Real-world outcomes from a series of patients with late onset Pompe disease who switched from alglucosidase alfa to avalglucosidase alfa

Introduction: Pompe disease is an inherited, progressive neuromuscular disorder caused by deficiency of lysosomal acid α-glucosidase and accumulation of glycogen in tissues, resulting in cellular dysfunction, muscle damage, and functional disabilities. Enzyme replacement therapy with alglucosidase alfa (Myozyme/Lumizyme) has led to better outcomes, but many patients have plateaued or declined despite treatment. The second-generation ERT avalglucosidase alfa (Nexviazyme) was designed to have enhanced cellular uptake via the conjugation of additional bis-mannose-6-phosphate residues. There have been trials comparing the efficacy of alglucosidase and avalglucosidase, but there remains a need for more real-world data on patients who switched from alglucosidase to avalglucosidase. Methods: A chart review was conducted on n = 15 patients with late-onset Pompe disease followed at a single center who switched from alglucosidase to avalglucosidase and continued for at least 6 months. Results: A total of n = 8/15 patients received alglucosidase for more than 3 years prior to switching, and n = 7/15 received it for more than 5 years prior to switching. There were statistically significant improvements in CK, Hex4, and AST with mean differences of −104.8 U/L, −3.0 mmol/molCr, and −14.7 U/L, respectively, post-switch. 6-Minute Walk Test; comfortable gait speed; Gait, Stairs, Gower, Chair; and Quick Motor Function Test scores improved or stabilized in most patients post-switch (n = 8/12, n = 11/12, n = 9/12, n =7/11, respectively). Of n = 7 patients with pulmonary function testing, n = 4/7 had improved upright FVC. Patient-reported outcomes revealed improvements in dyspnea (n = 4/4), physical function (n = 3/4), fatigue (n = 2/3), and lower back pain (n = 3/3). Avalglucosidase was well tolerated without infusion-associated reactions, and all n = 7 patients on home infusions continued receiving ERT at home. Anti-drug antibodies were seen in n = 9/10 of patients on alglucosidase and n = 8/13 of those on avalglucosidase, with titers below 12,800 in a majority of patients. We also present the first outcome data for a patient with LOPD who is non-ambulatory and a full-time wheelchair user; she demonstrated meaningful improvements in quality of life and motor function with the switch. Discussion: In summary, improved outcomes were seen in most patients, with a subset whose decline persisted. This study presents evidence that switching from alglucosidase to avalglucosidase may be associated with improved outcomes in certain patients with LOPD.

Hip and knee flex 1.1.6Supplementary Table 6.9-hole peg test (9-HPT) results for Patient 13F.Times in seconds for completion of the standard or modified easy grip 9-HPT are listed for patient 13F prior to and after the switch to avalglucosidase alfa.Items in blue met the MDC of 0.15 m/s and the lower MCID cutoff of 18.9% and those in blue with green outline met the most stringent MCID of 31.1%.Two patients (4M and 7F) had changes that were significant using both MCID cutoffs at their most recent visits, but their baseline walking speeds were so slow that these cutoffs were lower than the MDC of 0.15 m/s; patient 4M (in green) met both MCID cutoffs for significant improvement, and patient 7F (in red) met both MCID cutoffs for significant decline.A two-tailed Wilcoxon signed rank test, a non-parametric alternative to the paired samples t-test which does not share its distributional assumptions, was used because the normality assumption was violated, and was also significant based at best post-switch at an alpha value of .05,V = 54.00,z = -2.70,p = .007which indicates that the differences are not likely due to random variation.

Days
Supplementary Figure2.. Above: an overview of 6MWT percent-predicted at evaluations before and after the switch.Colors are based on baseline GSGC level of functional impairment [mildly impaired in green (n=6), moderately impaired in yellow (n=2), and severely impaired in red (n=4)].Below: full data of individual scores over time.Color-coded vertical bars represent the starting points of ERT regimens, as described in Figures1 and 3. 1.2.3 Supplementary Figure 3. Gait, Stairs, Gower, Chair (GSGC).Above: an overview of GSGC scores at timepoints before and after the switch.For patients seen more than twice after the switch, the most recent score was used for the last time point.GSGC scores range from 4 to 27 with score of 4 indicating normal function.Colors are based on baseline GSGC level of functional impairment [mildly impaired in green (n=6), moderately impaired in yellow (n=2), and severely impaired in red (n=4)].Below: full data of individual scores over time.Colorcoded vertical bars represent the starting points of ERT regimens, as described in Figures 1 (sit to stand) -Pre vs best post-switch (two-tailed Wilcoxon signed rank test)

Table 2 .
ALT and Hex4 Trends.Baseline values are the last known values prior to initiating ERT.Alglucosidase values are the last known values prior to the switch.Avalglucosidase values are the most recent values available in the chart.Other timepoints were taken into account when selecting these to ensure that general trends were reflected.Full data is available in Supplementary Figure1.

Table 3 .
Anti-alglucosidase Antibody Titers.Most recent and peak antialglucosidase antibody titers with months before switch to avalglucosidase.

Table 4 .
Anti-avalglucosidase Antibody Titers.Most recent and peak antiavalglucosidase antibody titers with months since switch to avalglucosidase.

Table 5 .
Quick Motor Function Test (QMFT).Changes in QMFT total score (green improved, blue stable, red declined) with additional breakdown by task item.No MCD or MCID has been established for this test.Scores range from 0 to 64, with a score of 64 indicating normal function.

Table 7 .
Comfortable gait speeds at each visit before and after the switch from alglucosidase to avalglucosidase.
All lab data available for CK, AST, and Hex4 graphed for all 15 patients by age.Color-coded vertical bars represent the starting points of ERT regimens, as described in Figures1 and 3.