Brick Mortar Non Profit Biotechs Opportunities for Preclinical by vqx13199

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									“Brick & Mortar” Non Profit Biotechs
   Opportunities for Preclinical Drug
           Development

            Steven Perrin, PhD
               CEO and CSO
    ALS Therapy Development Institute


                                        1
                                     ALS 101
• Loss of upper and lower motor           • Statistics
neurons                                        –   30,000 in US, 5,000+/ year
                                                     • 50% mortality in 18 months
• Complex pathophysiology                            • 20% survive 5 years
    • Neuron loss
    • Muscle wasting                      • ALS can be sporadic (90%) or
    • Astrocytosis                          familial (genetic) (10%)
    • Excitotoxicity                           –   20% FALS is caused by a mutation in
    • Microglial activation                        SOD1
    • Peripheral inflammation                  –   Clinical presentation for FALS and
    • Changes in axon transport                    SALS is indistinguishable
    • Synaptic remodeling
    • Protein folding
    • Endoplasmic reticulum stress
    • Mitochondrial dysfunction
    • Oxidative stress
    • ?.............
                                                                          3

            ALS-TDI: A Non Profit Biotech
• History
    • Founded 1999 by Heywoods
    • Annual budget of ~$12 million
    • 48 employees
    • 30 full time scientists

• Mission
     • Bridge the gap of ALS therapeutic development and facilitate the
     clinical development and commercialization of therapeutics for ALS
     patients

• Combines power of a 501(3)c non-profit with the best practices of a for-
profit biotech or pharmaceutical company
       ALS-TDI Focuses on Preclinical
      Therapeutic Development for ALS


 Study         Find a Drug    ⇒      Build     ⇒     Pre-Clinical     Clinical
          ⇒                                                       ⇒ Development
Disease           Target             Drug           Development

   Basic Research            Pre-Clinical Development                Clinical
                               Translational Research


                             Drug Development Gap
           ALS Market Analysis
• 2008 global ALS market: $300M (Rilutek)
   –   Annual treatment price: $7,000-10,000
   –   Penetration of Rilutek into the ALS market is low (<50%)
   –   Rilutek offers a marginal improvement in survival (60-90 days)
   –   No improvement in quality of life
• Growth Drivers for the Market:
   – Expandable market by increasing survival (increased prevalence)
   – More effective drugs command greater market penetration
   – More effective drugs can be priced at a premium
• Effective Drug will Drive the ALS Market
   – Estimated sales for more effective ALS drug: $2-4 billion annually
        • Treatment price of $50K/year
        • Improvement in survival by 2 years
        • 48% peak penetration
   – A 24 month improvement in survival will increase the ALS market size
     to approach the size of the MS market
      Opportunities and Challenges For ALS
          Therapeutic Development
• Opportunity
  –   High unmet medical need
  –   FDA Orphan drug status possible
  –   Specialty call point
  –   Active and passionate patient population
  –   ALS may share mechanisms with other neurodegenerative
      disorders


• Challenges
  –   Complex, multi organ disease
  –   Heterogeneous patient population
  –   Preclinical drug development is difficult
  –   Clinical translation unproven
          ALS Therapy Development:
              The Unmet Needs
• Discovery

• Rigorous preclinical testing

• Biomarker development

• Partnership for clinical development

                                         7
          ALS Therapy Development:
              The Unmet Needs
• Discovery

• Rigorous preclinical testing

• Biomarker Development

• Partnership for clinical development

                                         8
      ALS-TDI Focuses on Preclinical
     Therapeutic Development for ALS
                             Prototypical Pharmaceutical Timelines
        Drug                   Pre Clinical
                                                   Phase I            Phase II              Phase III
      Discovery               Development

     3.1 yrs                   1.4 yrs            1.7 yrs            2.7 yrs            1.9 yrs




Discovery         Disease        Therapeutic
  Tools           Models         Development
                  Clinical
                  Samples
                                                          Pk      Tolerability   Efficacy            PD
                                                        Studies     Studies      Studies           Studies




                                               Confidential
       ALS TDI Drug Discovery Pipeline
                                        shRNA Gene
                   Cloning                                                          Sub clone AD
                    LIMS                                      Sequence Verify                             Viral Production
                                                                                        Virus
                                        Clone Gene

