opening doors to cf clinical research: change is coming · 2017-05-18 · , 3:30 pm • poster...

Opening Doors to CF Clinical Research: Change is Coming

Disclosures Contracts with sponsors for clinical trials conducted at UNC-Chapel Hill:

▪ CFFT

▪ NIH/NHLBI

▪ AbbVie Inc.

▪ Aptalis Pharma US, Inc.

▪ Janssen Research & Development, LLC.

▪ Gilead Sciences

▪ Savara Pharmaceuticals

▪ Vertex Pharmaceuticals

Materials for slides provided by:

▪ Nivalis Therapeutics, Inc., Savara Pharmaceuticals

LLC

Consensus Guidelines

NACFC

PROSPECT

GOAL

Mental Health Task Force

National Cystic Fibrosis Research Foundation Founded By Parents - 1955

4

What We Learned from Plenary I ▪ The importance of therapies directed toward specific

CF gene mutations

▪ Assessing individual responses to therapy

▪ The need for effective therapies regardless of the CF gene mutation

▪ How to begin thinking about the application of personalized therapy to CF care

▪ Using new measurements and new tools for improving adherence and engagement

Pathophysiology of Cystic Fibrosis

CFTR Modulators

Mucus Obstruction

Infection

Inflammation

Scarring

CFTR gene defect

Abnormal CFTR protein

Defective ion transport

Airway surface liquid depletion

Delayed Mucociliary clearance

CFTR Modulators

Cycle of Destruction

End Stage Lung Disease

N91115: a GSNOR inhibitor (S-nitrosoglutathione reductase inhibitor)

▪ Orally bioavailable agent

▪ Increases S-nitrosoglutathione (GSNO) concentrations

▪ GSNO has a key role in modulating protein function

▪ May act as a new type of CFTR modulator

▪ Multiple potential sites of action

N91115 Affects CFTR Stability in F508del

Addition of N91115 to potentiator + corrector approach could improve patient outcomes Slide courtesy of Nivalis

Phase 1b Study of N91115

▪ Double-blind, randomized, placebo-controlled trial

▪ 51 total patients recruited at 19 TDN clinical sites

▪ Doses: 50, 100, 200 mg twice a day as monotherapy

▪ 28 days tx, followed by 2 week withdrawal & follow-up

▪ Primary endpoints – safety, pharmacokinetics

▪ Exploratory endpoints – Lung function, sweat chloride, inflammatory biomarkers

Phase 1b Study Conclusions

Good safety profile

N91115 was well-tolerated at all doses for 28 days

Sweat chloride response consistent with a “threshold dose effect”

• S. Donaldson: W14 Early Studies of Novel Small Molecule Therapies: Phase 1b study- N91115, a Stabilizer that Modulates CFTR Activity: From Bench to Bedside. Fri. Oct. 9th, 3:30 PM

• Poster #250: J. Taylor-Cousar: The Pharmacokinetics of N91115, an Inhibitor of S-Nitrosoglutathione Reductase, in Cystic Fibrosis Patients

• Poster #270: S Donaldson: Safety and Pharmacokinetics of N91115 In Patients with Cystic Fibrosis Homozygous for the F508del-CFTR Mutation.

Plans for N91115 Phase 2 Study

N91115 added to Orkambi® in adults homozygous for F508del

▪ Double-blind, randomized, placebo controlled, parallel group trial ▪ 3 treatment arms (45 patients each)

▪ Primary endpoint ▪ Absolute change in percent predicted FEV1

▪ Study Duration ▪ 12 weeks followed by 4-week follow-up period

▪ Study Start ▪ First Patient First Visit targeted for late 2015

▪ As we bring approved therapies to younger age groups how do we show efficacy?

▪ How do you test the efficacy of a therapy in patients with normal lung function?

Improving Pediatric Therapy

Multiple Breath Washout and Lung Clearance Index (LCI) ▪ Is it more sensitive than traditional lung function testing?

▪ Can it be used in children? And used in clinical trials?

