Summary CEI continued: Confidential stage opportunities, Opportunities recently sent for triage, Relook at past MONITOR/Decline, NeuroD Landscape Refresh, NeuroD Heat Map, 20220906 Triage live discussion (Cerevel / Neuron23 / Creus / Ionis / NLRP3 group / Transitions Bio / Wren / Fluidic / AC Immune / Blue Rock), Key Projects Rundown, Heat Map / Competitive Landscape, SE Core Team Meeting agenda

• Project Link (Cellivery), aMTD-Parkin construct for gene therapy (viral and non-viral)

Confidential stage opportunities and upcoming evaluation meetings

• Innomedica. Talineuren (GM1 ganglioside) development program for PD, ALS and AD. Confidential meeting to be scheduled
• Project Bon (Voyager). Following up on interest on novel systemic delivery brain targeted capsids. Note, Declined interest in Vectorized antibodies as alternative approach to target intracellular proteins. Revisit?
• Project Aflac (Affinia). Confidential meeting completed; waiting on NHP data in Aug/Sept, following up on interest on local delivery brain targeted capsids
• C5aR1 Antagonist PMx-318. Potential licensing opportunity from University of Queensland
• Oligomerix. Novel, first-in-class small molecule inhibitors targeting tau for neurodegeneration

Opportunities recently sent for triage:

• Amsterdam Neuroscience. Variety of capabilities looking to offer - 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
• T3D Therapeutics. T3D believes that Alzheimer’s is a metabolic disease of the brain related to poor energy metabolism and dysfunctional lipid metabolism. T3D’s lead compound, T3D-959, activates two nuclear receptors that are central regulators of normal glucose and lipid metabolism in the brain, can be taken orally once per day, and is a PPAR delta-activating compound that may have additive or synergistic effects in regulating malfunctioning brain glucose energy and lipid metabolism in Alzheimer’s disease
• Nuravax. Tau vaccine and DUAL (Aβ + Tau) vaccine
• Neuracle. 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
• Escape Bio. Company reached out again recently to update and inquiry about our interest in ESB1609 for S1P5 Selective Agonists program. Company also has LRRK2 program that we have discussed with in past but had concerns on manufacturability of molecules.

Relook at past MONITOR/Decline triage decisions:

• Gismo, focus is on targeting glycoaminoglycans with small molecules (at candidate stage) that can disrupt the GAG-aSYN complex and prevent oligomerization; Lead program is GTC-3062; binds to GAG preventing binding of amyloid.
• 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
• Others? I sent a separate email with company triage tables for review and follow-up. Are they any companies to reconsider? Everyone should have background materials in their emails but let me know and I can resend. Also, I will have a project manager load each past opportunity/company to sharepoint site

NeuroD Landscape Refresh:

• I sent landscape (~ one year old) to group to review and nominate any opportunities for outreach/Takeda initiation of partnering discussion. Please send your thoughts
• Also, I am looking to work with PVPS, Takeda Competitive intelligence or outside vendor to refresh. That said, whoever does the work, I will schedule time to discuss as a NeuroD SE core team on refreshing and expanding landscape parameters
  • Dementias (AD, FTD) / (Tau, MAPT). Other indications/targets? Modalities? Direct vs. indirect MoA?
  • (PD, MSA) / (alpha-syn, SNCA). Other indications/targets? Modalities? Direct vs. indirect MoA?
  • Neuroinflammation?
  • Modalities & Platforms & Enabling technology?
  • Other?

NeuroD Heat Map to enable Triage:

• From an upstream and but particularly downstream capabilities perspective, I think we can all agree that we are best set up to really prosecute
  • Dementias (AD, FTD) (Tau, MAPT)
  • PD/MSA (alpha-syn, SNCA)
• As a team, we have discussed creating a heat map that could inform how we could beyond the scope of the current capabilities and portfolio especially as it relates to New Frontier (Zero/First in Class) Disease areas and targets
  • Proteostasis
  • Neuroinflammation
  • Organelles
  • New pathways
  • Iron pathway modulation
• I will set up time at NeuroD SE Core Team call to discuss how and who can help create such a Heat Map. Maybe this could also be a topic at General NeuroD team meeting as well?

