Pipeline MSA — Disease-modifying / Symptomatic / Subtype

KM-819 (FAScinate), a potent inhibitor of FAF1

, a key regulatory protein in cell death pathways, apoptosis, and necrosis, and leads to neuronal cell protection in pre-clinical studies. A higher level of FAF1 is found in PD patients and could contribute to the early cell death. First patient dosed in Ph2 MSA study for KM-819 (20230418), Korean Ph2 study of Kainos, The ongoing Korean Ph2 study in MSA aims to evaluate safety and efficacy of KM-819 in slowing disease progression in MSA patients; Interim data expected in 1H24 Estimated enrolment: 78 participants; Expected PCD: Oct 2024 The study has two parts: Main study for 36 wks followed by open-label extension from wk 40 to 76 Primary endpoints: A novel imaging biomarker (% change at baseline vs. wk 36 in putaminal [18F]FP-CIT binding) UMSARS scores will also be assessed as one of the key secondary endpoints Ongoing Ph2 study (in the US) in PD aims to evaluate safety and tolerability of multiple-ascending doses of KM-819 in healthy older adults and PD patients Estimated enrolment: 330 participants; Expected PCD: Oct 2025

IkT-148009 (Inhibikase) risvodetinib:

IkT-148009 (Inhibikase): Inhibikase expects to file an IND for IkT-148009 for MSA treatment in Q2 2022, targets c-Abl kinase, 20230418 Clinical hold for IkT-148009 program in MSA lifted 1. The planned Ph2a '202' study in MSA aims to assess safety, tolerability, and PK of IkT-148009 in MSA patients over 6 months at 1 or 2 daily doses Endpoints: UMSARS*, quality of life, and orthostatic hypotension Biomarkers: NfL level in blood and CSF, phosphorylated α-syn levels in CSF, blood, and skin, and MSA progression as monitored by MRI 2. The ongoing Ph2a '201' study in PD to investigate safety and tolerability of IkT-148009 in untreated PD patients Estimated enrollment: 120 participants (55-75 years old) Primary endpoint: Treatment-emergent adverse events; Biomarkers: phosphorylated α-syn levels in CSF and skin 3. Previously, the clinical hold was placed in Nov 2022 for both PD and MSA programs of IkT-148009 Concerns with vision-related AEs and use of 200mg dose were cited as the reasons for the clinical hold (link) In Jan'23, partial hold on PD program was lifted for 50/10 mg doses; Hold on 200 mg dose to continue, addit'l data to be submitted to FDA in Apr'23 (Werner, 2024 #2653) A Phase I, Randomized, SAD, MAD, and PK Study of Risvodetinib in Older Adults and Parkinson's Disease

Key Ongoing Trials for MSA: Clinical Development Timelines

Lundbeck’s Lu AF82422 is the lead synuclein-targeting asset in MSA

Last updated: March 2022 — Takeda

Sponsor	Drug / Phase	Timeline notes	Study start date	Study label	Primary completion (PCD)
Lundbeck	Lu AF82422 Ph 2	If results from Ph2 AMULET study are positive, then Lundbeck plans to initiate a Ph3 study with Bayesian Response-adaptive treatment allocation and ~3 years in length	Nov'21	Ph2: AMULET Study	May'23
Alterity	ATH434 Ph 2 Planned	Trial recruitment status for Ph2 still shows "Not yet recruiting" Estimated study start date: Jan 2022, However, this is expected to be delayed Recruitment for New Zealand sites expected to initiate in Q2 2022 Recruitment for US and EU sites expected to initiate in H2 2022	Expected start date: Jan'22	Ph2: NCT05109091	Oct'23
IONIS / Biogen	BIIB101 Ph 1/2	Ionis considers this molecule in Ph1/2 However, Biogen considers it in Ph1	Jul'20	Ph1/2: HORIZON Study in MSA patients	Jul'22
MODAG / teva	Anle-138b Ph 1b	Current Ph1 ongoing in PD MODAG/Teva plans to develop Anle-138b for MSA as well	Dec'20	Ph1b: Study in PD Patients	Jun'22
vaxxinity	UB-312 Ph 1	Current Ph1 ongoing in PD Vaxxinity plans to develop UB-312 for MSA as well	Aug'19	Ph1: Study in Healthy volunteers and PD Patients	Dec'22
Takeda / AstraZeneca	TAK-341 / MEDI-1341 Ph 1		Oct'17	Ph1: Study in Healthy volunteers	Mar'21
			Aug'20	Ph1: Study in PD Patients	July'22

Legend: Study start Date · Primary completion · Data Readout — Phase 3 — Phase 2 — Phase 1 · PCD: primary completion date

Notes:

• ABBV-0805 (Anti-α-Syn mAb): Completed Ph1 study in healthy volunteers in 2019; Ph1 study in PD patients was withdrawn in 2020; No active study ongoing; Initiation of Ph2 study expected in 2022; Development plan also include MSA
• PD01/ACI-7104 (α-Syn Vaccine): Completed three Ph1 studies in PD patients between 2012 to 2017; No active study ongoing; AC Immune acquired PD01/ACI-7104 in 2021; Initiation of Ph2 study expected in H2 2022; Development plan also include MSA

46 | GPLS Team. 1Q 2022 Quarterly and Key Events Report - Neurodegeneration | April 2022 | Confidential - for internal use only

Symptomatic

(Mészáros, 2020 #1410)

