20240722_184223

Cell loss	neuronal loss axonal degeneration myelin degeneration with astrogliosis [20220214 QSP kickoff_meeting_MSA_QSP_021322] Symptoms are more severe in MSA than in PD. D2 receptor loss in MSA is two fold of that in PD. 63% MSA patients show 2 SD striatal D2R loss. 56% show 2.5 SD losses. Putamen volume loss is also two fold higher in MSA compared to PD. Stereological studies of the BG revealed a substantial loss of neurons in the SN, putamen, and GP, whereas astrocytes were more frequent in the putamen and caudate nucleus (CN).
Aβ?
tau	Cristian MJFF PPMI 2023 notes CAS: despite potential tau off-target binding of the current emerging α-syn PET tracers, this may not be an issue in MSA due to the hypothesized lack of tau pathology in MSA.
DeMyelination?	{Refolo, 2018 #1419} In mildly or moderately affected MSA brains no significant demyelination is detected [28].
microgliosis	Microglial activation in degenerated regions accompanies GCI pathology and is most abundant in white matter areas mild to moderate de-myelination and neuroinflammation [128, 129], with extensive CD4 and CD8 T-cell infiltration cf) GCI & Neuronal loss 모두 SN이외에도 CORTEX, brainstem, spinal cord등에 광범위 분포.
splice	(Brudek, 2016 #1425) αSyn 140 and 112 isoform levels are increased, whereas αSyn 126 is decreased, in SN, striatum & cbll

Pipeline MSA

		phase	patients	Admin route	Start	status	Pt #	Design	Tx duration	Primary outcome	Secondary
BIIB101/ ION464, (Biogen/Ionis) likely=	SNCA ASO, intracellular aSyn에도 효과, all forms of aSyn에 효과	Phase 1 (Horizon) Ionis considers this in Ph1/2 (뭔말?) However, Biogen considers it in Ph1	MSA (P or C), datscan-proven (probable or possible MSA, either (MSA-P) or (MSA-C)) DaT scan consistent with loss of dopaminergic signal in the striatum, per qualitative visual read Must be able to walk unassisted for at least 10 meters (approximately 30 feet) Excludes MoCA < 25	IT, high dose, low dose, and placebo	202007	expected primary completion date: July 13, 2022	34	NCT04165486), IT/once every 2~3 weeks, 3 doses of drug (vs placebo), Period of Evaluation: about 6 m
		preclinical	PFF (Cole, 2021 #1450) Prevention (mouse): (fig1) PFF2주전 aso → pff 8주후, ↓(빈)SNCA Mrna, ↓(100%) Prevention (rat): (fig3) PFF3주전 aso → pff 6달후, ↓(빈)paSYN Deposit, ↑TH ce Treatment: (fig4) pff 2-3주 후 ASO (like early PD patients) → PFF후 8주, 12주 70%)SNCA Mrna, ↓(~100%) paSYN Deposit (reversed, ie reduced below the day 21, IHC, fig4h, midbrain, ie cleared pre-existing aSyn deposit!), normalize loss Biodistribution, (mouse, NHP): ASO 13주 후, ↓mRNA (fig6e), ↓ protein (cortex에서 KD efficacy 최강, putamen에서 최소!, pons & midbrain은 ok 인듯, midbrain (Mrna)와 protein결과 상이) 하며 케바케, 75% reduction in MAPT RNA in brain hippocampus and entorhinal/temporal cortex at the highest dose tested in motor cortex and hippocampus at the highest dose tested (35 mg). Cf) IONIS MAPTrx Biodistribution, (2019 poster Narayanan), NHP: 36주결과, ~66 & 77% reduction was achieved in MAPT RNA in brain hippocampus, entorhinal/temporal cortex at the highest dose tested (35 mg). KD efficacy가 cord는 강한데) pons, medulla에 좀 약함, cbll, striatum은 아예 안 봤음. Cf) (Lim, 2011 #1451) in A53T (overexpression) mice: stopping aSyn expression (tetracycline-control system) for 3 m → almost completely cleared pre-existing aSyn (non-pSyn) in hippocampus (but not in mammillary bodies, olfactory bulb and serum)
ATH434, Alterity, (prana) PBT434	A small molecule, redistribute labile iron the potential launch is expected in H2 2028; 3. ATH434 is 2nd most advanced MSA disease modifying therapy,	a new open-label Ph2 biomarker trial	Estimated study start date: Mar 1, 2023; Estimated enrollment: 15 participants (30) Expected primary completion date: Oct 2024 Primary endpoint: Change in iron content as measured by brain MRI (week 52) All secondary endpoints are the same as the Ph2 placebo-controlled trial (baseline vs. week 52); Change in aggregating α-syn and NfL levels; Change in UMSARS and SF-36 scores Trial to enroll 15 MSA patients with more advanced MSA patients compared to the RCT trial • Interim analysis of biomarker data from the new trial planned before the Ph2 RCT data readout, to provide an early indication of efficacy
		P2, MSA DB RCD, placebo,	Early MSA with motor symptoms ≤ 3 years, Cf) they do NHx study ('BioMUSE') in MSA • Population: Early MSA patients Parkinsonism, ambulatory (assistance ok) No severe impairment on speech, swallowing, walking, falls	[Design] Design: Randomized, double-blind, placebo controlled, high dose / low dose / placebo Objectives: • Assess efficacy, safety and tolerability of ATH434 in subjects • Assess target engagement based on imaging and fluid biomarkers of disease progression • Evaluate the pharmacokinetics of ATH434 in target population • Sample size: 60 • Sites: ~25 - • Treatment: 6 months • - Efficacy Endpoints • MRI: Iron by QSM/R2*, neuromelanin, regional blood flow/cerebral metabolism, • Fluid/tissue biomarkers: NfL (CSF, plasma), Aggregating α-syn (CSF), phos-α-syn • Wearable movement sensors Clinical: Motor exam, UMSARS (function/ADL inventory), levodopa challenge, global assessments of severity and change • Functional: Timed Up and Go • Safety Endpoints: AE reporting, clinical laboratory parameters, 12-lead ECGs
		P1, HV	ACTRN12618000541202)	•	completed
ENT-01 (BY Enterin)	single prodromal MSA patient with ATP13A2 mutation, which predisposes to PD and MSA	ENT-01 is an α-syn inhibitor that displaces misfolded α-syn from enteric neurons	If treatment succeeds, ENT-01 may be studied for prevention of MSA progression • ENT-01 is also under development for PD-related constipation (Ph2b completed) and PD-related psychosis and dementia (Ph2 planned) Received IND
Verdiperstat, (Biohaven)	Myeloperoxidase inhibitor,	P3 M-STAR study (NCT03952806)	A Randomized, DB, Placebo-Controlled, Parallel-Group Study to Evaluate the Efficacy and Safety of BHV-3241 in Subjects With Multiple System Atrophy (M-STAR Study) enrollment completed in Q3 2020; Actual enrollment = 336; Expected PCD is October 20, 2021 20210929) failed on both primary and key secondary efficacy measures
Chelator and antioxidant NMBI (Irminix)(emeramide by EmeraMed)	Lipid soluble heavy metal chelator and thiol-redox antioxidant	P2a, NCT04184063[79]	Clinical diagnosis of PSP or MSA, with consistent brain MRI (js no detail)	Oral or iv,		Randomized, placebo-controlled,	16	28 days of dosing with NMBI	Primary: Change compared to placebo in PSPRS, and multiple Secondary:
						double blinded, cross-over		300 mg daily	Change from baseline compared to placebo in Parkinson's Disease Fatigue Score, Beck Depression Inventory, and Geriatric Depression Scale AEs

