Online SupplementalTable S4.Characteristics of IOPD patients receiving concomitant immune modulation therapies

Concomitant immuno-modulatory therapies / IgG titer trajectory / GAA Genotype / CRIM status / Other features / SAEs / IARs or potentially immune-mediated AEs / Week 52 efficacy outcomes
1. Rituximab, methotrexate, intravenous immunoglobulin; bortezomib / 3200 (Week −1);
6400 (Weeks 4–16); 3200 (Weeks 20–24); 6400 (Weeks 26–36); 3200 (Weeks 40–70); 6400 (Week 78);
3200 (Week 84);
1600 (Week 92);
6400 (Week 105);
1600 (Week 118);
3200 (Week 130) / Nonsense c.1654delC / c.2560C>T
(p.Leu552fs*26 / p.Arg854*) / Negative / Arrhythmia and cardiomegaly; decreased systolic function
Abnormal ECG
BLrestricted antigravity movement and invasive ventilation
Wheelchair/stander user / Aspiration pneumonitis / No IARs or potentially anaphylactic AEs reported / Stable (LVM-Z BL −3.83, Week 52 +3.43; GMFM-88 BL 9, Week 52 −3.1)
2. Rituximab, methotrexate / 3200 (Week -2);
1600 (Weeks 4–12); 6400 (Week 16);
3200 (Weeks 20–48) / Homozygous nonsense c.2560C>T / c.2560C>T (p.Arg854* / p.Arg854*) / Negative / BL: Noninvasive ventilation;
Died on extension (Week 53) of respiratory distress / Respiratory distress (2 events, the 2nd one fatal); pneumonia (2 events) / AEs potentially indicating anaphylaxis: cough, respiratory distress (2 events) / No week 52 data. Died at week 53 of respiratory distress
3. Rituximab, methotrexate, intravenous immunoglobulin / 200 (Weeks 0–9);
100 (Weeks 12–13); 200 (Week 16);
400 (Week 20);
800 (Weeks 24–28); 1600 (Week 32);
800 (Week 36);
100 (Weeks 40–48); <100(Weeks 52–88); 100 (Weeks 101–117) / Deletion c.2481+102_c.2646+31del / Missense c.307T>G
(p.Gly828_Asn882del / p.Cys103Gly) / Positive / BL: Invasive- ventilator- dependence; restricted antigravity movement; abnormal ECG / Peripherally inserted central catheter
Infection / No AEs potentially indicating anaphylaxis; no possibly/ probably related AEs within 48 hours of infusion / Stable (LVM-Z BL 1.21, Week 52 −0.24; GMFM-88 BL 1.6, Week −0.8)
4. Rituximab, methotrexate, intravenous immunoglobulin / 6400 (Week -2);
25,600 (Weeks 4–8);
12800 (Weeks 13–18); 6400 (Weeks 22–26); 3200 (Weeks 30–42) / Missing genotype data / Missing data / BL: history of allergy to
160L rhGAA; invasive- ventilator- dependence; restricted antigravity movement.
During the study: Abnormal ECG; IAR of tachypnea, wheezing and decreased blood pressure (possible allergy). Abnormal ALT at Week 42. / Respiratory failure; hypoxia; respiratory distress; cardiac arrest / IARs: tachypnea, wheezing, decreased blood pressure, tachycardia, low grade fever (2 events)—also potential anaphylactic or hypersensitiv-ity events
Potential IARs: hyperactivity / Died of cardiac failure at week 45.
LVM-Z BL 10.02, no week 26 data; GMFM-88 BL 7.1, Week 26 −6.7)
5. Rituximab, intravenous immunoglobulin; sirolimus / SN throughout / Nonsense c.1396delG / c.1705dupT(p.Val466 fs*11 /p.Tyr569fs*67) / Negative / Abnormal ECG; Sitter at BL / Urinary tract infection, congestive heart failure, mitral valve regurgitation, umbilical abscess; experimental gene therapy / IARs: edema
AEs potentially indicating anaphylaxis:Edema, increased cough, erythematous rash, cough (3 events) / Missing week 52 data/stable at week 26 (GMFM-88 BL 21.7, Week 26 −2.4; no Week 52 data)
6. Rituximab, intravenous immunoglobulin / 1600 (Week −1);
3200 (Week 2);
1600 (Week 4);
3200 (Weeks 8–16); 1600 (Week 20);
6400 (Week 24);
3200 (Weeks 30–32); 12,800 (Week 36);6400 (Week 40);
3200 (Week 52);
1600 (Weeks 64−74); 6400 (Week 79) / Frameshift/
Nonsense c.1292_1295dupTGCA / Nonsense c.2560C>T
(p.Gln433fs*74 / p.Arg854*) / Negative / Normal ECG at BL, Week 52, and extension; abnormal ECG at Week 26; Sitter and invasive- ventilator-dependent at BL / Broncho-scopy with granuloma removal requiring hospitaliza-tion; post- fractured Broviac line; local port infection; bacteremia; respiratory distress; metapneumo-virus / AEs potentially indicating anaphylaxis: increased cough (2 events); rash; respiratory distress / Improved (LVM-Z BL −0.78, Week 26 +0.88, missing data Week 52; GMFM-88 BL 19.2, Week 52 +25.8)
