Trinical trials. registries, natural histories, outcome measures and biomakers

Getting Ready For Clinical Trials: The Importance of Registries, Natural Histories,

Outcome Measures, and Biomarkers

Mitocon, Rome, ItalyMay 27, 2016

Michio Hirano, MDH. Houston Merritt Neuromuscular Research Center

Columbia University Medical CenterNew York, NY USA

Financial DisclosuresMichio Hirano, MD

• Research support from Santhera Pharmaceuticals and Edison Pharmaceuticals

• Consultant for MitoBridge (formerly MitoKyne), Stealth Peptides• Cofounder of MitoRainbow Therapeutics• Medical Director of the Columbia Molecular Neurogenetics

Diagnostic Laboratory

Getting Ready For Clinical Trials: The Importance of Registries, Natural Histories,

Outcome Measures, and Biomarkers

Registries: What is the disease? Who has the disease? Natural Histories: How does the disease begin and progress?Outcome measures and Biomarkers: How can we assess disease progression?

Getting Ready for Clinical Trials

“We identified 1,039 publications on treatments for mitochondrial diseases, only 35 of which included observations on more than five patients”

“Patients and physicians should no longer rely on potentially biased data,with the associated costs and risks.”

• Collaborative Clinical Research

• Public Resources and Education

• Centralized Data Coordination and

Technology Development• Training

DHHS-NIHORDR, NCATS, NINDS, NIAMS, NICHD, NHLBI, NIDDK, NIDCR,

NIAID, NCI, NIMH, ODS

The Data Management and Coordinating Center

Coalition of PatientAdvocacy Groups

(CPAG)

Rett Syndrome, MECP2 Duplications, and Rett-related Disorders Consortium

Frontotemporal Lobar Degeneration Clinical Research Consortium

Clinical Research in ALS and Related Disorders for Therapeutic Development

Brittle Bone Disorders Consortium

Developmental Synaptopathies Consortium

Rare Lung Diseases Consortium

16 sites

New York, New YorkMichio Hirano, MDSalvatore DiMauro, MDJ.L.P (Seamus) Thompson, PhDJohnston Grier, NAMDC Project ManagerColumbia University Medical Center

Akron, OhioBruce Cohen, MDAkron Children’s Hospital Boston, MAAmel Karaa, MDVamsi K. Mootha, MDMassachusetts General Hospital/Harvard Cleveland, OhioSumit Parik, MDCleveland Clinic Foundation Douglas Kerr, MD, PhDCharles Hoppel, MDCase Western Reserve University School of Medicine Denver, ColoradoJohann Van Hove, MDUniversity of Colorado

Gainesville, FloridaPeter Stacpoole, MD PhDUniversity of Florida College of Medicine

Houston, TexasWilliam Craigen, MD, PhDFernando Scaglia, MDBrett Graham, MD, PhDBaylor College of Medicine

Hamilton, Ontario, CanadaMark Tarnopolsky, MD, PhDMcMasters University

Palo Alto, CaliforniaGreg Enns, MD, PhDPackard Children’s Hospital

Philadelphia, PennsylvaniaMarni Falk, MD, PhDDavid Lynch, MD, PhDDouglas C. Wallace, PhDChildren’s Hospital of Philadelphia

Rochester, Minnesota Raliza Gavrilova, MDMayo Clinic San Diego, CaliforniaRichard Haas BChir, MRCPRobert Naviaux, MD, PhDUniversity of California San Diego Seattle, WashingtonRussell Saneto, DO, PhDSeattle Children's Hospital and Regional Medical Center Pittsburgh, PennsylvaniaGerald Vockley, MD, PhDAmy Goldstein, MDUniversity of Pittsburgh

Washington, D.C.Andrea Gropman, MDChiildren’s National Medical Center

United Mitochondrial Disease FoundationMuscular Dystrophy AssociationMitoAction


Patient Registries“an organized system that uses observational study methods to collect uniform data (clinical and other) to evaluate specified outcomes for a population defined by a particular disease, condition, or exposure, and that serves a predetermined scientific, clinical, or policy purpose(s).”

