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

Changing the Future of PCD:
A New Path

Primary Ciliary Dyskinesia
Kartagener Syndrome
Immotile Cilia Syndrome

1
© Copyright 2011 | PCD Foundation | Confidential

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


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


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


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’


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

2010: First ‘PCD &
2004: GDMCC Formed 2008: Ciliopathies Related Conditions’ Mtg
1999-2000: UNC PCD Research Site w/RDCRN Grant & PCD Workshop in St. Louis
Initiates 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


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 differential
Awareness: phenomenal patient group growth diagnosis when suspicious phenotype
Lack 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 diagnostic
have 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 & all
Availability: funded through GDMCC in North America major cities
Availability of care, expertise & Need to support & expand the existing Evolving standards of care based on
support—no published standards network as that funding will end soon evidence
of 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 clinical
Access: PCDF funding not sufficient for other & basic science initiatives
Access to clinical research: endeavors Continue natural history studies
1) Funding Limited industry interest for clinical Solid infrastructure to support future
2) Logistically: Little natural trials due to current patient population work
history data; Dx was a size/difficulty identifying endpoints.
mess; No research support
infrastructure


Obstacles to Overcome: Misconceptions

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


Obstacles to Overcome: “Normal” Life Expectancy

Age Gender Situs
0 M SI
0 F SA
0 F SA
Average Age at 0 M SA
Death: 24 F SA
24 M SS
46.6 years old 30 F SS
(excluding infants) 39 F SI
42 M SS
34.9 years old 45 F SI
47 M SS
(including infants) 50 F SI
55 F SS
64 M SA
66 F SS
73 F SI


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

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

PTCT Research

Evidence-
Based Care

Education
& Support


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 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


PCD Future Opportunities: Ciliopathies

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
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!


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.


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

• 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’ PCD
patient 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.


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  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 projects


PCD Clinical Centers: Overview
• 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)


PCD Clinical Centers: Support & Accreditation
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 . . .


Summary


A Path to Clinical Trials
• 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


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.


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

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