20220906 Triage live discussion

1. Triage. While we are actively triaging a number of opportunities, selected opportunities for live discussion

   • Cerevel. Company recently reached out for re-introduction their late-stage portfolio (5 data readouts next year), better understand Takeda’s areas of interest, and explore a few territory and asset specific opportunities. Looking to schedule a meeting Tavapadon - Still pass. CVL871-Pass. Emraclidine-Of possible interest, but need to contrast with Karuna’s KarXT and Cerevance’s M4 PAM. Darigabat-Pass (I do not recommend even for epilepsy given the MOA).
   • Neuron23. The company has received a term sheet from a Big Pharma company to acquire their IND stage LRRK2 program, and that they expect additional term sheets soon. We have consistently passed on the program in the past. Confirm - no interest This is a really crowded space. There would need to be very clear prospects for differentiation.
   • Project Creus. Potential global licensing opportunity for a phase 2 ready multiple sclerosis asset. The target is CXCR7, an immune modulator for remylination. WHITE SPACE as such high bar. Would team recommend more detailed discussion to possible act on? As discussed by email today this looks interesting. Maiko expressed some concerns. MS is not currently on strategy. More discussion needed.
   • Ionis. We triaged this in past and there was medium interest in looking at ITGAM (synapse loss disease, i.e., e.g., schizophrenia, TBI, AD) program. Recently, the company also communicated that it would be willing to also discuss it’s APOE (AD) program. As APOE is a core target assuming we would want to include. Has the ataxia/HD DAU considered their SCA programs (ATXN1 and ATXN7)? In terms of ApoE there is a good deal of uncertainty on the disease mechanism and KD of ApoE4 may not work. ITGAM is an interesting target as previously discussed. KD could reduce microglial phagocytic function and reduce neuron loss in AD. There is overlap with our C3aR program (it is the receptor for the complement C3 iC3b fragment). They are a good company and I would have no objections to speaking with them.
     • Ionis - Neuro Partnering - NonCon.pdf
     • BIO 2022 - Ionis Non-confidential.pdf
   • NLRP3. Recently a core group has triaged a number of NLRP3 opportunities. Have not pursued substantive discussions with any party.
     • Nodthera. Pass. Agree
     • Ventyx. Pass.
     • BioAge. Pass.
     • Ventus. Have spoken to before. Most likely not interested. Maybe contact
     • Halia Therapeutics. To be contacted.
     • Denali. Should we reach out?
     • AC Immune. Should we reach out? Very early discovery stage
   • Transitions Bio. Biomolecular Condensate biotech. BCs implicated in sequestration of essential proteins and linked to protein aggregation in neurodegenerative disorders. Tau as potential target? Looking to schedule confidential meeting. Should loop in DDS. This would be an early stage platform deal
     • PDF TBio Nonconfi Overview August 2022.pdf Agree with speaking with them.
   • Wren Therapeutics. Biotech with drug discovery platform for novel small-molecule medicines that block the production of toxic fleeting protein intermediates that are central to neurodegenerative disease pathways. Discovery stage program in tau. While monitored last direct engagement with company in 2019. Reached out to get update on progress
     • PDF Wren-Non-Confidential-BioEurope-November2019.pdf Agree with continuing to engage.
   • Fluidic Analytics. technology to measure alpha-syn seeds from human biological fluids in a highly quantitative manner. www.fluidic.com. Per Arthur - Help enable TAK-341 program and other PD and MSA programs that we may run in the future? Thanks for including, very important.
   • AC Immune. Feedback on recent meeting? ACI-7104 vaccine program would need to be tested in a prevention trial, which is becoming feasible (e.g. the PPMI platform trial). Showed reduced oligomeric aSYN in the CSF. I think that going into symptomatic PD (as they propose for Ph2) is a mistake.
   • Blue Rock. Microglia-based Cell Therapies for AD and other diseases. Based on initial feedback via email, looks like interest for confidential meeting
     • PDF BRTx - MG for AD Partnering Opportunity Summary.pdf I don’t agree with a cell therapy strategy for neurodegenerative.

2. Key Projects Rundown

   • Project Torchlight (Treventis). First-in-class, small molecule tau oligomer inhibitor. IND enabling stage opportunity but with areas of key concern regarding potency (in vitro and in vivo), efficacy, and translational strategy that will be address via a remediation workplan that will take 6-12 months Agree
   • Project Apex (Aprinoia). Alpha-syn (early lead stage)/tau PROTACs. Active preliminary DD and partnering discussions Agree
   • Project Turing. Tau aggregation inhibitor Screen and early drug discovery research collaboration utilizing Takeda compounds as starting point with the universities of Cambridge and Dundee Agree
   • Project Bon (Voyager). Discuss interest in moving forward for capsids with following targets: Parkin, GBA? Agree
   • Project Haven (Innomedica). Talineuren® internal evaluation of technology to move, GM1 ganglioside delivered across the BBB using company’s proprietary nanocarrier delivery system. Currently in Ph 1b in PD patients. Based on preliminary DD read-out, we will pass on a transaction. Do not feel the product as a 1x week IV infusion would be competitive in symptomatic as well as therapeutic future PD market. That said, we will review Ph 1b study results expected to be available in September 2022 Agree on passing.

3. Heat Map/Competitive Landscape

   • Late Stage Scan. Completed earlier in the year.
   • Exercise with Prescouter consultancy
     • i. Based partly on aligned Heat Map targets
       1. AD
       • a. Tau, TREM2, CD33, APOE, AQP4, EP2
       2. PD
       • a. Alpha-syn, NLRP3, GBA, Parkin, LRRK2, TRAP1, TMEM175, cGasi
     • ii. Internal Takeda SME interviews

4. Other

   • Conferences - insights
   • Open topic?

21030

Hi All,

See below Agenda for SE Core Team Meeting. Main topic will be related to

• Start of JP Morgan Planning. What companies would we recommend for meetings? New? We have triaged a lot of opportunities, revisits?
  • We will start planning via email and look to schedule adhoc meeting to discuss live.
• Heat Map/Competitive Landscape
  • Prescouter will present their late/interim report and solicit feedback on their work for AD
• We have triaged a lot of opportunities. That said, high quality on strategy programs of interest have been challenging to find. Additionally with later stage focus, less commitment to do platform deals that have been a key deal type especially for innovative small molecule approaches that directly target tau and a-syn such as molecular glues and RNA modulators. How do we enable the continued external innovation?
• Upstream, Early Stage
  • a. Closer alignment with VCs driving company formation in NeuroD? Share view of world as well as early access to companies coming out of stealth.
  • b. Leverage internal investment models such as Genesis labs for “right fit” initiatives? What proposals did NeuroD make, if any?
  • c. Small scale proof of technology partnerships with key academic institutions/thought leaders?
  • e. Explore Drug Discovery Consortium? Precedents here?

Uncertain Spans

location	transcription	uncertainty
Cerevel bullet	Looking to schedule a meeting Tavapadon-Still pass. CVL871-Pass. ...	Tavapadon line is appended to the Cerevel meeting-scheduling sentence in the source; preserved verbatim with its inline placement.