Gliklich R, Dreyer N. Registries for Evaluating Patient Outcomes: A User’s Guide. Rockville, MD: Agency for Healthcare Research and Quality; 2010. AHRQ Publication No. 10-EHC049.

Getting Ready for Clinical TrialsTraditional Patient Registries


Traditional Patient Registries: Researcher Generated

ProsStandardized data collectionHigh quality typically detailed dataValuable clinical information for characterizing diseasesPromotes collaborations among researchers

ConsLabor-intensiveExpensiveEnrollment restricted to participating sites


Traditional Patient Registries


Traditional Patient Registries

897 patients as of May 1, 2016


Patient Powered Registries

2088 registrants

~1,300 registrants


Patient Powered Registries

ProsInexpensiveRequires little effort from clinicians/researchersEngages patients in researchCaptures a large pool of patientsAllows rapid surveys of patients

ConsData quality may be suboptimalMay not collect detailed laboratory or clinical examination data


RDCRN contact registry surveys

• Attitudes towards oocyte mitochondrial replacement therapy

• Patient symptoms and attitudes towards research• Use of nutritional supplements among mitochondrial

disease patients• Patient diagnostic odessey


Natural History Studies:How does the disease begin and progress?

“Begin with the end in mind”


Natural History Studies:How does the disease begin and progress?

“Begin with the end in mind”Purpose: To inform drug development

• Progression of mitochondrial diseases is not adequately understood

• Goal of natural history studies is to fill the gaps in disease knowledge

NAMDC Natural History StudiesAlpers SyndromeMNGIEPyruvate dehydrogenase complex deficiencyPearson-CPEO-Kearns Sayre Syndrome


Outcome measures and biomarkers: How can we assess disease progression?

Challenges:• Clinical and genetic heterogeneity of mitochondrial disease• Typically complex multisystemic diseases• Wide range of manifestations and ages• mtDNA diseases confounded by variable heteroplasmy and

tissue distribution of mutations

One size does not fit all


Outcome measures

• Clinician-reported outcome (ClinRO) measures• Patient-reported outcome (PRO) measures• Observer-reported outcome (ObsRO) measures• Performance outcome (PerfO) measures

http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DrugDevelopmentToolsQualificationProgram/ucm284077.htm


“Clinical Outcome Assessments (COAs) measure a patient’s symptoms, overall mental state, or the effects of a disease or condition on how the patient functions.”

“For those measures that do not measure how patients feel or function in daily life, CDER reviews evidence of how the outcome is linked to survival or how patients feel or function in daily life.”




https://commondataelements.ninds.nih.gov/MITO.aspx#tab=Data_Standards

Toolbox of outcome measures for mitochondrial disease

Critical Path Innovation Meeting (CPIM)“Planning Clinical Treatment Trials in Mitochondrial Diseases”Mitochondrial Disease Clinical Trials Working Group Food and Drug Administration, Silver Spring, MDOctober 19, 2015

FDA stated that the lack of approved therapies for mitochondrial diseases means there is no precedent for drug development and no established endpoints. FDA may apply flexibility in the development and review of therapies to treat rare diseases (due to the limitations imposed by the restricted availability of patients with such conditions), however, approval of these therapies must be based on demonstration of “substantial evidence of effectiveness” from adequate and well-controlled investigations, a regulatory standard applied to all drug applications.

FDA Center for Drug Evaluation and Research Office of Translational Sciences (OTS) Immediate Office Shashi Amur, Ph.D., Biomarker Qualification Program Scientific Coordinator ShaAvhrée Buckman-Garner, M.D., Ph.D., F.A.A.P., Director James Kaiser, M.D., CPIM Scientific Lead Susan McCune, M.D., Deputy Director Ameeta Parekh, Ph.D., Senior Advisor for Scientific Collaborations Sarmistha Sanyal, Ph.D., ORISE Fellow Alicia Stuart, Project Manager

OTS Office of Clinical Pharmacology Michael Pacanowski, Pharm.D., M.P.H., Supervisory Pharmacologist,Vikram Sinha, Ph.D., Director, Division of Pharmacometrics Office of New Drugs (OND) Immediate Office Jonathan Goldsmith, M.D., FA.C.P., Associate Director, Rare Diseases Program

