Changing the Future of Primary Ciliary Dyskinesia (PCD): PCD Clinical Centers Kickoff

Welcome & Introductions• Welcome to the PCD Clinical Centers Kickoff – The Path Starts Here• Introductions – Michele Manion, Founder & Executive Director, PCD Foundation – Carey Kauffman, President, PCD Foundation – Mike Knowles, MD, Professor of Medicine, University of North Carolina, Chapel Hill – Margaret Leigh, MD, Director, Cystic Fibrosis Center, North Carolina Children’s Hospital – Stephanie Davis, MD, Chief, Division of Pediatric Pulmonology, North Carolina Children’s Hospital• Special Thanks – Bob Beall, CEO CF Foundation – CF Foundation – Dedicated PCD researchers and clinicians 2 © Copyright 2011 | PCD Foundation | Confidential

Agenda• WHAT Do Patients Need? – PCD Past, Present & Future• WHY Now? A New Path for the Future – Rationale for the Path to Clinical Trials (PTCT) Program• WHO Has PCD? – Defining PCD: Overview of Data from GDMCC Studies – Definition of PCD Clinical Phenotype• WHEN to Look for PCD/Initiate Therapies? – Illustrative Cases – Data from Longitudinal Studies 3 © Copyright 2011 | PCD Foundation | Confidential

Agenda• HOW to Confirm the Diagnosis of PCD – Addressing the Challenge of Diagnosis – Ciliary Biopsy and Motility Studies—Are There Better Options? – Update on PCD Gene Identification• NOW is the Time – Getting Clinical Centers Up & Running – Open Discussion• WHERE We Go From Here – Wrap Up – Action Items/Next Steps 4 © Copyright 2011 | PCD Foundation | Confidential

PCD Past: Where We Were What Do Patients Need?1991: Diagnosed – Probably have a ‘normal’ life expectancy – Large spectrum of disease severity – No other families to connect with – What was published did not necessarily match what we were dealing with – There would never be any research on PCD 5 © Copyright 2011 | PCD Foundation | Confidential

PCD Past: Where We Were What Do Patients Need?2000: UNC PCD Research Group2001: Requested seed money to start PCDF in 20012002: ATS debut of ‘PCD Foundation’2003: Creation of the GDMCC ‘The PCD (Primary Ciliary Dyskinesia) Foundation seeks to promote research, increase public awareness, and provide information and support services for individuals with inherited ciliary motility disorders and their caregivers’ 6 © Copyright 2011 | PCD Foundation | Confidential

PCD Past & Present: Where We’ve Been To Date What Do Patients Need? 2010: First ‘PCD & 2004: GDMCC Formed 2008: Ciliopathies Related Conditions’ Mtg1999-2000: UNC PCD Research Site w/RDCRN Grant & PCD Workshop in St. LouisInitiates Early Studies at ATS 2007: Kennedy, et al publish paper on PCD heterotaxy and 2002: First PCD Family Day congenital heart defects 2008: DNAH11 published. 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2007: First genetic test for 2003: ORDR Announces PCD becomes available 2002: PCDF Founded RDCRN Grants 2011: First International PCD 2006: Omran, et al Medical Mtg (Germany) publish DNAH5 gene 2002: Co-Sponsored First Mtg: Cilia, Mucus & MC Interactions 2011: PCD Clinical Centers Initiative Knowles predicts 1st PCD Gene test in 5 yrs 7 © Copyright 2011 | PCD Foundation | Confidential

What Do Patients Need? PCD Future: Where We Need To Be Where We Were: Where We Are: Where We Need to Be Battling the 3 ‘A’s’ Still Battling, Yet Poised for Greatly Impacting QOL & Means Major Growth to Find a Cure Better awareness has led to PCD included early in differentialAwareness: phenomenal patient group growth diagnosis when suspicious phenotypeLack of awareness leads to ‘Unmasking the Faces of PCD’ present.delayed/missed diagnosis & can campaign & others like it will move PCD Simpler and more accurate diagnostichave fatal consequences. into mainstream. process Still too many go undiagnosed or have delayed diagnosis. 7 centers for research & diagnosis PCD clinical centers in each state & allAvailability: funded through GDMCC in North America major citiesAvailability of care, expertise & Need to support & expand the existing Evolving standards of care based onsupport—no published standards network as that funding will end soon evidenceof care, insurance denials for No published standards of care. Access to clinical trials‘lack of evidence.’ Less need for ‘off label’ therapies GDMCC studies very successful, but Fully funded research plan for clinicalAccess: PCDF funding not sufficient for other & basic science initiativesAccess to clinical research: endeavors Continue natural history studies1) Funding Limited industry interest for clinical Solid infrastructure to support future2) Logistically: Little natural trials due to current patient population work history data; Dx was a size/difficulty identifying endpoints. mess; No research support infrastructure 8 © Copyright 2011 | PCD Foundation | Confidential