Yes Yes

LCI reflects the evenness or uniformity of ventilation in the lung Higher number means worse lung function

Subbarao, et al, Annals ATS, 215

Longitudinal Study of LCI ▪ Exciting results regarding MBW/LCI in children, from an NIH multicenter

trial led by Dr. Felix Ratjen, Toronto ▪ Feasibility of testing young children ▪ Performance or stability over time ▪ Impact of Pulmonary Exacerbations

▪ Critical information for use in clinical trials

▪ Use clinically to assess lung function

▪ Results presented at: ▪ F. Ratjen: Symposium 10.3, Friday 11:30 ▪ Posters:

▪ R. Jensen: Poster 191: Progression and Variability of LCI in Preschool Children with CF

▪ H Webster: Poster 242: Utility of the LCI to Monitor Pulmonary Exacerbations in Young Children with CF

▪ Symposium 20 - Pro-Con Debate, Saturday 2:30, discuss use of MBW/LCI

• VX14-809-109: MBW/LCI selected as primary outcome for efficacy. Ivacaftor/lumacaftor study in younger children with CF, ages 6-11 years

Ivacaftor and LCI outcome

Davies, et al. Lancet Respir Med 2013; 1: 630–38

• Cross-over study (UK, US, Canada) • Ivacaftor vs. placebo for 28 days • FEV1 >90% predicted • G551D mutation • ≥ 6 years age (range 8-43 yr.) • Results:

• Treatment difference -2.16

• FEV1 influenced by large airway flow resistance

• LCI measures evenness of distribution of ventilation—changes in peripheral airways

Saline Hypertonic In Preschoolers (SHIP) Study ▪ Hypertonic saline improves mucociliary clearance in older patients

with CF ▪ ISIS randomized, controlled trial (<6 years), HS did not affect rate of

pulmonary exacerbations (primary endpoint) ▪ In small pilot ISIS sub-study in Toronto (N=27), treatment effect of

HS seen in lung clearance index, driven by effect in preschool age ▪ HS also shown to improve LCI in school age children with CF ▪ SHIP Study (CFFT)

▪ 48 weeks of HS vs isotonic saline ▪ 3 to 6 years old ▪ Primary outcome is LCI by MBW ▪ PIs: S. Davis, F. Ratjen, M. Rosenfeld

16


MRSA Treatment

Mucus Obstruction

Infection

Inflammation

Scarring MRSA Treatment

CFTR gene defect







Up to 50% positive in some centers

25%

2%

MRSA prevalence in CF

Exacerbations treated with IV vancomycin or linezolid

Growing use of suppressive oral anti-MRSA antibiotics

Systemic toxicities and poor lung penetration of IV abx

Emerging use of off-label nebulized vancomycin

Limited Treatment Options for MRSA

Slide courtesy, Savara Pharmaceuticals

20

MRSA is a significant problem for some patients Can it be eradicated when first acquired?

How to manage chronic infection?

STAR-Too Trial

▪ Eradication of newly acquired MRSA

▪ PIs: M. Muhlebach and C. Goss, CFFT funding

▪ Treatment vs. Observation arms

▪ Outcome: presence or absence of MRSA at day 28

▪ Enrolled 45 patients, in 14 centers (86% <18 yrs)

▪ Treated group: 67% MRSA culture negative

▪ Observational group: 13% MRSA culture negative

C. Goss STAR-Too Trial Results: Symposium 11.3, Friday 11:30

STAR-Too Trial

Inhaled Vancomycin Therapy ▪ Need for suppressive therapy for those chronically infected

with MRSA

▪ Similar to suppressive therapy for Pseudomonas ▪ Inhaled tobramycin

▪ Inhaled aztreonam

▪ Inhaled colistin

Illustrations courtesy, Savara Pharmaceuticals

AeroVanc Phase II Study in CF

Screening

• ≥ 12 years old • Persistent

MRSA • FEV1 ≥30%

≤100%

32 mg bid

• 2 capsules bid • 20 on AeroVanc • 20 on placebo • 4 weeks

64 mg bid

• 4 capsules bid • 24 on AeroVanc • 23 on placebo • 4 weeks

Primary Endpoint • MRSA CFU reduction

Secondary Endpoints • FEV1 improvement • Decrease of respiratory symptoms (CFRSD) • Prolonged time to need of other antibiotics

Preparing to start Phase III in 2016 E. Dasenbrook: Symposium 11.4, Friday 11:55 Slide courtesy, Savara Pharma.


Pulmonary Exacerbations

Mucus Obstruction

Infection

Inflammation

Scarring

CFTR gene defect







44%

27%

CFF Patient Registry, 2013

6160 pts

3752 pts

Treating Pulmonary Exacerbations ▪ How do we treat pulmonary exacerbations? ▪ Which antibiotics? ▪ How long do we treat?

▪ What are outcomes and measurements of improvement?

