WEBCAST PATRICK SOSNAY, MD Assistant Professor of Medicine - - PowerPoint PPT Presentation

WEBCAST

PATRICK SOSNAY, MD Assistant Professor of Medicine Division of Pulmonary & Critical Care Medicine McKusick-Nathans Institute for Genetic Medicine Johns Hopkins Cystic Fibrosis Center Johns Hopkins University

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CREDIT DESIGNATION

LEARNING OBJECTIVES

• Explain how new CFTR modification advances point

to changes that have to be made in clinical practice.

• Describe the utility of genotype/phenotype

correlations beyond diagnosis in achieving more effective patient treatment.

• Integrate the patient into an individualized therapy

regimen to improve outcomes.

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FULL DISCLOSURE POLICY AFFECTING THE JOHNS HOPKINS UNIVERSITY ACTIVITIES

Faculty Relationship

Michael Boyle, MD Scientific Advisory Board: Genentech, Inc., Vertex Pharmaceuticals, Incorporated, Gilead Sciences, and Savara Pharmaceuticals Principal Investigator: Vertex Pharmaceuticals, Incorporated

The following relationships have been reported for this activity: PLANNERS

No other planners have indicated that they have any financial interest or relationships with a commercial entity.

ACKNOWLEDGEMENTS

EDUCATIONAL SUPPORT

• This activity is supported by an educational grant from

Vertex to Johns Hopkins University School of Medicine.

• All activity content and materials have been developed

solely by the Johns Hopkins activity directors, planning committee members and faculty presenters, and are free

• f influence from Vertex.

YESTERDAY -

OVERVIEW OF MUTATION CLASSES

• Describe how CFTR mutations can be

classified (by type, by class, by therapies).

• Discuss the variety of CFTR mutations.

LEARNING OBJECTIVES

…IN 1989

www.theatlantic.com lifesciencesfoundation.org www.npr.org

Class I: Defective protein production with premature termination of CFTR

• production. Examples: G542X, 1717-1G->A, CFTRdele2,3. No protein

produced. Class II: Defective processing or trafficking of CFTR. Examples: F508del,

• N1303K. No protein at the cell surface.

Class III: Defective regulation of CFTR. Examples: G551D, S549N. Adequate protein, no CFTR activity. Class IV: CFTR chloride transport through the channel is defective. Examples: R117H, D1152H. Adequate protein, reduced CFTR activity. Class V: Reduced amount of functional CFTR. Examples: 2789+5G->A, 3849+10kbC->T. Reduced protein at cell surface. Class VI: Increased turnover, Reduced protein at cell surface.

CFTR MUTATION CLASSES

hopkinscf.org

• The class of most of the ~2000 CFTR mutations is not

known

– It can be implied based on mutation type (for nonsense “X”

mutations, mutations to splice donor/acceptor sites “-1 or +1”, or mutations that cause a frameshift)

– Unknown for missense mutations

• Class is not always a simple assignment

PROBLEMS WITH CFTR MUTATION CLASSES

CHANGE TO HGVS NOMENCLATURE

Old “Legacy” Name HGVS name (by nucleotide) HGVS name (by protein)

F508del c.1521_1523delCTT p.Phe508del G551D c.1652G>A p.Gly551Asp 3849+10kbC->T c.3717+12191C>T no protein name CFTRdele2,3 c.54-5940_273+10250del21kb p.Ser18ArgfsX16

Description: http://www.hgvs.org/mutnomen/; Taschner PEM, den Dunnen JT. Hum. Mutat. 2011 Translators available on: http://cftr2.org/index.php, http://www.genet.sickkids.on.ca/app

RESIDUAL FUNCTION: YES/NO?

Discovery Magazine, June 2013

J Stuart Elborn, MD Professor, School of Medicine Dentistry and Biomedical Sciences Dean, School of Medicine Dentistry and Biomedical Sciences Centre for Infection and Immunity Queen’s University Belfast, Ireland

FINANCIAL DISCLOSURES CONSULTANT: Vertex Incorporated, Novartis RESEARCH FUNDING: Vertex Incorporated, Novartis

TODAY-

Ivacaftor and Beyond Small Molecule Therapy for Cystic Fibrosis

Off-Label Discussion lumacaftor, ivacaftor, and ataluren

• Describe how modulating and potentiating CFTR

improves clinically important outcomes in CF.

