Tx Nurr1:RXRa BRF110 program tail (TE / Neuroprotection / aSyn / neuroinflammation rows), Seelos / Herophilus / Myro Tx / AcureX / VesperBio / Priavoid / D&D Pharma (Neuraly), GLP-1R agonists clinical trials table, Summary CEI section opener

Tx — Nurr1:RXRa program (BRF110)

	TE	TE BM exisit?
Neuroprotection	MPTP	BRF110 (ip, 6d) → ↑ TH+ neurons count
	, 6OHDA mouse,	BRF110 (ip, 14d) → ↑ TH+ neurons count
	AAV aSyn mouse	BRF110 (ip?, why not PO?, BBB penetrace?, 14d) → ↑ TH+ neurons count
aSyn	AAV aSyn mice	BRF110 → ↑ aSyn (only in slide), detail? Quantified?
neuroinflammation	MPTP	BRF110 → ↓ microglia (only in slide, staining) detail? Quantified?
	6ohda mice	BRF110 → ↓ microglia (only in slide, staining) detail? Quantified?
	AAV aSyn mice	BRF110 → ↓ microglia (only in slide, staining) detail?

Companies CEI

Company	Note
Seelos Therapeutics	preclinical gene therapy program (SLS-004) for the treatment of Parkinson's disease (PD) and other synopathies, such as dementia with Lewy bodies (DLB). Key program highlights: - SLS-004 is a novel epigenome-editing CRISPR approach to modulate expression of SNCA gene mediated by modification of DNA-methylation (where the SNCA gene encodes alpha syn) - SLS-004 utilizes an all-in-one lentiviral vector harboring dCas9-DNA methyltransferase 3A (DNMT3A) to enrich DNA-methylation within CpG islands at the SNCA intron 1 region - In June 2022, Seelos announced in vitro data in a DLB model demonstrating a statistically significant (p<0.01) 19% downregulation of SNCA mRNA and a ~40% reduction of SNCA protein expression - In July 2021, Seelos announced positive in vivo data in a PD model demonstrating a single dose of SLS-004 produced a therapeutically desirable 27% reduction on SNCA mRNA and a 40% reduction in SNCA protein expression
Herophilus	[Sandy] - This is yet another phenotypic screening group - I am not sure that they add a whole lot of cleverness beyond what we already are working on If we wanted to work with them, it seems that we would be coming with our own hypothesis about the phenotype we would want to correct - And the ones of highest interest (protein lowering; etc.) we have already thought of and are pursuing Unless we have a great idea that we are dying to work on but have not been able to figure out a path forward (which I don't believe to be the case), I don't see the value from Herophilus I also don't believe that their annotated library is a slam dunk with respect to eventual deconvolution of a mechanism. It could be just as likely that any molecule identified would work though a different mechanism of action
Myro Tx	20221209 Arthur] - CSF1R inhibitor — Same pathway as TREM2. Pass. - GPR17 inhibitor — Inflammation relevant target but need more information. - TYK2 JH2 allosteric inhibitor — In Jak/Stat pathway but kinase targets are hard to develop due to safety issues. - Program 4 — Do not know enough to decide. Miro1, biomarker; PBMC-based Miro1 assay as a clinical biomarker of PD disease pathology and PD diagnostic tool.
AcureX	Antagonist to T-Type calcium channel CaV3.2
VesperBio	VES001: A Novel, Oral Sortilin PPI for FTD(GRN), Their non-confi slidedeck contains 'Therapeutic potential of regulating PGRN in Parkinson's'
Priavoid	Concentration, brain concentration: Plasma levels achieved in humans already after single oral dosing are in the same range of those observed in the highest dosed transgenic mice in successful Proof of Concept (PoC) studies. WHAT About brain conc? Disassemble fibrils that has already been formed (compare to competitors?) BBB penetration: 5-10%, bioavailability of single digit, main target is soluble species. Differentiation vs AC-IMMUNE (see ac I table), POC study planned in May 2024: pff+ A53T mice, what is the primary endpoint? P-aSyn pathology will be with the second study? No binding pocket but interacts with whole part of target proteins. Outstanding Qs: CSF biomarker to measure oligomer/fibril? 20240430 Eleni: My recommendation is as follows: AD program: based on my notes, there is ~10% brain penetration with their D-aa peptides and have not measured any of the key biomarkers to date. They plan to do so in the ongoing Ph2. Recommendation: monitor for Ph2 data readout. A-syn program: await till end of May 2024 or so for in vivo data.
D&D Pharma	- Neuraly (D&D Phamatech)'s NLY01, is in a p2 clinical NCT04154072 - 홍유석, 이슬기, 홍성훈 - Data room: Annafreud52!, secret question answer: vehicle → pride, • Hans • Differentiation of this asset is interesting base on academic study • They are in PD but AZ is already in clinical. From commercial prospective, the market is already established. Field is already clouded, it is not favorable asset. Table 1. GLP-1R agonists in clinical studies for Parkinson's disease. FDA-approved and novel (†) GLP-1R agonists either are currently in progress or have completed trials as of 2022 http://www.clinicaltrials.gov/, SR. sustained-release; PEG, polyethylene glycol. Company Intervention Drug ClinicalTrials.gov Identifier Recruitment Status Phase Reference AstraZeneca Exenatide Byetta® NCT01174810 Completed Phase 2 [36] Exenatide Bydureon® NCT01971242 Completed Phase 2 [76] NCT03456687 Active, not recruiting Phase 3 [235] NCT04305002 Recruiting Phase 2 [139] NCT04232969 Not yet recruiting Phase 1 [037] Peptron Exenatide SR †PT-320 NCT00964262 Completed Phase 2 [74] NCT04269642 Active, not recruiting Phase 2 Neuraly Exenatide and PEG †NLY01 NCT03672604 Completed Phase 1 NCT04154072 Active, not recruiting Phase 2 Novo Nordisk Liraglutide Victoza® NCT02953665 Completed Phase 2 Novo Nordisk Semaglutide Ozempic® NCT03659682 Recruiting Phase 2 Sanofi-Aventis Lixisenatide Adlyxin® NCT03439943 Active, not recruiting Phase 2 • Ross They said no other competitors. Hans found that AZ is in the field. Relying on KOL data. But not impressed by the team. Validating in the lab is problematic. We can revisit it when it finish phase2. • Jaya Agree with others. • If they have a positive phase 2, we should revisit it. • Masato Triaged 5 years ago, concluded that wait for GLP validation. This asset seems to not exceed exenatide. About 5 fold less CNS penetration. It works peripherally than central. Need to pay attention about this peripheral effect. Suggest to wait the phase 2 data. • Steve • Agree with Masato • Don't see better brain penetration. He was not too impressed with their asset.