▪ When do we start treatment? ▪ Early? With monitoring at home? ▪ When it’s convenient?

▪ Do we use steroids? ▪ Do we treat at home or in hospital?

Standardized Treatment of Pulmonary Exacerbations (STOP) -pilot, feasibility

▪ Design: Prospective, observational study of patients admitted to hospital for treatment of a pulmonary exacerbation (PEx) with intravenous abx.

▪ Antibiotic, dose and tx duration determined by the treating clinician (not dictated). Treating clinician specified treatment goals at start of therapy.

▪ Inclusion: Patients ≥ 12 years of age, hospitalized for acute PEx, IV abx.

▪ Exclusion: Recent IV antibiotics; pneumotx.; hemoptysis; ABPA, NTM tx

▪ Collected: PFTs, PRO, type and duration of treatment, duration in hospital. Data into the CFF Pt. Registry, over 28 days from time of admit

▪ Primary endpoints: Feasibility and clinical equipoise for future pragmatic interventional studies on the treatment of PEx (modules for CFF Pt. Reg).

PIs: C. Goss, P. Flume, S. Heltshe, D. VanDeVanter, DB Sanders, N. West

STOP Pilot Capture FEV1 and symptoms at key time points during treatment of a PEx to help future trial endpoint selection

Visit 1 2

Day 1 7

4

28

Start Abx

Symptom Diary Completed Daily

Discharge

Variable

3

End of IV Tx

End of Study

Study Visit PFTs

PFTs During Hospitalization (preferably 2-3 Days apart)

N=220 pts, over 1 year at 10 study sites

STOP Study Conclusions STOP-OB achieved its goals, necessary to plan first

interventional study of PEx—STOP 2 Provided data to establish equipoise for intervention

studies in exacerbation Was a critical step for refining outcome measures and

sample size estimates for next study

However, broader community input was needed… Feasibility and buy-in for study design Clinicians Patients and Caregivers

CF Adult and Family Advisor (AFA) group

Physician’s Rank of Key PEx Questions N=102

1 is most important and 5 least

0 10 20 30 40 50 60 70 80 90

Num

ber o

f res

pond

ents

1 2 4 2 5

N=102

Physician's Rank of Key Outcomes 0

100

200

300

FEV1 Symptoms Time to Next *Retreatment in 30 days

Num

ber o

f poi

nts

N=88

By attributing a point value to the responses (1 through 4) and multiplying by the number of response (lower total suggests greater interest)

N=88

Patient & Caregiver’s Goals of Treatment 77% of the patient/caregivers report symptom relief as the primary goal of treatment

0 5

10 15 20 25 30 35 40 45

Recover lung

function

Relief of symptoms

Other Don't know

Perc

ent o

f res

pond

ents

0 10 20 30 40 50 60 70 80 90

Recover lung function

Relief of symptoms to allow return to work or

school

Complete relief of

symptoms

Other

Perc

ent o

f res

pond

ents

However, respondents thought doctor’s primary goal of antibiotic treatment was equally recovery of lost lung function (43%) and relief of symptoms (40%)

Patient and Caregiver Survey Highlights ▪ Willing to participate in such a study

▪ Complete symptom resolution is a high priority

▪ They trust their physicians

▪ Expressed legitimate concerns regarding tx duration, too short or too long

NACFC 2015 Symposium 5, Thurs. Oct 8. Towards Rational Management of Pulmonary Exacerbations: Part III

eICE Trial ▪ Multicenter, randomized, non-blinded trial

▪ Started by Johns Hopkins and Univ. of Washington

▪ Enrollment began October 2011

▪ Expanded to 14 CF-TDN Centers October 2012

▪ Home monitoring (symptoms and spirometry) vs. Standard Care

▪ Hypothesis: Earlier identification of acute pulmonary exacerbation will improve lung function in CF (FEV1)

Did the Home Monitoring Trigger Visits?

▪ Yes ▪ Total no. of alarms in

intervention arm: 524

▪ No. in intervention arm with at least 1 alarm: 97 (72%)

64

32

4

0

10

20

30

40

50

60

70

Acute visit Phone contact No patient contact

Response to alarms

% o

f sub

ject

s w

ith a

t le

ase

1 al

arm

0 10 20 30 40 50 60 70 80

Decreased FEV1 Worsening symptoms

Both decreased FEV1 and worsening symtpoms

Distribution of Types of Alarms

% o

f tot

al a

larm

s

• Did Home Monitoring affect the outcome? • Answer at Workshop 26, Session III

Abstract 402: Saturday 11:25

What Studies are Underway or Starting Soon?

