CommentaryFunding

Parallel Discovery of Alzheimer’s Therapeutics

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Science Translational Medicine  18 Jun 2014:
Vol. 6, Issue 241, pp. 241cm5
DOI: 10.1126/scitranslmed.3008228
  • Fig. 1. Not on our side.

    Timeline of a hypothetical AD therapeutic–development program.

    CREDIT: V. ALTOUNIAN/SCIENCE TRANSLATIONAL MEDICINE
  • Fig. 2. Multiple shots are not independent.

    Heat-map representation of qualitatively determined pairwise correlation of success among 64 hypothetical AD therapeutics projects (as assessed by K.S.K. and C.H.), where 100% indicates perfect correlation (success and failure coincide for the pair), 0% indicates no correlation, and −100% indicates perfect negative correlation (success for one always implies failure for the other and vice versa). Red cells indicate estimated correlations of 90%, orange cells indicate 50%, yellow cells indicate 25%, and green cells indicate 10%.

    CREDIT: V. ALTOUNIAN/SCIENCE TRANSLATIONAL MEDICINE
  • Table 1. Potential AD projects.

    Proposed projects for an AD megafund portfolio and the estimated “degree of validation” for each. Uppercase entries indicate hypotheses, boldface entries indicate categories, and remaining entries indicate projects. In cases in which hypotheses and categories are more speculative, they may constitute single projects. Entries containing numbers in parentheses indicate multiple projects.

    ProjectsDegree of validation
    AMYLOID
    Aβ passive immunotherapy
    Aβ antibodies (6)High
    Pyro Aβ antibodies (3)High
    Antibodies against soluble oligomers (3)High
    Aβ synthesis
    β-secretase inhibitors (6)Medium
    γ-secretase inhibitors and modulators (3)Low
    α-secretase agonismLow
    Aβ antiaggregation inhibitors/beta-sheet breakersLow
    Aβ clearance
    Neprilsyn and plasminLow
    Insulin-degrading enzymeLow
    Low-density lipoprotein receptor overexpressionLow
    TAU PATHWAY
    Phosphorlyation inhibitors
    CDK5Low
    GSK3βLow
    MARK/par1Low
    PKCLow
    MAPKLow
    PKALow
    p70S6KLow
    Antiaggregants (TRx0237) Low
    Microtubule stabilizing agents (BMS 241027) Low
    Reduction of tau levels (Tau antibodies and antisense oligonucleotides) Low
    APOE4/LIPID METABOLISM
    Activated receptor gamma and liver X receptors in coordination with RXR’sLow
    SIRT1, sirtuinLow
    GIVA-PLA2Low
    NEUROINFLAMMATION
    Complement receptor 1Low
    TREM 2Low
    PPAR agonistsLow
    IL-1, IL-6, IL-12, IL-23Low
    TNFRLow
    P2X7RLow
    Monoacylglycerol lipaseLow
    AUTOPHAGY/PROTEASOME/UNFOLDED PROTEIN RESPONSE
    NilotinibLow
    Proteasome pathwaysLow
    Unfolded protein responseLow
    HORMONES/GROWTH FACTORS
    Inactivation of gonadotropin-releasing hormone (GnRH)Low
    AllopregnanoloneLow
    CERE-110: Adeno-associated virus delivery of nerve growth factorLow
    DYSREGULATION OF CALCIUM HOMEOSTASIS
    InsP3RLow
    CALHM1Low
    HEAVY METALS
    CopperLow
    ZincLow
    MITOCHONDRIAL CASCADE/MITOCHONDRIAL UNCOUPLING/ANTIOXIDANTS (3)Low
    DISEASE-RISK GENES (3)Low
    HDAC INHIBITORSLow
    GLUCOSE METABOLISMLow
  • Table 2. Costs and savings.

    Present values (in billions of 2010 constant dollars) of annual AD-related M&M expenses and potential cost savings as estimated by Alzheimer’s Association (10) over 10-, 20-, and 30-year horizons under the current trajectory (CT) and two hypothetical scenarios: a delayed-onset trajectory (T2) and a slowed-progression trajectory (T3). A 10% nominal cost of capital and a 5% inflation rate were used to discount the real cost estimates.

