non-naïve patients (age 1-60years at enrolment) was 1700 ng.h/mL at the therapeutic dose of 0.25 mg/kg or 5 mg. The observedmaximum 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 at0.15 mg/kg in RAINBOWFISH is 111 ng/mL.

Risdiplam was rapidly absorbed in the fasted state with a plasma tmax ranging from 1 to 4 hours afteroral administration. Based on limited data (n=3), food (high-fat, high calorie breakfast) had norelevant effect on the exposure of risdiplam. In the clinical studies, risdiplam was administered with amorning meal or after breastfeeding.

Risdiplam distributes evenly to all parts of the body, including the central nervous system (CNS) bycrossing the blood brain barrier, and thereby leading to SMN protein increase in the CNS andthroughout the body. Concentrations of risdiplam in plasma and SMN protein in blood reflect itsdistribution and pharmacodynamic effects in tissues such as brain and muscle.

The population pharmacokinetic parameter estimates were 98 L for the apparent central volume ofdistribution, 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 acidglycoprotein, 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 oraldose 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% inurine (8% unchanged risdiplam). Parent drug was the major component found in plasma, accountingfor 83% of drug related material in circulation. The pharmacologically inactive metabolite M1 wasidentified as the major circulating metabolite.

Body weight and age were identified as covariates in the population PK analysis. On the basis of suchmodel, the dose is therefore adjusted based on age (below and above 2 months and 2 years) and bodyweight (up to 20 kg) to obtain similar exposure across the age and body weight range. Limited PK dataare available in patients less than 20 days of age, since only one 16-day-old neonate received risdiplamat a lower dose (0.04 mg/kg) in clinical studies.

No dedicated studies have been conducted to investigate PK in patients with SMA above 60 years ofage. Subjects without SMA up to 69 years of age were included in the clinical PK studies, whichindicates 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 asingle oral administration of 5 mg risdiplam, the mean ratios for Cmax and AUC were 0.95 and 0.80 inmild (n=8) and 1.20 and 1.08 in moderate hepatic impaired subjects (n=8) versus matched healthycontrols (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 withoutsafety margins based on systemic exposures at the no observed adverse effect level (NOAEL). Theseeffects led to degenerated spermatocytes, degeneration/necrosis of the seminiferous epithelium, andoligo/aspermia in the epididymis. Sperm cell effects of risdiplam are likely related to an interferenceof 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 withrisdiplam.

No fertility and early embryonic development studies were conducted with concomitant administrationof risdiplam, as sperm cell arrest and embryotoxic potential under treatment was already identifiedwith treatment of rats and monkeys in other toxicity studies. No impairment on male fertility or femalefertility was observed in two studies in which rats were mated, either following completion of a13-week treatment period starting at weaning, or 8 weeks after completion of a 4-week treatmentperiod starting at 4 days of age.

Effect on retinal structure

Chronic treatment of monkeys with risdiplam yielded evidence for an effect on the retina in terms ofphotoreceptor degeneration starting in the periphery of the retina. Upon cessation of treatment, theeffects 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 therapeuticdose without safety margin based on systemic exposures at the NOAEL. No such findings wereobserved in albino or pigmented rats when dosed chronically with risdiplam at exposures exceedingthose in the monkey. Such findings have not been observed in clinical trials in SMA patients withregular ophthalmological monitoring (including SD OCT and visual function assessment).

Effect on epithelial tissues

Effects on skin, larynx and eyelid histology and the gastro intestinal tract were evident in rats andmonkeys treated with risdiplam. Changes started to be seen at high doses with treatment of 2 weeksand longer. With chronic treatment for 39 weeks in monkeys, the NOAEL was at an exposure inexcess of 2-fold the average exposure in humans at the therapeutic dose.

Effect on haematological parameters

In the acute bone marrow micronucleus test in rats, a reduction of more than 50% in the ratio ofpolychromatic (young) to normochromatic (adult) erythrocytes, indicative of substantial bone marrowtoxicity, was observed at the high dose level with exposure in excess of 15-times the average exposurein humans at the therapeutic dose. With longer treatment of rats for 26 weeks, the exposure margins tothe NOAEL were approximately 4-fold the average exposure in humans at the therapeutic dose.

