COMET: The first pivotal, head-to-head, ERT clinical trial in LOPD1-3

NEXVIAZYME® (avalglucosidase alfa-ngpt) COMET study design

COMET TRIAL DESIGN1,3

Select baseline characteristics

  • Naive to treatment with alglucosidase alfa or any investigational therapy for Pompe disease
  • Upright FVC levels ≥32% and ≤85% predicted
  • 6MWT distance between ≥118 m and ≤630 m
  • Median age was 49 years (range from 16 to 78)

Primary endpoint

Change in FVC (% predicted) in the upright position from baseline to week 49

Key secondary endpoint

Change in total distance walked in 6 minutes (6MWT) from baseline to week 49

Select additional measurements§

  • MIP (% predicted) and MEP (% predicted)
  • HHD upper and lower extremity score
  • QMFT, total score
  • SF-12
    •  PCS score
    •  MCS score

*Screening phase (up to 14 days), may be extended to up to 8 weeks in prespecified situations.
†Randomization at a 1:1 ratio with stratification factors based on baseline FVC, sex, age, and country (Japan or ex-Japan).
‡In the ETP (after week 49), participants who received NEXVIAZYME in the PAP continued on treatment (NEXVIAZYME arm) and participants who received alglucosidase alfa in the PAP switched to NEXVIAZYME (Switch arm).
§Select additional measurements are not included in the Prescribing Information.

qow=every other week; FVC=forced vital capacity; 6MWT=6-minute walk test; MIP=maximum inspiratory pressure; MEP=maximum expiratory pressure; HHD=hand-held dynamometry; QMFT=Quick Motor Function Test; SF-12=health-related quality of life 12-item short-form health survey; PCS=physical component summary; MCS=mental component summary.

NEXVIAZYME PHARMACODYNAMICS: ROLE IN GLYCOGEN DEGRADATION1,2

At week 145, NEXVIAZYME reduced urinary glucose tetrasaccharide (Glc4) levels in both the NEXVIAZYME and Switch arms compared with baseline.1

URINARY Glc4 % CHANGE FROM BASELINE TO WEEK 1451,2

Graph of urinary Glc4 % change from baseline to week 145 in the NEXVIAZYME (avalglucosidase alfa-ngpt) and switch arms

At week 49, urinary Glc4 compared with baseline was reduced1:

in patients
treated with
NEXVIAZYME

in patients
treated with
alglucosidase alfa

At week 145, NEXVIAZYME reduced urinary Glc4 compared with baseline1:

in the
NEXVIAZYME arm
(4.32 mmol/mol)

in the
Switch arm
(5.25 mmol/mol)

Cr=creatinine; SE=standard error.

What is Glc4?

In patients with LOPD, excess glycogen is degraded to hexose tetrasaccharide (Hex4), which is then excreted in urine. The urinary Hex4 assay measures its major component, Glc4.1

At week 49, NEXVIAZYME demonstrated a meaningful improvement in breathing compared with alglucosidase alfa and baseline1

At week 145, improvement in breathing was maintained in both the NEXVIAZYME and Switch arms.2

LS MEAN CHANGE IN FVC (% PREDICTED) BASELINE TO WEEK 1451,2

Graph of LS mean change in FVC (% predicted) baseline to week 145 in the NEXVIAZYME (avalglucosidase alfa-ngpt) and switch arms

At week 49, respiratory function compared with baseline improved1:

in patients
treated with
NEXVIAZYME

in patients
treated with
alglucosidase alfa

At week 145, respiratory function compared with baseline2:

in the
NEXVIAZYME arm*

in the
Switch arm†

The ETP LS mean analysis was not prespecified and included patients with assumed missing-at-random data points using all observed data. Due to the descriptive nature of the ETP and decreased sample size, LS mean data should be interpreted with caution and respect to sample mean values.

*In the NEXVIAZYME arm, the mean change in FVC (% predicted) was 1.7 (SD=8.6, 95% CI: -0.9, 4.2) from baseline to week 145.2
†In the Switch arm, the mean change in FVC (% predicted) was 0.5 (SD=8.3, 95% CI: -2.3, 3.4) from baseline to week 145.2

‡One participant’s FVC % predicted value at week 97 was excluded due to a physiologically implausible change between weeks 73-97 and weeks 97-121.
§Statistical superiority of NEXVIAZYME over alglucosidase alfa was not achieved (p=0.06).
SD=standard deviation; pp=percent predicted.

At week 49, NEXVIAZYME demonstrated a meaningful improvement in walking compared with alglucosidase alfa and baseline1

At week 145, walking ability improved compared with baseline in the NEXVIAZYME arm and was maintained near baseline in the Switch arm.2

LS MEAN CHANGE IN 6MWT DISTANCE (m) BASELINE TO WEEK 1451,2

Graph of LS mean change in 6MWT distance (m) baseline to week 145 in the NEXVIAZYME (avalglucosidase alfa-ngpt) and switch arms

At week 49, walking distance compared with baseline improved1:

in patients
treated with
NEXVIAZYME

in patients
treated with
alglucosidase alfa

At week 145, walking distance compared with baseline2:

in the
NEXVIAZYME
arm*

near baseline
in the
Switch arm†

The ETP LS mean analysis was not prespecified and included patients with assumed missing-at-random data points using all observed data. Due to the descriptive nature of the ETP and decreased sample size, LS mean data should be interpreted with caution and respect to sample mean values.

