Animal model treatment table tail, Korean Rx market, Tx pattern WW/Korea, Turning, and Types

Animal model (table tail)

AAV-GAD	Lewitt, STN, db, (adv)	Improve 23%	Improve 12%
Other GT	Prosavin, Stereotactic Injection to Striatum, (adv)	Improve 29% (12m)	NA	NA
CDNF	Infusion ( surgical implantation), small	Slight improve		Slight improve
AAV-Parkin	Sx 이면 placebo effect 없이도, 25%인데 해당 x, surgical 이면 placebo 받아서 29%, placebo 빼면 23% Sx 이거나 surgical 이면 그 자체로 (20% ) improve 구나, 근데, AAV-Parkin 은 둘다 아니므로 그냥 DM 효과들 간수해야 겠군. 근데 기존 DM 약과는 다를 것 (밑무 Placebo 효과 물 것, ) slowing down of slope 아니고, (효과 있다면) improve 겠네. DM+Placebo effect.			Icm 은 중간으로 여기? Ie surgical (improve)과 oral (worsening)의 중간. → net effect 가 zero 겠군.
DA	Pramipexol- early	Improve 25%		Worsening 7%
	Pramipexol-advance	Improve 37%	Improve 15%
	Ropinirole -early	Improve 22%	Worsening 4%
Other DM	Isradipine p3, early, 3y	Worsening 4.6		Worsening 4.5
	Venglustat: P2, early, 1y	Worsening) Part II+III 7.29		Worsening) Part II+III 4.71
	Prasinezumab, P2, early 1y	worsening 4p		worsening 6p
	Inosine, P3, early	(I-III) Worsening 11.1P/y (III) Worsening 6.92p/y		(I-III) Worsening 9.9P/y (III) Worsening 6.40p/y
	Exenatide, P2, (adv) 1y	Improve 2.7p		worsening 2.2 p
	Exenatide, P2, (adv) 1y	Improve 1.0 p		Worsen 2.1 p
	PD01A (aSy antibody)	12.3 → 8.6 (3 y?)		NA
	KW-6356, P2A, 3m	imp		imp
	Ambroxol, P2,	Improved 6.8p		NA
ICM

Korean PD drug list

성분명	제품명	회사	계열	매출 (2015)	시장점유율	평균
Rasagiline	Azilect	Teva	도파민분해 억제제	636	20.6%	393
Pramipexol	Mirapex	Boehringer Ingelheim	도파민 효현제	546	17.7%
Rotigotine	Neupro	UCB	도파민 효현제	408	13.2%
Ropinirole	Requip	GSK	도파민 효현제	295	9.6%
levodopa+carbidopa (isn't this Cinemet? Cinemet의 평균유지량은 (표준유지량 : 레보도파의 양으로 1회 200-250mg 1일 3회)	Duopa	Abbvie	도파민과 도파민분해 억제제의 2제 복합	247	8.0%
levodopa+carbidopa+entacapone	stalevo	Novartis	도파민과 도파민분해 억제제의 3제 복합	224	7.3%

Tx pattern WW

Below from Cerevel slide

MAO-A	MAO-B (아래 Fernandez)
Catecholamine을 분해 (dopamine, norepinephrine, and serotonin)	DA 분해
Vasopressors인 tyramine을 분해함, 따라서 MAO-A를 억제하면 → ↑ tyramine → ↑ BP ('cheese effect') when tyramine-rich food is present	clinically relevant inhibition of MAO-B is believed to occur at 80% inhibition (ED80).
MAO-A KO → ↑ agression (mouse)	Inhibitors: cxlv) Selegiline cxlvi) Rasagiline (Azilect): selegiline처럼 metabolite가 amphetamine이 아니라서 좋음. selegiline보다 potency 가 50배 더 좋음. Selectivity for MAO-B over … 증명, but human brain in vitro에선 비슷했음! Monkey에선 4배.

Cerevel slide: PD treatment-decision flow

	Early-Stage Parkinson’s	Mid-Stage Parkinson’s	Late-Stage Parkinson’s
Current Standards of Care	MAO-B Inhibitors or D2/D3 Agonists	MAO-B Inhibitors &/or D2/D3 Agonists ↓ L-Dopa	Escalating Doses of L-Dopa ↓ MAO-B Inhibitors &/or D2/D3 Agonists
Current Limitations	Limited Activity	Somnolence Impulsivity Hallucinations Hypotension	Dyskinesias and OFF-time with Prolonged L-Dopa
Tavapadon has the Potential to Deliver…	Improved Motor Control vs. MAO-Bs	Improved Tolerability vs. D2/D3s	Increased ON-time without Troublesome Dyskinesias and Reduced Risk of Debilitating Side Effects in Combo with L-Dopa