Risdiplam is not mutagenic in a bacterial reverse mutation assay. In mammalian cells in vitro and inbone marrow of rats, risdiplam increases the frequency of micronucleated cells. Micronucleusinduction 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 exposurein humans at the therapeutic dose. Data indicated that this effect is indirect and secondary to aninterference of risdiplam with the cell cycle of dividing cells. Risdiplam does not possess a potential todamage DNA directly.

In studies in pregnant rats treated with risdiplam, embryofoetal toxicity with lower fetal weight anddelayed development was evident. The NOAEL for this effect was approximately 2-fold above theexposure levels reached at the therapeutic dose of risdiplam in patients. In studies with pregnantrabbits, 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 wasapproximately 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 aslight delay in gestation length. Studies in pregnant and lactating rats showed that risdiplam crossesthe placental barrier and is excreted into milk.

Risdiplam did not reveal a carcinogenic potential in transgenic rasH2 mice over 6 months and in a2 year study in rats at equivalent exposures to those in humans receiving the maximum recommendedhuman dose (MRHD). Significantly increased tumours of the preputial gland in male rats and clitoralgland in female rats at 4 times the exposure of the MRHD are without human relevance, because bothare rodent-specific organs.

Juvenile animal data reveal no special hazard for humans.

mannitol (E 421)isomalt (E 953)strawberry flavourtartaric acid (E 334)sodium benzoate (E 211)macrogol/polyethylene glycol 6000sucraloseascorbic acid (E 300)disodium edetate dihydrate

Not applicable.

Powder for oral solution2 years

Constituted oral solution64 days stored in a refrigerator (2 to 8°C).

If necessary, the patient or their caregiver may store the oral solution at room temperature (below40˚C) for no more than a total of 120 hours (5 days). The oral solution should be returned to therefrigerator when it is no longer necessary to keep the bottle at room temperature. The total timeoutside the refrigerator (below 40˚C) should be monitored.

The oral solution should be discarded if it has been stored at room temperature (below 40°C) for morethan a total of 120 hours (5 days), or for any period of time kept above 40°C.

Powder for oral solution

Keep in the original amber glass bottle to protect from light.

Constituted oral solution

For storage conditions after constitution of the medicinal product, see section 6.3.

Keep the oral solution in the original amber glass bottle to protect from light and keep the bottlealways in an upright position with the cap tightly closed.

Amber type III glass bottle with a tamper-evident child resistant screw cap.

Each carton contains; one bottle, 1 press-in bottle adaptor, two re-usable 1 mL, two re-usable 6 mLand one re-usable 12 mL graduated amber oral syringes.

Evrysdi powder must be constituted to the oral solution by a HCP (eg. pharmacist) prior to beingdispensed.

Caution should be exercised in the handling of Evrysdi powder for oral solution (see section 4.4).

Avoid inhalation and direct contact with skin or mucous membranes with the dry powder and theconstituted solution.

Wear disposable gloves during constitution and while wiping the outer surface of the bottle/cap andcleaning the working surface after constitution. If contact occurs, wash thoroughly with soap andwater; rinse eyes with water.

Instructions for constitution:

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 or water for injection into the Evrysdi bottle to yield the0.75 mg/mL oral solution.4. Hold the medicine bottle on the table with one hand. Insert the press-in bottle adaptor into theopening by pushing it down with the other hand. Ensure the adaptor is completely pressed againstthe bottle lip.

5. Put the cap back on the bottle and close the bottle tightly. Ensure it is completely closed and thenshake well for 15 seconds. Wait for 10 minutes. You should have obtained a clear solution.

Afterwards, shake well again for another 15 seconds.

6. Write the “Discard after” date of the solution on the bottle label and carton. (The “Discard after”date is calculated as 64 days after constitution, the day of constitution is counted as day 0). Putthe bottle back in its original carton with syringes (in pouches), Package Leaflet, and Instructionsfor Use booklet. Store the carton in the refrigerator (2 to 8°C).

Discard any unused portion 64 days after constitution.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Roche Registration GmbH

Emil-Barell-Strasse 179639 Grenzach-Wyhlen,

Germany

EU/1/21/1531/001

Date of first authorisation: 26 March 2021

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.