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INSPIRE: A Phase 3 Open-Label, Multicenter Study to Evaluate the Safety and Tolerability of LIQ861 in Pulmonary Arterial Hypertension (PAH)

N. S. Hill; J. P. Feldman; S. Sahay; D. J. Levine; R. F. Roscigno; T. A. Vaughn; T. M. Bull

Presenter: N.S. Hill

April 3, 2019

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Relevant financial relationship disclosure statement

• INSPIRE: A Phase 3 Open-Label, Multicenter Study to Evaluate the Safety and Tolerability of LIQ861 in Pulmonary Arterial Hypertension (PAH)

– Presenter: N.S Hill, MD– I will discuss investigational use of the following drugs/devices: LIQ861 Dry Powder Inhalation of Treprostinil

• The following relevant financial relationships exist related to this presentation:

– N. S. Hill: Consultant - Liquidia Technologies Grant/Research Support Institution - Actelion, Bayer, Gilead, Liquidia Technologies, Reata, United

Therapeutics Scientific Medical Advisor - Liquidia Technologies

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PAH is a rare, progressive disease that results in right heart failureMultiple pathways are involved in pathogenesis

Source: Channick Advances in Pulmonary Hypertension Spring, 2002

• Abnormal changes in arteries of the lungs increase pressure in pulmonary arteries that leads to remodeling of the right ventricle

• Prostacyclin is essential to normal lung function– Continually released by lungs to bind local receptors

– Vasodilates the pulmonary arteries – Relaxes smooth muscle

– Inhibits platelet aggregation

• Goal of prostacyclin therapy is to maximize a patient’s exposure to the highest tolerable level of drug

ProstacyclinDeficiency Prostacyclin

Analogs

PAH Patient PAH Treatment

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Current prostacyclin-based products have clear tradeoffs

Source: Decision Resources, Pulmonary Hypertension Disease landscape & Forecast, November 2018; Recent advances in targeting the prostacyclin pathway in pulmonary arterial hypertension, November 2015

Infusion = (Continuous IV or SubQ) Effective, but…systemic toxicities & site pain, limitations on lifestyle

– Poses potential for risk of infection

Oral = Convenient, but… toxicities and limited symptom relief – Increased GI side effects

– Up-titration can be challenging given side effects

Nebulized = Local delivery, but… provides limited dose range – Due to throat, airway irritation, cough

– Inconvenient; requires assembly, cleaning and time to dose

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LIQ861 Dry Powder Formulation

LIQ861 particles are between 1-2 µm wide with trefoil shape

RS00 Model 8 Dry Powder Inhaler

Compact, disposable inhaler previously approvedby FDA and EMEA to be used in asthma products

LIQ861 applies PRINT® technology to treprostinil using proven DPI deviceUniform particles within the respirable range (<5.0 microns)

Source: Liquidia Technologies data on file

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Phase 1 pharmacokinetics

Sources: Ph 1 study design: 57 subjects enrolled; 43 on LIQ861, 14 on placebo; each cohort = 8 subjects in 3:1 ratio (LIQ861:placebo) – randomized, placebo-controlled; Royal M, Roscigno R, et al. Preclinical and Phase 1 Clinical Characterization of LIQ861, a New Dry Powder Formulation of Treprostinil [poster]. In: PVRI Annual World Congress; 2018 January 21-24; Singapore, Asia.

• n=57 healthy volunteers

• Single, ascending dose

• Dose proportional response

• No dose-limiting toxicities up to 150 mcg

LIQ861 Mean Concentration Over Time

Approx. Capsule (TRE fill wt.)Approx. Emitted Dose (mcg) 20 40 60 80 100 120

Breaths 1-2 1-2 1-2 1-2 2-4 2-4

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Phase 3: INSPIRE Study Design

Sources: https://clinicaltrials.gov/ct2/show/NCT03399604; PGI – prostacyclin; TEAEs – treatment-emergent adverse events; SAEs – serious adverse eventsTyvaso® is a registered trademark of United Therapeutics Corp.

WHO Group I (PAH)NYHA Class II, III and IV N > 100

Treatment phase forPrimary Endpoint Continued treatment up to 30 months

Add-On LIQ861<2 non-PGI oral PAH Rx

• Initiate 25 mcg capsule strength dose• Increase in 25 mcg increments weekly to tolerance and symptom relief

Tyvaso® TransitionsStable Doses > 3 mo.

• Initiate with comparable dose of LIQ861• Titrate in 25 mcg incremental doses to tolerance and symptom relief

Primary Endpoint • Incidence of TEAEs and SAEs at 2 months

Exploratory Endpoints • Sustained use after transition (Tyvaso® transitions)• 6 minute walk distance• NT proBNP• NYHA functional class• Quality of life questionnaire / Patient satisfaction with LIQ861

Day 0 Week 2 Month 1 Month 2 Month 4

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Summary of Demographics and Baseline Characteristics

No. Subjects (% of Study) at 2-month timepoint

LIQ861 Add-Ons(N=65)

Transitions(N=44)

Overall (N=109)

SexFemale 51 (78.5%) 39 (88.6%) 90 (82.6%)

Male 14 (21.5%) 5 (11.4%) 19 (17.4%)

Age at Screening (years) Mean ± SD 55 ± 14.7 54 ± 12.6 55 ± 13.9

BMI (kg/m²) Mean ± SD 29.5 ± 7.8 29.3 ± 7.5 29.4 ± 7.7

NYHA FunctionalClass at Screening

Class II 36 (55.4%) 36 (81.8%) 72 (66.1%)

