Neumora Therapeutics, Inc. · NASDAQ:NMRA

Neumora Therapeutics — BlackThorn Therapeutics — Kappa Therapeutics Conference 2019

16 slides from Neumora Therapeutics's conference presentation, March 2019

1. Slide 1: The Discovery and Initial Human Pharmacokinetics of BTRX-335140

   The Discovery and Initial Human Pharmacokinetics of BTRX-335140, a Selective Kappa Opioid Receptor (KOR) Antagonist Kappa Therapeutics Conference – March 2019 Seattle Transforming CNS Therapeutics

2. Slide 2: Disclosures

   Disclosures Employee and shareholder of BlackThorn Therapeutics Majority of the research was funded by BlackThorn Therapeutics (remainder from NIH Blueprint Grant # 1-UH3-NS093030-01) © 2019 2

3. Slide 3: BTRX-335140 – a kappa opioid antagonist for mood and anxiety disorders

   BTRX-335140 – a kappa opioid antagonist for mood and anxiety disorders Discovered by a Scripps Research Institute – BlackThorn Collaboration © 2019 3

4. Slide 4: Overview

   Overview  Interest in KOR antagonists as therapeutics  Historical challenges in KOR antagonist drug discovery  Identification and characterization of BTRX-335140  Phase 1 clinical data  Summary © 2019 4

5. Slide 5: The KOR-dynorphin system in stress and neurobehavioral disorders

   The KOR-dynorphin system in stress and neurobehavioral disorders KOR-peptide system identified to modulate dopamine signaling in key regions of the brain resulting in stress-induced dysphoria, anhedonia, and anxiety Van’t Veer and Carlezon, Psychopharmacology 2013 The first antagonists discovered ha

6. Slide 6: Historical challenges with the KOR antagonist chemical space

   Historical challenges with the KOR antagonist chemical space  Low brain penetration  Poor oral bioavailability  Long duration of action decoupled from plasma/brain exposure  Poor selectivity for KOR vs. MOR and other GPCRs © 2019 6

7. Slide 7: Breakthrough with chemical matter identified from the ML-SMR library

   Breakthrough with chemical matter identified from the ML-SMR library HTS Hit IC50 values IC50 values KOR = 410 nM MW = 419 MW = 412 tPSA = 100.5 KOR = 12.6 nM MOR = 4590 nM MOR = 323 nM tPSA = 74.2 DOR = >50000 nM cLogP = 2.3 cLogP = 2.9 DOR = 3500 nM  Increased potency  >25-fold selectivity  Goo

8. Slide 8: Key modifications improve potency and selectivity

   Key modifications improve potency and selectivity IC50 values MW = 371 IC50 values MW = 377 KOR = 1.3 nM tPSA = 82 KOR = 2.2 nM tPSA = 62 MOR = 31.1 nM cLogP = 2.2 MOR = 829 nM cLogP = 2.9 DOR = 2410 nM cpKa = 10.2 DOR = >10000 nM cpKa = 10.6 Ester to oxadiazole Pyridine to Quinoline  Better hepato

9. Slide 9: Additional modifications improve drug properties and reduce liabilities

   Additional modifications improve drug properties and reduce liabilities BTRX-335140 Mitigates quinoline oxidation Ethyl further improves potency and selectivity Improved human hepatocyte stability IC50 values MW = 354 KOR = 0.8 nM tPSA = 71 MOR = 110 nM cLogP = 2.4 Electron withdrawing group DOR = 6

10. Slide 10: Binding model elucidates selectivity and potency increases with key interactions

    Binding model elucidates selectivity and potency increases with key interactions BTRX-335140 JDTic Water kicked out here Asp138 Asp138 Tyr312 Tyr312 Model by Gary Brandt, PhD Similar binding site but different interactions may impart different duration of action properties Wu, et al. Nature 2012, 48

11. Slide 11: BTRX-335140 engages the KOR target and has <24 hour duration of action

    BTRX-335140 engages the KOR target and has <24 hour duration of action BTRX-335140, BTRX-335140 +U50488 BTRX-335140, 1 mg/kg ip oral 1 hour pretreatment BTRX-335140 +U50488 BTRX-335140, 1 mg/kg ip BTRX-335140, 24 hours pretreatment oral BTRX-335140 +U50488 Additional BTRX-335140 pharmacodynamic char

12. Slide 12: Human PK – Single oral doses

    Human PK – Single oral doses Tmax @ 6-8 h T1/2 of 32 h Exposure increases with dose, generally dose proportional No food effect (Cohort 7) © 2019 12

13. Slide 13: Human PK – Multiple oral doses (QD for 10 days)

    Human PK – Multiple oral doses (QD for 10 days) 2.5-4.5-fold accumulation upon repeat dosing; steady state reached by Day 9 © 2019 13

14. Slide 14: BTRX-335140 is well tolerated after 10 days of dosing in healthy volunteers

    BTRX-335140 is well tolerated after 10 days of dosing in healthy volunteers  No deaths or serious adverse events  No adverse cardiac signals by EKG  All adverse events classified as possibly related to treatment were Grade 1  No treatment-related discontinuations Adverse Events Occurring in >1 S

15. Slide 15: Review of KOR antagonist BTRX-335140 attributes and timelines

    Review of KOR antagonist BTRX-335140 attributes and timelines Highly potent, selective antagonist for KOR 2016 Exhibits on-target activity in a variety of pharmacological assays 2016 Excellent safety and tolerability profile in non-clinical toxicology studies 2017 Favorable tolerability and pharmaco

16. Slide 16: Acknowledgements

    Acknowledgements William J. Martin, PhD BTRX President and COO Annette Madrid, MD BTRX Atul Mahableshwarkar, MD BTRX Tanya Wallace, PhD BTRX Sarah Alvarez-Horine, PhD BTRX Kerensa Saljooqi BTRX Steven Smith, PhD BTRX Gary Brandt, PhD BTRX Mariangela Urbano, PhD TSRI and BTRX Edward Roberts, PhD TSRI

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