Clinical data with Myozyme^TM

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Study 1: Prolonged survival and ventilator-free survival in infants with early progressive disease^[1,2]

Randomised, open-label, historically-controlled trial

18 non-ventilated patients aged 6 months or younger at onset of treatment

Untreated historical cohort derived from a retrospective natural history study in patients with onset of symptoms of Pompe disease in the first year of life

After 52 weeks, patients treated with Myozyme™ demonstrated prolonged survival and prolonged survival free of invasive ventilator support as compared to survival in an untreated historical cohort (see below)

Note: Results are from a Cox proportional hazards regression analysis which includes treatment as a time-varying covariate, and also includes age of diagnosis and age at symptom onset. Subjects in the historical reference group were born in 1993 or later.

Proportion of Treated Patients Alive and Free of Invasive Ventilator Support vs. Proportion of Untreated Historical Control Patients Alive Both at 18 Months of Age^[2]

* 2 patients younger than 18 months of age after 52 weeks of treatment were censored in the analysis.

† In this analysis, the historical cohort included all patients born between 1982 and 2002, 6 were censored as their survival status was unknown. They were censored at the age at which they were last known to be alive.

Improvement or prevention of potentially fatal manifestations

After 52 weeks of treatment: ^[1,2]

All 12 patients with available data showed decreases in left ventricular mass (LVM)

as compared to baseline values (mean decrease in LVM index 57.6%)

Mean decrease in LVM z-score of 57.6% at Week 52

Continued acquisition of motor milestones

72.2% of patients made gains in motor function over baseline as measured by motor performance age-equivalent scores of the Alberta Infant Motor Scale (AIMS) after 52 weeks of treatment^[1]

Improvement or maintenance in growth parameters from baseline

Improvement or maintenance in growth parameters (weight, length and head circumference) from baseline after 26 weeks of treatment was seen in 72.2, 93.8 and 82.4% of patients respectively ^[1,3]

Study 2: Survival in patients with rapidly progressive, more advanced stage disease^[1]

Open-label trial in 21 patients aged 6 months to 3.5 years at treatment onset

Survival in treated patients was compared to similar cohort of untreated historical subjects derived from a retrospective natural history study in patients with onset of symptoms of Pompe disease from 6 months to 3.5 years of life

Survival of Treated Patients vs. Cohort of Untreated Historical Control Patients at 52 Weeks

Note: Results are from a Cox proportional hazards regression analysis which includes treatment as a time-varying covariate, and also includes age of diagnosis and age at symptom onset. Subjects in the historical reference group were born in 1995 or later.

Additional efficacy analyses completed after the 15th patient enrolled completed 52 weeks of treatment

After 52 weeks of treatment with Myozyme™, the survival rate was 73% (95% CI: 44.9, 92.2) compared to the corresponding survival figure of 37% (95% CI: 13.8, 61.2) in an untreated reference group. None of the deaths were assessed as treatment-related.

In 10 patients who were free of invasive-ventilator support at baseline, 50% remained so after 52 weeks of treatment

86.6% of patients demonstrated decreases in LVM

40% of patients had measurable gains in motor function (as determined by age-equivalent scores from baseline in the AIMS and/or Peabody Development Motor Scale (PDMS-2)

Improvement or maintenance in growth parameters (weight, length and head circumference) from baseline after 52 weeks of treatment was seen in 80, 93 and 92% of patients^[1,2] respectively

Early treatment critical to optimising outcomes

The totality of these data suggests that early treatment changes the natural disease course by slowing disease progression. Treating early may be critical to achieving the best outcomes.

Open-label, prospective, single-centre trial with five patients aged 5 to 15 years at treatment onset.

Interim analysis after 26 weeks of treatment.

