Establishing Treatment Effectiveness in Fabry Disease: Observation-Based Recommendations for Improvement
Abstract
:1. Introduction
2. Fabry Disease-Specific Therapies
2.1. Enzyme Replacement Therapy
2.2. Chaperone Therapy
2.3. Second Generation Enzyme Replacement Therapy
3. Meta-Analyses of FD-Specific Therapy
3.1. Meta-Analyses on the Effect of Enzyme Replacement Therapy
3.2. Evaluation of Meta-Analyses on the Effect of Enzyme Replacement Therapy
4. Recent Evaluations of FD-Specific Therapies
4.1. Recent Studies on the Effect of ERT (Agalsidase Alfa and Agalsidase Beta)
4.2. Evaluation of Recent Studies on the Effect of ERT
4.3. Phase 3 Studies on the Effect of Migalastat
4.4. Evaluation of Phase 3 Studies on the Effect of Migalastat
4.5. Phase 3 Study on the Effect of Pegunigalsidase Alfa
Study | Follow-Up | Analyzed FD Patients (% Male, if Combined) | Pegunigalsidase-α or Migalastat | Agalsidase-α or Agalsidase-β Treated | Outcomes | Results (IMP vs. Control) Mean ± SD/Mean (95% CI)/ %/Median [95% CI] | ||
---|---|---|---|---|---|---|---|---|
Treated | Age | Untreated | Age | |||||
Germain 2016 [35] Migalastat vs. untreated | 6 mos | Combined analysis of males and females | n = 28 (32.1%) | 41.5 ± 13 y/o | n = 22 (40.9%) | 45.1 ± 8 y/o | - LVMI † (g/m2) | −0.4 ± 8.2 vs. 6.3 ± 15.3 |
- eGFR ‡ (mL/min/1.73 m2) | 1.8 ± 1.5 vs. −0.3 ± 1.4 | |||||||
- mGFR # (mL/min/1.73 m2) | −1.19 ± 3.4 vs. 0.41 ± 2.0 | |||||||
- Urinary protein excretion (mg/24 h) | 2.2 ± 252 vs. −12.9 ± 224 | |||||||
Hughes 2017 [36] Migalastat vs. agalsidase alfa/ agalsidase beta | 18 mos | Combined analysis of males and females | n = 36 (44.4%) | 50.5 ± 2.3 y/o | n = 21 (42.9%) | 46.3 ± 3.3 y/o | - eGFR ‡ (mL/min/1.73 m2) | −0.40 (−2.27, 1.48) vs. −1.03 (−3.64, 1.58) |
- eGFR ¶ (mL/min/1.73 m2) | −1.51 (−3.43, 0.40) vs. −1.53 (−4.20, 1.13) | |||||||
- mGFR # (mL/min/1.73 m2) | −4.35 (−7.65, −1.06) vs. −3.24 (−7.81, 1.33) | |||||||
- LVPWT † (mm) | −0.35 (−0.77, 0.07) vs. 0.029 (−0.37, 0.94) | |||||||
- IVSWT † (mm) | 0.58 (−2.00, 1.40) vs. 0.37 (−0.51, 1.24) | |||||||
- LVEF † (%) | −1.07 ± 0.53 vs. −0.49 ± 1.1 ‡‡ | |||||||
- LVMI † (g/m2) | −6.6 (−11.0, −2.2) vs. −2.0 [−11.0. 7.0] | |||||||
- Clinical events †† | 29% vs. 44% | |||||||
Subgroup analysis: | - with LVH | n = 13 (30.8%) | NS | n = 5 (80%) | NS | - LVMI † (g/m2) | −8.4 (−15.7, 2.6) vs. 4.5 (−20.9, 30.0) | |
Wallace 2023 [39] Pegunigalsidase alfa vs. agalsidase beta | 24 mos | Combined analysis of males and females | n = 52 (55.8%) | 43.9 ± 10.2 y/o | n = 25 (72%) | 44.3 ± 10 y/o | - eGFR ‡ (mL/min/1.73 m2) | −2.51 [−3.79, −1.24] vs. −2.16 [−3.81, −0.51] |
Subgroup analysis: | - males | n = 29 | 42.6 ± 11.5 y/o | n = 18 | 46.5 ± 6.9 y/o | - eGFR ‡ (mL/min/1.73 m2) | −3.44 [−5.38, −1.50] vs. −2.01 [−3.98, −0.04] | |
- females | n = 23 | 45.6 ± 8.3 y/o | n = 7 | 41.7 ± 14.5 y/o | - eGFR ‡ (mL/min/1.73 m2) | −1.15 [−3.11, −0.81] vs. −2.79 [−6.28, 0.70] |
