Companies CEI / Individual report (T3D, Neuracle, Nuravax, Escape Bio, Amsterdam Neuroscience, Muna Tx, GNS Healthcare, BlueRock, Genuv, Lysogene, Sunnybrook, Vincent / TMEM175, Annovis Bio, amimod, ADRx)

Individual report

Company	Note
T3D	Alzheimer's is a metabolic disease of the brain related to poor energy metabolism and dysfunctional lipid metabolism
Neuracle	NS101 and the abstract of mechanisms of action report for FAM19A5-directed treatment of neurological disease The therapeutic antibody program holds a mechanism of action for multiple diseases relating to the dysfunction of synapses, not only AD but also other neurological diseases such as ALS
Nuravax	company is starting a phase 1 for a first product and getting 2 more INDs next year (Tau vaccine and DUAL (Aβ + Tau) vaccine). The company stated that they are getting a huge antibody titer (in monkeys is 10x+ higher than the best competitors in the clinic) which is crucial for CNS diseases and the elderly (aging of the immune system). They can understand if our team is perhaps not a big fan of the classic immunotherapy approach but would like the opportunity to tell their story and hope to change minds. https://www.biospace.com/article/is-a-vaccine-for-alzheimer-s-on-the-horizon-/ https://www.technologynetworks.com/biopharma/blog/developing-a-vaccine-for-alzheimers-disease-355081 www.nuravax.com Please send me your individual: Comments: Recommendation (decline, monitor, move to confidential review):
Escape Bio	1. ESB1609 for Genetic PD 2. LRRK2 3. APOE4 [Wheaton] Back in 2019 I think this was going into Niemann-Pick type C, but it looks like they are now going for GBA PD as the first indication. It doesn't seem like they will have very much more data than 2019 as the Phib which will read out is going to be in healthy patients, correct? From what I can recall from 2-3 years ago the fed/fasted PK was a concern, I also think maybe the half-life was a concern? I don't remember the Kpu,u. For some reason I remember something about phys chem or synthesis steps being problematic potentially but I don't have my notes in front of me (nor am I sure I could find them) Personally, I think it is fine to meet with them, but it seems unlikely we'll do anything with them prior to PhI readout unless healthy volunteer safety is really what has kept us from engaging more deeply with the company. If the TAU is interested in lipid processing (Yumanity and E-scape both are at least very superficially in this area for alpha-syn modulation) it might be good to understand biomarker confidence of the two companies and to give high level feedback on it.
Amsterdam Neuroscience	Dear All, Kentaro met with Amsterdam Neuroscience at Cell and Gene conference. Attached a general overview of our capabilities and interests. Given an initial conversation from the conference, the areas with they think that the most overlapping interest are: - AD: human cell-based models of pathology and functional genomics, human pathogenic protein (seeding) propagation in vivo, post-mortem tissue target validation - ALS/FTD: human neuron and animal modeling of the C9orf72 (genetic basis for FTD and ALS) - STBxP1 encephalopathy: human neuron and animal modeling of Munc18/STXBP1 +/- - Genetic leukodystrophies: iPSC and animal modeling of genetic white matter disorders like VWM and ALD Also they think that there is a wealth of information from our clinical and post-mortem cohorts that can form the basis for a new collaboration, as well as the capabilities of the PET imaging center to study (CNS) biodistribution of all biologicals Lastly, they wanted to address Takeda's recent deal with Immusoft. They were intrigued by the technology to use engineered B-cells as vessels for CNS-targeted protein/antibody production. If we see any opportunities for a (preclinical) collaboration there, they would be happy to further discuss.
