Avalglucosidase alfa

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

The safety and efficacy of avalglucosidase alfa in patients with moderate or severe renal impairment have not been evaluated and no specific dose regimen can be recommended for these patients.

Caution should be exercised when administering avalglucosidase alfa to patients susceptible to fluid volume overload or patients with acute underlying respiratory illness or compromised cardiac and/or respiratory function for whom fluid restriction is indicated. These patients may be at risk of serious exacerbation of their cardiac or respiratory status during infusion. Appropriate medical support and monitoring measures should be readily available during avalglucosidase alfa infusion, and some patients may require prolonged observation times that should be based on the individual needs of the patient.

There are no available data on the use of avalglucosidase alfa in pregnant women. Animal studies do not indicate direct harmful effects with respect to reproductive toxicity. Indirect foetal effects in mice were considered related to an anaphylactic response to avalglucosidase alfa. The potential risk for humans is unknown. No conclusions can be drawn regarding whether or not avalglucosidase alfa is safe for use during pregnancy. Avalglucosidase alfa should be used during pregnancy only if the potential benefits to the mother outweigh the potential risks, including those to the foetus.

There are no available data on the presence of avalglucosidase alfa in human milk or the effects of avalglucosidase alfa on milk production or the breast-fed infant. No conclusions can be drawn regarding whether or not avalglucosidase alfa is safe for use during breast-feeding. Avalglucosidase alfa should be used during breast-feeding only if the potential benefits to the mother outweigh the potential risks, including those to the breast-fed child.

Fertility

There are no clinical data on the effects of avalglucosidase alfa on human fertility. Animal studies in mice showed no impairment of male or female fertility.

Avalglucosidase alfa 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 use machines on the day of the infusion.

Summary of the safety profile

Serious adverse reactions reported in patients treated with avalglucosidase alfa solution for infusion were chills in 1.4% of patients and in 0.7% of patients each were headache, dyspnoea, respiratory distress, nausea, skin discoloration, chest discomfort, pyrexia, blood pressure increased, body temperature increased, heart rate increased, and oxygen saturation decreased. Hypersensitivity reactions were reported in 43.5% of patients, anaphylaxis in 1.4%, and IARs in 26.1% in patients. A total of 2.9% patients receiving avalglucosidase alfa in clinical studies permanently discontinued treatment; 0.7% patients each discontinued the treatment because of the following events considered to be related to avalglucosidase alfa: respiratory distress, chest discomfort, dizziness, cough, nausea, flushing, ocular hyperaemia, and erythema.

The most frequently reported adverse drug reactions (ADRs) (>5%) were pruritus (9.4%), rash (8%), headache (7.2%), urticaria (6.5%), fatigue (6.5%), nausea (5.8%), and chills (5.1%).

The pooled safety analysis from 4 clinical studies (EFC14028/COMET, ACT14132/mini-COMET, TDR12857/NEO, and LTS13769/NEO-EXT) included a total of 138 patients (118 adult and 20 paediatric patients) treated with avalglucosidase alfa solution for infusion. ADRs reported in patients treated with avalglucosidase alfa solution for infusion in the pooled analysis of clinical studies are listed in Table 1.

Tabulated list of adverse reactions

Adverse reactions (reported in at least 3 patients) 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 1. Adverse reactions occurring in patients treated with avalglucosidase alfa solution for infusion in a pooled analysis of clinical studies (N=138):

Table 1 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 patients aged 16 to 78 naïve to enzyme replacement therapy were treated either with 20 mg/kg of avalglucosidase alfa solution for infusion (n=51) or 20 mg/kg of alglucosidase alfa (n=49). Serious adverse reactions were reported in 2% of patients treated with avalglucosidase alfa solution for infusion 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 avalglucosidase alfa solution for infusion group permanently discontinued the treatment. The most frequently reported ADRs (>5%) were headache, nausea, pruritus, urticaria, and fatigue.

Description of selected adverse reactions

Hypersensitivity (including anaphylaxis)

In a pooled safety analysis, 60/138 (43.5%) patients experienced hypersensitivity reactions including 6/138 (4.3%) patients who reported severe hypersensitivity reactions and 2/138 (1.4%) patients who experienced anaphylaxis. Some of the hypersensitivity reactions were IgE mediated. Anaphylaxis symptoms included respiratory distress, chest pressure, generalised flushing, cough, dizziness, 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 respiratory failure, respiratory distress, and rash.

Infusion-associated reactions (IARs)

In a pooled safety analysis, IARs were reported in approximately 42/138 (30.4%) of patients treated with avalglucosidase alfa in clinical studies. Severe IARs were reported in 3/138 (2.2%) of patients including symptoms of chest discomfort, nausea, and increased blood pressure. IARs reported in more than 1 patient included chills, cough, diarrhoea, erythema, fatigue, headache, influenza-like illness, nausea, ocular hyperaemia, pain in extremity, pruritus, rash, rash erythematous, tachycardia, urticaria, vomiting, chest discomfort, dizziness, hyperhidrosis, lip swelling, oxygen saturation decreased, pain, palmar erythema, swollen tongue and tremor. 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 TEAEs (>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).

Immunogenicity

The incidence of ADA response to avalglucosidase alfa in avalglucosidase alfa solution for infusion-treated patients with Pompe disease is shown in Table 2. The median time to seroconversion was 8.3 weeks.

In treatment-naïve adult patients, the occurrence of IAR was observed in both ADA-positive and ADA-negative patients. Increase in the incidence of IAR 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 (61.5%) reported in the high ADA peak titre range ≥12,800, compared with an incidence of 17.2% in patients with intermediate ADA titre 1,600-6,400, an incidence of 7.1% 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 1 treatment-experienced patient developed anaphylaxis. The occurrences of IARs were similar between paediatric patients with ADA positive and negative status. There were no paediatric patients who developed anaphylactic reactions.

In clinical study EFC14028/COMET, 2 patients reported High Sustained Antibody Titres (HSAT) to avalglucosidase alfa solution for infusion but this was not associated with a loss of efficacy. ADA cross-reactivity studies showed that the majority of patients generate antibodies that are cross-reactive to alglucosidase alfa. At week 49, antibodies specific to avalglucosidase alfa were detected in 3 (5.9%) patients. ADA did not impact measures of efficacy while limited impacts on PK and PD were observed primarily with high titre patients.

Table 2. Treatment emergent ADA incidence in LOPD and IOPD patient population:

^a Includes one paediatric patient
^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 0.5-11.7 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 one 16-year-old paediatric patient with LOPD) were similar to those reported in adults.