4.6. Evaluation of Phase 3 Study on the Effect of Pegunigalsidase Alfa
5. Interpretation of the Results
6. Identified Problems and Recommendations for Future Studies
6.1. Problems: Comparisons of Dissimilar Groups, Lack of Accounting for Prognostic Factors, Inadequate Follow-Up, and Inappropriate Choice of Study Outcomes
6.2. Recommendations
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Appendix A
Appendix A.1. Search Strategy Meta-Analyses
Appendix B
Appendix B.1. Search Strategy Recent Studies
References
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Meta-Analysis | Included Studies (Follow-Up) | Analyzed FD Patients | FD Patients (% Male) and Number of Studies Reporting the Outcome | Outcomes | Results (Treated vs. Untreated) Mean (95% CI)/% (95% CI)/Median [IQR] | ||
---|---|---|---|---|---|---|---|
Treated | Untreated | ||||||
Alegra 2012 [20] Agalsidase alfa/agalsidase beta vs. untreated | 10 RCTs (NS) | Combined analysis of males and females | n = 50 (96%) 8 studies | n = 49 (100%) 8 studies | QRS-complex duration (ms) | No statistical difference | |
Rombach 2014 [21] Agalsidase alfa/agalsidase beta vs. untreated | 2 pooled analyses, 4 cohort studies (5 yrs) | Separate analysis of males † | |||||
- with baseline GFR >60 mL/min/1.73 m2 | n = 90 2 studies | n = 117 1 study | - GFR ‡ (mL/min/1.73 m2) | −2.57 (−3.21, −1.93) vs. −3.00 (−3.20, −2.80) | |||
- with baseline GFR <60 mL/min/1.73 m2 | n = 23 2 studies | n = 28 1 study | - GFR ‡ (mL/min/1.73 m2) | −3.04 (−4.99, −1.09) vs. −6.80 (−9.74, −3.86) * | |||
- with LVH at baseline | n = 20 2 studies | n = 18 1 study | - LVM § (g/m2.7) | 0.34 (−2.19, 2.88) vs. 6.59 (2.67, 10.51) * | |||
- w/o LVH at baseline (vs. untreated patients with and w/o LVH) | n = 41 2 studies | n = 39 1 study | - LVM § (g/m2.7) | 0.94 (0.41, 1.47) vs. 4.07 (3.76, 4.38) * | |||
Separate analysis of females † | |||||||
- with baseline GFR >60 mL/min/1.73 m2 | n = 52 2 studies | n = 42 1 study | - GFR ‡ (mL/min/1.73 m2) | −0.48 (−1.32, 0.36) vs. −0.90 (−2.66, 0.86) | |||
- with baseline GFR <60 mL/min/1.73 m2 | n = 6 2 studies | n = 13 1 study | - GFR ‡ (mL/min/1.73 m2) | −1.37 (−2.33, −0.41) vs. −2.10 (−5.24, 1.04) | |||
- with LVH at baseline | n = 38 2 studies | n = 15 1 study | - LVM § (g/m2.7) | −1.81 (−3.41, −0.21) vs. 3.77 (−0.13, 7.67) * | |||
- w/o LVH at baseline (vs. untreated patients with and w/o LVH) | n = 23 2 studies | n = 39 1 study | - LVM § (g/m2.7) | −0.57 (−1.37, 0.23) vs. 2.31 (2.06, 2.56) * | |||
Sheng 2019 [22] Agalsidase alfa/agalsidase beta vs. untreated | 2 RCTs, 7 cohort studies (4.5 yrs) | Combined analysis of males and females | n = 1471 (62.5%) 8 studies | n = 6042 (49.1%) 5 studies | - Ischemic stroke recurrence rate | 8.2% (3.8%, 12.6%) vs. 16% (10.2%, 21.7%) * | |
