NEXVIADYME 100mg powder for concentrate infusion solution medication leaflet

Nexviadyme 100 mg powder for concentrate for solution for infusion

Each vial contains 100 mg of avalglucosidase alfa.

After reconstitution, each vial contains a total extractable volume of 10.0 ml at a concentration of10 mg of avalglucosidase alfa* per ml.

*Avalglucosidase alfa is a human acid α-glucosidase produced in Chinese hamster ovary cells (CHO)by recombinant DNA technology, which is subsequently conjugated with approximately 7hexamannose structures (each containing two terminal mannose-6-phosphate (M6P) moieties) tooxidised sialic acid residues on the molecule, thereby increasing bis-M6P levels.

For the full list of excipients, see section 6.1.

Powder for concentrate for solution for infusion

White to pale yellow lyophilised powder

Nexviadyme (avalglucosidase alfa) is indicated for long-term enzyme replacement therapy for thetreatment of patients with Pompe disease (acid α-glucosidase deficiency).

Nexviadyme treatment should be supervised by a physician experienced in the management of patientswith Pompe disease or other inherited metabolic or neuromuscular diseases.

Patients may be pre-treated with antihistamines, antipyretics, and/or corticosteroids to prevent orreduce allergic reactions.

The recommended dose of avalglucosidase alfa is 20 mg/kg of body weight administered once every2 weeks.

Dose modification for IOPD patients

For IOPD (infantile-onset Pompe disease) patients who experience lack of improvement or insufficientresponse in cardiac, respiratory, and/or motor function while receiving 20 mg/kg, a dose increase to 40mg/kg every other week should be considered in the absence of safety concerns (e.g., severehypersensitivity, anaphylactic reactions, or risk of fluid overload).

In patients who do not tolerate avalglucosidase alfa at 40 mg/kg every other week (e.g., severehypersensitivity, anaphylactic reactions, or risk of fluid overload), consider decreasing the dose to20 mg/kg every other week. (see section 4.4).

No dose adjustment is required in patients >65 years.

The safety and efficacy of avalglucosidase alfa in patients with hepatic impairment have not beenevaluated and no specific dose regimen can be recommended for these patients.

No dose adjustment is required in patients with mild renal impairment. The safety and efficacy ofavalglucosidase alfa in patients with moderate or severe renal impairment have not been evaluated andno specific dose regimen can be recommended for these patients. (see section 5.2).

Paediatric population (patients 6 months of age and younger)

The safety and efficacy of avalglucosidase alfa in children 6 months of age and younger have not yetbeen established. There are no data available in patients 6 months of age and younger.

Nexviadyme vials are for single use only and the medicinal product should be administered as anintravenous infusion.

The infusion should be administered incrementally as determined by patient response and comfort.

It is recommended that the infusion begins at an initial rate of 1 mg/kg/hour and is gradually increasedevery 30 minutes if there are no signs of infusion-associated reactions (IARs), in accordance with

Table 1. Vital signs should be obtained at each step, before increasing the infusion rate.

Table 1 - Infusion rate schedule

Infusion rate (mg/kg/hour) Approximate

Recommended Dosestep 1 step 2 step 3 step 4 step 5 duration (h)20 mg/kg 1 3 5a 7a NA 4 to 54-step process 1 3 5 7 NA 740 mg/kg5-step processb 1 3 6 8 10b 5a For patients with a recommended dose of 20 mg/kg and body weight of 1.25-5 kg a maximum infusion rate of4.8 mg/kg/hour can be applied.b For IOPD patients who experience lack of improvement a dose increase to 40 mg/kg every other week isrecommended. For a body weight of 1.25-5 kg a maximum infusion rate of 9.6 mg/kg/hour can be applied.

In the event of anaphylaxis or severe hypersensitivity reaction or severe IARs, administration of

Nexviadyme should be immediately discontinued and appropriate medical treatment should beinitiated. In the event of mild to moderate hypersensitivity reactions or IARs, the infusion rate may beslowed or temporarily stopped and/or appropriate medical treatment initiated (see section 4.4).

Symptoms may persist despite temporarily stopping the infusion; therefore, the treating physicianshould wait at least 30 minutes for symptoms of the reactions to resolve before deciding to stop theinfusion for the remainder of the day. If symptoms subside, infusion rate should be resumed for30 minutes at half the rate, or less, of the rate at which the reactions occurred, followed by an increasein infusion rate by 50% for 15 to 30 minutes. If symptoms do not recur, the infusion rate should beincreased to the rate at which the reactions occurred and consider continuing to increase the rate in astepwise manner until the maximum rate is achieved.

Home infusion

Infusion of Nexviadyme at home may be considered for patients who are tolerating their infusionswell and have no history of moderate or severe IARs for a few months. The decision to have a patientmove to home infusion should be made after evaluation and upon recommendation by the treatingphysician. A patient’s underlying co-morbidities and ability to adhere to the home infusionrequirements need to be taken into account when evaluating the patient for eligibility to receive homeinfusion. The following criteria should be considered:

* The patient must have no ongoing concurrent condition that, in the opinion of the physician,may affect patient’s ability to tolerate the infusion.

* The patient is considered medically stable. A comprehensive evaluation must be completedbefore the initiation of home infusion.

* The patient must have received Nexviadyme infusions supervised by a physician withexpertise in management of Pompe patients for a few months that could be in a hospital or inanother appropriate setting of outpatient care. Documentation of a pattern of well-toleratedinfusions with no IARs, or mild IARs that have been controlled with premedication, is aprerequisite for the initiation of home infusion.

* The patient must be willing and able to comply with home infusion procedures.

* Home infusion infrastructure, resources, and procedures, including training, must beestablished and available to the healthcare professional. The healthcare professional should beavailable at all times during the home infusion and a specified time after infusion, dependingon patient’s tolerance prior to starting home infusion.

