Bonnie Ramsey, M.D

Bonnie Ramsey, M.D.CF Endowed Professor of Pediatrics, University of

Washington School of MedicineDirector, CFF Therapeutics Development Network

Coordinating Center

October 18, 2013

Roadmap to a Cure (II)A Clinical Research Path Ensuring

Benefit for All Patients with CF

Faculty Disclosure

In my capacity as Director of the Cystic Fibrosis Foundation Therapeutics Development Network Coordinating Center, I have received grants or contracts from the following companies in the past 3 years:

Bonnie W. Ramsey, M.D.

12th Man TechnologiesAchaogenAiresApartiaBayer Healthcare AGCeltaxsysBristol – Myers SquibbCornerstone TherapeuticsEli LillyGenentechGilead SciencesGlaxoSmithKlineGrifols Therapeutics, IncHall Bioscience

Insmed Corporation*KaloBios*Rempex Pharmaceuticals, Inc.N30 Pharmaceuticals, LLCNikan PharmaceuticalsNordmarkNovartis Pharmaceuticals Corp. PharmagenesisPTC Therapeutics, Inc.*Pulmatrix Savara Pharmaceuticals*TalecrisVectura Ltd.Vertex Pharmaceuticals Incorporated*

*Companies mentioned in this presentation

Our Dream

All patients with Cystic Fibrosis will live full, healthy

lives.

Mucociliary clearance and obstruction

TenaciousMucus

Periciliary Liquid(PCL)

Surface Epithelial

Cells

normal CF

CFTR

How much CFTR is enough?

Carriers

Adapted from Accurso et al JCF 2013 in press

Normal

CFPancreatic Insufficient

Pancreatic Sufficient

≈ 30% CFTR activity associated with symptom reduction

CF is Not One Genetic DisorderCFTR mutation classes

Adapted from http://www.umd.be/CFTR/W_CFTR/gene.html

Cl -Cl -Cl -

Cl -

Cl - Cl -

Normal

XClass I

synthesis

XClass II

maturation

X

Class IIIregulation

XCl -Cl -

X

Class IVconductance

Cl -Cl -

Class Vquantity

‘severe’ mutationspancreatic insufficiency

decreased survival

‘mild’ mutationspancreatic sufficiency

So, there must be mutation specific treatment approaches

Reduced Quantity Reduced Function

MacDonald et al. Pediatr Drugs 2007;9:1-10; Zielenski. Respiration 2000;67:117-33; Welsh et al. Cystic fibrosis In: Valle et al, eds. OMMBID. McGraw-Hill Companies Inc;2004:part 21,chap 201; O’Sullivan et al. Lancet 2009;373:1891-1904

Class I Class II Class V Class III Class IV

Little to noCFTR GatingSome

CFTR Conductance

Normal CFTR quantity and

function

Correctors PotentiatorsTreatment

approaches

Our challenge is finding therapies to correct CFTR for all CF mutations

CFFPR*Patients

First Allele Second Allele

Among 25,976 patients with at least one allele recorded in the 2012 CFFPR

*Cystic Fibrosis Foundation Patient Registry, 2012

Patients with two copies of F508del predominate in the US

CFFPR*Patients



CFFPR*Patients



Log scale

Our challenge is finding therapies to correct CFTR for all CF mutations

Cl -Cl -Cl -

Cl -Cl -Cl -

Proof-of-concept for mutation-specific therapy Class III gating mutations- G551D

XMost common CF gating mutation

Mutant protein is present on the epithelial cell surface - ion transport is reduced

High throughput screening of small molecules identified ‘potentiators’: molecules that increased G551D function at the cell surface

X

How Much CFTR is Enough?The Ivacaftor – G551D Benchmark

Adapted from Accurso et al New Engl J Med 2010

Study Baseline

150 mg

Ivacaftor has a profound impact on lung function

http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203188Orig1s000SumR.pdf.Ramsey, New Engl J Med, 2011J Davis, AJRCCM, 2012

The ivacaftor effect persists for many months

See: McKone et al. NACFC 2013 Poster #227

Open Label Follow-On

Effect of 150 mg BID ivacaftor on hospitalization rate in G551D patients

From the GOAL presentation and kindly provided by S. Rowe

Important lessons learned from approval of the CFTR potentiator ivacaftor

High throughput screening to find candidates

High throughput screening

In vitro models: HBE Cells

In vitro models


In vitro models


in vivo Biomarkers (Sweat Chloride)

In vivo biomarkers


In vitro models


Clinical Outcome (Lung Function)

In vivo Biomarkers

Clinical Outcome


In vitro models


Approval

In vivo biomarkers

Clinical outcome

Approval

A successful drug approval pathway

Yet, questions remain• For example, sweat chloride and lung

function changes correlate poorly for individual patients

Durmowicz Chest 2013

Ivacaftor coverage of G551D mutations in the US

CFFPR*Patients

19 homozygotes

1,138 patientsFirst Allele Second Allele


Progress towards our goal

Cystic Fibrosis Foundation Patient Registry, 2012

IvacaftorG551D4.4%*

*- at some point in their lives (no data in infants and young children)

95.6%Remaining

Are there other patients with CF who may benefit from ivacaftor monotherapy?