• Describe indication for potentiator and

combination therapy in CF.

LEARNING OBJECTIVES

PERSONALIZED/STRATIFIED/PRECISION MEDICINE FOR CYSTIC FIBROSIS

IMPROVED SURVIVAL WITH TREATMENT INNOVATION

Pancreatic Enzymes Antistaphylococcal antibiotics Antipseudomonal antibiotics rhDNase Inhaled tobramycin Airway clearance Azithromycin HTS Aztreonam TIP Colistin DPI Ivacaftor Mannitol Inhaled colistin

Age (years)

5 10 15 20 25 30 35 40

Stratified/Precision Medicine for CF RCTs CF gene identified NPD and Cl transport Neonatal screening Centre care Airways Clearance Mist tents 1st successful pregnancy 1st pathologic description Sweat chloride test developed Discovery

• f high salt

in sweat

Advances in therapy have been incremental

–

Individual benefit is modest but cumulative

–

Life expectancy greatly increased

CF AIRWAY DISEASE: PATHOPHYSIOLOGY

Normal CF

• Patients respond differently, and these responses can be organized into

groups

Mark R. Trusheim, Ernst R. Berndt & Frank L. Douglas Nature Reviews Drug Discovery 6, 287-293 (April 2007)

WHAT IS STRATIFIED/PRECISION MEDICINE?

• Over 1900 CFTR mutations identified

that result in a range of disease severity to no disease

• Range in disease severity among

people with the same CFTR mutations

• Modifier genes
• Environment
• Stage of disease at time of treatment

CHALLENGES FOR STRATIFIED MEDICINE IN CF

MUTATION CLASSES

European Cystic Fibrosis Registry

• A. Percent of patients with 1 or 2 class I mutations

• C. Percent of patients with 1 or 2 class II mutations

• B. Percent of patients with 1 or 2 nonsense mutations

• D. Percent of patients with 1 or 2 F508del mutations

Molecular Defect Nonsense or frameshift mutations causing premature stop codons leading to defective protein synthesis Functional Consequence No CFTR protein expressed Examples of Mutations W1282X, R553X, G542X

CLASS I CFTR MUTATIONS

X

Golgi mRNA CFTR Gene Cl- Cl-

ATALUREN IS AN ORALLY BIOAVAILABLE DRUG DESIGNED TO OVERCOME NONSENSE (PREMATURE STOP CODON) MUTATIONS

Premature Termination

Incomplete Protein Nonsense Codon (premature stop) Normal Stop Codon messenger RNA

ATALUREN IS AN ORALLY BIOAVAILABLE DRUG DESIGNED TO OVERCOME NONSENSE (PREMATURE STOP CODON) MUTATIONS

Premature Termination

Incomplete Protein Nonsense Codon (premature stop) Normal Stop Codon messenger RNA Full-length Protein

Ataluren

Nonsense Codon (premature stop) Normal Stop Codon messenger RNA Approximately 10% of CF patients have a nonsense mutation in the CFTR gene.

ATALUREN/PTC124 PHASE II TRIALS

PRIMARY ANALYSIS: MEAN RELATIVE CHANGE IN %-PREDICTED FEV1 AT WEEK 48 (ITT)

Kerem et al LRM 2014

∆ = 3.0%

8 16 24 32 40 48

• 8
• 6
• 4
• 2

2

Ataluren (N=116) Placebo (N=116)

Week 48 ∆ = 3.0% p = 0.124

Time, weeks Relative Change in % FEV1, Mean

• 5.5%
• 2.5%

FEV1 BY CHRONIC BASELINE INHALED AMINOGLYCOSIDE

8 16 24 32 40 48

• 8
• 6
• 4
• 2

2 4 6

Ataluren (N=44) Placebo (N=42) BL Time, weeks

• 4.5%
• 4.2%

∆ = -0.3% 8 16 24 32 40 48

• 8
• 6
• 4
• 2

2 4 6

Ataluren (N=72) Placebo (N=74)

BL

Time, weeks Change in %-Predicted FEV 1, Mean

• 0.2%
• 4.3%

∆ = 4.1%

No Inhaled Aminoglycosides

Average ∆ = 4.1% p = 0.0024* Average ∆ = -1.4% p = 0.59*

Any Inhaled Aminoglycosides

*Nominal p-values

Kerem et al 2014

Why is the overall clinical response modest?