If the patient experiences adverse reactions during the home infusion, the infusion process should bestopped immediately, and appropriate medical treatment should be initiated (see section 4.4).

Subsequent infusions may need to occur in a hospital or in an appropriate setting of outpatient careuntil no such adverse reaction is present. Dose and infusion rate must not be changed withoutconsulting the responsible physician.

For instructions on reconstitution and dilution of medicinal product before administration, see section6.6.

Life-threatening hypersensitivity to the active substance or to any of the excipients listed in section 6.1when re-challenge was unsuccessful. (see sections 4.4 and 4.8)

In order to improve the traceability of biological medicinal products, the name and the batch numberof the administered product should be clearly recorded.

Hypersensitivity reactions (including anaphylaxis)

Hypersensitivity reactions, including anaphylaxis, have been reported in Nexviadyme-treated patients(see section 4.8).

Appropriate medical support measures, including cardiopulmonary resuscitation equipment especiallyfor patients with cardiac hypertrophy and patients with significantly compromised respiratoryfunction, should be readily available when Nexviadyme is administered.

If severe hypersensitivity or anaphylaxis occur, Nexviadyme should be discontinued immediately, andappropriate medical treatment should be initiated. The risks and benefits of re-administering

Nexviadyme following anaphylaxis or severe hypersensitivity reaction should be considered. Somepatients have been re-challenged using slower infusion rates at a dose lower than the recommendeddose. In patients with severe hypersensitivity, desensitization procedure to Nexviadyme may beconsidered. If the decision is made to re-administer the medicinal product, extreme caution should beexercised, with appropriate resuscitation measures available. Once a patient tolerates the infusion, thedose may be increased to reach the approved dose.

If mild or moderate hypersensitivity reactions occur, the infusion rate may be slowed or temporarilystopped.

Infusion-associated reactions (IARs)

In clinical studies, IARs were reported to occur at any time during and/or within a few hours after theinfusion of Nexviadyme and were more likely with higher infusion rates (see section 4.8).

Patients with an acute underlying illness at the time of Nexviadyme infusion appear to be at greaterrisk for IARs. Patients with advanced Pompe disease may have compromised cardiac and respiratoryfunction, which may predispose them to a higher risk of severe complications from IARs.

Antihistamines, antipyretics, and/or corticosteroids can be given to prevent or reduce IARs. However,

IARs may still occur in patients after receiving pre-treatment.

If severe IARs occur, immediate discontinuation of the administration of Nexviadyme should beconsidered and appropriate medical treatment should be initiated. The benefits and risks of re-administering Nexviadyme following severe IARs should be considered. Some patients have been re-challenged using slower infusion rates at a dose lower than the recommended dose. Once a patienttolerates the infusion, the dose may be increased to reach the approved dose. If mild or moderate IARsoccur regardless of pre-treatment, decreasing the infusion rate or temporarily stopping the infusionmay ameliorate the symptoms (see section 4.8).

Treatment emergent anti-drug antibodies (ADA) were reported in both treatment naïve (95%) andtreatment-experienced patients (62%) (see section 4.8).

IARs and hypersensitivity reactions may occur independent of the development of ADA. The majorityof IARs and hypersensitivity reactions were mild or moderate and were managed with standardclinical practices. In clinical studies, the development of ADA did not impact clinical efficacy (seesection 4.8).

ADA testing may be considered if patients do not respond to therapy. Adverse-event-drivenimmunologic testing, including IgG and IgE ADA, may be considered for patients who have risk forallergic reaction or previous anaphylactic reaction to alglucosidase alfa.

Contact your local Sanofi representative or Sanofi EU Medical Services for information on the Sanofi

Speciality Care testing services.

Risk of acute cardiorespiratory failure

Caution should be exercised when administering Nexviadyme to patients susceptible to fluid volumeoverload or patients with acute underlying respiratory illness or compromised cardiac and/orrespiratory function for whom fluid restriction is indicated. These patients may be at risk of seriousexacerbation of their cardiac or respiratory status during infusion. Appropriate medical support andmonitoring measures should be readily available during Nexviadyme infusion, and some patients mayrequire prolonged observation times that should be based on the individual needs of the patient.

Cardiac arrhythmia and sudden death during general anaesthesia for central venous catheter placement

Caution should be used when administering general anaesthesia for the placement of a central venouscatheter or for other surgical procedures in patients with IOPD with cardiac hypertrophy.

Cardiac arrhythmia, including ventricular fibrillation, ventricular tachycardia, and bradycardia,resulting in cardiac arrest or death, or requiring cardiac resuscitation or defibrillation, have beenassociated with the use of general anaesthesia in IOPD patients with cardiac hypertrophy.

No interaction studies have been performed. Because it is a recombinant human protein,avalglucosidase alfa is an unlikely candidate for cytochrome P450 mediated drug-drug interactions.

There are no available data on the use of Nexviadyme in pregnant women. Animal studies do notindicate direct harmful effects with respect to reproductive toxicity. Indirect foetal effects in mice wereconsidered related to an anaphylactic response to avalglucosidase alfa (see section 5.3). The potentialrisk for humans is unknown. No conclusions can be drawn regarding whether or not Nexviadyme issafe for use during pregnancy. Nexviadyme should be used during pregnancy only if the potentialbenefits to the mother outweigh the potential risks, including those to the foetus.

There are no available data on the presence of Nexviadyme in human milk or the effects of

Nexviadyme on milk production or the breast-fed infant. No conclusions can be drawn regardingwhether or not Nexviadyme is safe for use during breast-feeding. Nexviadyme should be used duringbreast-feeding only if the potential benefits to the mother outweigh the potential risks, including thoseto the breast-fed child (see section 5.3).

There are no clinical data on the effects of Nexviadyme on human fertility. Animal studies in miceshowed no impairment of male or female fertility (see section 5.3).