Class III 29 (44.6%) 8 (18.2%) 37 (33.9%)

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Most patients remained on LIQ861 through 2-months of treatment

Sustained Therapy at 2 MonthsLIQ861

Add-onsTyvaso

Transitions Overall

Total Patients Started 65 44 109

Withdrawn < 2 Months 6 2 8

Sustained at 2 Months 59 42 101

% Patients Sustained 90.8% 95.5% 92.7%

• Patients withdrew due to: Adverse Events, Patient Choice, Investigator Decision, Lost to Follow Up

Preliminary data

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15 Serious Adverse Events (SAEs) unrelated to LIQ861

Injury

Nervous System disorders

• Fracture lower leg

• Possible seizure• Syncope

Respiratory, Thoracic and Mediastinal disorders

Infections

• Acute pulmonary embolism• Shortness of breath

• Parainfluenza virus• Viral illness• Sepsis• Hospital acquired pneumonia

Vascular disorders

• Hypertensive urgency• Fluid overload

Gastrointestinal disorders

• Gastrointestinal bleed

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Treatment Emergent Adverse Events (TEAEs) observed were consistent with inhaled prostacyclins and mild to moderate in severity

TEAEs at Month 2in ≥ 4% of Patients Receiving LIQ861

LIQ861 Add-ons Tyvaso Transitions Overall

No. (%)Subjects

No. of EventsNo. (%)Subjects

No. of EventsNo. (%)Subjects

No. of Events

Mld Mod Sev Mld Mod Sev Mld Mod Sev

Cough 30 (46.2%) 25 5 0 6 (13.6%) 5 1 0 36 (33.0%) 30 6 0Headache 11 (16.9%) 9 4 0 9 (20.5%) 8 2 0 20 (18.3%) 17 6 0Throat irritation 11 (16.9%) 12 2 0 4 (9.1%) 4 0 0 15 (13.8%) 16 2 0Dizziness 7 (10.8%) 7 0 0 4 (9.1%) 3 1 0 11 (10.1%) 10 1 0Diarrhoea 7 (10.8%) 5 2 0 2 (4.5%) 1 1 0 9 (8.3%) 6 3 0Oropharyngeal pain 5 (7.7%) 5 0 0 1 (2.3%) 1 0 0 6 (5.5%) 6 0 0Nausea 4 (6.2%) 3 1 0 2 (4.5%) 1 1 0 6 (5.5%) 4 2 0Dyspnea 3 (4.6%) 2 1 0 3 (6.8%) 3 1 0 6 (5.5%) 5 2 0Flushing 5 (7.7%) 5 0 0 1 (2.3%) 1 0 0 6 (5.5%) 6 0 0Chest discomfort 4 (6.2%) 3 1 0 1 (2.3%) 0 1 0 5 (4.6%) 3 2 0

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TEAEs are those expected with prostacyclin therapy

- 10 20 30 40

Cough

Throat irritation

Oropharyngeal pain

Chest discomfort

Headache

Nausea

Flushing

Diarrhea

Dizziness

Dyspnea

Patients

Pts w/ TEAESat 2-Months

Pts w/ TEAESat 2-weeks

Transition Patients (n=44)

- 10 20 30 40 50 60

Cough

Throat irritation

Oropharyngeal pain

Chest discomfort

Headache

Nausea

Flushing

Diarrhea

Dizziness

Dyspnea

Patients

Pts w/ TEAESat 2-Months

Pts w/ TEAESat 2-weeks

Add-On Patients (n=65)

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LIQ861 maintained 6MWD in Add-on and Transition PatientsSix Minute Walk Distance

• 4 months would be minimum time required to fully assess

Median6MWDmetersMax

Min

Median395 403 415 408

0

200

400

600

800

Baselinen=63

Week 2n=61

Month 1n=60

Month 2n=57

Add-On Patients

428 414 437 449

0

200

400

600

800

Baselinen=44

Week 2n=44

Month 1n=44

Month 2n=37

Transition Patients

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All domains from MLHFQ improved at 2 monthsMinnesota Living With Heart Failure Questionnaire (MLHFQ)

Note: A decrease in MLHFQ score is considered an improvement; http://license.umn.edu/technologies/94019_minnesota-living-with-heart-failure-questionnaire-mlhfq

MedianScore

37

3034

29

19

24

0

5

10

15

20

25

30

35

40

Add-On Patientsn=63, n=59

Transition Ptsn=44, n=40

All Patientsn=107, n=99

Overall Score (Day 1) Overall Score (Month 2)

• MLHFQ is a patient-oriented measure of the adverse effects of heart failure on a patient’s physical and emotional aspects of life

• A five (5) point change is the minimal clinically important difference

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LIQ861 met primary endpoint in pivotal Phase 3 INSPIRE studyA convenient, safe, well tolerated option for inhaled prostacyclin therapy

Serious Adverse Events (SAEs); Treatment Emergent Adverse Events (TEAEs)

• No study drug-related SAEs

• TEAEs expected and mostly mild in nature

• Most TEAEs occurred during first 2-weeks

• 93% of patients completed 2 months

• 6MWD maintained for at least 2 mos

• MLWHF Questionnaire registered improvements in both physical and emotional domains

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Liquidia Technologies would like to thank our Patients and Principal Investigators

*INSPIRE Steering Committee