aSyn - Vaccine / GT Transition

SAD Study - PK Data To Date / MEDI1341

SAD study - PK data to date
AstraZeneca / Takeda
 
MEDI1341 exposure

Parameter	70 mg	210 mg	400 mg	1200 mg
Dose increment	-	3.00	1.90	3.00
Increase in Cmax	-	3.75	1.51	3.17
DPF Cmax	-	1.25	0.79	1.06
Increase in AUC0-∞	-	3.44	2.04	2.58
DPF AUC0-∞	-	1.15	1.07	0.86

Dose proportionality based on preceding dose level and calculated using geometric mean values
DPF = Dose Proportionality Factor - ratio of fold increase in parameter divided by fold increase in dose
Note: dose proportionality was not assessed for AUC0-∞ as tlast increased with increasing dose level.
 
At the 1200-mg dose level, CSF/serum MEDI1341 concentration ratios were assessed on Days 8 and 15;
the respective geometric mean values (individual subject ranges) were 0.230% (0.161% to 0.366%) and
0.391% (0.349% to 0.467%).
 
ADA data for 1200 mg dose group not yet available;
None of the positive ADA results at lower dose levels appeared to have impacted PK and PD data.

PD01A / Long-Term Follow-Up Notes

visit - In the pooled 75 μg group, MDS-UPDRS part 3 scores were 12.3 (7.2) at baseline and 8.6 (7.7) at the last visit
(3.5y겠지).
종합하면, 75ug에서, ↓ oligo aSyn, MDS-UPDRS III 개선, 그런데 DATScan 은 안 개선!
 
Mean peak serum Ab concentration after booster injections was about 19.6 ug/ml.
Paper compares this with passive immunity studies (like TAK-341) where serum Ab levels are ~1000ug/ml range immediately post-infusion.
The slide below shows TAK-341 concentration (1200mg dose) post infusion (graph - green line).
Serum concentrations are relatively dose-proportional.
Immediate post infusion serum level is about 200ug/ml.
Targeted dose is 4800mg for TAK-341 which would likely give an estimated immediate post-infusion concentration of about 800ug/ml
vs. the 20 ug/ml from PD01A. CSF fractions are about 0.4% to 0.5% for TAK-341 vs. 0.3% for this vaccine.

PD01A / GBA-PD Row

field	transcription
phase / trial	P1, NCT02758730
patients	GBA-PD, (Heteroz), H&Y I/II/III, no dementia, no DLB, no MSA
route / design	SC, ONCE EVERY 4W INJECTION, 30 PATIENTS WITH GBA-PD, injection PERIOD is over 8 w. 2:1 randomization ratio, two arm: 75ug PD01A, & Placebo, observation is 52w
note	(이 기간동안에 3 injection), patient만 blind, estimated primary completion is 2017 Oct
primary / secondary outcome	Primary outcome is safety; secondary outcome: immunological activity (52w), imaging (52w): (11C-PIB), 18F-FDG-PET), resting-state functional magnetic resonance imaging (fMRI), diffusion-weighted/tensor magnetic resonance imaging (MRI), MRS, gba activity (52w), MDS-UPDRS I, II, III, IV, PDG-39, MOCA, Trail Making Test (TMF) A and B), Geriatric Depression Scale
annotation	actual enrollment is 0! / 죄측 것들도 PD01A 의 p1 Studies 라고 하네, 추후 확인해보자
related trial IDs visible	NCT01560899, NCT01885494, NCT02216188, NCT02618941

UB-312 / Vaxxinity

field	transcription
program	Ub-312 (UB312) (Vaxxinity)
target	target aggregated forms of aSyn
phase / trial	P1, NCT04075318
status/context	Preclinical / MSA model / (Lemos, 2020 #931) PLP-a-syn mouse model

Dosing initiated in Part B (PD) of the DB, placebo-controlled Phase 1 study (NCT04075318) of UB-312.
Part B is enrolling up to 20 PD patients, H&Y ≤ III, at the Center for Human Drug Research in the Netherlands.
Patients will be enrolled in one of two dosing cohorts with the primary objectives of safety and immunogenicity.
The study will also assess exploratory biomarker endpoints for target engagement, including Protein Misfolding Cyclic Amplification.
 