Nexviadyme may have a minor influence on the ability to drive and use machines. Because dizziness,hypotension and somnolence have been reported as IARs, this may affect the ability to drive and usemachines on the day of the infusion (see section 4.8).

Serious adverse reactions reported in patients treated with Nexviadyme were respiratory distress andchills in 1.4% of patients and in 0.7% of patients each were headache, dyspnoea, hypoxia, tongueoedema, nausea, pruritis, urticaria, skin discoloration, chest discomfort, pyrexia, blood pressureincreased or decreased, body temperature increased, heart rate increased, and oxygen saturationdecreased. Hypersensitivity reactions were reported in 60.6% of patients, anaphylaxis in 2.8%, and

IARs in 39.4% in patients. A total of 4.9% of patients receiving Nexviadyme in clinical studiespermanently discontinued treatment; 2.8% of patients each discontinued the treatment because of thefollowing events considered to be related to Nexviadyme: respiratory distress, chest discomfort,dizziness, cough, nausea, flushing, ocular hyperaemia, urticaria, and erythema.

The most frequently reported adverse drug reactions (ADRs) (>5%) were pruritus (13.4%), nausea(12%), headache (10.6%), rash (10.6%), urticaria (8.5%), chills (7.7%), fatigue (7.7%), and erythema(5.6%).

The pooled safety analysis from 4 clinical studies (EFC14028/COMET, ACT14132/mini-COMET,

TDR12857/NEO, and LTS13769/NEO-EXT) included a total of 142 patients (118 adult and 24paediatric patients (1 paediatric patient directly enrolled in the open-label extension period of Study1)) treated with Nexviadyme. ADRs reported in patients treated with Nexviadyme in the pooledanalysis of clinical studies are listed in Table 2.

Adverse reactions per System Organ Class, presented by frequency categories: 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) and not known (cannot be estimated from the available data).

Due to the small patient population, an adverse reaction reported in 2 patients is classified as common.

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 2 - Adverse reactions occurring in patients treated with Nexviadyme in a pooled analysisof clinical studies (N=142)

System organ class Frequency Preferred term

Infections and infestations Uncommon Conjunctivitis

Immune Disorders Very common Hypersensitivity

Common Anaphylaxis

Nervous system disorders Very common Headache

Common Dizziness

Common Tremor

Common Somnolence

Common Burning sensation

Uncommon Paraesthesia

Eye Disorders Common Ocular hyperaemia

Common Conjunctival hyperaemia

Common Eye pruritus

Common Eyelid oedema

Uncommon Lacrimation increased

Cardiac Disorders Common Tachycardia

Uncommon Ventricular extrasystoles

Vascular Disorders Common Hypertension

Common Flushing

Common Hypotension

Common Cyanosis

Common Hot flush

Common Pallor

Respiratory, thoracic, and mediastinal Common Coughdisorders Common Dyspnoea

Common Respiratory distress

Common Throat irritation

Common Oropharyngeal pain

Uncommon Tachypnoea

Uncommon Laryngeal oedema

Gastrointestinal disorders Very common Nausea

Common Diarrhoea

Common Vomiting

Common Lip swelling

Common Swollen tongue

Common Abdominal pain

Common Abdominal pain upper

System organ class Frequency Preferred term

Common Dyspepsia

Uncommon Hypoaesthesia oral

Uncommon Paraesthesia oral

Uncommon Dysphagia

Skin and subcutaneous tissue disorders Very common Pruritus

Very common Rash

Common Urticaria

Common Erythema

Common Palmer erythema

Common Hyperhidrosis

Common Rash erythematous

Common Rash pruritic

Common Skin plaque

Uncommon Angioedema

Uncommon Skin discolouration

Musculoskeletal and connective tissue Common Muscle spasmsdisorders Common Myalgia

Common Pain in extremity

Common Flank pain

General disorders and administration site Common Fatigueconditions Common Chills

Common Chest discomfort

Common Pain

Common Influenza-like illness

Common Infusion site pain

Common Pyrexia

Common Asthenia

Common Face oedema

Common Feeling cold

Common Feeling hot

Common Sluggishness

Uncommon Facial pain

Uncommon Hyperthermia

Uncommon Infusion site extravasation

Uncommon Infusion site joint pain

Uncommon Infusion site rash

Uncommon Infusion site reaction

Uncommon Infusion site urticaria

Uncommon Localized oedema

Uncommon Peripheral swelling

Investigation Common Blood pressure increased

Common Oxygen saturation decreased

Common Body temperature increase

Uncommon Heart rate increased

Uncommon Breath sounds abnormal

Uncommon Complement factor increased

Uncommon Immune complex level increased

Table 2 includes treatment related adverse events that are considered biologically plausibly related toavalglucosidase alfa based on the alglucosidase alfa SmPC.

In a comparative study, EFC14028/COMET, 100 LOPD (late-onset Pompe disease) patients aged 16to 78 naïve to enzyme replacement therapy were treated either with 20 mg/kg of Nexviadyme (n=51)or 20 mg/kg of alglucosidase alfa (n=49). During the double-blind active-controlled period of 49weeks, serious adverse reactions were reported in 2% of patients treated with Nexviadyme and 6.1%of those treated with alglucosidase alfa. A total of 8.2% patients receiving alglucosidase alfa in thestudy permanently discontinued treatment due to adverse reactions; none of the patients from the

Nexviadyme group permanently discontinued the treatment. The most frequently reported ADRs(>5%) in patients treated with Nexviadyme were headache, nausea, pruritus, urticaria, and fatigue.

The 95 patients who entered open-label extension period of EFC14028/COMET consisted of 51patients who continued treatment with Nexviadyme and 44 patients who switched from alglucosidasealfa to Nexviadyme.