7., Intravenous immunoglobulin (initiated before study entry and ongoing during the study; indication, “antibodies to rhGAA/immunomodulation”†) / SN (Weeks −1–16);
100 (Weeks 20–24); <100 (Week 28);
ND (Week 32);
100 (Week 36);
ND (Weeks 40–48);
200 (Week 52);
100 (Week 78);
200 (Week 98);
400 (Week 118) / Missense c.1933G>C / Nonsense c.2662G>T
(p.Asp645His /
p.Glu888*) / Positive / Cardiomegaly; gastrostomy tube and noninvasive ventilation at BL; used walker and wheelchair and has had multiple tendon release operations; sitter at BL; allergic to alglucosidase alfa / Respiratory distress, respiratory infection, pneumonia, respiratory distress, tracheitis / AEs potentially indicating anaphylaxis: respiratory distress (2 events), rash / Stable (LVM-Z BL −0.44, Week 52 −0.76; GMFM-88 BL 5.5, Week 52 +0.8)
8. Intravenous immunoglobulin (initiated and discontinued before study entry; indication: “decreased
immunoglobulins
because of
immuno-modulation
therapy prior to starting Myozyme”†) / ND (Weeks −1–28);
<100 (Week 32);
100 (Weeks 36–40); 200 (Weeks 44–52); 400 (Weeks 64–78), 200 (Weeks 92–116); 100 (Week 130) / Homozygous missense c.1844G>A / c.1844G>A
(p.Gly615Glu / p.Gly615Glu) / Positive / Cardiomegaly, Wolf-Parkinson-White syndrome,
short PR interval; ambulatory (supported stander) at BL; conductive hearing loss / Viral gastroenter-itis, urosepsis, sepsis, Mediport malfunction / IARs: Lack of improvement in myopathy
AEs potentially indicating anaphylaxis: Cough (7 events) / Improved (LVM-Z BL 10.26, Week 52 −4.54; GMFM-88 BL 59.2, Week 52 +22.5)
9. Intravenous immunoglobulin (initiated before study entry and overlapping the time of the study; indication: “immunodefi-ciency prevention”) / SN throughout / Homozygous nonsense c.2560C>T / c.2560C>T
(p.Arg854* / p.Arg854*) / Negative / Cardiomegaly, hypertrophic cardiomyopathy,supraventricular tachycardia; tube-feeding, wheelchair use, and nighttime invasive ventilation at BL; supported stander; patient received 160L rhGAA temporarily during study and returned to 4000L rhGAA / Pneumonia (2 events), supraventric-ular tachycardia, worsening gross motor function decline (2 events), acute respiratory infection / IARs: early repolarization, trace mitral and bicuspid regurgitation, right-sided voltage increase, right ventricular hypertrophy; AEs potentially indicating anaphylaxis: cough (5 events), hypoxemia, respiratory distress, right foot edema / Declined (LVM-Z BL −1.26, Week 52 −1.93; GMFM-88 BL 58.3, Week 52 −13.8)
10. Intravenous immunoglobulin (initiated after study entry and ongoing during the study; indication, “immunosup-pression”†) / SN throughout / Nonsense c.2237G>A / frameshift/nonsense c.1128_1129delinsC
(p.Trp746* / p.Trp376 fs*16) / Negative / Cardiomegaly
Ambulatory at BL
Patient had IAR of arthralgia when not seropositive; patient had SAE of LVH as an ECG finding due to decreased treatment response / Worsening bilateral eyelid ptosis, worsening left ventricular hypertrophy / IARs: upset stomach, bilateral weakness in wrists, worsening bilateral eyelid ptosis; AEs potentially indicating anaphylaxis: rash on upper back and left calf / Stable (LVM-Z BL 0.52, Week 26 +0.8, Week 52 missing data; GMFM-88 BL 87.9; Week 52 +7.4)

AE, adverse event; BL, baseline; CRIM, cross-reactive immunologic material; ECG, electrocardiogram; GMFM-88, Gross Motor Function-88; IAR, infusion-associated reaction; IgG, immunoglobulin G; IOPD, infantile-onset Pompe disease; LVH, left ventricular hypertrophy; LVM-Z, left ventricular mass Z-score; MedDRA, Medical Dictionary for Regulatory Activities; NA, not applicable; ND, not detected; rhGAA, recombinant human alpha-glucosidase (alglucosidase alfa); SAE, serious adverse event; SN, seronegative.

†Patients 7, 8, and 10had received other immunomodulatory treatment before ADVANCE enrollment; details of their prior immunomodulation are unavailable. Patients receiving intravenous immunoglobulin for immunosuppression or immunodeficiency prevention were not receiving it to alter anti-rhGAA IgG titers.