Foundation Funded Drug Discovery in a Virtual Model : Lessons Learned

Transcription

1 Fondation Fnded Drg Discovery in a Virtal Model : Lessons Learned Celia Domingez, Ph.D. Vice President, Chemistry IOM: Form on Neroscience and Nervos System Disorders Ventre Philanthropy Strategies Used by Patient Organizations to Spport Translational Research - A Workshop Rapidly discover and develop drgs that prevent or slow Hntington disease Celia.Domingez@chdifondation.org October 3,

2 What is CHDI? Otline Key Points for Translational Research Two Case Stdies: Compare and Contrast Company X vs Company Y What worked and what did not? Smmary of Key Points Page 2

3 CHDI Fondation: A New Model Page 3 In 2008, CHDI, Inc. and High Q Fondation (NYC) were combined into one organization: the CHDI Fondation, Inc. Non-for profit, 501 (c) (3) stats Motivated by time not money Private All monies are derived from private (anonymos) donors 2007 spend was >$60MM Virtal No wet lab space Exclsively focsed on 1 aim: Therapetics for Hntington s Disease Otsorcing >400 FTEs worldwide, chemistry, biology, pharmacology, PK, and formlation Internal organization 41 FTEs Discovery Biology Princeton Drg Discovery Los Angeles Clinical Development Princeton Administrative/Bsiness/Legal New York Internal expertise 25 PhDs/MDs Medicinal and comptational chemistry, cheminformatics, IT Biology: pharmacology, strctral, nerobiology, developmental, PK, toxicology, moleclar and celllar biology, bioinformatics Rapidly discover and develop drgs that delay or slow Hntington s disease

4 CHDI-driven flly integrated programs Target is believed of importance in the pathophysiology of HD bt is not being prosected within the pharma or biotech sectors We have primary responsibility for oversight and progression from m HTS throgh registration We generate the validating ligands We generate and own the intellectal property Leverage integrated biotech s Facilitate entry into HD by fnding an HD program Collaborative effort across both organizations We share the intellectal property Enable HD Translational Efforts Centralized biological and chemical repositories Oversight of qality & validation No IP constraints, minimal costs HD efficacy models Otreach Mission Enabling Strategies Access advanced validating ligands that have not been disclosed - the good stff! Access ndisclosed earlier stage componds We have in vivo capacity in or efficacy models to test yor componds Page 4

5 Key Points for Translational Research It s the patients stpid Nothing is more precios to a drg hnter than an observation in hmans Most nerodegenerative diseases (even monogenic ones like HD) have not been described to a sfficient level of detail to enable drg discovery We need to know which targets are well validated and how to modlate them Even in orphan diseases having a moleclar target & and well nderstood mechanism of action is key to sccess. Robst preclinical filtering gives componds a real at bat Formlation, profiling, PK Garantee exposre to give target coverage Pharmacodynamics and psedoefficacycan give yo confidence that it is worth waiting for the longer (clinically meaningfl) otcome Ensre target engagement Definitive ot come: Move forward with a drg candidate or eliminate a target/mechanism Consider novel approaches Alternate modalities Central delivery Combine the moleclar specificity of drgs with the spatial-temporal precision of devices Page 5

6 Key Points for Translational Research Intellectal Property (IP) Reagents, tools and animals models mst be free of IP to enable researchers in academic, fondation and indstry to do research. IP for composition of matter and freedom to operate mst obtained for the therapetic (i.e. the compond) to enable downstream development by the Biotech/Pharma indstry Leverage people/instittion s strengths Academic vs CRO vs Biotech/Pharma Understand people/instittion s motivations Academic vs Biotech/Pharma Fondation vs Biotech/Pharma Page 6

7 It Takes a Village with Different Skill Sets P Target ID & Validation P Target to Screen Screen to Hit Hit to Lead Lead Optimization Candidate Selection Long-term Toxicology Clinical Trials IND Basic Research Tools/Assays HTS development HTS Hit Confirmation References synth Flow chart screens SB/HTS/Screening Protein Hits to leads In vitro screens Modeling/MSD Lead to development candidate Medicinal Chemistry Preclinical Development ~ Componds to identify 1 Clinical Candidate Medicinal Chemistry Biology/ Animal Pharmacology SM Process Chemistry Preclinical Development P1 P2 P3 P4 Page 7

