Adverse reactions : תופעות לוואי

4.8    Undesirable effects

Summary of the safety profile
Serious adverse reactions reported in patients treated with Nexviazyme were respiratory distress and chills in 1.4% of patients and in 0.7% of patients each were headache, dyspnoea, hypoxia, tongue oedema, nausea, pruritis, urticaria, skin discoloration, chest discomfort, pyrexia, blood pressure increased or decreased, body temperature increased, heart rate increased, and oxygen saturation decreased. 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 Nexviazyme in clinical studies permanently discontinued treatment; 2.8% of patients each discontinued the treatment because of the 
following events considered to be related to Nexviazyme : 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 24 paediatric patients (1 paediatric patient directly enrolled in the open-label extension period of Study 1) treated with Nexviazyme. ADRs reported in patients treated with Nexviazyme in the pooled analysis of clinical studies are listed in Table 2.

Tabulated list of adverse reactions

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 Nexviazyme in a pooled analysis of 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           Cough disorders                                   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
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 spasms disorders                                   Common           Myalgia
Common           Pain in extremity
Common           Flank pain
General disorders and administration site   Common           Fatigue conditions                                  Common           Chills

System organ class                          Frequency                 Preferred term 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 to avalglucosidase alfa based on the alglucosidase alfa SmPC.

In a comparative study, EFC14028/COMET, 100 LOPD (late-onset Pompe disease) patients aged 16 to 78 naïve to enzyme replacement therapy were treated either with 20 mg/kg of Nexviazyme (n=51) or 20 mg/kg of alglucosidase alfa (n=49). During the double-blind active-controlled period of 49 weeks, serious adverse reactions were reported in 2% of patients treated with Nexviazyme and 6.1% of those treated with alglucosidase alfa. A total of 8.2% patients receiving alglucosidase alfa in the study permanently discontinued treatment due to adverse reactions; none of the patients from the Nexviazyme group permanently discontinued the treatment. The most frequently reported ADRs (>5%) in patients treated with Nexviazyme were headache, nausea, pruritus, urticaria, and fatigue.

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

During the open-label extension period , serious adverse reactions were reported by 3 (5.8%) patients continuing Nexviazyme treatment throughout the study and by 3 (6.8%) patients who switched to Nexviazyme. The most frequently reported adverse reactions (>5%) by patients continuing Nexviazyme treatment throughout the study were nausea, chills, erythema, pruritus, and urticaria. The most frequently reported adverse reactions (>5%) by patients who switched to Nexviazyme were pruritus, rash, headache, nausea, chills, fatigue, and, urticaria.

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

Description of selected adverse reactions

Hypersensitivity (including anaphylaxis)
In a pooled safety analysis, 86/142 (60.6%) patients experienced hypersensitivity reactions including 7/142 (4.9%) patients who reported severe hypersensitivity reactions and 4/142 (2.8%) patients who experienced anaphylaxis. Some of the hypersensitivity reactions were IgE mediated. Anaphylaxis signs and symptoms included tongue oedema, hypotension, hypoxia, respiratory distress, chest pressure, generalised oedema, generalised flushing, feeling hot, cough, dizziness, dysarthria, throat tightness, dysphagia nausea, redness on palms, swollen lower lip, decreased breath sounds, redness on feet, swollen tongue, itchy palms and feet, and oxygen desaturation. Symptoms of severe hypersensitivity reactions included tongue oedema, respiratory failure, respiratory distress, generalized oedema, erythema, urticaria, and rash.

Infusion-associated reactions (IARs)
In a pooled safety analysis, IARs were reported in approximately 56/142 (39.4%) of patients treated with avalglucosidase alfa in clinical studies. Severe IARs were reported in 6/142 (4.2%) of patients including symptoms of respiratory distress, hypoxia, chest discomfort, generalized oedema, tongue oedema, dysphagia, nausea, erythema, urticaria, and increased or decreased blood pressure. IARs reported 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 majority of IARs were assessed as mild to moderate.

In the comparative study EFC14028/COMET study, fewer LOPD patients in the avalglucosidase alfa group 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 in 2 patients in the alglucosidase alfa group (dizziness, visual impairment, hypotension, dyspnoea, cold sweat, and chills). The most frequently reported treatment-emergent IARs (>2 patients) in the avalglucosidase alfa group were pruritus (7.8%) and urticaria (5.9%) and in the alglucosidase alfa group 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 the alglucosidase alfa group.

During the open-label extension period , IARs were reported in 12 (23.5%) patients continuing Nexviazyme 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 Nexviazyme; 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. The number of IARs in both groups decreased over time.

Immunogenicity
The incidence of ADA response to avalglucosidase alfa in Nexviazyme -treated patients with Pompe disease 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 with higher IgG ADA titres. In treatment-naïve patients, a trend for increases in the incidence of IARs was observed 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 incidence of 33.3% in those who were ADA negative. In enzyme replacement therapy (ERT) experienced adult patients, the occurrences of IARs and hypersensitivity were higher in patients who developed treatment emergent ADA compared to patients who were ADA negative. One (1) treatment naïve patient and 2 treatment-experienced patients developed anaphylaxis. The occurrences of IARs were similar between paediatric patients with ADA positive and negative status. One treatment-experienced paediatric 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 Nexviazyme. Evaluation of ADA cross-reactivity at week 49 showed that patients generate antibodies that are cross-reactive to alglucosidase alfa and
Nexviazyme were detected in 3 (5.9%) patients. Variable impact on PK, PD, and efficacy measures were observed among high titre patients, however, in most patients there was no clinically significant effect of ADA on efficacy (see section 5.2).



Table 3 – Treatment emergent ADA incidence in LOPD and IOPD patient population Nexviazyme
Treatment-naïve         Treatment-experienced patientsb patients               Avalglucosidase alfa ADA
Avalglucosidase alfa ADAa
Adults            Adults        Paediatric    Paediatric
20 mg/kg every       20 mg/kg       20 mg/kg       40 mg/kg other week           every       every other       every other          week        other 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
59 (95.2)         36 (62.1)      1 (16.6)       9 (56.3)
ADA
Neutralizing antibody
Both NAb types                 14 (22.6)          5 (8.6)          0              0 Inhibition enzyme
5 (8.1)            6 (10.3)          0               0 activity, only
Inhibition of enzyme
12 (19.4)          15 (25.9)          0          2 (12.5%) uptake, only a
Includes two paediatric patients b
Treatment-experienced patients received alglucosidase alfa treatment before or during the clinical study within a range of 0.9-9.9 years for adult patients and 0. 6-11.8 years for paediatric patients.
c
Not determined

Paediatric population

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form https://sideeffects.health.gov.il/