Companies CEI / Individual report (continued): amimod hepatotox tail, ADRx tau, Nuravax follow-up, NeuroPn, Yumanity, Athira, Innomedica, Kyowa Kirin, BioVie NE3107, Logos Bio ADAD gene therapy / OGA, Creus CxCR7, Neuroinitiative Parkin activator, Tigen Minipig RD, Neurolixis NLX-112 / NLX-101 / NLX-204, Tx Nurr1:RXRa program (BRF110)

Individual report (continued)

Company	Note
	I don't understand the pivot from AD to DLB. And then proposed pivot back to AD, as opposed to PD. Is there any patent life left on this molecule? The hepatotox seems to be a concern, especially with 3x40mg per day. You might want to have Doug or Gvido look at the data. Any ALT or AST with a 4x margin will be difficult to manage for chronic diseases. Steve
Neuracle	FAM19A5
ADRx	small molecule therapeutics against amyloid (steric zipper) diseases and biomolecular condensates with a first program focused on small molecule inhibitors of tau.
Nuravax	For Nuravax, please see the response to question on titers and let me know if we are interested in meeting with the company?
NeuroPn	small molecule inhibitors of soluble epoxide hydrolase (sEH) as a non narcotic, neuroprotective and disease modifying therapy for Diabetic Peripheral Neuropathy (DPN) and Parkinson's Disease (PD)
Yumanity	(Daria) As you observed, there is no genetic association of SCD polymorphism with neurological conditions. What I think will be interesting to consider, if need will be, is at the dysregulation of pathways downstream to SCD and/or upstream to alpha-syn, primarily focusing on lipogenesis/membrane-related pathways/vesicle trafficking. Quite similar to the pathways that we looked up for AD (Plasma lipoprotein particle assembly, etc.) and association with biomarkers and progression. Also in addition to SCD, there are several papers with smaller sample sizes that identified an association of SREBF1 polymorphism with risk of PD in European (based on 23andme data) and Chinese populations. SCD expression is regulated by SREBF1 transcription factor. However, from a very quick check I didn't see this signal being reproduced in larger PD GWAS from Nalls, 2019 in IPDGC. If we would like to investigate it further, we could look it up in the internalized AMP-PD dataset (including gene expression).
Athira	I believe that we quickly touched based on Athira (formerly M3) and aligned that we are not interested in really any HGF/MET programs. That said I just wanted to confirm that we are not interested in a confidential meeting to review the company's progress since meeting with them ~3 years ago Athira's drug (ATH-1017) is in late-stage development for Alzheimer's and the company is also exploring Parkinson's Disease Dementia with a Phase 2 starting soon. ATH-1017 is a small molecule the promotes the HGF/MET neurotrophic system. Given the size of the markets, the company is exploring a potential partnership. Attached (also was on the teams site) is a corporate deck as well as the recent presentation from CTAD that outlines the company's clinical development strategy and the baseline characteristics (thus far) of the two studies that are underway. Arthur (TAU team) - as this a clinical stage opportunity, could you all particularly comment. David Hi David, No interest on my part. Of interest, their CEO is on leave of absence due to questions regarding integrity as she has been accused of fraud regarding her Ph.D. thesis which formed the foundation for the ATH-1017 program. Arthur
innomedica	Talineuren (GM1 ganglioside) development program for PD, ALS and AD. Confidential meeting to be scheduled delivery GM1 ganglioside across the BBB, using Innomedica's proprietary NeuroRegenosome delivery system.
Kyowa Kirin	Sandy. what differentiates an inverse agonist from an antagonist — I don't know how they come to the conclusion that there will be benefit across the entire spectrum of the disease, so I'd like to see the data that underscore that point willing to venture into symptomatics in neudodegen Js: how Differentiation from KW-2002 (IS THIS ISTRADEFYLLINE?) Small effect size (Antonio Laurenza)? Why is an inverse agonist better (or at least different) than an antagonist (SANDY)