Triage and Comments TEAMs Site called CEI NeuroD SE Core Team. Here is the link.

https://teams.microsoft.com/l/team/19%3aile901wkPcT5mSz-MRIEdN7mRM2BSRdJE5S89yoltvA1%40thread.tacv2/conversations?groupId=00161532-5ee8-410d-a1b0-36737e36&tenantId=57fdf63b-7e22-45a3-83dc-d37003163aae

I moved Tanaka-san’s Heat Map under “Files” to this site under its own channel. Here is the link:

https://teams.microsoft.com/l/channel/19%3a53f9b5861f4544dabfec94ea325ae360%40thread.tacv2/Heat%2520Map?groupId=00161532-5ee8-410d-a1b0-

• 12/12 Mon 4:00pm (PT) / 12/13 Tue 9:00am (KST/JST)
• 12/14 Wed 6:00pm (PT) / 12/15 Thur 11:00am (KST/JST)

Summary CEI

11/08

I hope everyone had a great weekend. Reaching out to summarize where we are on NeuroD BD Strategy and Execution:

1. Projects in DD/Partnering Discussions
2. Confidential stage opportunities and upcoming evaluation meetings
3. Opportunities recently send for triage
4. Relook at past MONITOR/Decline triage decisions
5. NeuroD Landscape Refresh
6. NeuroD Heat Map to enable Triage

I will schedule follow-up meeting(s) to discuss as a team as we push to end of this calendar and fiscal year end as well as gear up for next fiscal year 2022 goals. That said, please send any comments as well as complete the tasks indicated if any under each topic.

Projects in DD/Partnering Discussions:

• Primary effort has been on portfolio build
  • On-going targets rare/rare to common (Best in Class) strategy
  • Particular focus on tau/MAPT and alpha-syn/SNCA building in or supporting modalities/MOA with most favorable profiles
    • Protein degradation
      • PROTACS
      • Autophagy degrader molecules
    • SMOL RNA modulation
      • ASO/HDO
  • Also as a point of emphasis supporting gene therapy (GT) efforts (GBA, PARKIN)
    • Novel Capsids
    • Other GT enhancing tools
• Project Peru (Casma). tau, mHTT, alpha-syn autophagy degrader molecule programs
• Project Rhea (Remix). SCNA, DUX4, Regnase-1 small molecule RNA modulation (splicing)
• Project Cat (Autotac). tau autophagy degrader molecule program
• Project Apex (Aprinoia) alpha-syn protac/ alpha-syn target ligand. Possible secondary interest in tau

Uncertain Spans

location	transcription	uncertainty
BRF110 / BBB penetrace?	BBB penetrace?	possible source typo of BBB penetrance?.
GLP-1R table / Reference column	empty cells	reference column is clipped after the AstraZeneca block; only [74] is visible after that.
Summary CEI / Project Apex (Aprinoia)	alpha-syn protac/ alpha-syn target ligand. Possible secondary interest in tau	line clipped at right edge of photo.