5/16/2013 30 Years into the Era of SCI Research and the Hope for Clinical Trials in SCI… Cure: Where are We Today? …there is still no FDA-approved treatment for improving Dan Lammertse, MD neurological function Clinical Professor of Physical Medicine & Rehabilitation, University of Colorado Denver Medical Director of Research at Craig Hospital, and Co-Director, Rocky Mountain Regional SCI System nor a consensus standard of care to that end Sir Ludwig Guttmann Lecture ISCoS 2011 Washington, DC Our Agenda… • What happens to the spinal cord after trauma? • Why doesn’t the healing process reliably produce a recovery of function? • What do we know about natural recovery? • What are the opportunities for scientific intervention? • What is the evidence basis for determining the effectiveness and safety of a new treatment? • What is the process for regulatory approval? • Where are we today? • Gazing into the crystal ball… The Background Why is this research necessary? 1
5/16/2013 Complex Pathology A “Law of Nature”? Primary Contusive Injury • – Moment of impact • Fishes and some amphibians – Immediate paralysis Secondary Injury—hours to days • • Fetal mammals – Ischemia…the CNS is different – Biochemical Chain Reaction • Peripheral Nervous System Healing process • – Abortive regeneration – Limited repair – Sprouting/plasticity--neocircuitry – Glial Scar – Apoptosis Some Functional Recovery • – But not enough Natural Recovery Other Clues… Most Patients Get Some (but not enough) Better • Abortive Regeneration • Growth Factors • Inhibitory Factors – Inhibitory molecules – Perineural net From Fawcett 2007 “Natural Recovery” in SCI Opportunities for Intervention following SCI What do we need to improve upon? • Limit secondary damage • Most SCI patients experience improvement (12- – Neuroprotection 18mo) • Promote Regeneration • 70% of cervical patients will descend one level (Steeves 2010) – Growth Factors • 30% of cervical patients will descend 2 or more levels (Steeves 2010) – Suppress Inhibitory Factors • 20-25% of initial AIS A patients will become incomplete (Fawcett • Repair Damaged Cells 2007) • 8-10% of initial AIS A’s patients will improve to C or D (Fawcett – Remyelinization 2007) • Replace dead cells • Even “chronic” SCI can change (Kirshblum 2004) – Cell therapy implants • 3.5% of AIS A at one year improve to B • Promote Sprouting/Plasticity • 2.1% of AIS A at one year improve to C or D – Enhanced cellular environment • 20% improved motor level and NLI between 1 and 5 years – Rehabilitation: Activity-dependent Therapies 2
5/16/2013 Opportunities for Intervention The Basis of Evidence concepts and examples Building the Case for Effectiveness and Safety Drugs/Molecules Improving Neurological Function • – Growth factor-like The Variables • SUN13837 (Asubio trial) • Natural recovery—most patients improve some – Suppression of inhibition • Aspects of clinical care • Anti-Nogo antibody (ATI355 trial) – Ion Channel Blockade – Acute care surgery, blood pressure control, etc. • Riluzole—neuroprotection – Rehabilitation content/intensity/timing • Fampridine-SR—improved nerve function • Personal factors—motivation/effort Cell based therapies • – Autologous Schwann Cells (University of Miami) • Measurement variables – hESC-derived cells (GRNOPC1—Geron) – Precision – Neural Stem Cells (Stem Cells Inc and Neuralstem) – Bias – Bone Marrow-derived MSC (many examples) • Biological effect of the Experimental Treatment – Umbilical Cord Blood cells (China SCINet) The Basis of Evidence The Regulatory Context Building the Case for Effectiveness and Safety What does it take to get FDA approval? • If the patient gets better, which of the variables were • Preclinical (Animal Model) responsible? Which are the “active ingredients”? – Proof of Concept and Safety – Cause and Effect vs. Association • Human Studies—progressive trial phases • Narrowing the focus to the experimental Rx – Phase 1 (open label; 10-15)—feasibility, safety/tolerability • Elimination of bias—everyone is hoping for – Phase 2 (RCT; 20-80)—How to give, what/how to measure improvement • Delivery methods • Dose, timing, – Randomization • Refinement of primary outcome measure – Blinding – Phase 3 (multicenter rigorous RCT; 100’s)—pivotal trials • The “Gold Standard” • Definitive protocol – Randomized Placebo Controlled Double Blind Trial • Two confirmatory trials required for approval – Placebos and Blinding may not always be feasible • Five or more years, Hundreds of millions of $ • Clinician’s Gestalt/Patient Testimonials insufficient – The temptation to bypass this process is strong… The Kevin Everett Story The Kevin Everett Story Hypothermia Rx in SCI Injury in an NFL game 9/9/2007 Injury in an NFL game 9/9/2007 • Phase I trial—University of Miami Has had an “excellent” recovery Has had an “excellent” recovery – Report on 14 patients with cervical AIS A SCI (Levi, Neurosurgery 2010) – Appears “reasonably safe” (pulmonary, cardiac Touted in the press as a “miracle” Touted in the press as a “miracle” dysrhythmia AEs) – AIS Conversion rate 42.8% (3A → B; 2A → C; 1A → D) What is the explanation? What is the explanation? • Prospective observational trial underway • Natural Recovery? AIS A? • Natural Recovery? AIS A? • Can/will a RCT be conducted? • Early decompression? • Early decompression? • Should this therapy be a standard of care? • Methylprednisolone? • Methylprednisolone? • Balancing (potential) benefits and risks • Hypothermia Treatment? • Hypothermia Treatment? 3
5/16/2013 A Cautionary Tale… Where are we today? The Autologous Macrophage Trial • Basic Science: Explosive Knowledge Growth • Animal model studies encouraging – Fetal Cell → hESC → iPSC → iN cell • Phase 1 human trial “positive” • Translational Science: moving towards more clinical trials – AIS conversion rate 37.5% (3 of 8, A → C) – Expanding beyond acute to more chronic • Phase 2 multicenter RCT disappoints models – AIS conversion rate 27% in macrophage patients • Increasing number of clinical trials – AIS conversion rate 59% in control patients! underway: Drugs, Cells, Surgery, • The importance of rigorous science… Rehabilitation Current SCI Trials SCI Trials – Past, Present and Projected clinicaltrials.gov lists 203 SCI trials currently open The neighborhood is becoming increasingly populated with treatments 25 Restorative Trials (www.scope-sci.org) (small molecules, monoclonal antibodies, & cell transplants) Rehab/“Activity Based” Rx Trials “Restorative Trials” Locomotor Therapy 1980 1990 2000 2010 2020 ASBI13837 • • – Traditional BWSTT & Robotic AC105 (MgCl 2 -PEG) • FIRSTHAND system • Minocycline (2) • Patterned UE FES OPCs Macrophages Bone Marrow Stem Cells (5) • Methylprednisolone • (Geron) Complex Motion Stimulator Riluzole (Proneuron) Human Neural Stem Cells (2) • (NASCIS I, II, III) • Minocycline (NACTN) Somatosensory Stim/ Massed Cethrin • Adipose-derived Stem Cells (2) (U. Calgary) SUN 13837 • GM ‐ 1 Practice Training (BioAxone) Umbilical Cord Blood Cells (1) (Asubio) (Sygen), • Others… Lithium • Hu ‐ CNS ‐ SC Autologous Schwann Cells (1) Gacyclidine • (China Network) (Stem Cells) Riluzole (2) (Beaufour ‐ Ipsen) • ATI 355 Schwann cells Dalfampridine (Novartis) (U. Miami) • AC 105 Spinalon • Ampyra (4 ‐ AP) (Acorda) Human Growth Hormone (1) • NSI ‐ 566 (Acorda) Intermittent Hypoxia (3) • (Neuralstem) Decoy NOGO Recptr (Axerion) HGF (Japan) The Rehab Variable Technology • Activity-based Rehab Therapies have entered the • FES clinical mainstream… – and have been accepted as an important treatment • Neuroprostheses variable • Brain-Computer Interface • The “Black Box”: what has been proven effective? • Neuromodulation • Preclinical studies show synergy between “biological” and “rehab” interventions • Challenges of incorporating rehab into clinical trial protocols…how much…of what…started when…for how long? How will it be funded??? 4
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