AAV gene-therapy trial table tail, Yuhan section, VMAT2 PET ([18F]AV-133), and sample-size analysis
Animal model / clinical trial table tail (continues)
| decarboxylase, ↑ GABA) GT (Neurologix) → MeiraGTx | responsiveness for at least 12 m, UPDRS 3 score ≥ 25 | surgery and 22 to AAV2-GAD infusions; of those, 21 and 16, respectively, were analysed. [Sample size estimation] An effect size of 1.19 (derived from NCT00195143) was used, which corresponded to a sample size of 13 patients per group to achieve 80% power, '=0.05. group (1.5, 12.7%; p=0.003). (Niethammer, 2017 #1572) | 21) | open-label, | Not shown | PET scans revealed reduced thalamic metabolism on the implanted side which correlated with reduced pallidal activity | NCT00195143 | ||||
| P1 | hoehn and Yahr rating: 3 or greater and/or UPDRS: 30 or more in "off" state and/or Complications of l-dopa therapy limiting effective use | 12 | open-label | ||||||||
| VY-AADC02 (Voyager) (=NBIb-1817), | P2 RESTORE-1 | Advanced PD | into the brain. | 20201114) MRI abnormalities → FDA clinical hold → termination 202102 | 75-100 (before 40) | RCT DB, Placebo Surgery Controlled, | 12M | cxlvii) | cxlviii) | ||
| P1 | 2017 | 16 | open-label, one dose, 9.4 x 10^12 vector genomes o | AE's/SAE's) [: Baseline to 3 Y After | |||||||
| Gene Transfer | |||||||||||
| P1b | PD | 2013 | 15 | Three doses, (위보다 더 적은) | Safety & PD symptom: 3y, PET 6M | Putaminal coverage gadoteridol enhancement volumetrically, gadoteridol (a gadolinium-based contrast agent) | NCT01973543 | ||||
| NHP | |||||||||||
| hAADC (Jichi medical univ) | P1 | ||||||||||
| P1/2 | PD | 6 | Dose escalation (two doses) | 6m | |||||||
| AXO-Lenti-PD, (OXB-102 (Axovant) ProSavin | P1/2 | bilateral idiopathic PD Diagnosis of PD > five years H&Y 3 and 4 UPDRS (Part III) of between 20 and 60 in the "OFF" state | Prosavin: AADC + TH + GTP-cyclohydrolase 1 | 15 | OL Dose escalation | The first is an open-label phase where 3 escalating dose levels will be tested - ProSavin is a gene therapy designed to delivery three key enzymes involved in the synthesis of dopamine - Primary: safety (1y) - Secondary: UPDRS (6m) Results: A significant improvement in mean UPDRS part III motor scores off medication was recorded in all patients at 6 months (mean score 38 [SD 9] vs 26 [8], n=15, p=0.0001) and 12 months (38 vs 27 [8]; n=15, p=0.0001) compared with baseline | |||||
| P1/2 | H&y 3 or 4, UPDRS) (III) score of between 30 and 60 in the "OFF" medication Presence of motor fluctuations and/or dyskinetic movement | 32 | two parts to this phase 1/2 study… The second phase will take the optimal dose from part one into a RCT, DB phase in which patient will receive either active AXO-Lenti-PD or an imitation surgical procedure (ISP). | ||||||||
| NINDS - AAV2-GDNF | P1 | 25 | OL, Dose escalation (4 doses) | ||||||||
| AAV2-GDNF AskBio (a subsidiary of Bayer) | P1b, | o The study has two cohorts (Earlier-stage PD and Late-stage PD): 6 patients will be dosed in each cohort | 10 | cxlix) Primary Endpoint: The incidence of treatment-emergent adverse events (TEAEs, 5y) cl) Secondary: MDS-UPDRS, NMSS, DATSCAN: all 18 M o AAV2-GDNF gene therapy delivered to the putamen as a single dose infusion using novel bilateral image-guided neurosurgical delivery technology | |||||||
Yuhan 유한
| MC1 | Preclinical support | Predict from peripheral | Example: Aya, (GD | ||
|---|---|---|---|---|---|
| Retina | |||||
| Denali | |||||
| NHP spreading model | |||||
| Axon, DTI | |||||
| lysosome | MBM, protein degradation PRS |
VMAT Vesicular monoamine transporter-2
cli) Synaptic vesicle 의 membrane 에 낑겨 있으면서, monoamine 들을 (dopamine, serotonin, norepinephrine, epinephrine, and histamin) cytosol 로부터 vesicle 내로
VMAT PET
[18F]AV-133
- clii) distributed by Invicro to the north-east USA and northern California
- cliii) Adam 20200923: double effect size (low variance, js: because compensatory upregulation occurs more in postsynaptic and in the synaptic cleft, the upregulation is accountable for variance?), PPMI is targeting 550 PD patients (really?).