• Other gating mutations• Infants and toddlers with G551D• Mutations, like R117H, that result in residual CFTR function

Ivacaftor coverage of other gating mutations

• In vitro studies have shown that ivacaftor improves chloride transport in CF cells with other CFTR gating mutations1

• G178R, S549N, S549R, G551S, G970R, G1244E, S1251N, G1349D, S1255P

• KONNECTION Study: Blinded, placebo-controlled 8 week crossover study of ivacaftor in other CFTR gating mutations with open label extension2

• At 8 weeks, FEV1 change from baseline favored ivacaftor treatment by 10.7% predicted (P < .0001)

• Comparable to ivacaftor treatment effect seen at 24 weeks in G551D patients (10.6% predicted, P < .0001)

1- Yu et al. J Cyst Fibros. 2012;11(3):237-45.2- DeBoeck et al. NACFC 2013 Symposium 3.15 and Poster #241

Study Status: Crossover portion complete, supplemental New Drug Application filed

Kindly provided by Vertex Pharmaceuticals

Ivacaftor Phase 3 Study: VX770-108 KIWI (2-5 years)• A two-part, open-label study to evaluate

the safety, pharmacokinetics, and pharmacodynamics of ivacaftor

• Patients with CF aged 2 through 5 years with a CFTR gating mutation:

• G551D, G178R, S549N, S549R, G551S, G970R, G1244E, S1251N, G1349D, S1255P

Study Status: Fully enrolled with data anticipated second quarter 2014

Part BIvacaftor

Week 0 Wk 12Week -4 Wk 24

Part AMultiple dose

safety and PK trial


Phase 3 Study: R117H mutations - Konduct• Multi-center, randomized, double-blind, placebo-controlled study

Key Inclusion Criteria• ≥ 6 years of age• Sweat chloride ≥60 mmol/L • At least 1 R117H allele

Study Status: Fully enrolled with first results expected by end of 2013

RunIn

Ivacaftor 150mg q12h

Placebo

(1:1)

ScreenFollow

Up

W-5 W-2 0 W2 W4 W8 W16 W24 W28

FEV1 at screening• 6 – 11 years old, 40 to 105 % predicted• ≥ 12 years old, 40 to 90% predicted


Potential coverage of ivacaftor: infants and children, other gating mutations, R117H


93.2%Remaining

G551D/R117H 6.8%

cytoplasmicF508del CFTR

Cultured F508del/F508del-human bronchial epithelial cells

Van Goor et al., PNAS 2011

CFTR proteins with Class II mutations do not reach the cell surface

Cl -Cl -Cl -

Cl -

Cl - Cl -

NormalCFTR

XF508del

Class II mutation

cilia

nuclei

F508del dominates the Class II common mutations

F508delHomozygotes

48.0%

F508delHeterozygotes

40.1%

5.1%9.9%Remaining


(10,409 in US)

(12,469 in US)

G551D/R117H 6.8%


Lumacaftor increases the amount of F508del-CFTR at the cell surface

Cultured F508del/F508del-human bronchial epithelial cells

CFTR

cilia

nuclei

untreated + lumacaftor


The function of lumacaftor corrected F508del-CFTR can be further enhanced by a CFTR potentiator

F508del/F508del-HBE (N = 7 donor bronchi)

Chl

orid

e tra

nspo

rt (%

Nor

mal

CFT

R)

05

101520253035

Baseline Lumacaftor Lumacaftor +Ivacaftor

Phase 2: lumacaftor with and without ivacaftor in F508del homozygotes

Boyle et al NACFC 2012

Lumacaftor + ivacaftor Phase 3 studies: VX809-103 & 104, TRAFFIC & TRANSPORT

TRAFFIC (103)TRANSPORT (104)

Randomized, placebo-controlled double-blind Phase 3 studies in F508del homozygotes

● Primary Endpoints: – Relative change in FEV1 % predicted through Week 24 compared to placebo