During the open-label extension period, serious adverse reactions were reported by 3 (5.8%) patientscontinuing Nexviadyme treatment throughout the study and by 3 (6.8%) patients who switched to

Nexviadyme. The most frequently reported adverse reactions (>5%) by patients continuing

Nexviadyme treatment throughout the study were nausea, chills, erythema, pruritus, and urticaria. Themost frequently reported adverse reactions (>5%) by patients who switched to Nexviadyme werepruritus, rash, headache, nausea, chills, fatigue, and urticaria.

No adverse reaction or IAR was reported by the additional paediatric patient directly enrolled in theopen-label extension period.

Hypersensitivity (including anaphylaxis)

In a pooled safety analysis, 86/142 (60.6%) patients experienced hypersensitivity reactions including7/142 (4.9%) patients who reported severe hypersensitivity reactions and 4/142 (2.8%) patients whoexperienced anaphylaxis. Some of the hypersensitivity reactions were IgE mediated. Anaphylaxissigns and symptoms included tongue oedema, hypotension, hypoxia, respiratory distress, chestpressure, generalised oedema, generalised flushing, feeling hot, cough, dizziness, dysarthria, throattightness, dysphagia, nausea, redness on palms, swollen lower lip, decreased breath sounds, redness onfeet, swollen tongue, itchy palms and feet, and oxygen desaturation. Symptoms of severehypersensitivity reactions included tongue oedema, respiratory failure, respiratory distress, generalizedoedema, erythema, urticaria, and rash.

Infusion-associated reactions (IARs)

In a pooled safety analysis, IARs were reported in approximately 56/142 (39.4%) of patients treatedwith avalglucosidase alfa in clinical studies. Severe IARs were reported in 6/142 (4.2%) of patientsincluding symptoms of respiratory distress, hypoxia, chest discomfort, generalized oedema, tongueoedema, dysphagia, nausea, erythema, urticaria, and increased or decreased blood pressure. IARsreported in more than 1 patient included respiratory distress, chest discomfort, dyspnoea, cough,oxygen saturation decreased, throat irritation, dyspepsia, nausea, vomiting, diarrhoea, lip swelling,swollen tongue, erythema, palmar erythema, rash, rash erythematous, pruritus, urticaria, hyperhidrosis,skin plaque, ocular hyperaemia, eyelid oedema, face oedema, increased or decreased blood pressure,tachycardia, headache, dizziness, tremor, burning sensation, pain (including pain in extremity,abdominal pain upper, oropharyngeal pain, and flank pain), somnolence, sluggishness, fatigue,pyrexia, influenza like illness, chills, flushing, feeling hot or cold, cyanosis, and pallor. The majorityof IARs were assessed as mild to moderate.

In the comparative study EFC14028/COMET study, fewer LOPD patients in the avalglucosidase alfagroup reported at least 1 IAR (13/51 [25.5%]) in comparison to the alglucosidase alfa group (16/49[32.7%]). Severe IARs were not reported in patients in the avalglucosidase alfa group and reported in2 patients in the alglucosidase alfa group (dizziness, visual impairment, hypotension, dyspnoea, coldsweat, and chills). The most frequently reported treatment-emergent IARs (>2 patients) in theavalglucosidase alfa group were pruritus (7.8%) and urticaria (5.9%) and in the alglucosidase alfagroup were nausea (8.2%), pruritus (8.2%), and flushing (6.1%). The majority of IARs reported in 7(13.7%) patients were of mild severity in the avalglucosidase alfa group and 10 (20.4%) patients in thealglucosidase alfa group.

During the open-label extension period, IARs were reported in 12 (23.5%) patients continuing

Nexviadyme treatment throughout the study; IARs reported in more than 1 patient were nausea, chills,erythema, pruritus, pyrexia, urticaria, rash, and ocular hyperaemia. IARs were reported in 22 (50%)patients who switched to Nexviadyme; IARs reported in more than 1 patient were pruritus, headache,rash, nausea, chills, fatigue, urticaria, respiratory distress, feeling cold, chest discomfort, erythema,rash erythematous, rash pruritic, skin plaque, burning sensation, lip swelling, and swollen tongue. Thenumber of IARs in both groups decreased over time.

The incidence of ADA response to avalglucosidase alfa in Nexviadyme-treated patients with Pompedisease is shown in Table 3. The median time to seroconversion was 8.3 weeks.

In treatment-naïve adult patients, the occurrence of IARs was observed in both ADA-positive and

ADA-negative patients. Increase in the incidence of IARs and hypersensitivity were observed withhigher IgG ADA titres. In treatment-naïve patients, a trend for increases in the incidence of IARs wasobserved with increasing ADA titres, with the highest incidence of IARs (69.2%) reported in the high

ADA peak titre range ≥12,800, compared with an incidence of 33.3% in patients with intermediate

ADA titre 1,600-6,400, an incidence of 14.3% in those with low ADA titre 100-800 and an incidenceof 33.3% in those who were ADA negative. In enzyme replacement therapy (ERT) experienced adultpatients, the occurrences of IARs and hypersensitivity were higher in patients who developedtreatment emergent ADA compared to patients who were ADA negative. One (1) treatment naïvepatient and 2 treatment-experienced patients developed anaphylaxis. The occurrences of IARs weresimilar between paediatric patients with ADA positive and negative status. One treatment-experiencedpaediatric patient developed anaphylaxis (see section 4.4).

In clinical study EFC14028/COMET, 81 of 96 (84.4%) patients developed treatment-emergent ADA.

Majority of patients developed ADA titre in the low to intermediate range, with 7 patients reported

High Sustained Antibody Titres (HSAT) to Nexviadyme. Evaluation of ADA cross-reactivity at week49 showed that patients generate antibodies that are cross-reactive to alglucosidase alfa and

Nexviadyme were detected in 3 (5.9%) patients. Variable impact on PK, PD, and efficacy measureswere observed among high titre patients, however, in most patients there was no clinically significanteffect of ADA on efficacy (see section 5.2).

