Safety, tolerability, pharmacokinetics, pharmacodynamics, and exploratory efficacy of the novel enzyme replacement therapy avalglucosidase alfa (neoGAA) in treatment-naïve and alglucosidase alfa-treated patients with late-onset Pompe disease: A phase 1, open-label, multicenter, multinational, ascending dose study.

This multicenter/multinational, open-label, ascending-dose study (NCT01898364) evaluated safety, tolerability, pharmacokinetics, pharmacodynamics, and exploratory efficacy of repeat-dose avalglucosidase alfa (neoGAA), a second-generation, recombinant acid α-glucosidase replacement therapy, in late-onset Pompe disease (LOPD). Patients ≥18 years, alglucosidase alfa naïve (Naïve) or previously receiving alglucosidase alfa for ≥9 months (Switch), with baseline FVC ≥50% predicted and independently ambulatory, received every-other-week avalglucosidase alfa 5, 10, or 20 mg/kg over 24 weeks. 9/10 Naïve and 12/14 Switch patients completed the study. Avalglucosidase alfa was well-tolerated; no deaths/life-threatening serious adverse events (SAEs). One Naïve patient withdrew for study drug-related SAEs (respiratory distress/chest discomfort). Infusion-associated reactions (IARs) affected 8 patients. Most treatment-emergent AEs/IARs were non-serious with mild-to-moderate intensity. At screening, 5 Switch patients tested positive for anti-avalglucosidase alfa antibodies; on-treatment, 2 Switch and 9 Naïve patients seroconverted. Post-infusion, avalglucosidase alfa plasma concentrations declined monoexponentially (t1/2z∼1.0 h). AUC was 5-6 × higher in the 20 vs 5 mg/kg group. Pharmacokinetics were similar between Switch and Naïve groups and over time. Baseline quadriceps muscle glycogen was low (∼6%) in most patients, generally remaining unchanged thereafter. Exploratory efficacy parameters (pulmonary function/functional capacity) generally remained stable or improved. Avalglucosidase alfa's well-tolerated safety profile and exploratory efficacy results support further avalglucosidase alfa development.

Efficacy, safety profile, and immunogenicity of alglucosidase alfa produced at the 4,000-liter scale in US children and adolescents with Pompe disease: ADVANCE, a phase IV, open-label, prospective study.

PURPOSE: Pompe disease results from lysosomal acid α-glucosidase (GAA) deficiency and its associated glycogen accumulation and muscle damage. Alglucosidase alfa (recombinant human GAA (rhGAA)) received approval in 2006 as a treatment for Pompe disease at the 160 L production scale. In 2010, larger-scale rhGAA was approved for patients up to 8 years old without cardiomyopathy. NCT01526785 evaluated 4,000 L rhGAA efficacy/safety in US infantile- or late-onset Pompe disease (IOPD, LOPD) patients up to 1 year old transitioned from 160 L rhGAA. METHODS: A total of 113 patients (87 with IOPD; 26 with LOPD) received 4,000 L rhGAA for 52 weeks dosed the same as previous 160 L rhGAA. Efficacy was calculated as the percentage of patients stable/improved at week 52 (without death, new requirement for invasive ventilation, left ventricular mass z-score increase >1 if baseline was >2, upright forced vital capacity decrease ≥15% predicted, or Gross Motor Function Measure-88 decrease ≥8 percentage points). Safety evaluation included an extension ≤20 months. RESULTS: Week 52 data was available for 104 patients, 100 of whom entered the extension. At week 52, 87/104 (83.7%) were stable/improved. Overall survival was 98.1% overall, 97.6% IOPD, 100% LOPD; 92.4% remained invasive ventilator-free (93.4% IOPD, 88.7% LOPD). Thirty-five patients had infusion-associated reactions. Eight IOPD patients died of drug-unrelated causes. CONCLUSIONS: Most Pompe disease patients were clinically stable/improved after transitioning to 4,000 L rhGAA. Safety profiles of both rhGAA forms were consistent.