   Genetics
                                           Therapeutic Development                                 In Vitro             Validation
Gene Expression    GE                                               SM                               LIMS               Expression
                  Data                                             LIMS
  Proteomics      Prot                 Small Molecule or         Synthesis/In                                        Functional Assay
                                                                                       Formulation
                  Data                  Protein Biologic           License
  Literature                                                                                                    In vitro/vivo
                    Approved Project                                                                               Testing
                                                                                                                         In Vivo
Discovery                                                                                                            Pharmacokinetic
                                                               Knowledge Sphere                                          Studies
                                                                                                         Phar
   New Lead                                                                                               m          In Vivo Surrogate

                    PM                                        Validation                                 LIMS             Studies

                   LIMS
                                                                                                                      In Vivo Efficacy
                                                                                                                          Studies
                              GE                 Affymetrix                        Luminex
                             Data
 Archive Lead
                                                   QPCR                           Immunoblot                   IB
                             QPCR
                                                                                                              LIMS
                             LIMS
                                                     ISH                             IHC                      IHC
                              ISH
                                                                                                              LIMS
                             LIMS
Study Design: Whole Genome Expression
          Profiling SOD1 Mice
   Animals re genotyped
    for copy number and          Disease onset
     assigned to a study         Tail Paralysis                         End stage disease


    d30      d45      d50            d70-80           d80-120               D120-150



  Animals          Treatment                   Disease progression
 Genotyped          Initiation                Paralysis hind limbs to
                                                    forelimbs


  • 5 non transgenics, 5 SOD1G93A and 5 wtSOD1 transgenic animals per group
  • Groups harvested at 10 day intervals starting at day 50
  • Tissues extracted and flash frozen on dry ice
  • Brain, spinal cord, skeletal muscle, brown fat, white fat, sciatic nerve, blood
  • Laser captured motor neurons and surrounding tissue
  • Profiled on Affymetrix MOE430vII gene chips and Affymetrix Ex1.0 exon arrays
 Activation of Co Stimulatory Pathway




  Spinal Cord                     Muscle                     Sciatic Nerve

• Drugable pathway present in 3 diseased tissues in the hSOD1 preclinical model
                                                             -1         0         1

                                                            d50   d60 d80 d90 d100 d110
          ALS Therapy Development:
              The Unmet Needs
• Discovery

• Rigorous preclinical testing

• Biomarker Development

• Partnership for clinical development

                                         13
    Minocycline Enhances Disease Progression and
              Mortality in Phase III Trial



                                      Clinical Translation



                                                       Summary
                                                       • ALSFRS Score
                                                              • Decreased 9.4 units in placebo
 * Zhu et al., Nature 2002
                                                              • Decreased 11.7 units in Minocycline
Conclusions                                            • Failure endpoint was higher in Minocycline Group
• Minocycline delays disease onset                            • 32 in placebo
• Minocycline extends survival                                • 41 in Minocycline
• Minocycline inhibits cytochrome c                    • “ Four published reports have shown that minocycline
release from mitochondria                              delays disease progression in the ALS transgenic mouse.”
                                                       “Our results suggest either that the current approach to
                                                       translational neuroscience is unsatisfactory or the
                                                       transgenic mouse model is a poor representation of ALS.”




                                                                             * Gordon et al., Lancet 2007
              Control Noise Variables in the
                    Preclinical Model
Optimized Study Design                                                                  Effect of increasing 'n' on Noise for Each Study Design Variable

1. 48 total mice.                                                             60.00%


2. Tx group 12m+12f




                                       Noise: Frequency of Apparent Effects
                                                                              50.00%


3. Control group 12m+12f.                                                     40.00%


4. Gender & litter matching                                                   30.00%


5. Blinded scoring                                                            20.00%


6. Confirm transgene copy number                                              10.00%


7. Censor non ALS deaths                                                       0.00%
                                                                                          n=4     N=10     N=16     N=20     n=24     n=30     n=40        n=50
8. Log rank and Cox proportional                                              -10.00%
                                                                                                                   Number Per Group
hazard model for statistical testing
                                                                                        UU+Censored & Low Copy         UU+Censored           UU            MB




                                                                                                                  Scott et al., 2008 ALS J.
ALSTDI 00846 is Efficacious in SOD1G93A Mice
                                                                               1.00

         Females:                                                                      A                                                           B




                                               Proportion at Peak
                                                                               0.75
  5.22 mg/kg loading dose
     1 mg/kg weekly IP                                                         0.50