Table 3 - Treatment emergent ADA incidence in LOPD and IOPD patient population

Nexviadyme

Treatment-naïve Treatment-experienced patientsbpatients Avalglucosidase alfa ADA

Avalglucosidasealfa ADAa

Adults Adults Paediatric Paediatric20 mg/kg every 20 mg/kg 20 mg/kg 40 mg/kgother week every other every other every otherweek week week(N=62) (N=58) (N=6) (N=16)

N (%) N (%) N (%) N (%)

ADA at baseline 2 (3.3) 43 (74.1) 1 (16.7) 2 (12.5)

Treatment emergent ADA 59 (95.2) 36 (62.1) 1 (16.6) 9 (56.3)

Neutralizing antibody

Both NAb types 14 (22.6) 5 (8.6) 0 0

Inhibition enzyme activity, only 5 (8.1) 6 (10.3) 0 0

Inhibition of enzyme uptake, only 12 (19.4) 15 (25.9) 0 2 (12.5%)a Includes two paediatric patientsb Treatment-experienced patients received alglucosidase alfa treatment before or during the clinical study withina range of 0.9-9.9 years for adult patients and 0.6-11.8 years for paediatric patients.c Not determined

Adverse drug reactions reported from clinical studies in the paediatric population (19 paediatricpatients with IOPD between 1-12 years of age (mean age of 6.8) and two paediatric patients (9 and 16years old) with LOPD) were similar to those reported in adults.

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.*

Excessive infusion rate of Nexviadyme may result in hot flush. In a clinical study, paediatric patientsreceived doses up to 40 mg/kg of body weight once every 2 weeks and no specific signs andsymptoms were identifies following the higher doses. For management of adverse reactions, seesections 4.4 and 4.8.

Pharmacotherapeutic group: Alimentary tract and metabolism products - enzymes, ATC code:

A16AB22.

Avalglucosidase alfa is a recombinant human acid α-glucosidase (rhGAA) that provides an exogenoussource of GAA. Avalglucosidase alfa is a modification of alglucosidase alfa in which approximately7 hexamannose structures each containing 2 terminal mannose-6-phosphate (bis-M6P) moieties areconjugated to oxidized sialic acid residues on alglucosidase alfa. Avalglucosidase alfa has a 15-foldincrease in mannose-6-phosphate (M6P) moieties compared with alglucosidase alfa. Binding to M6Preceptors on the cell surface has been shown to occur via carbohydrate groups on the GAA molecule,after which it is internalised and transported into lysosomes, where it undergoes proteolytic cleavagethat results in increased enzymatic activity to degrade glycogen.

Clinical studies in patients with LOPD

Study 1, EFC14028/COMET, was a multinational, multicentre, randomised, double-blinded studycomparing the efficacy and safety of Nexviadyme and alglucosidase alfa in 100 treatment-naïve

LOPD patients aged 16 to 78 years of age at the initiation of treatment. Patients were randomised in a1:1 ratio based on baseline forced vital capacity (FVC), gender, age, and country to receive 20 mg/kgof Nexviadyme or alglucosidase alfa once every other week for 12 months (49 weeks).

Study 1 included an open-label extension treatment period where all patients in the alglucosidase alfaarm were switched to Nexviadyme and continued treatment up to at least week 145. Overall, 95patients entered the open-label period (51 from the Nexviadyme arm and 44 from the alglucosidasealfa arm). An additional paediatric patient was enrolled directly into the extension treatment periodwith Nexviadyme.

The primary endpoint of study 1 was the change in FVC % predicted in the upright position frombaseline to 12 months (week 49). At week 49, the LS mean change (SE) in FVC % predicted forpatients treated with Nexviadyme and alglucosidase alfa was 2.89% (0.88) and 0.46% (0.93),respectively. The clinically significant LS mean difference of 2.43% (95% CI: -0.13, 4.99) between

Nexviadyme and alglucosidase alfa in FVC % predicted exceeded the pre-defined non-inferioritymargin of -1.1 and achieved statistical non-inferiority (p=0.0074). The study did not demonstratestatistical significance for superiority (p=0.0626) and the testing of the secondary endpoints wasperformed without multiplicity adjustment.

The results for the primary endpoint are detailed in Table 4.

For patients who switched from alglucosidase alfa to Nexviadyme treatment after week 49, the LSmean change in FVC % predicted from week 49 to week 145 was 0.81 (1.08) (95% CI: -1.32, 2.95). Astabilization in FVC % predicted was maintained after the switch to Nexviadyme in the alglucosidasealfa group with similar values to the Nexviadyme group at week 145. Patients who continued in the

Nexviadyme arm maintained an improvement in FVC % predicted compared with baseline.

Table 4 - LS Mean change from baseline to week 49 in FVC % predicted in upright position

Nexviadyme (n=51) Alglucosidase Alfa (n=49)

Forced Vital Capacity % predicted in upright position

Pre-treatment baseline Mean (SD) 62.55 (14.39) 61.56 (12.40)

LS mean (SE) change

Week 13 3.05 (0.78) 0.65 (0.81)from baseline

LS mean (SE) change

Week 25 3.21 (0.80) 0.57 (0.84)from baseline

LS mean (SE) change

Week 37 2.21 (1.00) 0.55 (1.05)from baseline

Week 49 Mean (SD) 65.49 (17.42) 61.16 (13.49)

Estimated change frombaseline to week 49 LS mean (SE) change2.89a (0.88) 0.46a (0.93)(MMRM) from baseline

Estimated difference

LS mean (95% CI) 2.43a (-0.13,4.99)between groups inp-value b 0.0074change from baseline top-value c 0.0626week 49 (MMRM)

MMRM: mixed model repeated measure.a On the basis of MMRM model, the model includes baseline FVC % predicted (as continuous), sex, age (inyears at baseline), treatment group, visit, interaction term between treatment group and visit as fixed effects.b Non-inferiority margin of -1.1%c Superiority not achieved

The key secondary endpoint of study 1 was change in total distance walked in 6 minutes (6-Minute

Walk Test, 6MWT) from baseline to 12 months (week 49). At week 49, the LS mean change frombaseline (SE) in 6MWT for patients treated with Nexviadyme and alglucosidase alfa was 32.21 m(9.93) and 2.19 m (10.40) respectively. The LS mean difference of 30.01 m (95% CI: 1.33,58.69)showed numerical improvement with Nexviadyme compared with alglucosidase alfa. The results forthe 6MWT are detailed in Table 5.

