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

1 © Copyright 2011 | PCD Foundation | Confidential

Primary Ciliary DyskinesiaKartagener Syndrome

Immotile Cilia Syndrome

Changing the Future of PCD:A New Path

© Copyright 2011 | PCD Foundation | Confidential2

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


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


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


What Do Patients Need?

PCD Past: Where We Were

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 weredealing with

– There would never be any research on PCD



PCD Past: Where We Were

2000: UNC PCD Research Group

2001: Requested seed money to start PCDF in 2001

2002: 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’


2002: PCDF Founded

2007: Kennedy, et al publish paper on PCD heterotaxy and congenital heart defects

2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011

1999-2000: UNC PCD Research Site Initiates Early Studies

2007: First genetic test for PCD becomes available

2002: First PCD Family Day

2002: Co-Sponsored First Mtg:Cilia, Mucus & MC Interactions

2003: ORDR AnnouncesRDCRN Grants

2004: GDMCC Formedw/RDCRN Grant

Knowles predicts 1st

PCD Gene test in 5 yrs

2006: Omran, et al publish DNAH5 gene

2008: Ciliopathies & PCD Workshop at ATS

2008: DNAH11 published.

2011: First International PCD Medical Mtg (Germany)

2010: First ‘PCD & Related Conditions’ Mtgin St. Louis

2011: PCD Clinical Centers Initiative


PCD Past & Present: Where We’ve Been To Date


PCD Future: Where We Need To BeWhere We Were:

Battling the 3 ‘A’s’Where We Are:

Still Battling, Yet Poised for Major Growth

Where We Need to BeGreatly Impacting QOL & Means

to Find a Cure

Awareness:Lack of awareness leads to delayed/missed diagnosis & can have fatal consequences.

Better awareness has led to phenomenal patient group growth‘Unmasking the Faces of PCD’ campaign & others like it will move PCD into mainstream.Still too many go undiagnosed or have delayed diagnosis.

PCD included early in differential diagnosis when suspicious phenotype present.Simpler and more accurate diagnostic process

Availability:Availability of care, expertise & support—no published standards of care, insurance denials for ‘lack of evidence.’

7 centers for research & diagnosis funded through GDMCC in North AmericaNeed to support & expand the existing network as that funding will end soonNo published standards of care.

PCD clinical centers in each state & all major citiesEvolving standards of care based on evidenceAccess to clinical trialsLess need for ‘off label’ therapies

Access:Access to clinical research:1) Funding2) Logistically: Little natural

history data; Dx was a mess; No research support infrastructure

GDMCC studies very successful, but PCDF funding not sufficient for other endeavorsLimited industry interest for clinical trials due to current patient population size/difficulty identifying endpoints.

Fully funded research plan for clinical & basic science initiativesContinue natural history studiesSolid infrastructure to support future work



Obstacles to Overcome: Misconceptions


Misconceptions• PCD is a mild, non-progressive

disorder• Consequences of PCD only affect

older patients• It is impossible to confirm the

diagnosis of PCD• Treatments already exist: They are

the same as for cystic fibrosis (CF)• PCD is incredibly rare and only

affects a few thousand people• Situs inversus is a benign condition• ‘Normal’ life expectancy

Reality• Progressive disorder that can result

in serious lung disease• Infants can have severe lung

disease; Neonatal mortality• It can be accurately diagnosed

(current = 30% misdiagnosed)• PCD and CF are different genetic

disorders. No PCD EBM to date. • PCD is poorly understood and

under-reported (Est. 400K WW) • Not necessarily; Myth leads to

delayed diagnosis• Wrong on two counts


Obstacles to Overcome: “Normal” Life Expectancy

Age Gender Situs0 M SI0 F SA0 F SA0 M SA24 F SA24 M SS30 F SS39 F SI42 M SS45 F SI47 M SS50 F SI55 F SS64 M SA66 F SS73 F SI


Average Age at Death:

46.6 years old (excluding infants)

34.9 years old (including infants)


The Role of the PCDF

• Improved– Diagnosis– Quality of Life– Prognosis

• Education & Support– Patients, Families &

Caregivers– Scientific & Medical

Communities

• Awareness & Advocacy– Legislators, Policy

Makers– Medical Communities– General Public



The Role of the PCDF

To support these goals, our primary focus is to:• Support research efforts that will benefit the PCD patient

community• Sponsor research directly

We 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



Research Holds the Key

Research

Evidence-Based Care

Education & Support

PTCT



PCD Future Opportunities

Ware, S., et al. Clinical Spectrum of Ciliopathies; PATS. Vol. 8: Sept, 2011



PCD Future Opportunities: Newborn Screening


• 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


PCD Future Opportunities: Newborn Screening


• In the past decade, the role of sensory monocilia in a vast array of human diseases has been established