~70% of PD Patients     ~30% of PD Patients

Tx pattern in Korea

• 환자들의 과거 치료법을 조사한 결과, 도파민 효능약을 복용하지 않는 경우(30%)와 levodopa 단독 또는 병용 요법(60%)을 하는 경우가 대부분이었다.
• 첫번째 조사 시점(1st visit)에서는 도파민 효능약 복용 환자가 30%, 도파민 효능약과 levodopa 병용 요법 환자는 45%로 가장 많았다.
• 두번째 조사 시점(2nd visit)에서는 큰 변화는 없으나 도파민 효능약 복용 환자가 27%로 약 10% 감소하였고, 도파민 효능약과 levodopa 병용 요법 환자는 45%로 약간 보였다.

http://www.docdocdoc.co.kr/66450

• Ropinirole의 한국 평균 사용용량
• Schapira

Turning

Definition

• Changing of walking direction

In PD

• Turning performance is compromised in PD, leading to a significant disability, freezing of gait, falls, and loss of function (E. Stack & Ashburn, 2008).
• {Mancini, 2015 #1257} PD showed impaired quality of turning compared to healthy control subjects (Turn Mean Velocity: 43.3±4.8°/s versus 38±5.7… of steps 1.7±1.1 versus 3.2±0.8).

Types

Motor		mixed group	Non-motor
TREMOR TYPE	RIGIDITY TYPE
{Lian, 2019 #2500} tremor-dominant (PD-TD), : PD-TD tend to have slower disease progression (Moretti et al., 2017), fewer non-motor symptoms (Ba et al., 2016), more chances of improvement when using levodopa and higher survival rates (Rajput et al., 2017) compared to patients with PD-PIGD,	Akinetic-rigid: postural instability and gait difficulty-dominant (PD-PIGD), {Weil, 2018 #2501} Greater likelihood of evolving into the PD-MCI and PDD phenotypes	a (Isai et al., 2011).
dopamine depletion in the globus pallidus is associated with the severity of a clinical tremor (Helmich et al., 2011). The tremor-associated drive from the subthalamic nucleus (STN) to the muscles has been confirmed, so STN may also be directly involved in tremor generation (Guan et al., 2017).	{Hu, 2015 #2497} probably 2nd, severer neuronal loss in the regions that are highly relevant to RBD [2], such as locus coeruleus [21], (but the two reference doesn't show such data?)
	{Selikhova, 2009 #2498} postmortem study. a significantly higher mean overall LB score than patients with tremor-dominant PD, and, more specifically, they show significantly more cortical LBs in the frontal brain than do patients with tremor-dominant PD.
MDS-UPDRS tremor score MDS-UPDRS PIGD score MDS-UPDRS rigidity score MDS-UPDRS axial score	[Espay 2017 #2449] PPMI: , only low a-syn, but not changes in this or other biomarkers, was associated with the PIGD phenotype and also with worse cognitive performance (e.g., PD-MCI/PDD).13 In another PPMI analysis, however, the 2-y conversion to PD-MCI (n5286 participants without MCI at baseline) was associated with lower mean baseline CSF Ab1-42 (343.8 vs. 380.4 pg/mL; P<0.01), but not a-syn.

[espay 2017 #2449 Within a year of enrollment in the PPMI study, the mean values of the two common motor phenotypes, TD and PIGD, defined using the scoring of related subitems from the UPDRS, 20 shifted by nearly 40% and 20%, respectively, regardless of dopaminergic treatment.21

{Simuni, 2016 #2478} There is a substantial body of literature on the clinical sub classification of PD into TD versus PIGD subtype. However, there are limited data on the stability of this classification especially in early disease.

Methods: Parkinson’s Progression Markers Initiative (PPMI) is a longitudinal case control study of de novo, untreated PD participants at enrollment. Participants undergo a number of assessments including the Movement Disorder Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS). TD versus PIGD subtype was defined based on the previously published formula. We report one-year analysis data.

Results: 320 of 423 PD recruited subjects had data on subtype classification at year 1 and were included in the analysis. 228 (71%) were classified as TD, 56 (18%) as PIGD and 36 (11%) as indeterminate at baseline. At 12 months, 39% PIGD and 18% TD shifted subtypes: 29% PIGD shifted to Indeterminate; 10% TD shifted to PIGD and 8% to Indeterminate. The classification was not affected by the dopaminergic treatment (p ¼ 0.59).

Conclusions: TD versus PIGD subtype classification has substantial variability over first year in PD de novo cohort specifically for PIGD subtype. Dopaminergic therapy does not impact the change of the PD subtype. This instability has to be taken into consideration specifically when establishing correlations with the biomarkers and for long term prognostication.

Biopank

Uncertain Spans

location	transcription	uncertainty
Types mixed group cell	trailing fragment a (Isai et al., 2011).	parent sentence is clipped at the right edge of the photo.