Pipeline of GD & GBA-PD
Two Group Proportion Comparison
| progression window | scenario | control / base progression | target reduction | treated progression | confidence | power | tail | sample size per arm |
|---|---|---|---|---|---|---|---|---|
| GBA activity tertile | ↓30% | 13.2% | 95% | 80% | 2 | 469 | ||
| GBA activity tertile | ↓30% | 13.2% | 95% | 70% | 2 | 369 | ||
| GBA activity tertile | ↓40% | 12% | 95% | 80% | 2 | 329 | ||
| GBA activity tertile | ↓40% | 12% | 95% | 70% | 2 | 259 | ||
| 3yr (1.7) | patients with progression to MCI or dem | 38.4% | ↓40% | 23.04% | 95% | 70% | 2 | 111 |
| 1yr (위의 값들을 임의로 3으로 나눔) | patients with progression to MCI or dem | 12.8% | ↓40% | 7.68% | 95% | 70% | 2 | 433 |
GBA-PD / sPD / HC Biomarker Matrix
| row | GBA-PD | sPD | HC | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| GlcCer brain | GlcCer CSF | GlcSph brain | GlcSph CSF | GlcCer brain | GlcCer CSF | GlcSph brain | GlcSph CSF | GlcCer brain | GlcCer CSF | GlcSph brain | GlcSph CSF | |
| Tx goal | 그냥 PM bm | 그냥 PM bm | ||||||||||
| Increase? |
Huh에서 ↑18% 이니 brain도 ↑겠지. 반론: = (Gegg et al. 2015, PMID 26096906) | ↑18% (Huh et al. 2021, PMID 34811369) PPMI |
Plasma (Surface 2022 #2573)에서 크게 올랐으니 증가로 인정, but n=20? (Gundner et al. 2019, PMID 30236861 FIG S3: 본문과 달리 GBA+PD/DLB만 모아놓음. Cortex에서만 통계적 유의 & 1.6x SN & Putamen에서는 안 통계유의), = (Gegg et al. 2015, PMID 26096906), = (Leyns, 2022 #2182), (Huebecker et al. 2019, PMID 31703585): non-significant increase to ~165% in patients aged 70-79 y and a statistically significant increase to ~215% in patients aged >80. | GAP!! |
=, (Huh et al. 2021, PMID 34811369) PPMI ↑ (Lerche, 2021 #2575, PPMI) | |||||||
| GBA GT (literature) | No data | No data | No data in WT | No data in WT | ||||||||
| Prevail | ↓75% CSF | 크게 낮췄겠지 (ie NHP DMPK 에서 GlcCer ↓~84% associated with GlcSph ↓~53%). 그러니 거의 50% 줄었겠지. | 원래 안 올랐는데도 ↓(mice) | ↓(25%) Sardi 2017 fig.s2 WT mice | ↓(NHP, DMPK) (↓60% plasma) | ↓(NHP, DMPK) | ↓(NHP, DMPK) | |||||
| GBA GT (Tsho NHP) | GlcSph measure in brain is on hold prioritizing other pivotal PKPD studies. | CSF GlcSph was not significantly reduced after administration of AAV1/5/9. | ||||||||||
Cognitive Readouts
| readout / row | PD-all | PD-N | PD-MCI | PDD |
|---|---|---|---|---|
| MOCA | ||||
| MMSE / Longi progression | -(Burton, 2005 #630) MMSE: -1.3 (3.8) | |||
| vMRI / Longi progression | (Hanganu, 2014 #834) (n=17) Cortical thickness: -1.34% per 19.8 month | (Burton, 2005 #630) - Rate of atrophy (whole brain) per year (%): 1.12 ± 0.98 | ||
| Longi Correlation with MOCA | (Hanganu, 2014 #834) correlated with MOCA | |||
| Neuronal loss / Cross-sectional | (Gratwicke, 2015 #869) 2nd, The NBM degenerates in Parkinson's disease, with human neuropathological series showing 32% cell loss in non-demented patients, rising to 54-70% in PDD, which is closely associated with increasing cortical cholinergic deficits and worsening cognitive impairment (Whitehouse et al., 1983; Gaspar and Gray, 1984; Perry et al., 1985; Hall et al., 2014) | |||
| LB / Cross-sectional | (Irwin et al. 2012, PMID) CLB/LN pathology is the most significant correlate of dementia. | |||
| (Dues 2023) / Pff mouse |
↓ NeuN in CA2/3 Hippocampus. Cognitive performance is associated with neuronal loss in the CA2/3 subfield but not residual α-synuclein burden. | |||
Summary
GD type 3에는 Venglustat 밖에 없으니 무주공산이구나!