–‘Random’ read through –No evidence of translational read-through activity for

PTC124 (McElroy et al PLOS Biology 2013)

–Nonsense mediated mRNA decay? –Certain stop codons may respond better

WHY DID ATALUREN NOT WORK?

Molecular Defect Amino acid deletion or missense mutations causing defective CFTR protein processing and trafficking Functional Consequence Misfolded CFTR protein fails to reach cell surface or present only in very small amount Examples of Mutations F508del, N1303K

CLASS II CFTR MUTATIONS

X

Golgi mRNA CFTR Gene CFTR protein Cl- Cl-

F508DEL RESULTS IN LITTLE TO NO CFTR PROTEIN AT THE CELL SURFACE

ER Golgi Nucleus Proteasome CFTR

Cl– Cl–

Few F508del-CFTR channels at the cell surface Normal quantity of CFTR channels at the cell surface

IVACAFTOR POTENTIATES F508DEL-CFTR DELIVERED TO THE CELL SURFACE BY LUMACAFTOR IN HUMAN BRONCHIAL CELLS

Ussing chamber studies using human airway cells (HBE) (Van Goor et al., PNAS 2011)

F508del

Homozygous

F508del

5 10 15 20 25 30 35

F508del/F508del-HBE Chloride transport (% Normal CFTR)

Baseline Lumacaftor + Ivacaftor Lumacaftor

lumacaftor 600 mg qd + ivacaftor 250 mg q12h lumacaftor 400 mg q12h + ivacaftor 250 mg q12h Placebo

Day 1 Week 24 Week 16 Week 8 Week 4 Week 2

F508del homozygous Rollover Safety Study (105) Safety Follow-up Visit

TRAFFIC

lumacaftor 600 mg qd + ivacaftor 250 mg q12h lumacaftor 400 mg q12h + ivacaftor 250 mg q12h Placebo

Day 1 Week 24 Week 16 Week 8 Week 4 Week 2

F508del homozygous Rollover Safety Study (105) Safety Follow-up Visit

TRANSPORT

PHASE 3 TRIALS

FEV1

TRAFFIC TRANSPORT

TRAFFIC/TRANSPORT POOLED: EXACERBATIONS

* p < 0.0056 Note: Pooled analysis of TRAFFIC and TRANSPORT

TTF Pulmonary Exacerbation

39 to 61% reduction for patients in combination groups 45 to 56% reduction for patients in combination groups

Events requiring hospitalization Events requiring IV antibiotics

–39% p=0.00 28 –61% P<0. 0001 –45% P<0.0 001

Exacerbations

Lumacaftor 400mg q12h Ivacaftor 250mg q12h Lumacaftor 600mg qd q12h Ivacaftor 250mg q12h Placebo

Study Day LUM 600mg qd/IVA 250 mg q12h LUM 400mg q12h/IVA 250 mg q12h Placebo 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Proportion of Event-free Subjects 1 15 29 43 57 71 85 99 113 127 141 155 169

BMI CFQ-R

TRAFFIC/TRANSPORT POOLED: NUTRITION

• 3% improvement in FEV1
• Reduced time to next exacerbation and fewer

hospitalizations

• Improved BMI
• Improved QoL

Less improvement than in G551D treated with ivacaftor KEY ENDPOINTS & ADDITIONAL ANALYSES, TRAFFIC/TRANSPORT POOLED

F508del CFTR STABILITY

CFTR CORRECTORS ACTING ON DIFFERENT REGIONS OF F508DEL-CFTR CAN BE ADDITIVE IN VITRO

Van Goor et al., 2012 Okiyoneda et al., Nature Chemical Biology 2013

Lumacaftor Stabilizes MSD1 to promote domain assembly 2nd Corrector Stabilizes interactions between NBD1 and MSD2

• CFTR is a drug-able target
• Ataluren has a limited impact on clinical outcomes in CF
• Lumacaftor/ivacaftor is a promising combination
• More potent correctors and potentiators are currently

under development and soon to start clinical trial

CONCLUSIONS

Thanks to

• all the people with CF and parents who participated in clinical trials
• PIs (TDN & ECFS-CTN)
• study teams who participated in clinical trials to improve treatment for CF

