Baseline patient characteristics are summarized in . Three patients (D, E, and H) had sibling(s) with classic infantile Pompe disease who had died of cardiorespiratory failure before they reached 1 year of age. All patients had marked cardiomyopathy at presentation. Four patients had the frog-legged posture and “floppy baby” appearance characteristic of patients with an advanced stage of disease progression; 3 of these patients required tube feeding. Although no patients required ventilator assistance at study entry, 4 patients required supplemental oxygen.
Patient demographics and baseline characteristics
Six patients were CRIM-positive by using Western blot; 2 patients were CRIM-negative. The association between CRIM status and the type of GAA gene mutations was examined in 6 patients for whom consent was obtained to perform both analyses (). The 4 patients who were CRIM-positive with available mutation data showed various combinations of missense alleles, deletions, and premature stop codons, indicating that they made detectable but nonfunctional GAA proteins. Of the 2 patients who were CRIM-negative, patient B had a large deletion allele and a frameshift allele; patient H had 2 premature stop codon alleles.
CRIM status and GAA gene mutation analysis
Treatment with rhGAA was generally well tolerated. Safety data are reported here for the entire study period including the extension (as long as 153 weeks from the first rhGAA infusion). All patients experienced at least 1 AE; most were mild to moderate, were caused by complications of Pompe disease, and were deemed unrelated to rhGAA therapy. Seven of 8 patients experienced at least 1 IAR, including skin rash (urticaria-like, maculopapular, or erythematous), fever, rigors, blood pressure or heart rate changes, or bronchospasm; no IARs were considered severe. IARs were effectively treated by slowing or transiently interrupting the infusion or with acetaminophen, antihistaminics, and/or corticosteroids (administered before infusion or during reactions). No patient had IAR sequelae or discontinued rhGAA treatment because of unmanageable recurrent IARs.
IgG antibodies to rhGAA developed in all 8 patients by week 8 of treatment with rhGAA (). After 52 weeks of treatment, anti-rhGAA IgG titers significantly decreased (>4-fold) in patients A and E and remained unchanged in the other patients. Patients F, G, and H each had a single positive test for IgE; all tested negative at subsequent assessments and continued to receive rhGAA without difficulty. No patients had evidence of inhibitory antibodies (capable of inhibiting >10% of rhGAA activity) with an in vitro assay.
Antibody titers against rhGAA with time. Log dilution titer is shown in the left y-axis; dilution titer is shown in the right y-axis.
Six of 8 patients completed the full 52-week treatment period. Patients B and G died at ages of 14.7 months and 18.3 months, after 43 and 16 weeks of rhGAA therapy, respectively; neither death was rhGAA-related. Patient B, who started ERT at 4.8 months of age, died after a hospitalization for progressive respiratory distress and pulmonary edema. Patient G, who started ERT at 14.6 months of age with very advanced disease, died of respiratory insufficiency caused by pneumonia and cardiac arrest.
After 52 weeks of treatment, 5 of 8 patients were alive without invasive ventilator support, and 1 patient was alive with invasive ventilator support. Patient H became ventilator-dependent at age 11.3 months, after a pneumonia episode occurring 15 weeks after treatment initiation.
All patients, regardless of disease stage at study entry, showed sustained improvements in cardiomyopathy as measured by means of LVMI (). At baseline, all 8 patients showed elevated LVMI. The mean improvement rate for the 6 patients with LVMI data at both baseline and week 52 (patients A, C, D, E, F, and H) was 68.7%. Two patients (patients B and G) who died before completing 52 weeks of treatment also showed marked LVMI decreases during treatment ().
Changes in left ventricular mass index
LVMI results with time. LVMI was calculated from 2-dimensional echocardiography by a central cardiologist reader.
As shown in , 4 patients (patients B, C, D, and G) entered the trial at a very advanced stage of the disease and were unable to bear weight on their lower limbs. The remaining 4 patients showed severe or generalized hypotonia and head-lag. During the first 52 weeks of rhGAA treatment, 5 patients showed consistent gains in AIMS raw scores and motor-age equivalents (data not shown). The 3 patients with the most marked AIMS gains (patients A, E, and F) ultimately walked independently; the AIMS scores for patients A and E were higher than the 5th percentile for chronological age at week 52. Two patients with more modest AIMS gains (patients C and D) demonstrated improved trunk and upper limb strength and eventually became able to sit independently and roll over, respectively. Patients B and H had only transient gains in AIMS raw scores and motor age equivalents; patient G showed no measurable motor gains at any point.