OND Division of Gastroenterology and Inborn Errors Products Dragos Roman, M.D., Ph.D., Acting Deputy Director, Laurie Muldowney, M.D., Acting Clinical Team Leader Dina Zand, M.D., Medical Officer

Center for Food Safety and Applied Nutrition Office of Nutrition, Labeling, and Dietary Supplements (ONLDS) Shawne Suggs-Anderson, MMSc, R.D., Consumer Safety Officer, Infant Formula and Medical Foods Staff Carrie Assar, Pharm.D., M.S., Acting Director, Infant Formula and Medical Foods Staff

ONLDS Division of Dietary Supplement Programs Robert Durkin, Esq., M.S., R.Ph. Acting Director Cara Welch, Ph.D., Acting Deputy Director

Requester Discussants Mitochondrial Disease Clinical Trials Working Group (MDCTWG) Kathryn Camp, M.S., R.D., Office of Dietary Supplements (ODS), National Institutes of Health (NIH) Marni Falk, M.D., Children’s Hospital of Philadelphia, University of Pennsylvania Richard Haas, M.B., B.Chir., M.R.C.P, University of California San Diego Michio Hirano, M.D., Columbia University, North American Mitochondrial Disease Consortium (NAMDC) Danuta Krotoski, Ph.D., National Institute of Child Health and Human Development, NIH Frank Sasinowski, J.D., M.P.H., M.S., National Organization for Rare Disorders J.L.P. (Seamus) Thompson, Ph.D., Columbia University, NAMDC Philip Yeske, Ph.D., The United Mitochondrial Disease Foundation (UMDF)

Representative Academic Researchers in Mitochondrial Disease Therapeutics Carlos Moraes, Ph.D., University of Miami Peter Stacpoole, Ph.D., University of Florida

Representative Pharmaceutical Companies in Active Mitochondrial Disease Clinical Trials Matthew B. Klein, M.D., Edison, Pharmaceuticals, Inc. William Lang, M.D., Raptor Pharmaceuticals, Inc. Colin Meyer, M.D., Reata Pharmaceuticals, Inc. Nicholas Coppard, Ph.D., Santhera Pharmaceuticals Holding Ltd. John C. Campbell, Stealth BioTherapeutics

Family and Advocacy Group Representatives Charles Mohan, UMDF CEO Richard Leach, J.D., Parent Elizabeth Kennerly, Patient

CPIM Participants

Biomarkers for mitochondrial disease

A characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention

To be used as a clinical outcome measure, biomarkers must be: • reproducible within patients• responsive to clinically meaningful changes in disease activity• defined with respect to its temporal relationship with disease

activity• change in expected direction with known effective treatments• lies in the causal pathway of the disease.

Biomarkers for mitochondrial disease

• For mitochondrial disease: venous or CSF lactate, FGF-21, GDF-15, and creatine are biomarkers but have not been demonstrated to correlate with disease severity.

• For MNGIE: plasma thymidine and deoxyuridine are excellent biomarkers

• CPIM: FDA stated that it might be useful to screen multiple biomarkers for their association with different phenotypes of disease to determine the usefulness of those biomarkers in a clinical trial.

•Early onset: from birth to 30 months•Progressive weakness of skeletal and respiratory muscles•Elevated CK and lactic acid•Mean age of death: 2.6 years

Disease Spectrum of 90 TK2-deficient PatientsInfantile myopathy 34 (37.8%)

Childhood-onset myopathy 32 (35.6%)

Adult-onset myopathy 24 (26.7%)

Onset 0-12 months 1-11 years Adolescence-adulthood

Symptoms Diffuse muscle weakness, respiratory insufficiency

Proximal muscle weakness, areflexia

Muscle weakness

EMG Myogenic +/-neuropathic pattern

Myogenic +/-neuropathic pattern

Myogenic pattern

CK ↑↑↑ ↑↑↑ normal-↑↑

mtDNA depletion

+++ +++ +/-

mtDNA deletions

_ _ +++

Other signs/symptoms

Nephropathy 1, encephalopathy 4, rigid spine 1, facial diplegia 2, cognitive dysfunction 3, seizure 6, coma episodes 1, ptosis 1, multiple bone fractures 1, cardiomyopathy 1, bi-ventricular hypertrophy 1, arrhythmia 1, and dysphagia 2