Disease-modifying

{Mészáros, 2020 #1410}
Table 2. Drug targets and current clinical trials in MSA (status 02/2020, non-comprehensive).

Therapeutic Targets	Drug Therapy	Clinical Trials
Therapeutic Targets	Drug Therapy	Phase	NCT Number	Ref.
α-Syn aggregation	Vaccines Affitope PD01A and PD03A	1	NCT02270489 (see vaccine section)	[77]
α-Syn aggregation	Epigallocatechin gallate (EGCG)	3	NCT02008721	[78]
Neuroinflammation	MPO inhibitor verdiperstat	3	NCT03952806	[80]
Neuroinflammation	CD20-antibody rituximab	2	NCT04004819	[81]
Neuronal loss	Bone marrow-derived mesenchymal stem cells (MSCs)	1	NCT03265444	[82]
		1	NCT02315027	[83]
		n.a.	NCT02795052	[84]
	Intranasal insulin	1		[85]
	mTOR inhibitor sirolimus	2	NCT02064166	[86]
	Antioxidant inosine 5'-monophosphate	2	NCT03589976	[87]

mechanistic target of rapamycin (mTOR), myeloperoxidase (MPO), not applicable (n.a.), and reference (ref).

Verdiperstat – Phase 2: NCT02388295

Asset name(s)	Verdiperstat; BHV-3241; AZD3241	First-in-class, potent, selective, brain-penetrant, irreversible myeloperoxidase (MPO) enzyme inhibitor. Irreversibly inhibits an enzyme, myeloperoxidase, which catalyzes the production of cytotoxic compounds. May help preserve neurons through inhibition of MPO-induced pathological oxidative stress. AstraZeneca progressed the asset through Phase 2 (total of 7 clinical ...).
Mechanism	Myeloperoxidase inhibitor
Route of administration	Oral; BID
Sponsor	AstraZeneca
Study Design	Randomized, double blind, placebo-controlled, parallel group 1:1:1 randomization; verdiperstat low dose / high dose / placebo
Sample Size	59 enrolled
Subject Population	• Probable or possible MSA according to the Gilman et al 2008 consensus criteria (continues on next page)
Period of Evaluation	12 weeks of dosing
Endpoints/Objectives	Primary: Change from baseline in microglial activation in striatum in TSPO PET Secondary: MPO inhibition in plasma Exploratory: UMSARS, change from baseline

Uncertain Spans

location	transcription	uncertainty
ENT-01 patient cell	`single prodromal MSA patient with ATP13A2 mutation, which predisposes to PD and MSA`	The cell is left-aligned in the body and refers to a single-patient case description; preserved in full.
Verdiperstat asset card right column	full mechanism description	The right-hand mechanism description is partially cropped at the right edge; the trailing “(total of 7 clinical …)” is truncated by the photo edge and preserved with an ellipsis.