BioVie	NE3107 is a first in class, small molecule that crosses the BBB and selectively modulates inflammatory ERK pathway while sparing homeostatic ERK 80% of Alzheimer's patients have insulin resistance or diabetes, suggesting a pathophysiologic connection between the disease states NE3107 modulates neuroinflammation and insulin-resistance in neurons, leading to preserved neuronal function and amelioration of disease NE3107 demonstrated increased insulin sensitivity in both Phase 2 (Type II Diabetes patients) and Phase 1 (impaired glucose tolerance patients) trials leading to improvement in several AD indicators NE3107 is promotoric, LiD suppressive, and neuroprotective in marmoset PD model U.S. Pivotal Phase 3 trial started in AD patients, with data readout targeted for H1 2023 Phase 2 to begin in PD patients soon, with pivotal Phase 3 expected by Q4 2022 BioVie Triage Response Table 2022.xlsx 20240303 https://www.globenewswire.com/news-release/2024/03/01/2838786/0/en/BioVie-s-NE3107-Demonstrates-Potential-Improvements-in-Motor-and-Non-motor-Symptoms-for-Parkinson-s-Disease-Patients-and-May-Be-Realigning-Physiological-Processes-for-Alzheimer-s-P.html : A Phase 2A, Placebo-Controlled Study will be presented at 15:10 GMT on March 9, 2024 and suggest improvements of NE3107-treated patients with non-motor symptoms. NE3107-treated patients experienced a significant improvement of -2.4 points for the sleep/fatigue domain of the Non-Motor Symptom Scale (NMSS) in Parkinson's Disease, whereas placebo patients experienced a worsening of +1.0 points (p=0.0159). Sleep/fatigue domain improvements correlated with motor score improvements (r=0.51; p=0.0259). More patients on NE3107 had improvements in the NMSS sleep/fatigue domain, while more patients on placebo worsened. NMSS changes for NE3107-treated patients were driven by improvements of -0.87 in fatigue/lack of energy (p=0.0005) and improvement of -2.91 on the urge to move legs/restlessness in legs (p=0.0036). Placebo patients saw no significant change of -0.39 on fatigue (p=0.1242) and -0.71 on leg restlessness (p=0.5141). The new data on non-motor improvements complements previously presented data1 showing NE3107-treated patients saw a 3+ points advantage compared to placebo on MDS-UPDRS III. In patients younger than 70 years old, the advantage was over 6 points. Furthermore, 26% of NE3107-treated patients experienced improvement in their ability to move, having Part 3 scores prior to their first morning dose of carbidopa/levodopa that were equal to or better than Part 3 scores associated with their being in the "on" state after carbidopa/levodopa treatment at the start of the study, whereas none of the placebo patients had the similarly improved morning Part 3 scores. The difference was statistically significant (p=0.046).
Vaccines	[Sarah] The vaccine field in general and also specifically for neurodegenerative diseases/proteinopathies has significantly evolved since the first trials in AD leading to severe cases of encephalitis In general we should monitor the field and be aware of any potential break throughs For our current specific exercise with trying to find an asset that can be launched within the next 2-5 years, it is very unlikely that any of the currently developed assets will fall in that time frame considering the duration and size of these trials
Logos Bio	1. A first-in-class gene therapy to treat patients with genetically defined AD a. Therapy directly addresses genetic cause of ADAD b. Large body of data supports key role of presenilin 1 in age-related neuronal survival, synaptic function, neurotransmitter release, calcium homeostasis and cognitive function c. Well-defined patient population with strong patient network d. Streamlined clinical strategy - smaller trials, younger patients, defined biomarkers & cognitive endpoints e. ADAD gene therapy will be eligible for Orphan Drug Designation 2. Preclinical package: nearing initiation of NHP studies (Q1, 2022) a. Preclinical proof of concept studies (mouse models and hPSEN1 cell lines) are in progress b. Proof of "doability" studies (biodistribution in NHP brain) scheduled to start