Symptoms	Drug Therapy	Clinical Trials
		Phase	NCT Number	Ref.
Parkinsonism	MAO-B inhibitor safinamide	2	NCT03753763	[50]
Cerebellar ataxia	NMDA receptor modulator Tllsh2910	3	NCT03901638	[51]
Orthostatic hypotension	α1-receptor inhibitor midodrine	1	NCT02897063	[52]
	Norepinephrine prodrug droxidopa (L-threo DOPS)	1	NCT02897063	[52]
		4	NCT02586623	[53]

Symptoms	Drug Therapy	Clinical Trials
		Phase	NCT Number	Ref.
	Selective NET inhibitor atomexetine	2	NCT02796209	[54]
	NRI ampreloxetine (TD-9855)	2	NCT03750552	[55]

Monoaminooxidase B (MAO-B), norepinephrine transporter (NET), N-methyl-D-aspartic acid (NMDA), norepinephrine reuptake inhibitor (NRI), Reference (ref).

Subtype

		MSA with predominant parkinsonism (MSA-P)	MSA with cerebellar features (MSA-C)	MSA-PC, (MSA with combinations of parkinsonism and cerebellar ataxia with no predominance)
Clinical		EPS predominate. (= striatonigral degeneration, parkinsonian variant.)	cerebellar ataxia predominates. (= sporadic olivopontocerebellar atrophy.)
		= PD, but less resting tremor and no response to levodopa	↓ coordination and balance (ie multiple muscles at the same time)
		(Stankovic, 2019 #1649) half of MSA-P patients show additional cerebellar signs,	(Stankovic, 2019 #1649) 75% of MSA-C patients develop parkinsonism during the disease course.11,12
	Autonomic nervous system dysfunction is common (eg BP due to medulla in brain stem) (Sakakibara, 2000 #1448)

Figure 1 — Urinary and orthostatic symptoms in patients with MSA

Bar chart values transcribed from the figure (% of patients):

Symptom group	Symptom	%
Urinary symptoms	Urinary symptoms (overall)	96
	Difficulty of voiding	79
	Nocturnal frequency	74
	Sensation of urgency	63
	Urge incontinence	63
	Diurnal frequency	45
	Enuresis	19
	Urinary retention	8
Orthostatic symptoms	Orthostatic symptoms (overall)	43
	Postural faintness	43
	Blurred vision	38
	Syncope	19

X-axis: 0–100 (%). Annotation: p < 0.01.

Figure 3 — Urinary and orthostatic symptoms in three variants of MSA

Bar chart values transcribed from the figure (% of patients; orthostatic symptom = dark bar, urinary symptom = light bar; annotation p < 0.01 over each pair):

Variant (n)	Orthostatic symptom (%)	Urinary symptom (%)
Total (n = 121)	43	96
OPCA type (n = 48)	10	92
SND type (n = 17)	6	94
Shy-Drager type (n = 56)	82	100

After about 5 years, symptoms tend to be similar regardless of which disorder developed first.

Pathology

Pathology	BG	cbll
(Kuzdas-Wood, 2014 #2131) degeneration of autonomic brainstem nuclei plays a role for characteristic autonomic failure in MSA patients. SND, striatonigral degeneration; OPCA, olivopontocerebellar atrophy; SCN, suprachiasmatic nucleus; PVN, paraventricular nucleus; VML, ventrolateral medulla; DMV, dorsal motor nucleus of the vagus; NA, nucleus ambiguus; IML, intermediolateral column of cord; LDT, laterodorsal tegmental nucleus; PPT, pedunculopontine tegmental nucleus; PAG, periaqueductal gray

Source-figure labels for the four anatomical schematics (left → right):

• Healthy brain
• MSA-P (SND): striatum, substantia nigra pars compacta
• MSA-C (OPCA): pons, inferior olive, cerebellum
• Degeneration of autonomic brainstem nuclei: SCN, PVN, Raphe, LC, VML, DMV, NA, IML, LDT, PPT, PAG

(Jellinger, 2018 #2132) more detailed pathology picture

Prevalence (partially visible at bottom edge)

Prevalence	HORC-MSA	Clinical (Kim, 2011 #1391)
	29.9%	55%
	58.2%	17%	28%

Age at onset was significantly older in MSA-P patients tan in the other types: 62.3 ± 6.8.5 years for MSA-P, 58.2 ± 6.8.8 years for MSA-C, and …

Uncertain Spans

location	transcription	uncertainty
Symptomatic table — Cerebellar ataxia row	NMDA receptor modulator Tllsh2910	Drug name token reads Tllsh2910 per source visual; may be an OCR-typical confusion of Tilsh2910 / Tlsh2910.
Notes — ABBV-0805 entry	Initiation of Ph2 study expected in 2022	Right margin is partially clipped; the year may be H2 2022 as in the PD01 row but the digit sequence is not fully legible in this scan.
Prevalence row	62.3 ± 6.8.5 years for MSA-P, 58.2 ± 6.8.8 years for MSA-C	Decimal points after 6.8 appear duplicated/blurred; the original may read 6.8 (single decimal) for both values.
Status-bar partial line	tan in the other types	Likely “than” but the second character is partly clipped at the bottom edge of the page.
Subtype clinical row	↓ coordination and balance (ie multiple muscles at the same time)	Source uses a downward-arrow glyph; the bracketed clarification reads ie without period.