           Males:
                                                                               0.25
   6.75 mg/kg loading dose                                                                                CTRL
                                                                                                          DRUG
    1.34 mg/kg weekly IP                                                       0.00
                                                                                      30   40   50   60   70   80     15     25    35   45    55   65

            Day 50 start                                                               pVal= 0.286             Time (days)    pVal= 0.046


                                                Proportion Onset or Survival
                                                                               1.00
A. Time required to attain peak body weight.
 Time to peak was not significantly changed                                            C                                                           D
 B. Time from peak body weight until death.                                    0.75
 BW maintenance was significantly improved
       C. Time to disease onset (Ns =2).
  Disease onset was significantly delayed by                                   0.50
    D. Survival was significantly prolonged

                                                                               0.25


                                                                               0.00
                                                                                      95   105 115 125 135 145        110    120    130      140   150

                                                                                      pVal= 0.001              Age (days)         pVal= 0.003
ALS TDI Preclinical Drug Screening Pipeline

                            % Change in Median Survival
   8%
                                                                                             ALS TDI 00846

   6%



   4%
                                            Cyclosporine
                                                         Florouracil             Tamoxifen               Apocynin
   2%   Riluzole       Thalidomide
                                                                Hydroxyurea
                                    Ceftiaxone
   0%
           Celebrex                         Clioquinol             Ritonavir

  -2%                 Minocycline                                                       Lithium
                                                            Sodium Phenyl Butyrate

                                                                                      Sodium Valproate
  -4%


                   • Screened ~100 compounds                                   MR1 is the only compound
                   • Repeated preclinical studies                                TDI has tested that:
                                                                                  • Delayed disease onset
                                                                                  • Delay body weight loss
                                                                                  • Improve survival
          ALS Therapy Development:
              The Unmet Needs
• Discovery

• Rigorous preclinical testing

• Biomarker Development

• Partnership for clinical development

                                         18
ALS TDI 00846 Reduces Axonal Recruitment of Macrophages
                                                                             CD68+ Cell Counts
                                                                               By Treatment




                            S100b+ Distal Nerve (5 fields/count)
                                   CD68+ Cell Counts
          No treatment:




                                                                           - Tx       + Tx Cnt

                                                                   All age matched females, 18 ug/week, I.p.
                                                                        50 day start, sacrificed at 103 days
                                                                   Biological replicates; double blind analysis


        00846 treatment
           ALS is a Heterogeneous Disease

Biomarker Development Efforts

• Molecular Profiling
    • 300 ALS blood samples
    • 50 skeletal muscle biopsies
    • Skin and adipose collections 2010

• Goal
    • Utilize historical database to facilitate phase II
    design
    • Patient enrollment and drug response



                                                           controls         ALS
                                                                                               20
                                                                  Potential response outcome
          ALS Therapy Development:
              The Unmet Needs
• Discovery

• Rigorous preclinical testing

• Biomarker Development

• Partnership for clinical development

                                         21
           Business Development Strategy
• ALS TDI will de risk the preclinical development
• ALS TDI will generate an IP portfolio around the target and drug
• Partner committed to building an ALS franchise
   – Ability to move quickly
   – Committed resources for development and commercialization
• Partner must agree to active ALS TDI participation in development
   – Preclinical work
   – Development plan
   – ALS TDI representative on development team
• Partner must agree to recognizing TDI after commercial launch
   – Publications
   – ALS-TDI branding
              ALS TDI Investment in ALS TDI 00846
                               Prototypical Pharmaceutical Cost & Timelines
          Drug                   Pre Clinical
                                                     Phase I            Phase II              Phase III
        Discovery               Development

       3.1 yrs                   1.4 yrs            1.7 yrs           2.7 yrs             1.9 yrs
       ($10M)                    ($20M)             ($10M)            ($30M)             ($100M)

                                            ALS TDI Cost & Timelines
  Discovery         Disease        Therapeutic
    Tools           Models         Development
                    Clinical
 0.75 yrs           Samples        1 yr                     Pk      Tolerability   Efficacy            PD
 ($0.6M)                           ($0.8M)                Studies     Studies      Studies           Studies

                                                           1.5 yrs
• ALS TDI 00846 preclinical development: $2.5M            ($1.2M)
• 40% of investment is in therapeutic development, pk, and tolerability



                                                 Confidential
            ALS TDI Drug Development Pipeline
Target ID       Biological Process      Target       Drug            In Vitro Assay   Pk &              Pd and      Efficacy   IP Filing
                                        Validation   Manufacturing   Development      biodistribution   biomarker   Testing
ALS TDI 00898   Metabolism