TRANSLATIONAL RESEARCH IN CF

MEGHAN RAMSAY, MS, CRNP Adult Clinical Coordinator Cystic Fibrosis Center Johns Hopkins University School of Medicine

TODAY -

MANAGEMENT OF PATIENT EXPECTATIONS

Off-Label Discussion: hypertonic saline

• Define better ways to manage patient

expectations about new therapies. LEARNING OBJECTIVE

MANAGING PATIENT EXPECTATIONS

Courtesy of Dr. Michael Boyle

50% 50%

Variation in lung function = Genes + Environment + Stochastic CFTR Modifier genes Exposures Treatment Adherence Access

“As a parent, this is such a dream come true,” Camille said. “Dylan has started growing and gaining weight, and he’s missing fewer school

• days. Overall he’s feeling much better.”

(Children’s Hosp Colorado Website - Story Ivacaftor Offers Hope to Cystic Fibrosis Patients)

“New wonder drug can heal lungs of CF sufferers”

(www.dailymail.co.uk Aug 25 2012)

MIRACLE OR HOPE

MANAGING PATIENT EXPECTATIONS

• Adherence
• Routine CF Treatments and Care
• Educating Patients and Families

MANAGING PATIENT EXPECTATIONS

TO SUMMARIZE:

• What we may not be able to change?
• Communicating with patients and families.
• HOPE for some now and in the future for others?

MANAGING PATIENT EXPECTATIONS

JOSEPH PILEWSKI, MD Associate Professor of Medicine, Cell Biology, Pediatrics, and Clinical and Translational Sciences University of Pittsburgh Pittsburgh, PA

FINANCIAL DISCLOSURES CONSULTANT Vertex Pharmaceuticals Incorporated SPEAKERS BUREAU (resigned Dec.31, 2013) Vertex Pharmaceuticals Incorporated GRANTS Cystic Fibrosis Foundation Therapeutics, Vertex Pharmaceuticals Incorporated, N30

TOMORROW-

TRANSFORMING CF CARE ONE MECHANISM AT A TIME

Off-Label Discussion Ivacaftor, lumacaftor, VX- 661, QBW251, and P- 1037

• Explain how new CFTR modification advances

point to changes that have to be made in clinical practice.

• Describe the utility of genotype/phenotype

correlations beyond diagnosis in achieving more effective patient treatment.

• Demonstrate how to integrate the patient into

an individualized therapy regimen to improve

• utcomes.

LEARNING OBJECTIVES

• Pathogenesis: what causes mucus obstruction and

susceptibility to infection?

• Personalized medicine: future of small molecule

potentiators and correctors

• Other approaches to correct CFTR

– Gene therapy – Gene editing

OVERVIEW

PATHOPHYSIOLOGY OF CYSTIC FIBROSIS

Abnormal CFTR Protein

CFTR gene defect End Stage Lung Disease Infection Inflammation Mucus Obstruction Delayed mucociliary clearance Abnormal CFTR protein Airway surface liquid depletion Defective ion transport Bronchiole/bronchiectasis http://www.cftr2.org/

WHAT ARE THE CAUSES OF MUCUS OBSTRUCTION IN CF?

• Dysregulated surface fluid movement

leads to volume depleted airway surface

Matsui et al., Cell 1999

CLASSES OF CF MUTATIONS AND THERAPEUTIC APPROACHES

Adapted from Rowe et al., New Engl J Med 2005

Stop mutations

G542X, W1282X, others Translational read through

Gating/regulation

G551D, R117H, R1070W, others

Potentiator F508del CFTR biogenesis

F508del, possibly others

Corrector

• Pivotal phase 3

studies in patients >12 with G551 mutation

• Ivacaftor improved

FEV1, sweat chloride, BMI, and reduced exacerbation frequency IVACAFTOR IMPROVES LUNG FUNCTION IN PATIENTS WITH CF AND GATING MUTATIONS

Ramsey et al., NEJM 2011

IVACAFTOR RESULTS IN CF PATIENTS WITH G551D PROVIDE INSIGHT TO CORRECTION EFFICIENCY

CFTR-R Adapted from Wilschanski et al., AJRCCM 2006; Rowe et al.