Clinically meaningful improvements (defined as ≥11% compared to baseline^[4]) in forced vital capacity (FVC) in 2 of 3 patients with significant pulmonary involvement at baseline^[1]

Clinically meaningful increase (defined as 37 meters^[5]) in the 6-Minute Walk Test conducted at fast speed in 3 patients^[6]

Measurable gains in patients with advanced disease

Data from 10 advanced disease patients (10 of 10 patients wheelchair bound; 9 of 10 ventilator dependent) aged 9 to 54 years at treatment onset. Patients were treated for 6 months to 2.5 years^[1]

35% improvement in FVC in 1 patient

Significant reduction (10-12 hours/day) in number of hours of ventilator support in 2 patients

Regaining of lost motor skills in some patients

Loss of need for wheelchair in 1 patient

Improvement in daily living

Additional findings, based on physicians’ narratives in 18 patients (10 patients noted previously plus 8 patients from the Expanded Access Programme AGLU02603), provide further effects of therapy: ^[2]

5 of 18 patients showed clinically significant decreases in the number of hours of non-invasive ventilation (from approximately 20 h/day to 10 h/day)

4 of 18 patients had increased ambulation

Many patients gained weight, and many reported improved quality of life

Safety and tolerability Profile^[1]

Studies 1 and 2: Undesirable effects

Adverse drug reactions (ADRs) reported in 39 patients with rapidly progressive disease are listed in table below

ADRs were mild to moderate in intensity and almost all were infusion-associated reactions (IARs)

No patients discontinued treatment due to an ADR

Adverse drug reactions in patients with advanced disease

Adverse drug reactions (ADRs) reported in 2 of 9 patients with advanced disease included increased heart rate, hypertension, headache, peripheral coldness, paraesthesia, flushing, infusion site pain, infusion site reaction, increased blood pressure, and dizziness. These two patients did not experience the same ADRs, which were mild in intensity and assessed as IARs.

Infusion-associated reactions (IARs)

Defined as any related adverse event occurring during the infusion or during 2 hours following infusion

In the 39 infantile clinical trial patients, IARs occurred in 46% (18/39) of patients, all of which were of mild or moderate severity

Most common IARs included urticaria, flushing, pyrexia and rash

Serious infusion reactions included urticaria, rales, tachycardia, decreased oxygen saturation, bronchospasm, tachypnoea, periorbital oedema, and hypertension, all of which occurred in a single patient, except urticaria (2 patients)

Reduction of the infusion rate, temporary interruption of the infusion, or pre-treatment, generally with oral antihistamine and/or antipyretics may effectively manage reactions

A tendency was observed in patients treated with a higher dose (40 mg/kg) to experience more symptoms when developing IARs

Patients with an acute underlying illness at the time of Myozyme™ infusion appeared to be at greater risk for IARs, thus careful consideration should be given to the patient’s clinical status prior to administration of Myozyme™

The majority of patients developed anti-Myozyme™ IgG antibodies

A tendency was observed for patients treated with a higher dose (40 mg/kg) to develop higher titres of antibodies

No correlation was observed between onset of IARs and the time of antibody formation; antibody titres should be regularly monitored

Important Note

Genzyme strongly recommends that you read the Myozyme™ Safety Information Packet, including the section on Infusion Management and the risk for potentially severe hypersensitivity reactions. This packet, along with other safety related information can be obtained by contacting us

References

1. Myozyme™ Summary of Product Characteristics

2. European Public Assessment Report (EPAR) Myozyme: EPAR Summary for the Public. European Medicines Agency. London 2006 http://www.emea.eu.int/humandocs/Humans/EPAR/myozyme/myozyme.htm

3. Data on file. Genzyme Corporation

4. American Thoracic Society. Lung function testing: selection of reference values and interpretive strategies. Am Rev Respir Dis 1991; 144:1202-18.

5. Redelmeier DA, Bayoumi AM, Goldstein RS, Guyatt GH. Interpreting small differences in functional status: the Six Minute Walk test in chronic lung disease patients. Am J Respir Crit Care Med 1997; 155:1278-82.

6. van der Ploeg A, Reuser A, Van Cappelle C. Early signs of benefit in children with late-onset Pompe disease following the first 6 months of treatment with enzyme replacement therapy (ERT) with recombinant human acid alpha glucosidase (rhGAA) in an open-label study. Abstract presented at The American College of Medical Genetics Annual Clinical Genetics Meeting, March 23-26, 2006, San Diego, CA.