Muna Tx	Muna Tx, probably a pass BUT as Sandy has jointed group to focus on Neuroinflammation would like group to consider for small molecule approach to targets that we are comfortable with our competitive positioning: TREM2, Progranulin, Kv1.3 Inhibition
GNS Healthcare	GNS Healthcare recently announced our partnership to advance Alzheimer's R&D by leveraging a biomarker database and AI for innovation to create virtual patients that help uncover the complex biology driving Alzheimer's Disease. GNS GAP Press Release With Takeda's focus in neuroscience coupled with assets in Parkinson's Disease, would we find GNS Virtual Patient insights valuable? For example: - PD model has identified subpopulations of fast progressors. Identified several prognostic markers that show strong differentiation between risk populations. Developed scoring algorithm from model to be applied in patient screening for rapid progressors. - AD model has driven the discovery of several novel targets that have been cross validated across multiple patient cohorts and across brain tissue and blood (beyond and proximal to tau biology)
BlueRock therapeutics	Dear Sandy and all, Would we be interested in Microglia-based Cell Therapies for AD and other diseases? Please take a look and let me know if folks support a confidential meeting with BlueRock and I'll arrange. Additionally, beyond our Core team, are there any folks focus on cell therapies in Neuro that we should reach out to? This would be a platform type of deal leveraging the companies technology/capabilities. BR, David BRTx - MG for AD Partnering Opportunity Summary.pdf BlueRock Triage 2022.xlsx
Genuv	https://genuv.com/about/overview-en Genuv takes a new, simple approach: restoring brain functions by inducing the differentiation of neural stem cells in the patient's brain, thereby generating new nervous tissue. We also restore and maintain the homeostasis of the nervous system. Our lead drug candidate, SNR1611, has been shown to restore CNS functions in preclinical models of amyotrophic lateral sclerosis and Alzheimer's disease, devastating neurodegenerative diseases. Moreover, this drug candidate is available through simple oral administration Please review and let me know our interest in the rare disease CNS gene therapy opportunity described below. Note that this is a public company opportunity. The company is considering a variety of potential strategic transaction which would include acquisition and not just partnering of individual programs.
Lysogene	Opportunity Overview Lysogene, a French public gene therapy company, which is considering a variety of potential strategic transactions. Takeda has had discussions with the company back in 2018 and at that time, Lysogene entered into an ex-EU partnership for its lead asset, LYS-SAF302 for MPSIIIA, with Sarepta. - LYS-GM101: an AAVrh10 program for GM1 Gangliosidosis for which the company recently began a Ph1/2 trial (n=16) in the US and Europe In GM1 mice, LYS-GM101 reversed enzyme deficiency and substrate accumulation in the brain LYS-GM101 also achieved appropriate target activity in NHP brain and spinal cord studies 2 patients dosed so far - Fragile X program: an AAVrh10 program for which the company has established preclinical POC in the Fmr1 mouse model, reversing behavioral phenotypes This program uses a unique construct that targets diacylglycerol kinase kappa (DGKκ), a major mRNA target of FMRP in neurons, a novel mechanism that has the potential to avoid the deleterious AEs associated with the overexpression of FMRP - Additional discovery stage programs focused on neuropathic Gaucher and GBA1-PD which the company has an exclusive option to license - An active internal effort to develop novel AAV capsids with enhanced and targeted CNS tropism LYS-SAF302: An AAVrh10 program for MPSIIIA that is in a fully enrolled pivotal trial ("AAVance") with data readout in 2H22 In the AAVance trial, LYS-SAF302 showed a ~30% decrease in pathological heparan sulfate in cerebrospinal fluid 12 months after treatment, and a ~40% decrease in pathological GM2 and GM3 gangliosides in cerebrospinal fluid 12 months after treatment. Lysogene is liaising with the FDA regarding additional follow up to clear the clinical hold currently in place following asymptomatic MRI white matter changes observed in the pivotal trial. The clinical hold currently in place has no impact on the data analysis of the enrolled patients and the company expects the data and the associated benefit / risk profile will inform FDA's decision regarding the clinical hold This program is partnered with Sarepta ex-EU Lysogene is listed in France, with an equity market capitalisation of only circa €35m, which poses a number of financial and strategic issues for the Company in its efforts to progress its pipeline on a standalone basis. The company is reaching out to selected parties to explore potential interest in the company and/or Lysogene's programs.
Sunnybrook	MR-guided focused ultrasound (MRgFUS) as a noninvasive, spatially precise technology that enhances drug delivery across a temporarily permeable BBB? https://www.science.org/doi/10.1126/scitranslmed.abj4011?_ga=2.165308541.350385860.1634147770-260867539.1625762286 Hi David Pls see link. I had set up a CDA with Sunnybrook in the past, . should NS revisit ? Vincent Vincent Ling, Ph.D. Senior Director - Takeda Pharmaceuticals Drug Delivery Technologies Search and Evaluation CEI - Business Development 40 Landsdowne St Cambridge MA 02139 Office: 617-444-2377 WebEx Room : https://onetakeda.webex.com/meet/VINCENT.LINGTAKEDA.COM
therapeutics	TMEM175 program is: The TMEM are essentially in the target-to-hit phase. The company will have first data in about 12 months from now. They are aware that we're quite early. From company "Our differentiation at this point is certainly the interaction driven targeting approach which you will find to be unique for both targets (TMEM175 and LRRK). So the question is rather if there's enough interest to join already into these first steps with a very limited investment - to then have that foot in the door when we reach that next value inflection point. If the early stage is not an insurmountable hurdle per se, the confidential presentation and a discussion should certainly be helpful for your team to at least set the stage for follow-up discussion at later time as well as build relationship."