IVACAFTOR INCREASES MUCOCILIARY CLEARANCE

Pre 90 days Post

Courtesy Tim Corcoran, Landon Locke

RESTORING CFTR FUNCTION INCREASES MUCOCILIARY CLEARANCE (MCC) AND REDUCES INFECTIOUS BURDEN

G551D Observational (GOAL) study: Multiple endpoints before and after initiation of ivacaftor

• FEV1, sweat Cl, CFQ-R
• significant increases in MCC

Rowe et al., AJRCCM 2014

• dds of P. aeruginosa

positivity in the year after ivacaftor initiation reduced by 35% (OR=0.65, p<0.001) after adjusting for specimen type and number of cultures

• Heltshe et al.,

Abs195, W24 Saturday

IVACAFTOR IMPROVES LUNG FUNCTION IN ADULT PATIENTS WITH R117H MUTATIONS

Van Goor et al., J Cyst Fibros 2014; Moss et al., Abstract 17

IVACAFTOR IN RESIDUAL FUNCTION MUTATIONS: ‘N OF 1’ STUDY

Van Goor, J Cys Fibros 2014; clinicaltrials.gov; Nick et al., Symposium 16 R117H, E56K, P67L, D110E, D110H, R117C, R347H, R352Q, A455E, D579G, S945L, L206W, R1070W, F1074L, D1152H, S1235R, D1270N, 2789+5G->A, 3849+10kbC->T, 3272-26A->G, 711+5G->A, 3120G->A, 1811+1.6kbA->G, 711+3A->G, 1898+3A->G, 1898+1G->A, 1717-1G->A, 1717-8G->A, 1342-2A->C, 405+3A->C, 1716G/A 1811+1G->C, 1898+5G->T, 3850-3T->G, IVS14b+5G->A, 1898+1G->T, 4005+2T->C, 621+3A->G, 621+1G->T

P

IVA IVA P 1 2 3 4 Cycle 1 Cycle 2 Open-Label

P

IVA

P

IVA IVA

P

IVA

P

IVA

P P

IVA

Ivacaftor Ivacaftor Ivacaftor Ivacaftor

2

Duration (weeks)

2 2 2 4 4 8

*

*

IVA, ivacaftor; F/U, follow-up; P, placebo.

Randomization

Washout

*No washout within cycles.

Washout Washout Washout Washout Washout Washout Washout Washout Washout Washout Washout

2

Determine response based on “standard” assessments (FEV1, sweat chloride, LCI, CFQ-R) 1 Identify short term measures/markers that may be predictive of later response 2

Nick et al., Abstract 196, S16, Saturday

IVACAFTOR N-OF-1 STUDY DESIGN

Nick et al., Abstract 196, S16, Saturday

IVA IVA W W

20 30 40 50 60 70 80 90 100

Percent Predicted FEV1

Ivacaftor P P

IVA, ivacaftor; P, placebo; W, washout period.

Baseline Sweat Chloride 27 mmol/L

Absolute change from baseline at end of open-label treatment period

• 9.5 mmol/L

+15.8 +16 +11.5

Not representative of all patients

EXAMPLE OF RESPONDER

LUNG FUNCTION IN THE 2-WEEK AND 8-WEEK TREATMENT PERIODS

2-Week Cycles 8-Week Open-Label Placebo (n=24) Ivacaftor (n=24) Ivacaftor (n=21)

Bayesian Hierarchical Model Mean treatment effect vs placebo, absolute change in ppFEV1 from baseline 2.3 95% C.I. (0.4 - 4.1) – Mixed Effects Model Repeated Measures Mean absolute change in ppFEV1 from baseline, % 0.6 2.8 4.7 (p<.0001) † Treatment difference vs placebo 2.1 (p=0.004)* – Mean relative change in ppFEV1 from baseline, % 0.9 4.9 7.8 (p=0.0001) † Treatment difference vs placebo 4.0 (p=0.002)* –

*P for difference between ivacaftor and placebo.

†P for difference from baseline.

F508DEL RESULTS IN LITTLE TO NO CFTR AT THE CELL SURFACER

CFTR, cystic fibrosis transmembrane conductance regulator. Boyle MP, et al. NACFC, October 11, 2012, Orlando, FL.

