Table 2.
Potential therapies for GNE myopathy
| Potential therapy | Preclinical evidence | Clinical trials in GNE myopathy patients | ||
|---|---|---|---|---|
| Mouse model (year) | Trial design (ClinicalTrials.gov Identifier) | Dosing, trial duration (number of patients) | Sponsor year |
|
| Substrate replacement therapies | ||||
| ManNAc |
Gne Met743Thr knock-in (2007, 2012) [68, 91] Gne Asp207Val transgenic (2009) [67] |
Phase 1, randomized, double-blind, placebo-controlled (NCT01634750) [1] | Oral, single dose of 3 g, 6 g, and 10 g (n = 22) |
NHGRI/NCATS 2013–2014 |
| Phase 2, open label (NCT02346461) | Oral 6 g BID, 30 months (n = 12) |
NHGRI/NCATS 2015–2017 |
||
| Phase 3, randomized, double-blind, placebo-controlled | Oral 4 g TID, 24 months (tbd) | Planned 2018 | ||
| Neu5Ac | Gne Asp207Val transgenic (2009) [67] | Phase 1, open label (NCT01236898) | oral sialic acid, single and multiple doses, up to 800 mg TID for 5 days (n = 6) |
Tohoku University 2010–2011 |
| Phase 1, open label (NCT01359319) | Ace-ER single and repeat dosing (n = 26) |
Ultragenyx 2011–2012 |
||
| Phase 2, randomized, double-blind, placebo-controlled (NCT01517880) [94] | Ace-ER 3 or 6 g/day, 48 weeks (n = 47) |
Ultragenyx 2012–2013 |
||
| Phase 2, open label (NCT01830972)* | Ace-ER/SA-IR 3 g, 6 g, 12 g/day, 48 weeks (n = 59) |
Ultragenyx 2013–2017 |
||
| Phase 2, open label, safety (NCT02731690) | Ace-ER 6 g/day, 48 weeks (n = 45) |
Ultragenyx 2016–2018† |
||
| Phase 3, randomized, double-blind, placebo-controlled (NCT02377921) | Ace-ER 2 g TID, 48 weeks (n = 89) |
Ultragenyx 2015–2017 |
||
| Phase 3, open-label extension (NCT02736188) | Ace-ER 2 g TID, 24 months (n = 144) |
Ultragenyx 2016–2020† |
||
| Peracetylated ManNAc | Gne Asp207Val transgenic (2012) [82] | None | – | – |
| Sialylated glycan therapies | ||||
| Sialyllactose | Gne Asp207Val transgenic (2009, 2014) [67, 83] | None | – | – |
| IVIG | – | Phase 1, open label (NCT00195637) [92] | IVIG 1 g/kg, 400 mg/kg, 4 weeks (n = 4) |
NHGRI, NIH 2005–2006 |
| Gene-based therapies | ||||
| GNE cDNA-Lipoplex | BALB/c wild type [111] | Single patient “compassionate use” (not on ClinicalTrials.gov) [110] | Intramuscular, multiple doses GNE cDNA-lipoplex (n = 1) |
Gradalis Inc. 2008–2009 |
| Single patient “compassionate use” (not on ClinicalTrials.gov) [102] | Intravenous GNE cDNA-lipoplex, every 60 days, 7 doses total (n = 1) |
Gradalis Inc. 2009–2010 |
||
| AAV8-GNE cDNA |
C57BL/6 wild-type mice [84] GNE myopathy human myoblasts [84] |
– | – | – |
| AAV8 trans-splicing | GNE myopathy human myoblasts [104] | – | – | – |
Ace-ER = extended-release sialic acid; BID = twice daily; IVIG = intravenous immunoglobulin; NHGRI = National Human Genome Research Institute; NCATS = National Center for Advancing Translational Sciences; SA-IR = immediate-release sialic acid; TID = three times a day
*Results posted on ClinicalTrials.gov
†Studies ended prematurely