Obstacles to Overcome: Misconceptions What Do Patients Need?Misconceptions Reality• PCD is a mild, non-progressive • Progressive disorder that can result disorder in serious lung disease• Consequences of PCD only affect • Infants can have severe lung older patients disease; Neonatal mortality• It is impossible to confirm the • It can be accurately diagnosed diagnosis of PCD (current = 30% misdiagnosed)• Treatments already exist: They are • PCD and CF are different genetic the same as for cystic fibrosis (CF) disorders. No PCD EBM to date.• PCD is incredibly rare and only • PCD is poorly understood and affects a few thousand people under-reported (Est. 400K WW)• Situs inversus is a benign condition • Not necessarily; Myth leads to• ‘Normal’ life expectancy delayed diagnosis • Wrong on two counts 9 © Copyright 2011 | PCD Foundation | Confidential

Obstacles to Overcome: “Normal” Life Expectancy What Do Patients Need? Age Gender Situs 0 M SI 0 F SA 0 F SA Average Age at 0 M SA Death: 24 F SA 24 M SS46.6 years old 30 F SS(excluding infants) 39 F SI 42 M SS34.9 years old 45 F SI 47 M SS(including infants) 50 F SI 55 F SS 64 M SA 66 F SS 73 F SI10 © Copyright 2011 | PCD Foundation | Confidential

What Do Patients Need?The Role of the PCDF• Improved • Education & Support • Awareness & Advocacy – Diagnosis – Patients, Families & – Legislators, Policy – Quality of Life Caregivers Makers – Prognosis – Scientific & Medical – Medical Communities Communities – General Public 11 © Copyright 2011 | PCD Foundation | Confidential

The Role of the PCDF What Do Patients Need?To support these goals, our primary focus is to:• Support research efforts that will benefit the PCD patient community• Sponsor research directlyWe will measure success based on the impact of efforts to:• Diagnose more PCD patients overall and earlier in life• Enhance quality of life and prognosis for people with inherited disorders of motile cilia (and related ciliopathies)• Improve access to affordable, effective therapeutics and appropriate medical care• Expand visibility of PCD with key public/private institutions, medical professionals and the general public 12 © Copyright 2011 | PCD Foundation | Confidential

PCD Future Opportunities: Newborn Screening What Do Patients Need?• Recommendation from HHS that all infants be screened for CCHD via pulse oximetry• Positive screens will have cardiology follow up• Opportunity to educate neonatologists, cardiologists & families about the CHD/cilia connection• Could result in much earlier diagnosis of PCD 15 © Copyright 2011 | PCD Foundation | Confidential

PCD Future Opportunities: Newborn Screening What Do Patients Need?• In the past decade, the role of sensory monocilia in a vast array of human diseases has been established• Tremendous interest in disease Explosion of pathophysiology & potential interest in therapeutic targets related to cilia cilia &• Initially, ‘primary’ (sensory) ciliary ciliopathies in disorders & motile ciliary the research disorders were thought to be community distinct, but there is growing evidence of overlap 16 © Copyright 2011 | PCD Foundation | Confidential

PCD Future Opportunities: Ciliopathies What Do Patients Need? PCD Ciliopathies Nephronophthisis Ciliopathies Leber Congenital Amaurosis PCD Associated with Associated with ARPKD Meckel Gruber Syndrome Heart Defects Pulmonary ADPKD Bardet-Biedl Syndrome Disease Jeunechondrodysplasia McKusick-Kaufman Syndrome Alstrom Syndrome (COPD) Ellis van Creveld Syndrome Oral Facial Digital Syndrome Heterotaxy Ellis van Creveld Syndrome Alstrom Syndrome Heterotaxy Joubert syndrome PCD Bardet-Biedl Leber Congenital Amaurosis Alstrom syndrome Ciliopathies Retinitis Pigmentosa Associated Eye Jeunechondrodysplasia DiseaseWare, S., et al. Clinical Spectrum of Ciliopathies; PATS. Vol. 8: Sept, 2011 17 © Copyright 2011 | PCD Foundation | Confidential

What is the PCDF Path to Clinical Trials (PTCT)? A New Path: Why Now? A strategy designed to establish credible, evidenced-based knowledge of PCD, the most important factor in fulfilling our mission to provide education, support & better therapeutic options to affected individuals.19 © Copyright 2011 | PCD Foundation | Confidential

Why Is the PTCT The Right Strategy? A New Path: Why Now? Better treatment options/cures require (1) Research & (2) Access to clinical trials• The PTCT provides a scalable framework to accelerate research efforts & patient access to clinical trials• The PTCT is a proven, successful model based in insight from: – Clinical advisors & research partners at NIH – Non-profit colleagues • Bob Beall, CF Foundation (CFF) • Sue Byrnes, LAM Foundation 20 © Copyright 2011 | PCD Foundation | Confidential

How Does It Work? Two Critical Building Blocks A New Path: Why Now?• Network of PCD Clinical Care Centers• Patient Registry – 2-tiered approach to improve patient numbers Contact (Patient-Reported) Clinical (Physician-Reported) 21 © Copyright 2011 | PCD Foundation | Confidential