Mental and Behavioral Development
Although there are no data to suggest that patients with Pompe disease develop cognitive impairment, patients with infantile-onset Pompe disease that is untreated typically do not live long enough or are too ill for cognitive function to be reliably evaluated. Clear and consistent gains in BSID-II mental raw scores and developmental age equivalents were observed in 7 of 7 patients during the first 52 weeks, indicating the continued acquisition of cognitive, language, and personal and social development skills (data not shown). Scores for patient G were excluded because evaluations could not be administered in a standardized manner after the patient was invasively ventilated in an intensive-care unit.
During the first 52 weeks of treatment, 7 of 8 patients showed continuous increases in body weight and length (), resulting in maintenance or improvement in percentile rankings on the basis of Center for Disease Control/National Center for Health Statistics weight and length growth charts. Weight remained unchanged in patient G, whose percentile rank thus dropped by the time of death, 16 weeks after rhGAA treatment began.
Mean weight and length z-scores with time.
The 3 patients (patients A, E, and F) who eventually walked independently also had normal hearing at baseline and throughout the study, including the extension phase. The remaining patients had abnormal hearing either at baseline (patients D and G) or at various other points, including the extension phase (patients B, C, and H). Frequent middle ear effusions complicated interpretation; however, flat OAE, abnormal wave latencies in BAER, or both suggest that, at least in some cases, there was inner ear, auditory nervous system pathology, or both contributing to these abnormal test results.
Analysis of Skeletal Muscle
GAA activity and glycogen content were measured in the quadriceps muscles of 6 patients at baseline and at treatment weeks 12 and 52. In all 6 patients, muscle GAA activity was lower than detectable limits at baseline, increased substantially after the first 12 weeks of treatment, and remained higher than baseline through 52 weeks of treatment (). The effect on glycogen in skeletal muscle varied among the patients. Of the patients who walked independently, 1 patient (patient F) showed stabilization of baseline muscle glycogen content and 2 patients (patients A and E) showed marked glycogen reduction. The remaining patients showed either no change (patients B and G; week 12 biopsy) or an increase in glycogen content (patients C, D, and H; week 52 biopsy).
Muscle GAA activity and glycogen content results (quadriceps muscle)
Six of 8 patients were enrolled into the extension trial, the results of which include evaluations performed after the first 52 weeks of treatment; the total duration of rhGAA treatment (initial plus extension) was as long as 153 weeks. Although in some patients variability in LVMI measurements was observed, all 6 patients showed further decreases in LVMI, which remained significantly lower than at baseline. Similarly, gains in growth parameters after the first 52 weeks of treatment were also observed in all patients who survived. All patients except patient H achieved new motor milestones and maintained previously acquired ones. Patients A and E became able to climb up and down stairs, kick a ball, and ride a tricycle; both are currently >3 years old. Patient F also walked independently. The 4 patients (patients A, C, E, and F) who underwent BSID-II all demonstrated gains in mental raw scores and developmental age equivalents. However, 4 patients died during the extension phase of ERT (patients C, D, F, and H). Patient C died at age 33.8 months after sustaining neurological injury after prolonged resuscitation maneuvers for respiratory insufficiency caused by acute pneumonia. Patient D died of pneumonia and respiratory failure (the family declined invasive ventilation) at the age of 24.8 months. Patient F died unexpectedly at age 32.1 months of a respiratory infection. She had demonstrated marked decreases in LVMI, remained ventilator-free, and was able to walk independently at the time of her death. After becoming ventilator-dependent after an episode of pneumonia, patient H discontinued treatment at the age of 18.5 months in accord with family wishes and died approximately 5 months later. The median age at death (or treatment withdrawal) for all 6 patients who died during the initial 52-week trial and its extension phase was 21.7 months (range, 14.7–33.8 months).