in 1Q22 Preclinical (DC) O-GlcNAcase (OGA) program Previous aligned view on OGA was that we were not interested in this target. Feedback was as follows: Tau modulation via mechanisms of actions with the potential to address copathologies associated with neurodegeneration is a growing area of strategic interest. However, while there is the potential to believe based on strong biochemical evidence demonstrating that O-GlcNAcase (OGA) inhibitors block deleterious post-translational modifications of tau, likely due to steric effects, the mechanism of OGN inhibitors has not been directly supported by genetics or post-mortem biology. Therefore, the team would recommend passing on this particular opportunity as it is not squarely on core strategy and the high level investment likely required. Any change in view? Competitive Programs: Asceneuron (Phase 1), Lilly (Phase 2 studies ongoing for LY3372689, readout May 2024)
Creus	Just to be clear - this opportunity is NOT ON CORE STRATEGY but in any area of potential adjacency that our NDU was asked to provide some feedback on in our forum. There probably with be additional separate meetings to discuss the project and our interest in more detail. That said, everyone's view based on any experiences would be appreciated. Project Creus is a potential global licensing opportunity for a phase 2 ready multiple sclerosis asset. The target is CxCR7, an immune modulator for remylination. See the Treaser attached for further but limited background.
Neuroinitiative	Parkin activator
Sincere Tigen	Minipig and RD
Neurolixis	Neurolixis PD and Rett programs. Neurolixis is a French clinical stage Biotech developing novel drugs for the treatment of human central nervous system disorders including Parkinson's disease, Rett syndrome, Fragile-X, depression, and pain. Neurolixis was founded by highly experienced pharmaceutical industry professionals, with a world-class track record of CNS drug discovery, drug development, and clinical trials. We last spoke with the company in 2019 but decline to engage. Feedback as follows: NLX-112: PD-LiD is not an attractive target; older compound originally developed by Pierre Fabre; use patent through 2035 NLX-101: Low interest; symptomatic treatment for Rett; expect limited effect over time due to 5HT1a autoregulation change That said, the company has reached out with the following developments: The Ph2A trial of NLX-112 is on track to LPLV by the first week of January! We expect to be able to present the validated results in February/March latest. The field of interest for NLX-112 has gradually broadened from PD-LiD and now also covers other movement disorders (including orphan disease Spinocerebellar Ataxia3) and to non-motor symptoms, including pain and depression. The work on NLX-101 has also expanded from respiratory dysfunction in Rett syndrome to cognitive and mood deficits in Fragile X and other rare Autism Spectrum Disorders (i.e. NLX-101 should also address the neuropsychiatric component of those disorders). The early stage program NLX-204 is targeting depression and pain with a mechanism of action which has strong connections with the exciting work on psychedelics (the latter also activate 5-HT systems, like the NLX compounds). A broad overview of Neurolixis can be found here, or more detailed information on the programs here: NLX-112 and NLX-101. Neurolixis NeuroD Triage Form 2022.xlsx Neurolixis DEE Triage Form 2022.xlsx

Tx — Nurr1:RXRa program (BRF110)

Discovery/screening	BRF110	→	↑ DR5 luciferase	iPS	mRNA, protein?
			↑ Transcription
			Biosynthesis TH
	WT mouse	BRF110 single dose (ip) → ↑ TH Mrna, ↑ triatal DA, =DOPAC, ↑ HVA			What happens on chronic dosing?
	aSyn TG mice	BRF110 single dose (ip) → ↑ triatal DA, =DOPAC, ↑ HVA

Uncertain Spans

location	transcription	uncertainty
BioVie / LiD suppressive	LiD suppressive	reads as written; could be LID suppressive (Levodopa-induced Dyskinesia); preserved verbatim.
Tx Nurr1:RXRa table	first three columns are partially clipped on the left edge	the leftmost row label Discovery/screening spans rowspan=3 over BRF110 sub-rows; column alignment for sub-rows beyond the first is uncertain.