*In the NEXVIAZYME arm, the mean change in 6MWT was 24.9 (SD=68.6, 95% CI: 4.8, 44.9) from baseline to week 145.1
†In the Switch arm, the mean change in 6MWT was -4.1 (SD=90.4, 95% CI: -34.1, 25.8) from baseline to week 145.1

‡P value for the difference between groups was at nominal level, without multiplicity adjustment (p=0.04).

Select additional measurements in patients receiving NEXVIAZYME compared with alglucosidase alfa3

Differences between treatment groups in changes from baseline to week 49.3

SELECT ADDITIONAL MEASUREMENTS3,*
LS MEAN DIFFERENCE (95% CI)

Select additional measurements in patients receiving NEXVIAZYME® (avalglucosidase alfa-ngpt) compared with alglucosidase alfa chart

MIP + MEP: Measures respiratory muscle strength

HHD: Measures extremity muscle strength

QMFT: Measures motor function

SF-12: Assesses health-related quality of life

Limitations: Statistical superiority of NEXVIAZYME over alglucosidase alfa was not achieved at week 49 (p=0.06) in COMET pivotal trial. P values for secondary endpoints are provided at the nominal level. The subsequent analyses could represent chance findings as multiplicity has not been applied.1

*Figure adapted from Diaz-Manera J, Kishnani P, Kusha H, et al. Lancet Neurol. 2021;20:1012-1026. †MIP and MEP includes posthoc analysis. Four participants (two in each group) with implausibly high MIP % predicted and MEP % predicted values at baseline were excluded from all MIP and MEP analyses.

MIP=maximum inspiratory pressure; MEP=maximum expiratory pressure; HHD=hand-held dynamometry; QMFT=Quick Motor Function Test; SF-12=health-related quality of life 12-item short-form health survey; PCS=physical component summary; MCS=mental component summary.

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IMPORTANT SAFETY INFORMATION AND INDICATION 

IMPORTANT SAFETY INFORMATION 

WARNING: SEVERE HYPERSENSITIVITY REACTIONS, INFUSION-ASSOCIATED REACTIONS, and RISK OF ACUTE CARDIORESPIRATORY FAILURE IN SUSCEPTIBLE PATIENTS

Hypersensitivity Reactions including Anaphylaxis

Patients treated with NEXVIAZYME have experienced life-threatening hypersensitivity reactions, including anaphylaxis. Appropriate medical support measures, including cardiopulmonary resuscitation equipment, should be readily available during NEXVIAZYME administration. If a severe hypersensitivity reaction (e.g., anaphylaxis) occurs, NEXVIAZYME should be discontinued immediately and appropriate medical treatment should be initiated. In patients with severe hypersensitivity reaction, a desensitization procedure to NEXVIAZYME may be considered.

Infusion-Associated Reactions (IARs)

Patients treated with NEXVIAZYME have experienced severe IARs. If severe IARs occur, consider immediate discontinuation of NEXVIAZYME, initiation of appropriate medical treatment, and the benefits and risks of readministering NEXVIAZYME following severe IARs. Patients with an acute underlying illness at the time of NEXVIAZYME infusion may be at greater risk for IARs. Patients with advanced Pompe disease may have compromised cardiac and respiratory function, which may predispose them to a higher risk of severe complications from IARs.

Risk of Acute Cardiorespiratory Failure in Susceptible Patients

Patients susceptible to fluid volume overload, or those with acute underlying respiratory illness or compromised cardiac or respiratory function for whom fluid restriction is indicated may be at risk of serious exacerbation of their cardiac or respiratory status during NEXVIAZYME infusion. More frequent monitoring of vitals should be performed during NEXVIAZYME infusion.


WARNINGS AND PRECAUTIONS

Hypersensitivity Reactions Including Anaphylaxis: See Boxed WARNING. Prior to NEXVIAZYME administration, consider pretreating with antihistamines, antipyretics, and/or corticosteroids. The risks and benefits of readministering NEXVIAZYME following severe hypersensitivity reaction (including anaphylaxis) should be considered. If a mild or moderate hypersensitivity reaction occurs, the infusion rate may be slowed or temporarily stopped.

Infusion-Associated Reactions: See Boxed WARNING. IARs may still occur in patients after receiving pretreatment. If mild or moderate IARs occur regardless of pretreatment, decreasing the infusion rate or temporarily stopping the infusion may ameliorate the symptoms.

Risk of Acute Cardiorespiratory Failure in Susceptible Patients: See Boxed WARNING.