● Examples of Key Secondary Endpoints: – Absolute change in body mass index (BMI) from baseline at Week 24– Number of pulmonary exacerbations through Week 24– Safety and tolerability assessments

Study Status: Fully enrolled and data anticipated mid 2014

lumacaftor 600mg QD + ivacaftor 250mg q12h

lumacaftor 400mg q12h + ivacaftor 250mg q12h

placebo

Rollover/ExtensionUp to 96 Weeks

lumacaftor 600mg QD + ivacaftor 250mg q12h

ORlumacaftor 400mg q12h +

ivacaftor 250mg q12h

Week 1 24

HomozygousF508del

Kindly provided by Vertex Pharmaceuticals, Inc.

CFTR correctors

• Good news: significant progress in patients who have two F508del mutations

• Ongoing challenges:• Correction is a multi-step process which

may require more than one drug

• If a patient has only one F508del mutation (i.e., F508del heterozygote), the overall clinical response is often reduced.

Strategic planning for back-up correctors began 4 years go

• Reviewed lessons learned from first generation correctors

• Created road map for more robust second generation compounds

• Strong partners in place

• Amazing progress Novel screens developed Up to 6 million compounds will be reviewed

36

N1 N2

CL1 CL4

F508

Wild-type CFTR channel formationFolding and assembly of membrane and

cytoplasmic domains

Reachescell surface

Thomas et al. FEBS Lett. 1992;312(1):7-9. Du et al. Nat Struct Mol Biol. 2005;12(1):17-25Rabeh et al. Cell. 2012;148(1-2):150-63. Mendoza et al. Cell. 2012;148(1-2):164-74.

Phenylalanine508

M1

M1 M2

M1

N1 N1

M1 M2

N2

M1 M2

N1

M= membrane spanning domainN= nuclear binding domain

Multiple correctors may be required for optimal F508del folding

Okiyoneda, Nature Chem Biol 2013

cotranslational folding posttranslational folding

M1

N1

M1 M2

N1

R

M1 M2

N1R

N2

M1 M2

N1R

N2Target 2

M1 M2

N1

R

M1 M2

N1R

N2

Target 3

M1 M2

N1

RN2

M1 M2

N1

R

N2

Folded CFTR

Target 1

A second corrector further enhances in vitro F508del CFTR function

F508del/G542XF508del/F508del


Remaining CFTR genotypes

G551D, R117H, F508del90.1%

9.9%Remaining

NonsenseMutations

8.8%

7.1%Remaining

2.8%

Class I nonsense mutations

Adapted from Schmitz A, Famulok M. Nature 2007

Nonsense mutation

Readthrough compound

Shortened proteinFull-length protein

Ataluren (PTC 124) induces functional CFTR protein in nonsense (Class I) -mutation-mediated mouse model of CF

Du X et al., PNAS 2008

atalurencontrol

No Chloride Channel Activity

Chloride Channel Activity

Transepithelial Short-Circuit Current

Novel molecule discovered by high throughput screening

Induces selective dose-dependent ribosomal readthrough of premature stop codons but not normal stop codons

Activity in nonsense-mutation-mediated mouse models of CF and DMD

Ataluren Phase 3: Mean relative change in FEV1 % predicted at week 48

Konstan, M. – European CF Conference, Dublin 2012 Kindly provided by Temitayo Ajayi, PTC Pharmaceuticals

Inhaled aminoglycosides may affect ataluren response

In 2014, PTC is initiating an ataluren Phase 3 efficacy and safety trial in patients not receiving inhaled aminoglycosides

Konstan, M. – European CF Conference, Dublin 2012

Week 48 ∆ = 5.7%p = 0.008*

Week 48 ∆ = -1.4%p = 0.43*

Kindly provided by Temi Ajayi

Class I (nonsense mutation) next generation possibilities

• Cystic Fibrosis Foundation has initiated new discovery programs with both academic and industry partners

• With support from CFF, University of Alabama and Southern Research Institute, are currently screening approved drugs for read-through activity

• in vitro proof of concept studies using primary nasal epithelial cell cultures from Y 122 X homozygotes to test topical gentamicin effect in progress*

* personal communication – Isabelle Sermet-Gaudelus

CFFPR*Patients



How close are we to our goal using allele-specific approaches?

> 90% are covered

Both alleles One allele Unidentified alleles

CFFPR*Patients



How close are we to our goal using allele-specific approaches?