ER Golgi Nucleus Proteasome CFTR Cl– Cl–

Normal quantity of CFTR channels at the cell surface Few F508del- CFTR channels at the cell surface

• ivacaftor monotherapy was not found to have a clinically

relevant effect in patients homozygous for the F508del mutation (Flume et al, Chest 2012)

• lumacaftor and VX-661 are both CFTR correctors that

increase F508del-CFTR activity in vitro both alone and in combination with ivacaftor

• VX-661 compared to lumacaftor:

– longer half-life – little potential for interactions with ivacaftor, azoles, and other drugs

CFTR MODULATORS FOR F508DEL

VX-661 PHASE 2 STUDY DESIGN

• Total (N=128)

– Approximately twice

as many patients in combination arms as in monotherapy arms

• Placebo (n=24, pooled across

all groups)

Monotherapy arms Combination therapy arms

Group 2 Group 3 Group 4 Group 5 Group 1

(n=8); placebo (n=2) (n=8) (n=8) (n=9) (n=18) (n=19) (n=17); placebo (n=5)

VX-661 10 mg QD VX-661 10 mg QD + Ivacaftor 150 mg Q12h VX-661 30 mg QD VX-661 30 mg QD + Ivacaftor 150 mg Q12h VX-661 100 mg QD VX-661 100 mg QD + Ivacaftor 150 mg Q12h VX-661 150 mg QD VX-661 150 mg QD + Ivacaftor 150 mg Q12h Days 1–28

Placebo (n=4) Placebo (n=7) Placebo (n=6) (n=17)

QD, once daily; Q12h, every 12 hours.

Donaldson et al., ECFS 2014

ABSOLUTE CHANGE FROM BASELINE FOR COMBINATION RESPONSES IN % PREDICTED FEV1

Combination Washout

Mixed-Effects Model Repeated Measures Summary Statistics

• 5

5 10 15 Mean Absolute Change from Baseline in % Pred FEV1 (%)

Pooled placebo VX-661 10 mg + ivacaftor 150 mg VX-661 30 mg + ivacaftor 150 mg VX-661 100 mg + ivacaftor 150 mg VX-661 150 mg + ivacaftor 150 mg

Baseline Day 7 Day 14 Day 21 Day 28 Day 28 Day 35 Day 42 Day 56

Donaldson et al., ECFS 2014

RELATIVE AND ABSOLUTE CHANGES IN LUNG FUNCTION FOR COMBINATION RESPONSES FROM BASELINE TO DAY 28

Group n

% Predicted FEV1

Relative change, % LS mean (P Value) Absolute change, % points LS mean (P Value) Pooled placebo (within group) 23 0.03 (NS) –0.4 (NS) VX-661 10 mg + ivacaftor 150 mg vs placebo 17 4.1 (NS) 2.3 (NS) VX-661 30 mg + ivacaftor 150 mg vs placebo 17 5.4 (NS) 3.4 (NS) VX-661 100 mg + ivacaftor 150 mg vs placebo 15 9.0 (0.01) 4.8 (0.01) VX-661 150 mg + ivacaftor 150 mg vs placebo 16 7.5 (0.02) 4.5 (0.01) NS, not significant. Donaldson et al., ECFS 2014

• 18 patients were randomized 4:1 treatment: placebo
• Placebo patients were included to ensure the study was blinded
• Treatment and follow-up periods evaluated on-treatment and
• ff-treatment effects

VX-661 AS ADD-ON FOR PATIENTS WITH F508DEL/G551D MUTATIONS

N=4 N=14

VX-661 100 mg QD + Ivacaftor 150 mg Q12h Placebo + Ivacaftor 150 mg Q12h

Patients receiving physician- prescribed ivacaftor for ≥28 days

Day 0 Day 28 Day 56

Ivacaftor 150 mg Q12h

Treatment period Follow-up period

Donaldson et al,. Abstract 260

ADDITION OF VX-661 LED TO IMPROVEMENT IN LUNG FUNCTION AFTER 28 DAYS

Outcome Measure

Day 0 through 28 VX-661 100 mg + Ivacaftor 150 mg (n=14) Day 28 to 56 Washout (no VX-661) Ivacaftor 150 mg (n=4)