Ptosis 7, facial diplegia 7, cognitive decline 1, encephalopathy 1, prolonged QT 1, arrhythmia 1, hearing loss 2, multiple bone fractures 1, renal tubulopathy 1, and esophageal atresia 1

PEO 9, ptosis 14, dysphagia 6, and gynecomastia 1, cardiomyopathy 2, respiratory insufficiency 5

Garone et al. in preparation


Deoxynucleoside/deoxynucleotide for TK2 deficiency

Molecular bypass therapy


Deoxynucleoside/deoxynucleotide for TK2 deficiency

Substrate enhancement therapy


Garone C, MD, PhD, Taylor RW, PhD, FRCPath, Nascimento A, MD, Poulton J, MD, Fratter C, MPhil, Domínguez-González C, MD, Evans JC, PhD, Loos M, MD, Isohanni P, MD PhD, Suomalainen A, MD PhD, Ram D, MBBS, Hughes MI, MBBS, Mc Farland R,, MRCPCH, PhD, Barca E, MD, Lopez Gomez C, PhD, Jayawant, S, Thomas N, MD, Manzur A, MD, Kleinsteuber K, MD, Martin-Casanueva MA, PhD, Kerr T, MD, Gorman GS, FRCP, PhD, Sommerville EW, MSc, Chinnery PF, MD, Hofer M, FRCPath, Karch C, MD, Ralph J, MD, Cámara J, PhD, Mandruga-Garrido M, MD,PhD, Domínguez-Carral J, MD, Ortez C, MD, Emperador S, PhD, Montoya J, PhD, Chakrapani A, MD, Rahman S, MD, Donati MA, MD, DiMauro S, MD, Hirano M, MD

Phenotypic Spectrum and Retrospective Natural History of Thymidine Kinase 2 Deficiency

TK2 therapy in patients

• Twelve patients with TK2 deficiency have been treated with dTMP+dCMP or dT+dC: Spain (8), US (1), Chile (1), Venezuelan living in US (1), Italy (1) for up to 4 years.

• FDA emergency and single-patient INDs have been granted to US patients (one patient on therapy, second awaiting IRB approval)

• European and South American local ethical committees have granted approvals for use of the therapies in their countries.

• Ages: 5-27 years-old

• Most have gained weight and have shown stabilization or improvements in strength.


Potential Outcome Measures for TK2 Therapy

The Mitochondrial Disease Successor Trial (MiST) Program

Seamus (J. L. P.) Thompson PhD, Michio Hirano MD, Bruce Levin PhD

• Ambitious program to assess efficacy of nutritional supplements as therapies for mitochondrial diseases

• Adaptive cumulative strategy with 3 wave 1 trial asessing single supplements with placebo controls

• Patients with choose one of 6-8 primary outcome measure domains (one PRO and one objective CRO or PerfO)

• Will require 2000 patients in a multicenter international trial.

The Mitochondrial Disease Successor Trial (MiST) Program

Seamus (J. L. P.) Thompson PhD, Michio Hirano MD, Bruce Levin PhD

• Once 1 supplement is found effective, it becomes Standard of Care (SOC).

• A set of combination therapies, each combining this new SOC with 1 additional supplement, and using new SOC as active control, is then tested.

• Once a combination of 2 supplements is found effective, it becomes the new SOC.

AcknowledgementsColumbia University Medical CenterBilli DiMauro, MD Caterina Garone, MD, PhDJohn (Seamus) Thompson, PhD Valentina Emmaneule, MD, PhDBruce Levin, PhD Emmanuele Barca, MDXiomara Rosales, MDKris Engelstad, MS United Mitochondrial Disease FoundationRichard Buchsbaum Chuck MohanJohnston Grier Phil Yeske, PhDAlexandra Sanford, MSJoshua Kriger, MS NIHTaylor Bracken, MS Katrina Gwinn, MD, NINDS

Danuta Krotoski, PhD, NICHDKathryn Camp, PhD, ODS

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Trinical trials. registries, natural histories, outcome measures and biomakers