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New Compounds for Spinal Muscular Atrophy Jill Heemskerk, PhD Office of Translational Research National Institute of Neurological Disorders and Stroke.

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Presentation on theme: "New Compounds for Spinal Muscular Atrophy Jill Heemskerk, PhD Office of Translational Research National Institute of Neurological Disorders and Stroke."— Presentation transcript:

1 New Compounds for Spinal Muscular Atrophy Jill Heemskerk, PhD Office of Translational Research National Institute of Neurological Disorders and Stroke Jill Heemskerk, PhD Office of Translational Research National Institute of Neurological Disorders and Stroke CONFIDENTIAL

2 Why NIH Chose SMA for a Drug Development Pilot u Urgent unmet medical need Number one genetic killer of infantsNumber one genetic killer of infants Incidence: 1 in 6000 live birthsIncidence: 1 in 6000 live births No available treatmentsNo available treatments u Scientific opportunity Known cause = loss of SMN1 geneKnown cause = loss of SMN1 gene Defined treatment strategy: increase SMN2Defined treatment strategy: increase SMN2 Compounds identified that increase SMN2 in vitroCompounds identified that increase SMN2 in vitro

3 Indoprofen: Starting Point for Medicinal Chemistry Indoprofen increases SMN protein in vitro: SMN reporter assay SMN protein in patient fibroblasts Indoprofen improves in utero survival of SMA mice -B. Stockwell: Lunn et al, 2004

4 Optimizing Indoprofen for SMA Lactam Phenyl Acetic Chain Substitutions: alkyl, halo, methoxy, cyano, amino, aryl, heteroaryl Substitutions: alkyl, halo, methoxy, aryl, heteroaryl Varied at methyl site, length of chain, and CO 2 H Varied heterocycle Chemistry Goals u Increase potency u Eliminate toxicity Cox Inhibition u Improve BBB penetration Chemistry Goals u Increase potency u Eliminate toxicity Cox Inhibition u Improve BBB penetration Benzo CONFIDENTIAL

5 Chemistry Improves Potency and Activity ~1300 Indoprofen analogs synthesized and tested Log concentration (µM) luminescence CONFIDENTIAL ex6ex8ex7Luciferase Androphy/Zhou SMN-2 reporter assay -AMRI

6 Untreated 5mM VPA 100nM SP869 SMA Project Compounds Increase SMN-containing Gems in Patient Fibroblasts M. Lorson, University of Missouri Confidential

7 Pt C D Actin SMN 1 2 3  0.0 0.5 1.0 1.5 2.0 2.5 Carrier DMSO Patient DMSO 0.1 uM Drug SMN:Actin SMA Project Compounds Increase SMN Protein in Patient Fibroblasts: Western Blots Patient Brenda Fung, CombinatoRx CONFIDENTIAL

8 SMA Project Compounds Stimulate Translational Read-through -Courtesy Ellen Welch, PTC Therapeutics UGA + Compound - Compound Luciferase Activity AUGUAA Stop codon interrupts Luciferase: CONFIDENTIAL

9 Positive Control Indoprofen -E. Welch, A. Bhattacharyya PTC Therapeutics SMA Project Compounds Induce Translational Read Through CONFIDENTIAL

10 Indoprofen Chemical Analogs are Drug-like PK: Good brain penetrance Orally bioavailable Rodent half lives around 2 hours Excellent human microsome stability Tox: Well-tolerated in rodents (up to 50mg/kg, neonatal mice, 14 day dosing) Favorable CYP, genotox, hERG, broad target profiles Abolished Cox inhibition IP: 2 NIH patents cover composition of matter Half-life Efficacy Potency Safety Chemistry IP Brain/Plasma Pharmaceutics CONFIDENTIAL

11 SMA Project FLOW PLAN C andidate August 2010 Confidential

12 Timeline to Phase I Clinical Trial 3Q ‘10 1Q’11 4Q’10 28-Day GLP Tox Formulation Development 2Q’11 ADME GMP Synthesis Safety Pharmacology First in Human Trial GLP Synthesis 3Q’11 Regulatory Submission Radio Synthesis 14-Day GLP Tox Dose Ranging Tox 200gm Synthesis CONFIDENTIAL 12

13 Acknowledgements Lead Development  John McCall  Graham Johnson  Paul Pearson  Keith Houck  Tony Bannon NINDS  Amelie Gubitz SAIC  Sabina Robinson  Jim Romano CombinatoRx  Jane Staunton  Brenda Fung  Yang Wang  Shakira Olanrewaju AMRI Albany  Keith Barnes  John Lippert  Nick Mayhew  Ping Chen  Steve Steffke  Michelle Pilato AMRI Bothell  Svetlana Dobritsa  Michelle Luche  Sangeeta Chitnis RTI  Jim Matthews  Ronnie Maitra  Kimberly Ehman Lorson Lab  Chris Lorson  Virginia Mattis  Monique Lorson PTC Therapeutics  Ellen Welch  Nikolai Naryshkin  Sergey Paushkin  Anu Bhattacharyya Key Contributions  Elliot Androphy  Jianhua Zhou  Brent Stockwell  Charlotte Sumner  Arthur Burghes  Glenn Morris  Meg Winberg  Jill Jarecki


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