ADVERSE REACTIONS

The most common adverse reactions (>5%) were headache, fatigue, diarrhea, nausea, arthralgia, dizziness, myalgia, pruritus, vomiting, dyspnea, erythema, paresthesia and urticaria.

INDICATION

NEXVIAZYME (avalglucosidase alfa-ngpt) is indicated for the treatment of patients 1 year of age and older with late-onset Pompe disease [lysosomal acid alpha-glucosidase (GAA) deficiency].

Please see full Prescribing Information for complete details, including Boxed WARNING.

References: 1. NEXVIAZYME (avalglucosidase alfa-ngpt) [prescribing information]. Genzyme Corporation, Cambridge, MA. 2. Straub S, Kishnani P, Diaz-Manera J, et al. Efficacy and safety of avalglucosidase alfa in participants with late-onset Pompe disease after 145 weeks of treatment during the COMET trial. Poster presented at: Muscular Dystrophy Association (MDA) Clinical & Scientific Conference; March 19–22, 2023; Dallas, TX. 3. Diaz-Manera J, Kishnani P, Kusha H, et al. Lancet Neurol. 2021;20:1012-1026.

IMPORTANT SAFETY INFORMATION AND INDICATION 

IMPORTANT SAFETY INFORMATION 

WARNING: SEVERE HYPERSENSITIVITY REACTIONS, INFUSION-ASSOCIATED REACTIONS, and RISK OF ACUTE CARDIORESPIRATORY FAILURE IN SUSCEPTIBLE PATIENTS

Hypersensitivity Reactions including Anaphylaxis

Patients treated with NEXVIAZYME have experienced life-threatening hypersensitivity reactions, including anaphylaxis. Appropriate medical support measures, including cardiopulmonary resuscitation equipment, should be readily available during NEXVIAZYME administration. If a severe hypersensitivity reaction (e.g., anaphylaxis) occurs, NEXVIAZYME should be discontinued immediately and appropriate medical treatment should be initiated. In patients with severe hypersensitivity reaction, a desensitization procedure to NEXVIAZYME may be considered.

Infusion-Associated Reactions (IARs)

Patients treated with NEXVIAZYME have experienced severe IARs. If severe IARs occur, consider immediate discontinuation of NEXVIAZYME, initiation of appropriate medical treatment, and the benefits and risks of readministering NEXVIAZYME following severe IARs. Patients with an acute underlying illness at the time of NEXVIAZYME infusion may be at greater risk for IARs. Patients with advanced Pompe disease may have compromised cardiac and respiratory function, which may predispose them to a higher risk of severe complications from IARs.

Risk of Acute Cardiorespiratory Failure in Susceptible Patients

Patients susceptible to fluid volume overload, or those with acute underlying respiratory illness or compromised cardiac or respiratory function for whom fluid restriction is indicated may be at risk of serious exacerbation of their cardiac or respiratory status during NEXVIAZYME infusion. More frequent monitoring of vitals should be performed during NEXVIAZYME infusion.


WARNINGS AND PRECAUTIONS

Hypersensitivity Reactions Including Anaphylaxis: See Boxed WARNING. Prior to NEXVIAZYME administration, consider pretreating with antihistamines, antipyretics, and/or corticosteroids. The risks and benefits of readministering NEXVIAZYME following severe hypersensitivity reaction (including anaphylaxis) should be considered. If a mild or moderate hypersensitivity reaction occurs, the infusion rate may be slowed or temporarily stopped.

Infusion-Associated Reactions: See Boxed WARNING. IARs may still occur in patients after receiving pretreatment. If mild or moderate IARs occur regardless of pretreatment, decreasing the infusion rate or temporarily stopping the infusion may ameliorate the symptoms.

Risk of Acute Cardiorespiratory Failure in Susceptible Patients: See Boxed WARNING.

ADVERSE REACTIONS

The most common adverse reactions (>5%) were headache, fatigue, diarrhea, nausea, arthralgia, dizziness, myalgia, pruritus, vomiting, dyspnea, erythema, paresthesia and urticaria.

INDICATION

NEXVIAZYME (avalglucosidase alfa-ngpt) is indicated for the treatment of patients 1 year of age and older with late-onset Pompe disease [lysosomal acid alpha-glucosidase (GAA) deficiency].

Please see full Prescribing Information for complete details, including Boxed WARNING.

References: 1. NEXVIAZYME (avalglucosidase alfa-ngpt) [prescribing information]. Genzyme Corporation, Cambridge, MA. 2. Straub S, Kishnani P, Diaz-Manera J, et al. Efficacy and safety of avalglucosidase alfa in participants with late-onset Pompe disease after 145 weeks of treatment during the COMET trial. Poster presented at: Muscular Dystrophy Association (MDA) Clinical & Scientific Conference; March 19–22, 2023; Dallas, TX. 3. Diaz-Manera J, Kishnani P, Kusha H, et al. Lancet Neurol. 2021;20:1012-1026.