For patients who switched from alglucosidase alfa to Nexviadyme treatment after week 49, the LSmean change in 6MWT (distance walked in meters) from week 49 to week 145 was -2.3 m (10.6),95% CI: -23.2, 18.7. At Week 145, a stabilization in 6MWT was observed after the switch from thealglucosidase alfa group to Nexviadyme. The Nexviadyme arm participants sustained theimprovement compared with baseline.

Additional secondary endpoints of the study were maximum inspiratory pressure (MIP), maximumexpiratory pressure (MEP), Hand-held dynamometry (HHD) summary score, quick motor function test(QMFT) total score, and SF-12 (health-related survey on quality of life, both physical and mentalcomponent scores). The results for these endpoints are detailed in Table 5.

In treatment-naïve LOPD patients aged 16 to 78, who started on Nexviadyme 20 mg/kg every otherweek, the mean percentage (SD) change in urinary hexose tetrasaccharides from baseline to week 49was -53.90% (24.03), which was maintained at week 145 at -53.35% (72.73) in patients whocontinued treatment with Nexviadyme. In patients who started on alglucosidase alfa 20 mg/kg everyother week, the mean percentage (SD) change in urinary hexose tetrasaccharides from baseline toweek 49 was -10.8% (32.33), further decreased to -48.04% (41.97) at week 145 after switching fromalglucosidase alfa to Nexviadyme.

Table 5 - LS mean change from baseline to week 49 for additional secondary endpoints

Endpoint Nexviadyme Alglucosidase Alfa LS mean difference

LS mean change (SE) LS mean change (SE) (95% CI)6-minute walk test(6MWT) distance 32.21 (9.93) 2.19 (10.40) 30.01 (1.33, 58.69)(meters)a,b

Maximum Inspiratory

Pressure (MIP) (% 8.71 (2.09) 4.33 (2.19) 4.38 (-1.64, 10.39)predicted)c

Maximum Expiratoryc 10.97 (2.84) 8.35 (2.97) 2.61 (-5.61, 10.83)

Pressure (% predicted)

Hand-held dynamometry260.69 (46.07) 153.72 (48.54) 106.97 (-26.56, 240.5)(HHD) summary scores

Quick Motor function Test3.98 (0.63) 1.89 (0.69) 2.08 (0.22, 3.95)(QMFT) total score

Health-related survey on PCSd score: 2.37 (0.99) 1.60 (1.07) 0.77 (-2.13, 3.67)quality of life (SF-12) MCSe score: 2.88 (1.22) 0.76 (1.32) 2.12 (-1.46, 5.69)aThe MMRM model for 6MWT distance adjusts for baseline FVC % predicted and baseline 6MWT (distancewalked in meters), age (in years, at baseline), gender, treatment group, visit, and treatment-by-visit interactionas fixed effects.b LS mean (SE) change from baseline at Weeks 13, 25, and 37 was 18.02 (8.79), 27.26 (9.98), and 28.43 (9.06),respectively, in the avalglucosidase alfa group and 15.11 (9.16), 9.58 (10.41), and 15.49 (9.48), respectively, inthe alglucosidase alfa group.c Post-hoc sensitivity analysis excluding 4 patients (2 in each treatment arm) with supraphysiologic baseline MIPand MEP values.d Physical Component Summary.e Mental Component Summary.

In an open-label, uncontrolled study in LOPD patients, the FVC % predicted and 6MWT showedmaintenance of effect during the long-term treatment with avalglucosidase alfa 20 mg/kg every otherweek for up to 6 years.

Clinical study in patients with IOPD

Study 2, ACT14132/mini-COMET, was a multi-stage, phase 2, open-label, multicentre, multinational,repeated ascending dose cohort of Nexviadyme in paediatric IOPD patients (1-12 years of age) whodemonstrated either clinical decline or sub-optimal clinical response while on treatment withalglucosidase alfa. The study enrolled a total of 22 patients; cohort 1 had 6 patients who demonstratedclinical decline and received 20 mg/kg every other week for 25 weeks, cohort 2 had 5 patients whodemonstrated clinical decline and received 40 mg/kg every other week for 25 weeks, and cohort 3 had11 patients who demonstrated sub-optimal response and received either Nexviadyme at 40 mg/kgevery other week for 25 weeks (5 patients) or alglucosidase alfa at their stable pre-study dose (rangingbetween 20 mg/kg every other week and 40 mg/kg weekly) for 25 weeks (6 patients).

The primary objective of study 2 was to evaluate the safety and tolerability of administering

Nexviadyme. The secondary objective was to determine the efficacy of Nexviadyme. Data showedstabilization or improvement in efficacy outcomes of gross motor function classification measure-88(GMFM-88), quick motor function test (QMFT), Pompe paediatric evaluation of disability inventory(Pompe-PEDI), left ventricular mass (LVM) Z score, eyelid position measurements in patientspreviously declining or insufficiently controlled with alglucosidase alfa. Treatment effect was morepronounced with 40 mg/kg every other week compared to the 20 mg/kg every other week. Two out ofsix patients treated with Nexviadyme at 20 mg/kg every other week (cohort 1) demonstrated furtherclinical decline and received dose increase from 20 to 40 mg/kg every other week at week 55 and 61respectively. All patients who received 40 mg/kg every other week maintained this dose for theduration of the study without further clinical decline.