8 Biotech Case Stdy # 1 CHDI interested in a particlar enzymatic platform with lead like molecles that were amendable to be BBB permeability Company X Strength: Prified Enzyme Platform available Selectivity profiling Celllar assays: engagement of moleclar target in a celllar context Pharmacodynamic markers On mechanism assays Pharmacokinetic Experienced medicinal chemists (proven track record) Experienced moleclar pharmacologist Company X Weakness: Smaller Biotech Limited resorce & CNS expertise Limited financial resorces Company stability Company Motivations/Drivers: Science based Interested in Nero-degeneration Desire to help the fondation Pressre to meet VC demands Page 8

9 Biotech Case Stdy # 2 CHDI interested hits or lead componds with activity in primary neronal assays Company Y Strengths: Expertise in primary neronal assay Company Y Weakness Target nknown Mechanism nknown No medicinal chemistry expertise No Pharmacodynamic markers Small Biotech Limited resorces & lack medicinal chemistry expertise Limited financial resorces Company Stability Company Motivation/Driver: Science based Pressre to meet VC demands Clinical candidate Page 9

10 What worked and What did not? Collaboration X: Excellent commnications Good nderstanding of the challenges in R & D Good biochemical Platform Good celllar Platform Confirm activity cell Mechanism of action PK/PD readot Confirm in vivo engage of target and or pathway Otcome: Potent componds with SAR BBB permeable Confirmed engagement of target via PD marker ex vivo Proof of concept molecle in HD Tg stdies ongoing Generated novel IP Collaboration Y: Commnication not optimal No moleclar target nknown Celllar assay was not robst Highly variable Phenotypic assay Flat SAR Chemistry no path forward Otcome: No molecle prsed Only one hit wonder No IP Termination of collaboration Utilization of primary neronal assay as general tertiary screen Page 10

11 Key Points for Translational Research Intellectal Property (IP) Reagents, tools and animals models mst be free of IP to enable researchers in academic, fondation and indstry to do research. IP for composition of matter and freedom to operate mst obtained for the therapetic (i.e. the compond) enable downstream development by the Biotech/Pharma indstry Even in orphan diseases having a moleclar target & and well nderstood mechanism of action is key to sccess. Biochemical Celllar assays-expression moleclar target PK/PD-coverage of target Compond engages target in vivo Leverage people/instittion s strengths Academic vs CRO vs Biotech/Pharma Understand people/instittion s motivations Academic vs Biotech/Pharma Fondation vs Biotech/Pharma Page 11

12 Thank Yo! CHDI LA, NY & Princeton Collaborators and HD Researchers Page 12

13 Drg Discovery: A Medicinal Chemist s s Perspective Chemically tractable- does not have to be easy Moleclar target key player in pathway Biochemical Assay- Moleclar Target (Hman + other species) Robst and sensitive assay to allow SAR Species difference or not Celllar Assay: Moleclar target expressed in cells Relevant to animal model Mechanism of action: engagement of target in celllar context Possible readot adapted as a PD marker Celllar Assay as primary screening Needs to be robst and sensitive to drive SAR (max 10 fold difference) Pathway screening can lead to a hit, bt need to find moleclar target Phenotypic screens difficlt to drive SAR Good secondary or tertiary screens Identify hit we need to fine the moleclar target Pharmacodynamic readots: Linked to target engagement and ideally disease progression Enables nderstanding of PK/PD relationships Understanding of dose and target engagement (IC 25, IC 50 or IC 90 ) Disease Animal Model Target expressed Target important in disease PD readot to be the same as in the clinic or vice versa Safety margins Page 13

14 Biological and Chemical Tractability htt Caspase-6 Target Validation Haps BDNF/TrkB HDACs TG-2 A2a >280 targets mglrs Target Drgability Page 14