Ortiz 2020 [23] Agalsidase beta vs. untreated | 2 RCTs, 8 cohort studies (2.9 ± 1.4 yrs) | Combined analysis of males and females | n = 133 (68.3%) 8 studies | n = 182 (92.9%) 3 studies | - eGFR ¶ (mL/min/1.73 m2) | −1.01 [−3.64, 1.10] vs. −3.47 [−7.74, 0.17] * | |
Lee 2022 [24] Agalsidase alfa/agalsidase beta vs. untreated | 2 RCTs, 5 cohort studies (4.1 yrs) | Combined analysis of males and females | n = 267 (55.1%) 7 studies | n = 285 (44.6%) 7 studies | - LVMI § (g/m2) | −0.149 (−0.431, 0.132) # | |
Meta-Analyses | Included Studies (Follow-Up) | Analyzed FD Patients | FD Patients and Number of Studies Reporting the Outcome | Outcomes | Results (Agal-α vs. Agal-β vs. Untreated) % (95% CI) | ||
Agal-α | Agal-β | Untreated | |||||
El Dib 2017 [15] Agalsidase alfa vs. agalsidase beta vs. untreated | 39 cohort studies (NS) | Combined analysis of males and females | n = 344 6 studies | n = 1053 2 studies | n = 812 6 studies | - All-cause mortality | 9% (3%, 16%) vs. 4.4% (0.2%, 20.1%) vs. 10.8% (2.05%, 25.2%) |
n = 168 6 studies | n = 1044 1 study | n = 1698 11 studies | - Renal complications †† | 15.3% (4.8%, 30.3%) vs. 6% (4%, 7%) * vs. 21.4% (15.2%, 28.4%) | |||
n = 524 4 studies | n = 1096 3 studies | n = 5854 14 studies | - Cardiovascular complications †† | 28% (7%, 55%) vs. 7% (5%, 8%) * vs. 26.2% (14.9%, 39.4%) | |||
n = 461 7 studies | n = 1062 3 studies | n = 5544 15 studies | - Cerebrovascular complications †† | 11.1% (5.8%, 17.9%) vs. 3.5% (2.4%, 4.6%) ** vs. 17.8% (12.3%, 24%) | |||
Sensitivity analysis: | Excluding children | n = 309 4 studies | n = 1053 2 studies | n = 812 6 studies | - All-cause mortality | 12% (6%, 20%) vs. 4.4% (0.2%, 20.1%) vs. 10.8% (2.05%, 25.2%) | |
n = 152 5 studies | n = 1044 1 study | n = 1698 11 studies | - Renal complications †† | 16.8% (4.1%, 35.6%) vs. 6% (4%, 7%) * vs. 21.4% (15.2%, 28.4%) | |||
n = 426 3 studies | n = 1053 4 studies | n = 5854 14 studies | - Cardiovascular complications †† | 35% (11%, 65%) vs. 7% (5%, 8%) * vs. 26.2% (14.9%, 39.4%) | |||
n = 339 5 studies | n = 1062 3 studies | n = 5544 15 studies | - Cerebrovascular complications †† | 10.5% (4.3%, 19%) vs. 3.5% (2.4%, 4.6%) ** vs. 17.8% (12.3%, 24%) |
Study | Follow-Up | Analyzed FD Patients (% Male, If Combined) | Treated | Age | Untreated | Age | Outcomes | Results (Treated vs. Untreated) Mean ± SD/ Median [Range]/% |
---|---|---|---|---|---|---|---|---|
Hongo 2018 [29] Agalsidase alfa/agalsidase beta vs. untreated | 11.6 ± 2.4 yrs | Separate analysis of males | n = 17 | 30.7 ± 9.5 y/o | n = 39 | 31.3 ± 11.9 y/o | - LVM † indexed to height (g/ht2.7/year) | 1.25 ± 1.39 vs. 4.07 ± 1.03 * |
Subgroup analysis: | - with LVH | n = 6 | NS | n = 18 | NS | - LVM † indexed to height (g/ht2.7/year) | 1.51 ± 1.32 vs. 6.59 ± 8.5 | |
- w/o extensive LVH | n = 14 | 27.8 ± 8.1 y/o | n = 39 | 31.3 ± 11.9 y/o | - LVM † indexed to height (g/ht2.7/year) | 1.00 ± 1.36 vs. 4.07 ± 1.03 * | ||