In paediatric IOPD patients (<18 years of age) treated with Nexviadyme at 40 mg/kg every other weekwho demonstrated either clinical decline (cohort 2) or sub-optimal clinical response (cohort 3) whileon treatment with alglucosidase alfa, the mean percentage (SD) change in urinary hexosetetrasaccharides from baseline was -40.97% (16.72) and -37.48% (17.16), respectively, after 6 months.

In patients previously declining treated with Nexviadyme at 20 mg/kg every other week, mean (SD)percentage change was 0.34% (42.09).

The long-term effects of treatment with Nexviadyme were evaluated in 10 patients at week 49, 8patients at week 73, and 3 patients at week 97. In patients with IOPD previously declining withalglucosidase alfa, the efficacy on specific parameters of decline, including motor function, cardiacleft ventricular mass, and eyelid position measurements, was sustained up to 2 years.

Nineteen paediatric patients aged from 1 to 12 years with IOPD previously treated with alglucosidasealfa have been treated with Nexviadyme (see section 4.2 and 4.8) and two paediatric patients aged 9 and16 years with LOPD was treated with Nexviadyme.

The European Medicines Agency has deferred the obligation to submit the results of studies with

Nexviadyme in one or more subsets of the paediatric population for the treatment of Pompe disease(see section 4.2 for information on paediatric use).

Pompe registry

Medical or healthcare professionals are encouraged to register patients who are diagnosed with Pompedisease at www.registrynxt.com. Patient data will be anonymously collected in this registry. Theobjectives of the “Pompe registry” are to enhance the understanding of Pompe disease and to monitorpatients and their response to enzyme replacement therapy over time, with the ultimate goal ofimproving clinical outcomes for these patients.

Patients with late-onset Pompe disease (LOPD)

The pharmacokinetics of avalglucosidase alfa was evaluated in a population analysis of 75 LOPDpatients aged 16 to 78 years who received 5 to 20 mg/kg of avalglucosidase alfa every other week.

Patients with infantile-onset Pompe disease (IOPD)

The pharmacokinetics of avalglucosidase alfa was characterized in 16 patients aged 1 to 12 years whowere treated with avalglucosidase alfa, which included 6 patients treated with 20 mg/kg and 10patients treated with 40 mg/kg doses every other week. All patients were treatment-experienced.

In LOPD patients, for a 4-hour IV infusion of 20 mg/kg every other week, the mean Cmax and mean

AUC2W were 273 µg/mL (24%) and 1220 µg∙h/ml (29%), respectively.

In IOPD patients, for a 4-hour IV infusion of 20 mg/kg every other week and 7-hour IV infusion for40 mg/kg every other week, the mean Cmax ranged from 175 to 189 μg/ml for the 20 mg/kg dose and205 to 403 µg/ml for 40 mg/kg dose. The mean AUC2W ranged from 805 to 923 μg∙hr/ml for the20 mg/kg dose and 1720 to 2630 μg∙hr/ml for 40 mg/kg dose.

In LOPD patients, the typical population PK model predicted central compartment volume ofdistribution of avalglucosidase alfa was 3.4 L.

In IOPD patients treated with avalglucosidase alfa 20 mg/kg and 40 mg/kg every other week, the meanvolume of distribution at steady state ranged between 3.5 to 5.4 L.

In LOPD patients, the typical population PK model predicted linear clearance was 0.87 L/h. Following20 mg/kg every other week, the mean plasma elimination half-life was 1.55 hours.

In IOPD patients treated with avalglucosidase alfa 20 mg/kg and 40 mg/kg every other week, meanplasma clearance ranged from 0.53 to 0.70 L/h, and mean plasma elimination half-life from0.60 to 1.19 hours.

The exposure to avalglucosidase alfa increased in a dose-proportional manner between 5 to 20 mg/kgin LOPD patients and between 20 and 40 mg/kg in IOPD patients. No accumulation was observedfollowing every other week dosing.

In the study 1, EFC14028/COMET, 95.2% (59 of 62 patients) receiving Nexviadyme developedtreatment-emergent ADA. Given the variability in ADA response, no clear trend of ADA peak titreand impact on PK was evident in patients at week 49.

Population pharmacokinetic analyses in LOPD patients showed that body weight, age, and gender didnot meaningfully influence the pharmacokinetics of avalglucosidase alfa.

The pharmacokinetics of avalglucosidase alfa has not been studied in patients with hepaticimpairment.

No formal study of the effect of renal impairment on the pharmacokinetics of avalglucosidase alfa wasconducted. On the basis of a population pharmacokinetic analysis of data from 75 LOPD patientsreceiving 20 mg/kg, including 6 patients with mild renal impairment (glomerular filtration rate:

60 to 89 ml/min; at baseline), no relevant effect of renal impairment on avalglucosidase alfa exposurewas observed.

Non-clinical data reveal no special hazard for humans based on conventional studies of repeat dosetoxicity that included safety pharmacology endpoints.

Avalglucosidase alfa caused no adverse effects in a combined male and female fertility study in miceup to 50 mg/kg IV every other day (9.4 times the human steady-state AUC at the recommendedbiweekly dose of 20 mg/kg for patients with LOPD) (see section 4.6).

In an embryo-foetal toxicity study in mice, administration of avalglucosidase at the highest dose of50 mg/kg/day (17 times the human steady-state AUC at the recommended biweekly dose of 20 mg/kgfor patients with LOPD) produced increased post-implantation loss and mean number of lateresorptions. No effects were seen at 20 mg/kg/day (4.8 times the human steady-state AUC at therecommended biweekly dose of 20 mg/kg for patients with LOPD). Avalglucosidase alfa does notcross the placenta in mice, suggesting that the embryo-foetal effects at 50 mg/kg/day were related tomaternal toxicity from the immunologic response. No malformations or developmental variations wereobserved.