Both alleles One allele Unidentified AND MISSING alleles

1,768 patients

100% of patients with CF should have two identified mutations – the Mutation Analysis Program• Genetic testing is available free of charge

to all U.S. patients with CF who do not have 2 identified mutations

• For more information, go to cff.org

http://www.cff.org/LivingWithCF/AssistanceResources/MAP

CFTR2: An Emerging Tool for Diagnosis, Prognosis, and Therapeutics (supported by CFF)

http://www.cftr2.org/

What about other rare mutations? Personalized medicine 2013 and beyond

Clinical trial model for screening drug effects on rare alleles

Model for studying rare mutations: Individual (n=1) trials for clinical response to CFTR modulators

Vertex is currently using this approach to study ivacaftor response in patients with residual CFTR function and splice variants

• Single-center, randomized, double-blind, multiple within-subject (N-of-One) crossover study in patients with rare mutations

ActiveDrug

Cycle 1 Cycle 2

Daily Home Monitoring

Open-Label

Wk 16Wk -2 Wk 24 Wk 12 Wk 8 Wk 4 Day 1

Key outcome measures:• Primary: Change from baseline in % predicted FEV1 after 2

weeks of treatment• Multiple secondary outcomes may be measured


Our Goal: Develop Disease Modifying Therapies for 100% of Patients with CF

• Other non-allele specific therapeutic approaches are being pursued to achieve this goal

gene replacement gene repair mRNA replacement protein replacement

• An excellent example: UK Cystic Fibrosis Gene Therapy Consortium

Current status of UK CF Gene Therapy Consortium double blind, placebo controlled multidose trial

• Nebulized treatment regimens− CFTR+liposome in 5ml of 0.9% saline

− 0.9% saline alone (placebo)

• Twelve monthly doses

• Eligible patients− Diagnosis of CF− Age: > 12 years

• Primary endpoint , FEV1

• Current status: 123 patients dosed

• Results available in Autumn 2014!Kindly provided by Eric Alton

Beyond CFTR: will we still need new therapies to treat symptoms of CF?

• Yes, because CFTR modulators are not expected to reverse existing organ dysfunction (lung, pancreas, liver, GI tract)

• Prevention of organ damage is critical until CFTR modulator therapy is available to 100% of patients in infancy

Normal Airway CF Airway

CFF Pipeline is critical to patients with CF

cff.org clinicaltrials.gov

Advances in Anti-microbial Therapies

Pseudomonas aeruginosa

Advances in antibiotics to treat Pseudomonas aeruginosa (Pa)

tobramycin inhalation solution approved

US oral azithromycin study completed

dry powder tobramycin approved

dry powder colistimethate

approved (EMA)

aztreonam for inhalation solution approved

Phase 3 study of inhaled levofloxacin completedPhase 3 multi-cycle study of liposomal amikacin for inhalation (LAI) in

206 patients is ongoingInhaled aztreonam/tobramycin cycling study in process

Symposium S11, Friday 10:40am: What have we learned from recent antimicrobial trials?

A novel target to disarming Pa: Gallium nitrate

Can gallium complement in vivo antibiotics treating P. aeruginosa?

• Iron (Fe) is essential for bacterial growth and biofilm formation• Gallium is a similar size as Fe but not biologically active

• Gallium replaces Fe in essential functions and disables the bacteria• An FDA-approved formulation of gallium is available

• Gallium and conventional antibiotics kill different biofilm subpopulations

green = alivered = dead

Gallium Tobramycin

inside killed

outside killed

Kindly provided by Pradeep Singh

IV gallium improves CF lung function from baseline in infected patients

Kindly provided by Chris Goss

ManagementChange

ExperimentalIntervention

Epidemiology & Outcomes

Detection

Beyond Pseudomonas: Developing therapies for other emerging pathogens

P. aeruginosa

NTM MRSA

S. maltophilia A. xylosoxidans

B. cepacia complex

LiPuma, Chronic Airways Infection 2007

Pathway from identification of “new” CF pathogen to change in practice

Survival by methicillin-resistant Staph aureus (MRSA) prevalence in CF

Dasenbrook et al, JAMA 2010

Studying MRSA interventions• Three ongoing trials assessing MRSA

treatment strategies• ‘Eradication’ of initial MRSA infection(Sponsor: CFFT)

• STAR-Too study ( M. Muhlebach and C. Goss)• Testing the efficacy and durability of an oral antibiotic regimen at

14 US sites

• ‘Eradication’ of established MRSA infection(Sponsor:CFFT)• Persistent MRSA Eradication Protocol ( E. Dasenbrook and M