- matched on LVM | n = 8 | 36.3 ± 7.6 y/o | n = 39 | 31.3 ± 11.9 y/o | - LVM † indexed to height (g/ht2.7/year) | 1.59 ± 1.23 vs. 4.07 ± 1.03 * | ||
7.4 ± 3.0 yrs | Separate analysis of females | n = 25 | 40.6 ± 14.2 y/o | n = 39 | 36.3 ± 17.4 y/o | - LVM † indexed to height (g/ht2.7/year) | 0.78 ± 1.23 vs. 2.31 ± 0.81 * | |
Subgroup analysis: | - with LVH | n = 7 | NS | n = 15 | NS | - LVM † indexed to height (g/ht2.7/year) | 1.54 ± 1.37 vs. 3.77 ± 7.7 | |
- w/o extensive LVH | n = 22 | 39.1 ± 14.4 y/o | n = 39 | 36.3 ± 17.4 y/o | - LVM † indexed to height (g/ht2.7/year) | 0.70 ± 1.17 vs. 2.31 ± 0.81 * | ||
- matched on LVM | n = 16 | 46.5 ± 14.1 y/o | n = 39 | 36.3 ± 17.4 y/o | - LVM † indexed to height (g/ht2.7/year) | 1.00 ± 1.25 vs. 2.31 ± 0.81 * | ||
Nordin 2019 [30] Agalsidase alfa/agalsidase beta vs. untreated | 1.1 ± 0.2 yrs | Combined analysis of males and females | n = 20 (35%) | 49 ± 10 y/o | n = 18 (16.7%) | 41 ± 12 y/o | - LVMI ‡ (g/m2) | Unchanged vs. Increased |
- Native T1 (ms) | Increased vs. Decreased | |||||||
- T2 (ms) | Unchanged vs. Unchanged | |||||||
- Troponin T (ng/L) | Unchanged vs. Increased | |||||||
Van der Veen 2022 [31] Agalsidase beta vs. untreated | Cross-sectional | Separate analysis of males | n = 7 | 24 [14, 26] y/o | n = 23 | 22 [13, 27] y/o | - LVM † (g/m2) | 80 [67, 84] vs. 94 [59, 149] * |
- LVM ‡ (g/m2) | 53 [46, 59] vs. 68 [53, 99] * | |||||||
- uACR (mg/mmol) | 0,4 [0, 8.8] vs. 3,7 [0, 248] * | |||||||
- eGFR § (mL/min/1.73 m2) | 116 [92, 132] vs. 116 [46, 165] | |||||||
- LGE | 0% vs. 0% | |||||||
- IRBBB | 0% vs. 31% | |||||||
- Sinus bradycardia | 14% vs. 52% | |||||||
- WML | 14% vs. 27% | |||||||
Pogoda 2023 [32] Agalsidase alfa/agalsidase beta vs. untreated | 6.3 ± 3.3 yrs | Separate analysis of females | n = 24 | 48 [25, 71] y/o | n = 30 | 28 [16, 68] y/o | 20 morphological and function echocardiography parameters (see Table 3 in original article) |
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Veldman, B.C.F.; Schoenmakers, D.H.; van Dussen, L.; Datema, M.R.; Langeveld, M. Establishing Treatment Effectiveness in Fabry Disease: Observation-Based Recommendations for Improvement. Int. J. Mol. Sci. 2024, 25, 9752. https://doi.org/10.3390/ijms25179752
Veldman BCF, Schoenmakers DH, van Dussen L, Datema MR, Langeveld M. Establishing Treatment Effectiveness in Fabry Disease: Observation-Based Recommendations for Improvement. International Journal of Molecular Sciences. 2024; 25(17):9752. https://doi.org/10.3390/ijms25179752
Chicago/Turabian StyleVeldman, Bram C. F., Daphne H. Schoenmakers, Laura van Dussen, Mareen R. Datema, and Mirjam Langeveld. 2024. "Establishing Treatment Effectiveness in Fabry Disease: Observation-Based Recommendations for Improvement" International Journal of Molecular Sciences 25, no. 17: 9752. https://doi.org/10.3390/ijms25179752