Prospective exploratory muscle biopsy, imaging, and functional assessment in patients with late-onset Pompe disease treated with alglucosidase alfa: The EMBASSY Study.

BACKGROUND: Late-onset Pompe disease is characterized by progressive skeletal myopathy followed by respiratory muscle weakness, typically leading to loss of ambulation and respiratory failure. In this population, enzyme replacement therapy (ERT) with alglucosidase alfa has been shown to stabilize respiratory function and improve mobility and muscle strength. Muscle pathology and glycogen clearance from skeletal muscle in treatment-naïve adults after ERT have not been extensively examined. METHODS: This exploratory, open-label, multicenter study evaluated glycogen clearance in muscle tissue samples collected pre- and post- alglucosidase alfa treatment in treatment-naïve adults with late-onset Pompe disease. The primary endpoint was the quantitative reduction in percent tissue area occupied by glycogen in muscle biopsies from baseline to 6months. Secondary endpoints included qualitative histologic assessment of tissue glycogen distribution, secondary pathology changes, assessment of magnetic resonance images (MRIs) for intact muscle and fatty replacement, and functional assessments. RESULTS: Sixteen patients completed the study. After 6months of ERT, the percent tissue area occupied by glycogen in quadriceps and deltoid muscles decreased in 10 and 8 patients, respectively. No changes were detected on MRI from baseline to 6months. A majority of patients showed improvements on functional assessments after 6months of treatment. All treatment-related adverse events were mild or moderate. CONCLUSIONS: This exploratory study provides novel insights into the histopathologic effects of ERT in late-onset Pompe disease patients. Ultrastructural examination of muscle biopsies demonstrated reduced lysosomal glycogen after ERT. Findings are consistent with stabilization of disease by ERT in treatment-naïve patients with late-onset Pompe disease.

Distal femoral osteotomy: is internal fixation better than external?

BACKGROUND: Distal femoral osteotomies (DFO) can be used to correct deformities around the knee. Although osteotomies can be fixed with either internal or external fixation techniques, the advantages of one over the other are unclear. QUESTIONS/PURPOSES: We asked whether (1) for both techniques, we could accurately correct the deformities based on our preoperative goals for mechanical axis deviation (MAD) and lateral distal femoral angle (LDFA), and (2) intraoperative times, (3) preoperative and postoperative knee ROM, and (4) complications differed. PATIENTS AND METHODS: We identified 26 patients (34 limbs) who underwent femoral osteotomies. We compared accuracy of correction (based on correction of the MAD and the LDFA), duration of surgery, preoperative and postoperative knee ROM, and complications. The minimum followup was 20 months (mean, 29 months; range, 20-40 months). RESULTS: We achieved the desired MAD within 10 mm of the goal in 18 of 21 limbs with the unilateral frame and in 12 of 13 limbs using fixator-assisted plating. Operative time for fixator-assisted plating was longer (122 ± 34 minutes) than when using a unilateral frame (94 ± 65 minutes). Preoperative and postoperative knee ROMs were similar for both techniques and there were no major complications. CONCLUSIONS: We obtained accurate correction of deformities with both fixation techniques. Our experience suggests the method to be used should be left to the discretion of the surgeon and the needs and wishes of the patient after adequate explanation of the advantages and disadvantages. LEVEL OF EVIDENCE: Level III, therapeutic study. See the Guidelines for Authors for a complete description of levels of evidence.

Ipsilateral fibular transport using Ilizarov-Taylor spatial frame for a limb salvage reconstruction: a case report.

Segmental bone defects of the tibia present a challenging problem, particularly when they are associated with soft tissue injuries or instability. Various techniques have been reported to treat bone loss in the tibia. This case report describes a patient with massive segmental bone loss associated with a soft tissue injury, which required a flap for coverage. The injury was treated with an ipsilateral fibular transport utilizing an Ilizarov/Taylor spatial frame. At one and a half year follow-up, the patient was able to walk without any support at home and wore a protective shell for outdoor activities. The outcome of this case study indicates that ipsilateral fibular transport using the Ilizarov method is a valuable technique for limb salvage reconstruction.