Overcoming Obstacles: Geography, Numbers &Mis(sed)diagnosis A New Path: Why Now? • Geographically dispersed & small patient population • Misdiagnosis was a big problem—became clear to us as patient group started communicating and interacting:Need for clinical centers and a • ‘Selective’ PCDpatient registry were identified back when the PCDF was • Highly suspect inheritance patterns founded, but we were faced with monumental obstacles, • Clinical centers claiming to have large #’s of including: PCD pts.22 © Copyright 2011 | PCD Foundation | Confidential

Overcoming Obstacles: GDMCC Paved the Way A New Path: Why Now? The Genetic Disorders of Mucociliary Clearance Consortium (GDMCC) Paved the Way to the PTCT • University of North Carolina at Chapel Hill - Chapel Hill, NC • Childrens Hospital Colorado - Denver, CO • Childrens Hospital & Regional Medical Center - Seattle, WA • The Hospital for Sick Children, Toronto, Ontario, Canada • National Institute of Allergy and Infectious Diseases • Stanford University Medical Center, Palo Alto, CA • Washington University in St. Louis, MO23 © Copyright 2011 | PCD Foundation | Confidential

Overcoming Obstacles: Lessons from the GDMCC A New Path: Why Now? Refined the definition of  Accelerated gene the clinical phenotype in identification providing ‘classic’ PCD & identified basis for more variants comprehensive genetic Verified that PCD test (14 verified genes - mutations do not always more on the way) result in defects that are  Expanded PCD research visible on biopsy network to include Created 1st genetic test international collaborators for PCD (2 genes) & basic science Validated the center researchers working on model for PCD other cilia-related projects24 © Copyright 2011 | PCD Foundation | Confidential

PCD Clinical Centers: Overview A New Path: Why Now?• The PCDF will work with key constituents in North America to define, recruit, launch & support PCD expert/satellite centers• Clinical Care Centers will provide expert care for people living with PCD• Clinical Care Centers will be based on the model established by the Cystic Fibrosis Care Goals Center Network  Reliable diagnosis • Identified by the NIH as a model of effective & efficient  Consistent, high-quality, appropriate care health care delivery for chronic disease  Comprehensive data collection through the North American PCD Registry (NAPCDR) 25 © Copyright 2011 | PCD Foundation | Confidential

PCD Clinical Centers: Support & Accreditation A New Path: Why Now?Centers Will Support:• A ’Certification’ process for ensuring expertise in diagnosis & treatment• Local patient registry entry• Contributions to evolving PCD Standards of Care including ongoing education & trainingAccreditation Standards• Multidisciplinary team: Board-certified Pulmonologists (pediatric & adult), ENT Specialists• Defined number of patients with PCD• Age-appropriate care: Outpatient (clinic), Inpatient (hospital) care• Specialist availability: Cardiology, Nephrology, Fertility• Applies guidelines for diagnosis and care• Teaching: Medical, Allied health students• Research: Basic &/or Clinical 26 © Copyright 2011 | PCD Foundation | Confidential

PCD Clinical Centers: Projecting Future Growth A New Path: Why Now? Expansion of centers based on: • The ability to identify centers who meet agreed up on criteria • The ability of the PCDF to fund centers coming online A starting point: Launch . . . • 7 current GDMCC sites to form basic core • X additional sites Year 1 • X additional sites Year 5 • X additional sites Year 10 . . .27 © Copyright 2011 | PCD Foundation | Confidential

SummaryWhat Do Patients Need? A Path to Clinical TrialsA New Path: Why Now?• Better diagnostics = Rapid PCD patient population growth – Can support clinical trials• Unprecedented interest & Together, we can change collaboration – Window of opportunity the future of PCD . . . and• Infrastructure to support more. growth 28 © Copyright 2011 | PCD Foundation | Confidential

Who Has PCD?Topics Covered*• Defining PCD: Overview of Data from GDMCC Studies• Definition of PCD Clinical Phenotype* Slides for this section are not included in this presentation 29 © Copyright 2011 | PCD Foundation | Confidential

When to Look For PCD/Initiate Therapies?Topics Covered*• Illustrative Cases• Data from Longitudinal StudiesDefining PCD: Overview of Data from GDMCC Studies* Slides for this section are not included in this presentation 30 © Copyright 2011 | PCD Foundation | Confidential

How to Confirm PCDTopics Covered*• Addressing the Challenge of Diagnosis• Ciliary Biopsy and Motility Studies—Are There Better Options?• Update on PCD Gene Identification* Slides for this section are not included in this presentation 31 © Copyright 2011 | PCD Foundation | Confidential

Now is the TimeTopics Covered*• Getting Clinical Centers Up & Running• Open Discussion: Sample topics – Demographics • How many pts to justify effort? • Okay to start small with expectation of growth? • How small is too small? – Diagnosis • Do we need designated centers for EM? – Logistics • Access to specialists (card, etc)? • Access to dx? • IRB concerns (registry)? – Budgeting • CF per capita model sufficient? • Additional staffing needs?* Information for this section is not included in this presentation 32 © Copyright 2011 | PCD Foundation | Confidential

Changing the Future of Primary Ciliary Dyskinesia (PCD): PCD Clinical Centers Kickoff

by PCD Foundation on Nov 10, 2011

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Changing the Future of Primary Ciliary Dyskinesia (PCD): PCD Clinical Centers Kickoff — Presentation Transcript