No adverse effects were observed in an embryo-foetal toxicity study in rabbits administeredavalglucosidase alfa up to 100 mg/kg/day IV (91 times the human steady-state AUC at therecommended biweekly dose of 20 mg/kg for patients with LOPD).

There were no adverse effects in a pre- and post-natal developmental toxicity study in mice followingadministration of avalglucosidase alfa once every other day. The NOAEL for reproduction in the damsand for viability and growth in the offspring was 50 mg/kg every other day IV.

In juvenile mice, avalglucosidase alfa was generally well tolerated following administration for 9weeks at doses up to 100 mg/kg every other week IV (~2 to 5 times the human steady-state AUC atthe recommended biweekly dose of 40 mg/kg for patients with IOPD). However, the highest dosetested in juvenile animals is not enough to discard a potential risk for IOPD patients at 40 mg/kg basedon exposure margin.

Histidine

Histidine hydrochloride monohydrate

Glycine

Mannitol

Polysorbate 80

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts.

Unopened vials: 4 years

After reconstitution, chemical, physical, and microbiological in-use stability has been demonstratedfor 24 hours at 2°C - 8°C.

From a microbiological point of view, the reconstituted product should be used immediately.

If not used for dilution immediately, in-use storage times and conditions prior to dilution are theresponsibility of the user and would normally not be longer than 24 hours at 2°C - 8°C.

After dilution, chemical, physical and microbiological in-use stability has been demonstrated between0.5 mg/ml and 4 mg/ml for 24 hours at 2°C - 8°C, followed by 9 hours at room temperature (up to25°C) to allow for infusion. Use Aseptic Techniques.

From a microbiological point of view, the medicinal product should be used immediately. If not usedimmediately, in-use storage times and conditions are the responsibility of the user and would normallynot be longer than 24 hours at 2°C - 8°C, followed by 9 hours at room temperature (up to 25°C) toallow for infusion.

Store in a refrigerator (2°C - 8°C).

For storage conditions after reconstitution and dilution of the medicinal product, see section 6.3.

100 mg of powder for concentrate for solution for infusion in a vial (type I glass) with a stopper(elastomeric rubber), seal (aluminium) and a flip off cap.

Each pack contains 1, 5, 10, or 25 vials.

Not all pack sizes may be marketed.

Vials are for single use only.

Aseptic technique should be used during reconstitution.

1. The number of vials have to be determined to be reconstituted based on individual patient’sweight and the recommended dose of 20 mg/kg or 40 mg/kg.

Patient weight (kg) × dose (mg/kg) = patient dose (in mg). Patient dose (in mg) divided by100 mg/vial = number of vials to reconstitute. If the number of vials includes a fraction, itshould be rounded up to the next whole number.

Example: Patient weight (16 kg) × dose (20 mg/kg) = patient dose (320 mg). 320 mg dividedby 100 mg/vial = 3.2 vials; therefore, 4 vials should be reconstituted.

Example: Patient weight (16 kg) × dose (40 mg/kg) = patient dose (640 mg).

640 mg divided by 100 mg/vial = 6.4 vials; therefore, 7 vials should be reconstituted.

2. The required number of vials needed for the infusion should be removed from the refrigeratorand set aside for approximately 30 minutes to allow them to reach room temperature.

3. Each vial should be reconstituted by slowly injecting 10.0 ml of water for injections (WFI) toeach vial. Each vial will yield 100 mg/10 ml (10 mg/ml). Forceful impact of the WFI on thepowder and foaming should be avoided. This is performed by slow drop-wise addition of the

WFI down the inside of the vial and not directly onto the lyophilised powder. Each vial shouldbe tilted and rolled gently to dissolve the lyophilised powder. It should not be inverted,swirled, or shaken.

4. Immediate visual inspection should be performed on the reconstituted vials for particulatematter and discoloration. If upon immediate inspection particles are observed or if the solutionis discoloured, the reconstituted medicinal product should not be used. The solution should beallowed to become dissolved.

Dilution5. The reconstituted solution should be diluted in 5% glucose in water to a final concentration of0.5 mg/ml to 4 mg/ml. See Table 6 for the recommended total infusion volume based on thepatient weight.

6. The volume of reconstituted solution from each vial should be slowly withdrawn (calculatedaccording to patient’s weight).

7. The reconstituted solution should be added slowly and directly into the 5% glucose solution.

Foaming or agitation of the infusion bag should be avoided. Air introduction into the infusionbag should be avoided.

8. To mix the infusion bag solution, gently invert or massage the infusion bag to mix. It shouldnot be shaken.

9. To avoid administration of inadvertently introduced particles during dose IV preparation, it isrecommended to use an in-line, low protein binding, 0.2 μm filter to administer Nexviadyme.

After the infusion is complete, the intravenous line should be flushed with glucose 5% inwater.

10. Nexviadyme should not be infused in the same intravenous line with other medicinal products.

Table 6 - Projected intravenous infusion volumes for Nexviadyme administration by patientweight at 20 and 40 mg/kg Dose

Patient Weight Range Total infusion volume for 20 mg/kg Total infusion volume for 40 mg/kg(kg) (ml) (ml)1.25 to 5 50 505.1 to 10 50 10010.1 to 20 100 20020.1 to 30 150 30030.1 to 35 200 40035.1 to 50 250 50050.1 to 60 300 60060.1 to 100 500 1000100.1 to 120 600 1200120.1 to 140 700 1400140.1 to 160 800 1600160.1 to 180 900 1800180.1 to 200 1000 2000

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

Sanofi B.V.

Paasheuvelweg 251105 BP Amsterdam

The Netherlands

EU/1/21/1579/001

EU/1/21/1579/002

EU/1/21/1579/003

EU/1/21/1579/004

Date of first authorisation: 24 June 2022

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

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