Annovis Bio	BERWYN, PA., November 9, 2021 -- Annovis Bio, Inc. (NYSE American: ANVS) ("Annovis" or the "Company"), a clinical-stage drug platform company addressing Alzheimer's disease (AD), Parkinson's disease (PD), and other neurodegenerative diseases, today announced that Vice President of Research, Cheng Fang, Ph.D. will present the ANVS401 mechanism of action via a poster presentation, on display both onsite and online, during the 14th Clinical Trials on Alzheimer's Disease (CTAD) Conference. The poster presentation, titled "Translational inhibition of neurotoxic aggregating proteins leads to efficacy in Alzheimer's and Parkinson's patients", can be viewed in person in the Statler Room of the Boston Park Plaza Hotel, Boston, MA during lunch and coffee breaks. The digital version of the poster is now available on the CTAD digital platform to registered conference attendees. All abstracts will also be published in the Journal of Prevention of Alzheimer's Disease (JPAD). Annovis' lead compound, ANVS401, is an oral translational inhibitor of neurotoxic aggregating proteins (TINAP) currently being developed for AD, AD in Down Syndrome (AD-DS), and PD. The mRNAs of neurotoxic aggregating proteins, including Amyloid-β precursor protein (APP), t-Tau and p-Tau, as well as α-Syn (α-Syn), have a unique sequence which regulates translation of these proteins. ANVS401 acts on that sequence to inhibit the translation of neurotoxic proteins. By preventing the overexpression of these neurotoxic proteins, ANVS401 reverses the downstream toxic cascade that leads to neurodegeneration. Slight reductions in neurotoxic proteins at the beginning of the toxic cascade have been shown in the Company's animal studies and Phase 2a clinical trials in AD and PD to reinstate homeostasis and to lead to statistically significant improvements in cognition in AD patients and motor function in PD patients. impact on gait in DLB
amimod	Shimojo Masato: First, I do not support this MOA due to safety concern. P38alpha is ubiquitously expressed in body and plays important roles in cell proliferation and tumorigenesis. Actually P38alpha KO mice is lethal. Even conditional KO 'at adult age causes proneness to cancer development and lung dysfunction. Originally this MOA has been recognized as a target for RA and cancer for long time. However to my knowledge none succeed in launch. However as you may know recent clinical data of this compound is promising. So, if the inhibition' of P38alpha by this compound is mild and tolerable in clinical settings and clinical efficacy is solid, we may consider this opportunity. So my recommendation is closely monitor. Arthur: I also have concerns about toxicity. So far the safety for this molecule looks good. They actually did long term toxicology up front given the mechanism and the safety in humans is good, but of course long-term follow up is needed. I am not suggesting that we partner with them. Rather, I think that this program is interesting to us in terms of the role of cholinergic neuron loss in DLB and the impact on gait and falls, which is very relevant to TAK-071. If TAK-071 succeeds in Ph2 we may want to think about other programs that target the cholinergic system in a way that is disease modifying. The hepatotox seems to be a concern, especially with 3x40mg per day. ... 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

Uncertain Spans

location	transcription	uncertainty
Lysogene / DGKκ token	diacylglycerol kinase kappa (DGKκ)	OCR rendered as DGKk; preserved verbatim with the Greek κ from the source font.
Sunnybrook / Vincent row	row label	the leftmost cell on this row is labeled only with a continuation of the prior Sunnybrook topic; the Vincent / TMEM175 content actually belongs to a new row (label clipped at the left edge). Preserved as a therapeutics placeholder label with an Uncertain Span note.
ADRx tail	small molecule therapeutics against amyloid (steric zipper) diseases and biomolecular condensates with a first program focused on small molecule	sentence is clipped at the right edge.