2015 Studies CFTR Modulators:

1. ProQR PQ-010-001

2. Novartis QBW251

3. PTC124124-GD-021 (Ataluren)

4. Bayer BAY 63-2521/17020 (Riociguat)

5. Vertex 661-106 (Homozygous)

6. Vertex 661-107 (Heterozygous)

7. Vertex 661-108 (Residual Function)

8. Vertex 661-109 (Gating Mutation)

9. Vertex 809-109 (Pediatric Efficacy)

10. Vertex 809-106 (Advanced Lung Disease)

11. Nivalis SNO4

12. Nivalis SNO6


▪ QR-010, QBW251, SNO4, SNO 6, Riociguat, Ataluren, Vertex 661 (106, 107, 108, 109), Vertex 809 (106, 109)

Anti-Inflammatories 1. Celtaxsys CTX-443)

2. Corbus JBT-101 (Resunab)


▪ QR-010, QBW251, SNO4, Riociguat, Ataluren, Vertex 661 (106, 107, 108, 109), Vertex 809 (106, 109)

Anti-Inflammatories: ▪ Celtaxsys, JBT-101

Anti-Infectives: 1. OPTIMIZE-IP-12 (TOBI with/without Azithromycin)

2. IGNITE (Gallium)

3. Novoteris Inhaled NO




Anti-Infectives: ▪ OPTIMIZE, IGNITE, Inhaled NO

Restore Airway Surface Liquid: 1. Parion P-1037 CLEAN-CF (ENaC Inhibitor)

2. SHIP (Hypertonic Saline in Preschoolers)\

3. Mannitol





Restore Airway Surface Liquid: ▪ Parion P-1037, SHIP, Mannitol

Nutrition: 1. Anthera SOLUTION (Liprotomase)

2. Alcresta






Nutrition: ▪ Anthera SOLUTION, Alcresta

Observational: 1. PROSPECT 2. TOBI Podhaler 3. GOAL e2 4. Validation of Predictive Sputum Biomarkers 5. Longitudinal MBW/LCI




Anti-Infectives: ▪ Optimize, IGNITE, Inhaled NO


Nutrition: ▪ Anthera SOLUTION, Alcresta

Observational: ▪ PROSPECT, TOBI Podhaler, GOAL e2, Validation of Predictive Sputum

Biomarkers, Longitudinal MBW/LCI

Number of Clinical Research Studies: Starting Up and Total

Growing Demand for Patient Participation

What doors need to be opened to improve access for everyone?

Manage the steadily increasing needs of our clinical research programs, our care centers and our patients

The Role of a Research Network CF Therapeutics Development Network (TDN) est. 1998

▪ Established the same time as the CFF’s Therapeutics Development Program to accelerate the pace of evaluating new therapies in CF

▪ Evolved to develop the highest standards for patient safety, best study design and optimum number of patients needed in a trial--enough for a conclusion, but not more than necessary

▪ Address the safety and optimization of trials with study sponsors

▪ Reflect the research priorities of the CF community

Increasing Capacity

We have a Worldwide Network CF Centers in many continents and countries

▪ North America: Canada and the United States

▪ Australia, New Zealand

▪ Europe: ▪ Clinical Trials Network ▪ ECFS CTN, est. 2008 ▪ Expansion to 43 sites ▪ 15 countries, 17,500 pts

Given this large world-wide network do we have any worries?

▪ 48 TDN sites responded

Survey of Research Teams Barriers to Completing Research

0 = not a barrier 1 2 3 4 5 = most

significant barrier

RC time 8.3% 8.3% 12.5% 20.8% 25.0% 25.0%

Restrictive Protocols 2.1% 8.3% 12.5% 31.3% 29.2% 16.7%

Willingness of patients to participate

6.3% 14.6% 22.9% 27.1% 10.4% 18.8%

Faculty time 17.0% 12.8% 31.9% 23.4% 6.4% 8.5%

>50%

Time to change the perception, end the myth…

Listening to the CF Community Results of a Survey of 760 adults with CF and Parents of Children with CF

Results of Survey with Adults

85% Very Interested

76% Very Interested

Interest in trials of therapies to treat the basic defect of CF, like

ivacaftor combined with other potential drugs

Trials of therapies to treat the serious and chronic problems of

CF, like studies of antibiotics and anti-inflammatories … as well as

treatments to improve nutrition and digestion

Somewhat Somewhat

Not Not

56 N=760

Data from Patients and Parents: With what member of the CF Care

team would you most prefer discussing participation in a clinical

trial?

