New TLD Indication: Asthma RELIEF-1 Study Nick ten Hacken, MD Study Co-Principal Investigator

The Burden of Asthma

WW Adult Asthma Prevalence

230.5 Million

Mild/Intermittent 161.9 Million

(70%)

Moderate 39.2 Million

(17%)

Severe Refractory 11.5 Million

(5%)

Severe less refractory

17.9 Million (8%)

•  Asthma control is suboptimal and prevalence is increasing worldwide •  80% of costs are driven by 20% of asthma population •  WW 250,000 lives lost annually

Sources: Global asthma prevalence in adults: world health survey. BMC Public Health 2012, 12:204; Global burden of asthma: GINA report. Allergy 2004: 59:469-478; Costs of asthma in the United States: 2002-2007. J Allergy Clin Immunol 2011 Jan; 127(1):145-52; The Global Asthma Report 2011, ISAAC; Global Asthma Network 2014; AAAAI Asthma Statistics. 2017.

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Is TLD also Effective in Asthma?

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Targeted •  Anatomically to only the lung •  To a depth where the nerves are

located

Denervation •  Disrupt parasympathetic nerves to

decrease release of acetylcholine Lung •  Decrease smooth muscle tone •  Decrease mucus production

Is TLD also Effective in Asthma? •  Asthma and COPD are “look a

likes” (Dutch hypothesis) -  Both have increased cholinergic tone -  Suggestions of a cholinergic

phenotype •  Surgical vagotomy improves airway

obstruction in severe asthma •  Anticholinergic inhalers reduce airway

obstruction and protect against a specific stimuli in asthma

•  LAMA reduces inflammation and remodeling in animal studies…….

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Liccardi, Respir Med 2016; 117: 150-153 5

Growing Role of LAMAs in Asthma

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Kerstjens, JACI 2011; 128: 308-14

Tiotropium on top of corticosteroids + LABA

Impact of LAMAs in severe Asthma

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Tiotropium on top of corticosteroids + LABA

Rodrigo, Chest 2015; 147: 388-96

Impact of LAMAs in Severe Asthma

Tiotropium on top of corticosteroids + LABA (PEF)

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Impact of LAMAs on Severe Asthma

Kerstjens, NEJM 2012;367:1198-207

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Tiotropium on top of corticosteroids + LABA

GINA Adds Tiotropium as “Other Controller Option”

Other controller

options

RELIEVER

STEP 1 STEP 2 STEP 3 STEP 4

STEP 5

Low dose ICS Consider low

dose ICS Leukotriene receptor antagonists (LTRA)

Low dose theophylline* Med/high dose ICS

Low dose ICS+LTRA (or + theoph*)

As-needed short-acting beta2-agonist (SABA)

Low dose ICS/LABA**

Med/high ICS/LABA

PREFERRED CONTROLLER

CHOICE

Refer for add-on

treatment e.g.

tiotropium,*� omalizumab,

mepolizumab*

As-needed SABA or low dose ICS/formoterol#

Add tiotropium*� High dose ICS + LTRA (or + theoph*)

Add low dose OCS

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RELIEF-1 CLINICAL TRIAL

A pRospective, multicenter, single-arm study EvaLuating the safety and feasIbility of Targeted

Lung Denervation (TLD) for the trEatment oF severe asthma

First-in-Human Protocol StudyOverview(NCT#02872298)

Design Prospec3ve,mul3center,single-arm

Objec?ve Evaluatesafety&technicalfeasibilityofTLDinsevereuncontrolledasthma

PrimaryEndpoint Freedomfromdevicerelatedtherapeu3cinterven3ons

MajorSecondaryEndpoints

•  AQLQ&ACQ•  Adverseevents/exacerba3ons•  PeakExpiratoryFlow•  MethacholineChallenge•  Medica3onu3liza3on•  Inflammatorymarkers(brush,wash&biopsy)

Pa?entnumber 30

Follow-up •  3years•  3monthairwayinspec3on/markercollec3on•  1yearCT

PrincipalInves?gators PallavShah,UKNicktenHacken,NL

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Site Hospital Site Principal Investigator

Heidelberg, DE Thoraxklinik Heidelberg Felix Herth

Grenoble, FR CHU de Grenoble Christophe Pison

Groningen, NL University Medical Centre Groningen Nick ten Hacken

Amsterdam, NL Academisch Medisch Centrum (AMC) Peter Bonta

London, UK Royal Brompton & Harefield NHS Trust Pallav Shah

Glasgow, UK Queen Elizabeth University Hospital Steve Bicknell

Nottingham, UK NUH Nottingham City Hospital Dominick Shaw

Southampton, UK Southampton General Hospital Paddy Dennison

Trial Locations

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Study Criteria •  Major Inclusion

!  ≥ 21 to ≤ 65 years old !  Diagnosis of severe asthma as defined by GINA and taking meds !  Post-BD FEV1 ≥ 60% on stable 4 week medication run-in !  At lease 2 days of asthma symptoms during run-in !  Non-smoker for at least 6 months

•  Major Exclusion x  Intensive care for asthma in last 2 years x  ≥ 3 respiratory infections or asthma hospitalizations in last year x  Steroid burst or change in maintenance medications in last 6 weeks x  Prior lung or chest procedure x  Other chronic disorder with asthma-like symptoms

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Projected Study Timeline

2017•  EnrollmentStart

2018•  EnrollmentComplete

•  Earlysafetyanalysis•  Inflammatorymarkerassessment

2019•  Longertermsafetyanalysis

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Thank you