• Tremendous interest in disease pathophysiology & potential therapeutic targets related to cilia

• Initially, ‘primary’ (sensory) ciliarydisorders & motile ciliarydisorders were thought to be distinct, but there is growing evidence of overlap

Explosion of interest in

cilia & ciliopathies in the research community


PCD Future Opportunities: Ciliopathies

PCDNephronophthisis

Leber Congenital AmaurosisARPKDADPKD

JeunechondrodysplasiaAlstrom Syndrome (COPD)

Oral Facial Digital Syndrome Ellis van Creveld Syndrome

HeterotaxyJoubert syndrome

PCDBardet-Biedl

Leber Congenital AmaurosisAlstrom syndrome

Retinitis Pigmentosa Jeunechondrodysplasia

PCDMeckel Gruber Syndrome Bardet-Biedl Syndrome

McKusick-Kaufman SyndromeEllis van Creveld Syndrome

HeterotaxyAlstrom Syndrome

CiliopathiesAssociated with

Pulmonary Disease

Ciliopathies Associated with Heart Defects

CiliopathiesAssociated Eye

Disease

Ware, S., et al. Clinical Spectrum of Ciliopathies; PATS. Vol. 8: Sept, 2011



Patients Need A Path to Clinical Trials

Now is the Time!



A New Path: Why Now?

What is the PCDF Path to Clinical Trials (PTCT)?

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.


Why Is the PTCT The Right Strategy?


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


How Does It Work? Two Critical Building Blocks


• Network of PCD Clinical Care Centers• Patient Registry

– 2-tiered approach to improve patient numbers

Contact(Patient-Reported)

Clinical(Physician-Reported)


Overcoming Obstacles: Geography, Numbers & Mis(sed)diagnosis

Need for clinical centers and a patient registry were identified

back when the PCDF was founded, but we were faced with monumental obstacles,

including:

• Geographically dispersed & small patient population

• Misdiagnosis was a big problem—became clear to us as patient group started communicating and interacting:• ‘Selective’ PCD• Highly suspect inheritance patterns • Clinical centers claiming to have large #’s of

PCD pts.



Overcoming Obstacles: GDMCC Paved the Way

The Genetic Disorders of Mucociliary Clearance Consortium (GDMCC) Paved the Way to the PTCT


• University of North Carolina at Chapel Hill - Chapel Hill, NC• Children's Hospital Colorado - Denver, CO• Children's 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, MO


Overcoming Obstacles: Lessons from the GDMCC


Refined the definition of the clinical phenotype in ‘classic’ PCD & identified variants

Verified that PCD mutations do not always result in defects that are visible on biopsy

Created 1st genetic test for PCD (2 genes)

Validated the center model for PCD

Accelerated gene identification providing basis for more comprehensive genetic test (14 verified genes -more on the way)

Expanded PCD research network to include international collaborators & basic science researchers working on other cilia-related projects


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 Center Network• Identified by the NIH as a

model of effective & efficient health care delivery for chronic disease

Goals Reliable diagnosis Consistent, high-quality,

appropriate care Comprehensive data

collection through the NorthAmerican PCD Registry (NAPCDR)


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 & training

Accreditation 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


PCD Clinical Centers: Projecting Future Growth


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 . . .




A Path to Clinical Trials

Summary

• Better diagnostics = Rapid PCD patient population growth– Can support clinical trials

• Unprecedented interest & collaboration– Window of opportunity

• Infrastructure to support growth

Together, we can change the future of PCD . . . and more.


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


When to Look For PCD/Initiate Therapies?

Topics Covered*• Illustrative Cases • Data from Longitudinal StudiesDefining PCD: Overview of Data

from GDMCC Studies



How to Confirm PCD

Topics Covered*• Addressing the Challenge of Diagnosis• Ciliary Biopsy and Motility Studies—Are There Better Options?• Update on PCD Gene Identification



Now is the Time

Topics 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


Where We Go From Here

• Wrap Up• Action Items/Next Steps

Together, we can change the future of PCD . . . and more.

Documents

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