- cliv) Adam 20210129: a PPMI add-on study to acquire longitudinal scans from ~50 participants, to try and confirm this. So far, we have baseline scans on 10-15 participants, but things got held up with Covid. In any case, we could use VMAT2 PET tomorrow if we wanted (at imaging sites in the NE USA, California and China). As with any biomarker, it is important to demonstrate in non-clinical studies that a treatment effect is expected.
20190403 Schwarz – NS imaging strategy
P56: The sample sizes shown here are calculated for a 50% slowing of dopamine signal decrease over 12 months. These calculations are based on N=345 subjects for DaTscan but only N=133.
위의 effect size: 분자가 치료제 없이 계산 한 것임. 위의 sample size: 내가 계산해 보니, two-sided, two arms의 total 임.
(Three “Signal change” % change (12 mo) bar charts compare DaTscan vs [18F]AV-133 with paired blue/orange columns each labeled DaTscan and [18F]AV-133. Effect size and Per arm (two sided) labels appear below the charts.)
20220622 Cristian Salina
Mean % Change AV-133 SBR and Ioflupane DAT by Year and Sample Size Estimate for Hypothetical Trial
| Ioflupane or AV-133 % Change Mean Striatum n=30 | ||||
|---|---|---|---|---|
| 1 Yr | 2 Yr | |||
| AV-133 | Ioflupane | AV-133 | Ioflupane | |
| Mean | -10.8 | -11.0 | -19.6 | -17.0 |
| SD | 12.1 | 15.1 | 9.5 | 16.1 |
| Signal:noise | 0.89 | 0.73 | 2.1 | 1.05 |
| Power = 0.8 | Total Sample Size (two arms) | |||
| Sample 50% effect | 158 | 238 | 30 | 114 |
| Sample 25% effect | 632 | 948 | 120 | 45 |
Sample size per arm: Assumes two arms, double-blind, placebo-controlled trial with 80% power to detect a 50 or 25% slowing of the percent loss of SBR at 1 and 2 years follow-up, p<0.05, two-tailed.
I think there is a typo in this slide, the very last cell (lower right). I think it should say 450 not 45.
DaTscan: ~90% power to detect 50% change @1year(α=0.2) with N=100 per arm
[18F]AV133: ~70% power to detect 50% change @ 1 year (α=0.2) with N=30 per arm
, the only and latest estimates we are using are those J. Seibyl presented at last PPMI in May (see above). On a related note, I’m working with Invicro (the main imaging CRO for PPMI) to obtain a larger than N=30 data set to make generate more accurate estimates of rates of change.
(Two power-vs-effect-size curves: 1 year power vs effect size (AV133, N=30, @1 year vs DaTscan, N=100, @1 year, dashed lines at 90% and 68%) and 2 year power vs effect size (AV133, N=30, @2 ye… vs DaTscan, N=100, @2…). Y-axis Power (α = 20.0%), X-axis Effect size 0–1.)
| AV-133 | Original COHORT | Early PD COHORT | TOTAL | |
|---|---|---|---|---|
| Baseline scans | 34* | 24 | 58 | |
| 6 MONTHS | 0 | 4 | 4 | |
| 1Y | 21 | 2 | 23 | |
| 4Y | 9 | 0 | 9 | |
| 80 | 26 | 115 |
Uncertain Spans
| location | transcription | uncertainty |
|---|---|---|
| Cristian Salina lower-right cell | 45 | reads as 45 but the operator annotation in the slide (I think there is a typo … I think it should say 450 not 45) flags this as a possible source typo; transcribed verbatim as 45 and the operator annotation is preserved. |
| Trial table column structure | columns labeled implicitly across multiple cells | the wide trial table has 11 columns; some rows are partially blank and column boundaries blur across crops; structure reconstructed using body_full and adjacent crops. |