% Predicted FEV1: Absolute Change, % Points LS Mean (P value) 4.6 (0.012)

• 3.4 (0.010)

% Predicted FEV1: Relative Change, % LS Mean (P value) 7.3 (0.0115)

• 5.4 (0.008)

Sweat Chloride: Absolute Change, mmol/L LS Mean (P value)

• 7.0 (0.05)

12.3 (0.001) CFQ-R Score (respiratory domain): Absolute Change LS Mean (P value) 3.8 (NS)

• 1.3 (NS)

Donaldson et al,. Abstract 260

Mendoza et al., Cell 2012 Rabeh et al., Cell 2012

F508del CFTR DEFECTS: FOLDING AND DOMAIN ASSEMBLY

TMD1 TMD2 NBD1 NBD2 Phe508 ICL4

F508del PROCESSING

Okiyoneda and Lukacs, JCB 2012

CLASSES OF CORRECTORS

Okiyoneda and Lukacs, JCB 2012 Class I Class II Class III

STRUCTURE BASED DEVELOPMENT OF NEW CORRECTORS

Okiyoneda et al., Nat Chem Biol 2013

Class I: lumacaftor, VX-661 Class II: C4, core-cor II Class III: Glycerol, myo-inositol

PATHOPHYSIOLOGY OF CYSTIC FIBROSIS

Abnormal CFTR Protein

CFTR gene defect End Stage Lung Disease Infection Inflammation Mucus Obstruction

Delayed mucociliary clearance

Abnormal CFTR protein

Airway surface liquid depletion

Defective ion transport Bronchiole/bronchiectasis

Hypertonic saline, Mannitol ENaC inhibitors CFTR modulators Lung transplantation Antibiotics Exercise/ clearance DNase

http://www.cftr2.org/

CF gene therapy/ editing

Parion P-1037 VX-661/ lumacaftor / ivacaftor / QBW251

GENE THERAPY

• Efforts to date hampered by

limited efficiency of gene transfer with multiple vectors

• UK consortium: single dose safe

and partially restores Cl- secretory response

• Phase 3 randomized, multiple

dose study in progress (NCT #01621867)

• Monthly doses of CpG free, promoter
• ptimized plasmid in lipid complex
• ver one year

Alton et al., Lancet 1999

GENE EDITING

Schwank et al., Cell Stem Cell 2013

Technologies being developed to correct specific mutations (eg. F508del) in airway cells or inducible pleuropotent stem cells (iPS cells)

GENE EDITING

Schwank et al., Cell Stem Cell 2013

• Novel RNA antisense oligonucleotide based

therapies

• QR-010 is being developed for CF patients with

F508del (homozygotes and compound heterozygotes)

• Preclinical data suggests that QR-010 results

in expression of functional CFTR

• Phase 1b Safety and Tolerability in CF patients

will potentially begin late 2014

QR-010 FOR CYSTIC FIBROSIS

• Sub-clinical phase: asymptomatic - newborn to

early childhood

• Early clinical phase: normal lung function but

intermittent infections and mild bronchiectasis

• Late phase: chronic infections, reduced lung

function, and progressive bronchiectasis

STAGES OF CF LUNG DISEASE AS FRAMEWORK FOR CFTR MODULATORS

CLINICAL TRIAL NETWORKS: TDN/CTN

OPPORTUNITY TO BROADLY TRANSFORM THE TREATMENT OF CF

GOAL: Treat the vast majority of CF patients and continue to enhance the benefit for those we treat

Addressable Cystic Fibrosis population

>17,000 F508del heterozygous >5,000 Gating/ R117H/ Residual CFTR >2,000 G551D

ivacaftor monotherapy Next gen correctors triple combinatons ivacaftor + corrector ivacaftor Complex regimens

vast majority of all CF patients > 28,000 F508del homozygous

• Clear understanding of CF from organ dysfunction to

gene mutations to protein structure to cell biology to medicinal chemistry has led to CFTR modulators that are likely to further improve survival

• Multi-disciplinary efforts by patients and families/CF

Foundation, clinical investigators, basic scientists in academia and industry, health care providers: brink of corrective therapies for majority of patients

SUMMARY

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