ALS TDI 00897   Metabolism

ALS TDI 00883   Cellular Stress

ALS TDI 01006   Complement Inhibition

ALS TDI 00847   Complement Inhibition

ALS TDI01002    Complement Inhibition

ALS TDI 01001   Immune Modulation

ALS TDI 00879   Immune Modulation

ALS TDI 00846   Immune Modulation

ALS TDI 00900   Immune Modulation

ALS TDI 00878   Immune Modulation

ALS TDI 00903   Immune Modulation

ALS TDI 00894   Immune Modulation

ALS TDI 01004   Immune Modulation

ALS TDI 01005   Immune Modulation

ALS TDI 01003   Immune Modulation
ALS TDI 00904   Synapse Remodeling

ALS TDI 00874   Synapse Remodeling




                                                                                                                                           24
     Critical Inflection Point for Drug Discovery

• Annual 2008 budgets
• Average = $66M
• STD = $87M
• Top Quartile = $213M
• 2nd Quartile = $54
• 3rd Quartile = $16M
• 4th Quartile = $2M

• Average Cost $800M
• Need > $15M annual
• Need long term revenue




                                                    25
         ALS-TDI Focuses on Preclinical
        Therapeutic Development for ALS

 Study                       Find a Drug             ⇒      Build      ⇒        Pre-Clinical     Clinical
               ⇒                                                                             ⇒ Development
Disease                         Target                      Drug               Development




         Discovery Budget                                   Drug Development                     In Vivo testing
  Basic Research                                  Pre-Clinical Development                                 Clinical
 $4.0                                                $5.0                            $8.0

 $3.0                                                $4.0                            $6.0
                                                     $3.0
 $2.0                                                                                $4.0
                                                     $2.0
 $1.0                                                                                $2.0
                                                     $1.0
                                                      $-                              $-
  $-
        2007   2008   2009   2010   2010   2011
                                                       Development
                                                  Drug2007 2008 2009 2010 2010 2011 Gap     2007 2008 2009 2010 2010 2011
                                     Opt                                 Opt                                    Opt
    ALS TDI Partnership and Collaborations
• Discovery                        • Biomarker
•   Ocimum Biosolutions              Development
•   Applied Proteomics             •   Muscular Dystrophy Association
•   Scitegic                       •   UC Irvine
•   Ariadne Genomics               •   Methodist Hospital
•   Allen Brain Institute          •   University of Arizona
• Gene Therapy                     •   University North Carolina
•   Microbix                       •   Prize4Life
•   Asklepios Biopharma
•   Oxford Biomedica Inc
•   University of Massachusettes   • Qventis
                                   • California Stem Cell

                                                                        27
      ALS TDI Executive & Scientific Board
• Executive Board                     • Scientific Review Board
•   Chairman: Augie Nieto             •   Sharon Hesterlee
•   Vice Chairman: Leslie Michelson   •   Stan Appel
•   Jamie Heywood                     •   John McCoy
•   John Heywood                      •   Lee Sweeney
•   Rob Rodin                         •   Spiros Jamas
•   Alex Cappello
•   Keith Melanson




                                                                  28
                        Summary
• ALS is strategically a commercially attractive disease indication

• ALS therapeutics may be efficacious in related neurodegenerative
  disease indications

• ALS preclinical model is challenging but can be effectively utilized

• Drug development is expensive and risky
   – Need robust discovery efforts
   – Pipeline of opportunities to screen
   – Partnership strategy
• Plan requires a long term revenue stream of >$20M annually


                                                                         29
                    Acknowledgements
•   Sean Scott              •   Al Gill
                            •   Jeyanthi Ramasubbu
•   John Lincecum           •   Fernando Vieira
•   Monica Wang             •   Ken Thompson
•   Annette Ferrari         •   Harveen Dhillon
•   Samantha Crocker        •   Carlos Maya
                            •   Andy Moreno
•   Jerry DeZutter          •   Matt Ferola
•   Reenu Pandey            •   Josh Kidd
•   Guande Li
•   Michael Kaufmann        •   Bashar Al-Nakhala
                            •   Shawn Sullivan
•   Wei Qun Zhang
•   Trang Tieu              Support
                            MDA
•   Beth Levine             DOD
•   Vladimir Morozov        RGK Foundation
                            ALS Patients & Families

								
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