[results]
The UB-312-induced antibodies showed preferential binding to aggregated aSyn and almost no binding to normal monomeric aSyn,
as measured by dot blot. After a single priming regimen, those treated with UB-312 in the 300/100/100μg dosing group showed
a 20% decrease from baseline in aggregated aSyn in the CSF compared to a 3% increase in the placebo group (p<0.05),
as measured by a Seed Amplification Assay (SAA).
Further, a post hoc analysis showed that patients with detectable UB-312-induced antibodies in the CSF exhibited improvement
in activities of daily living as measured by the MDS-UPDRS II clinical scale (p<0.01).
These data also suggest a correlation between reduction in aggregated aSyn in the brain and change in MDS-UPDRS II (R=0.52, p=0.001).
 
Previously, Vaxxinity completed Part A of Phase 1 FIH study (NCT04075318) of UB-312 in healthy volunteers.
In Part A, UB-312 was found to be generally well-tolerated at multiple dose levels.
Serum and CSF anti-alpha-Syn antibody titers were dose-dependent and indicated that antibodies crossed the BBB with a CSF:Serum ratio up to 0.2%.
 
[PD-cohort results]
UB-312 was immunogenic in PD serum & csf.
UB-312-induced antibodies preferentially bind aggregated aSyn (affinity purification using oligomer-specific antibody, MJFR-14-6-4-2).
UB-312 → ↓ SAA signal in PD CSF.

Active versus passive immunisation: Pros and Cons

Pros	Cons
Long lasting immune response	Possible immune tolerance
Large interdose intervals	Robust immune response
Sc/im administration	Avoid T.cell mediated toxicity

GT

GT
phase
patients
Admin route
Start
status
Pt #
Design
Tx duration
Primary outcome
Secondary

AAV2-GAD / MeiraGTx

field	transcription
program	AAV2-GAD (glutamic acid decarboxylase, so ↑ GABA) (Neurologix) → MeiraGTx
phase	P2
patients	Refractory PD (Duration of disease for at least 5 y; Levodopa responsiveness for at least 12 m; UPDRS 3 score ≥ 25)
admin route	Intra-STN
status	terminated
pt #	44 (약:16, sham 21)
design	DB, RCT; 23 were randomly assigned to sham surgery and 22 to AAV2-GAD infusions; of those, 21 and 16, respectively, were analysed.
tx duration	6m
primary outcome	(LeWitt, 2011 #201) At 6m, UPDRS score for the AAV2-GAD group decreased by 8.1 points (SD 1.7, 23.1%; p<0.0001) and by 4.7 points in the sham group (1.5, 12.7%; p=0.003).
source/trial ID	NCT00643890

(Niethammer, 2017 #1572)
PET scans revealed reduced thalamic metabolism on the implanted side which correlated with reduced pallidal activity.

Uncertain Spans

location	text/status	reason
page label	Page 1008 of 1018	previous photo showed Page 1008 of 1017; status bar here clearly reads 1018, but the denominator changed.
MEDI1341 PK table	AUC0-∞, tlast, Cmax labels	values are legible, but subscript/symbol formatting should be checked.
PD01A / GBA-PD row	long design/outcome text	dense table row; OCR and visual crop agree partially but manual review is needed.
Korean annotations	3.5y겠지, 그런데 DATScan 은 안 개선, 추후 확인해보자	handwriting/spacing and OCR noise make exact phrasing worth checking.
UB-312 dosing group	300/100/100μg	visible but small; verify against crop.
AAV2-GAD row	patient counts and trial ID	lower table is dense; verify 44, 23/22, 21/16, and NCT00643890.
GT lower rows	AXO-Lenti / other rows	visible at page bottom but not fully reconstructed in this draft.