Boyle)• Testing efficacy of 28 days inhaled vancomycin and oral antibiotics

at 2 US sites

• Chronic suppression of established MRSA infection (Sponsor: Savara Corp)

• Dry powder inhaled vancomycin( AeroVanc)• Testing change in sputum MRSA density and lung function

Non-tuberculous mycobacteria• Prevalence 13-23% in patients with CF

worldwide− Annual screening culture recommended for patients who expectorate

sputum and/or receive chronic macrolides

• Most common species in CF− Mycobacterium avium complex (MAC) in 64%− Mycobacterium abscessus in 36%

• Impact of infection of CF lung disease− Associated with nodular bronchiectasis and /or cavitary disease by

chest CT− More rapid decline in lung function with M. abscessus

• Treatment− MAC

Asymptomatic patients may require no treatment Symptomatic patients usually respond to multi-antibiotic regimens

− M. abscessus no drug regimen is proven to be effective for M. abscessus lung disease

Binder, AJRCCM 2013Olivier, AJRCCM 2002Griffith, AJRCCM 2007

Nontuberculous mycobacteria (NTM): Liposomal amikacin for inhalation (LAI):

* Inclusion criteria: • NTM culture-positive at screening• 2007 ATS/IDSA criteria with nodular bronchiectasis and/or cavitary disease by chest CT• 3+ positive NTM cultures in prior 2 years, at least one within prior 6 months• Receiving ATS/IDSA guideline-based treatment for ≥6 months prior to screening

12 Weeks

D1

12 Weeks

Follow-Up

4 Weeks

Phase 2 Study (TR02-112)

1:1

D84

D85 D169

Screening* Day -42 to Day -4

LAI QD + Usual Care

Placebo QD + Usual Care

LAI QD + Usual Care

90 subjects stratified by CF vs. Non-CF, MAC vs. M. abscessus

Efficacy Endpoint:Reduction in bacterial density

Kindly provided by Insmed Corp.

Advances in Anti-Inflammatory Therapies

Inflammatory signaling in the normal lung

Konstan and SaimanNACFC 2009; Plenary Session IIAdapted from Ziady and Davis. Prog in Resp Res 2006

Konstan and SaimanNACFC 2009; Plenary Session IIAdapted from Ziady and Davis. Prog in Resp Res 2006

Inflammatory signaling in the CF lung

Signaling in the infected CF lung

Adapted from Ziady and Davis. Prog in Resp Res 2006Konstan and Saiman

NACFC 2009; Plenary Session II

Current progress in reducing airway inflammation• One proven efficacious therapy

• High dose ibuprofen slows FEV1 rate of decline in children1 and is associated with improved survival2

• Progress has been slow• Very complex, redundant system• Current clinical trial endpoints not well-suited to

measuring anti-inflammatory effects• Timeline is much longer (i.e., months to years)• Biomarkers such as neutrophil elastase, though

encouraging, are not yet validated as surrogate efficacy endpoints

• Studies of several approved therapies have been unsuccessful

1- Konstan et al JAMA 1995, 2- VanDevanter et al NACFC 2012

Reducing airway inflammation: the next steps• Points of future emphasis

• Encourage innovation in this area• KB001A – targeting P aeruginosa Type III

secretion pathway is currently in Phase 2 for CF1

• Alpha-1-antitrypsin development continues

• CFF is initiating a strategic planning process in 2014 to re-evaluate the approach to development of anti-inflammatory therapies

1- Milla et al Pediatr Pulmonol 2013

Our Success Has Been and Will Continue to Be a World-Wide Effort

The international community is making a huge investment in future research: Clinical Trials Networks

CFF Therapeutic Development

Network Australia CF Federation

European Clinical Trials

Network

Canada>3,800

The international community is making a huge investment in future research: National CF registries

Recent estimates of CF patients in registries world wide (2009-2012 data)

USA>27,000

UK>9,500

New Zealand>400

Australia>3,100

Norway>250 Europe*

>19,000

*- 20 countries, 10 of which have country registries

WE ARE ALMOST THERE!

Acknowledgements:

Fred van GoorSteve RoweChris Goss

Jill Van DalfsenRenu GuptaMike Boyle

Charles JohnsonIsabel Sermet-Gaudelus

Alex ElbertTemitayo Ajayi

Eric AltonCystic Fibrosis

FoundationTaneli Jouhikainen

Frank Accurso

Many thanks to the patients and families who participatein our studies, to the clinical sites for all their hard work, and

to the following individuals who contributed to this presentation.

A special thanks to Dutch VanDevanter and Laurel Feltz

Thanks!

Documents

Bonnie Ramsey, M.D