| category | therapy / program | GD type | PD | status | route | dosing interval | dose |
|---|---|---|---|---|---|---|---|
| ERT | imiglucerase (Cerezyme; Genzyme Corp) | Type 1 (ped and adult) | marketed | IV (over 1-2h) | 2 week | Maximal dose: 1U/kg/min = 60 u/kg/h | |
| ERT | velaglucerase alfa (Vpriv; Shire HGT). | market-ed | |||||
| ERT | A plant-cell-expressed recombinant GBA (Taliglucerase; Protalix/Pfizer). | Clinical trial | |||||
| GCSi | iminosugar N-butyldeoxinojirimycin (Miglustat; Zavesca, Actelion). | Type 1 (mild to moderate patients who are unsuitable for ERT (EMA) or in whom ERT is not a therapeutic option (FDA)). | NA | Marketed | Oral | TID | |
| GCSi | Eliglustat tartrate Cerdelga® Genzyme |
Type 1: for the longterm treatment of adult GD1. 2,3상을 9-12m간 ERT 안 받은 환자 대상으로 했고, 장기임상도 했음. | ? | marketed | Oral | 80mg bid (EM), 80 qd (PM) | |
| GCSi | venglustat | 1+3 -> 3 only | GBA+PD (Heteroz) | Clinical trial | |||
| GBA activator | Ambroxol | 1 | GBA+PD (Heteroz) vs PD only; PDD | ||||
| test | test | - |
Isofagomine
| compound | section | phase | disease | primary outcome | secondary |
|---|---|---|---|---|---|
| Isofagomine | Mechanism / Clinical trials | P2 | GD | All patients experienced an increase in GBA activity in blood cells, but only 1 patient demonstrated a meaningful reduction in disease symptoms. | Secondary |
Eliglustat
Glucosylceramide, GlcSph, a-syn
| trial / phase | target patient | No | design | Tx | primary outcome | secondary / notes | trial ID |
|---|---|---|---|---|---|---|---|
| P3 ENCORE | GD type 1 adults (≥18 years) who had received ERT for 3 years or more -> will be switched to oral eliglustat | 160 | randomized, OL, non-inferiority trial | 12m |
% change in hematological variable and organ volumes. Eliglustat group showed 85% versus imiglucerase group 94% were stable. Overall, oral eliglustat therapy was non-inferior to imiglucerase. | % in hemoglobin concentrations, platelet count, and spleen and liver volumes. | NCT00943111 |
| P3 ENGAGE | Untreated (for the past 9 m) GD1, no Sx of splenectomy | 40 | Eliglustat vs placebo | 9m | spleen volume | hemoglobin level and percent changes in liver volume and platelet count from baseline | NCT00891202 |
| P3 EDGE | QD vs BID of eliglustat in patients with GD1 who have demonstrated clinical stability on eliglustat twice daily | 171 | 8 y f/u results published 2018 Lukina | NCT00358150 |
Uncertain Spans
| location | unresolved text | reason |
|---|---|---|
| biomarker matrix row label | GBA GT (Tsho NHP) | Internal shorthand is faint; Tsho is the best visual reading. |
| biomarker matrix citation | Surface 2022 #2573 | Citation key is very small; OCR alternated, but Surface is the best visual reading. |
| cognitive readouts | (Irwin et al. 2012, PMID) | PMID number is not visible in this photo. |
| bottom eliglustat table | P3 EDGE design/outcome cells | Right-side cells in this row are clipped by the photo’s lower edge. |