    Trajectory10-year
    2015-2025
    20-year
    2015-2035
    30-year
    2015-2045
    Current trajectory (CT)143627664250
    Delayed onset (T2)122719612737
    Slowed progression (T3)128022983438
    (CT – T2)2088041513
    (CT – T3)156468813
  • Table 3. AD megafund risk and return to taxpayers.

    Investment returns and risks with respect to M&M cost savings from the AD megafund over a 13-year investment period for various combinations of probabilities of success (p), pairwise correlations (ρ), and probabilities of at least one hit (p1) under the AA model (10) for the economic impact of new AD therapies that either delay the onset of AD (T2) or slow its progression (T3). The row labeled “KSK–CH” uses pairwise correlations and success probabilities calibrated qualitatively by K.S.K. and C.H. for each of the 64 hypothetical projects. E[R], expected return; SD[R], return standard deviation.

    Horizon (years)
    102030102030102030102030
    Parameters (%)
    pρ p1E[R]: Delayed-onset (T2)SD[R]: Delayed-onset (T2)E[R]: Slowed-prog. (T3)SD[R]: Slowed-prog. (T3)
    509610.222.328.321.824.125.37.717.322.421.323.224.2
    510902.613.819.535.038.840.70.39.213.934.237.238.8
    54069−21.5−13.0−8.653.259.061.9−23.3−16.5−12.952.056.659.0
    58040−54.0−48.9−46.456.162.365.4−55.0−51.0−48.954.959.762.3
    10010014.426.933.23.94.44.611.821.727.03.84.24.4
    10109912.825.231.413.815.316.010.320.025.313.514.715.3
    1040914.515.921.732.335.937.72.211.216.031.634.435.9
    108046−46.8−41.0−38.057.163.466.5−48.0−43.4−40.955.860.863.4
    15010014.527.033.30.60.70.711.921.827.10.60.70.7
    151010014.226.733.15.35.96.211.721.626.85.25.75.9
    15409812.324.630.815.817.518.49.819.524.715.516.817.5
    158062−29.1−21.3−17.455.661.764.7−30.6−24.5−21.254.459.261.7
    KSK-CH87−0.410.516.038.542.744.8−2.66.010.637.641.042.8

Supplementary Materials

  • www.sciencetranslationalmedicine.org/cgi/content/full/6/241/241cm5/DC1

    Introduction

    Computing expected returns and variances

    IID Bernoulli Trials Correlated Trials

    Fig. S1. Probability of success

    Simulating correlated Bernoulli trials

    Fig. S2. Heat map of pairwise correlations

    Fig. S3. Heat map of positive-definite correlation matrix

    Megafund investment performance

    Table S1. AD projects and estimated probabilities of success

    Table S2. Returns

    Cost/benefit analysis

    Table S3. Trajectories

    Table S4. Medicare and Medicaid cost savings

  • Supplementary Material for:

    Parallel Discovery of Alzheimer's Therapeutics

    Andrew W. Lo,* Carole Ho, Jayna Cummings, Kenneth S. Kosik

    *Corresponding author. E-mail: alo@mit.edu

    Published 18 June 2014, Sci. Transl. Med. 6, 241cm5 (2014)
    DOI: 10.1126/scitranslmed.3008228

    This PDF file includes:

    • Introduction
    • Computing Expected Returns and Variances
    • IID Bernoulli Trials
    • Correlated Trials
    • Fig. S1. Probability of success
    • Simulating Correlated Bernoulli Trials
    • Fig. S2. Heat-map of pairwise correlations
    • Fig. S3. Heat-map of positive-definite correlation matrix
    • Megafund Investment Performance
    • Table S1. AD projects and success
    • Table S2. Returns
    • Cost/Benefit Analysis
    • Table S3. Trajectories
    • Table S4. Medicare and Medicaid cost savings

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