37%

47%

96%

94%

Non-research CF Physicians

Clinical Nurses

Research Coordinators

Study PI

RC, 16%

Other, 14%

70% prefer discussing CT participation with physician

Data from PIs and RCs: Who at your center talks to patients about clinical trials? (check all that

apply)

Sources of Information

Participating in Clinical Trials

Yes, 15%

No, 78%

Don’t Know, 7%

Have you/your child ever been asked to participate in a clinical

trial? (Among those who have not participated,

n=385) 62%

45%

36%

23%

30%

42%

Someone at my care center usually

approaches me

I ask my care team

I actively research on my own

Participated in Clinical Trial(s)

Hasn't Participated

How do you find out about clinical trials?

Barriers to Participation

Not qualifying Not being asked

Not knowing about them Concern over possible negative side effects

Travel distance to study site Scheduling conflicts

Time commitment involved Not wanting to go off current medications

Not wanting to potentially receive a placebo instead of an active drug

Concern about study procedures Don’t have enough information

Concern over access to trial drug when the trial ends Concern that the study drug isn’t going to work

What are some reasons that you/your child have not or would not participate in a CF clinical trial? (Adults with CF and Parent)

= Main reason you have not participated

Increasing Comfort with Participation

1%

2%

3%

5%

8%

19%

23%

38%

9%

16%

18%

28%

27%

66%

63%

70%

Most

2nd Most

3rd Most

What would make you most comfortable with participating in a CF clinical trial? (Adults with CF and Parents)

Knowing closely monitored, pulled out immediately if negative health effects

Knowing the risks and benefits of participation

Knowing exactly what the trial entails

Discussing trial with CF Care Center team

Knowing that the cost of participation is covered by the study

Hearing about the experiences of others

Knowing it is okay to leave at any time

Knowing family and friends support the decision to participate

► ►

►

Conversations about Clinical Research as Part of Clinic Visits

▪ What to discuss? ▪ What’s the latest news in CF research ▪ Basics about participating in clinical research

▪ Discuss specific trials our patients may ask about ▪ Where’s quick access to the information to answer the questions?

▪ Provide information about specific clinical trials ▪ How do you find out about the trials open or upcoming?

▪ Dual roles of physician talking about clinical care and research

▪ Addressing risk and safety is a HIGH PRIORITY

▪ Inform all physicians on team about research studies ▪ Physician can introduce the trial before the RC talks with them

Dealing with Physician Time Constraints

▪ Increasing demands on clinical productivity

▪ In future, a greater emphasis on outcomes

▪ Benefits of CF quality improvement programs for clinical care

▪ Apply the same approach to including discussions about CF research ▪ Address recent research accomplishments, put them into context

▪ Our patients want to know, “What does the result mean?”

▪ Answer questions about participating in research studies

▪ We need more tools to enhance our efficiency when talking about research

Improving Web Tools

Clinical Team Outreach

Find on CFF.org

Clinical Trial Educational Material

To order email: [email protected]

mailto:[email protected]

Current and Future Resources for Centers

▪ Update and expand resources for CF care centers ▪ New educational and awareness material ▪ Resources on safety and DSMB role in clinical trials ▪ Send ongoing clinical trial spreadsheet to all centers

▪ Send out patient list for specific trials ▪ Plan system changes to improve access to

information about trials ▪ Would be patient-specific ▪ Accessible through a secure link for clinicians

No CF Center can offer every research study to their patients

How to Share

Referral Resources for Clinicians, Care Teams ▪ Research centers have tools to help structure the referral

of patients to other centers for research studies. ▪ Seamless integration of clinical care and research ▪ Good communication and coordination

▪ Development of regional collaborations among Centers

▪ Support for Referrals ▪ Compensation for the extra work required to provide records,

coordinate visits and communication ▪ Clinical Research Referral Support Program-CRRSP

▪ Will be discussed at Center Directors’ Meeting on Saturday ▪ Details to follow after NACFC

2015 2014 2013 2012

2011 2009 2008

”There’s a cure, you know. They just haven’t found it yet.” -Wells Clark (2007)

- Parent of a child with CF

Change is happening now

“We don’t have time to waste.”

opening doors to cf clinical research: change is coming · 2017-05-18 · , 3:30 pm • poster...

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