Inhaled prostacyclins-usefulness and practility

Usefulness and Practicality

Sarfraz Saleemi MDKing Faisal Specialist Hospital & Research Center

Pulmonary hypertension - historical perspective

• Ibn Nafees – described pulmonary circulation in ~1250

• Dresdale et al, 1951

– Reported three patients with unexplained pulmonary hypertension

– Clinical, hemodynamic, and pathological features

– Coined the term Primary Pulmonary Hypertension (PPH )

– First attempt at treatment using tolazoline(Priscoline), an adrenergic inhibitor

Dresdale, Am J Med, 1951Dresdale, Bull NY Acad Med, 1954

Humbert M et al. N Engl J Med. 2004;351:1425-1436.

Targets for current PAH-specific therapy

Big Endothelin

Endothelin-converting

Enzyme

EndothelinReceptor A

EndothelinReceptor B

Vasoconstrictionand

Proliferation

EndothelinReceptor

Antagonists

Endothelin-1

Endothelin Pathway

Arginine

Nitric OxideSynthase

Vasodilatationand

Antiproliferation

Nitric Oxide

cGMP ExogenousNitric Oxide

Phosphodiesterase Type-5

PhosphodiesteraseType-5 Inhibitors

Nitric Oxide Pathway

Arachidonic Acid

ProstacyclinSynthase

Vasodilatationand

Antiproliferation

Prostacyclin

cAMP

ProstacyclinDerivatives

ProstacyclinDerivatives

Prostacyclin Pathway

Group 1 PAH

<1995 1995 2001 2002 2004 2005 2007 2009 2013

CCBAnticoagulationDigitalisDiuretics

IV Epoprostenol

Bosentan

SC Treprostenol

IV Treprostenol

Inhaled Iloprost

Sildenafil

Ambrisartan

Tadalafil

Inhaled Treprostinil

Macitentan

Riociguat

Pulmonary Hypertension Treatment Timeline

IV Sildenafil

Dysregulated prostacyclin pathwayin pulmonary hypertension

Voltage gatedK+ channel

Reduced prostacyclin synthase in PH

Tuder et al. Am J Respir Crit Care Med 1999,159:1925

Pharmacological targets of prostacyclin

ArteriesSmooth muscle cells

FibroblastsEndothelial cells

LeucocytesMonocytes, macrophages,polymorphonuclear cells,

T cells

Platelets

Gomberg-Maitland M, Olschewski H. Eur Respir J 2008;31:891–901.

VasodilatationAnti-

inflammation

MAPK

iNOS Matrix secretion

Anti-proliferation

Anti-coagulation

Prostacyclin

Anti-inflammatory/Anti-proliferative

Prostacyclins for PH

Prostacyclin Approved

IV Epoprostenol iPAH, PAH-CTD (USA, Canada) 1995PAH (EU) 1996

Inhaled Iloprost PAH (USA) 2004iPAH (EU)

IV Iloprost iPAH, PAH-CTD, CTEPH (New Zealand)

SC Treprostenol PAH (USA, Canada) 2002iPAH (EU)

IV Treprostenol PAH (USA, Canada) 2004

Inhaled Treprostenol PAH (USA) 2009

Beraprost oral PAH (Japan, Korea)

Treprostinil oral – resubmitted for approval in Sep 2013

awaiting response in March 2014

Epoprostenol- Discovered in 1976 by the Nobel Prize-winning team of John Vane

Inhaled Prostacyclins –selective action

muscular

Partly muscular

Partly intermediate

intermediate

Pericyte level

0.5–3 μm

1. Olschewski H et al. Ann Intern Med 1996;124:820–24; 2. Olschewski H et al. Chest 2003;124:1294–304;

3. Bayer Pharma AG. Ventavis (inhaled iloprost) summary of product characteristics, 2012.

Inhaled iloprost

3

4

5

50

75

CO

(L

/min

)PA

P

(mm

Hg)

MA

P

(mm

Hg)

0 30 60 90

Minutes

MAP

PAP

CO

120

80

2.8 μg of iloprost over 15-minute

inhaled Prostacyclin: selective action

inhaled Prostacyclin: selective action

No significant V/Q mismatchSelectively dilates pulmonary arteries vs systemic arteriesSelectively dilates arteries in well-ventilated vs poorly ventilated areas

. 1. Ghofrani HA. Nat Rev Drug Discov 2006;5:689–702

2. Krug S et al. Vasc Health Risk Manag 2009;5:465–74 3. Olschewski H et al. Ann Intern Med 1996;124:820–4

Normal lung: V/Q matching PH lung: V/Q mismatch

Blood flow

Efficient oxygenation

Blood flow

Poor oxygenation

Chest 2003;124;1294-1304

inhaled Prostacyclin: selective action

FDA approved inhaled Prostacyclins

Iloprost

Treprostinil

ACCF/AHA Consensus PAH Treatment Algorithm

McLaughlin VV et al. J Am Coll Cardiol. 2009;53:1573-1619.

Atrial septostomyLung transplant

Reassess – considercombo-therapy

ERAs or PDE-5 Is (oral)

Epoprostenol or Treprostinil (IV)

Iloprost (inhaled)

Treprostinil (SC)

No

Anticoagulate ± Diuretics ± Oxygen ± Digoxin

Sustained Response

Positive

Oral CCB

Continue CCB

Yes

Negative

Lower Risk

Epoprostenol or Treprostinil IV

Iloprost (inhaled)ERAs or PDE-5 Is (oral)

Treprostinil (SC)

Higher Risk

Investigational Protocols

Acute Vasoreactivity Testing

Inhaled Iloprost

• Iloprost is a carbacyclin analog of prostacyclin• Plasma half-life of 20-30 min • Dose 2.5-5 μg 6-9 times • Aerosolized particles (median diameter 0.5–3 μm)

Apprved Nebulizer Devices for Iloprost

Halolite prodose I-NEB Venta-NEB

Inhaled iloprost

Compact, portable, lightweight, hand-held nebulizerRuns on 2 AA batteries, Accurate, Quiet.Vibrating Mesh Technology.Continuous Delivery system.

Omron- MicroAir- NE-U22VThe I-neb™ AAD® system

• Compact, portable, lightweight, hand-held nebulizer

• Delivers precise individualized dosing with continuous monitoring and adjustment

Inhaled iloprost – Dose adjustment

Dose per inhalation session: 2.5 µg or 5 µg

Frequency of dosing?

Bayer Pharma AG. Ventavis (inhaled iloprost) summary of product characteristics, 2012.

Initiateinhaled iloprost

2.5 µg dose

Uptitrateinhaled iloprost

5 µg dose

Well tolerated?

Well tolerated?

Poorlytolerated?

Maintain 5 µg

Downtitrate: 2.5 µg

6–9 inhalations per day

According to individual need and tolerability

Idiopathic Pulmonary Arterial Hypertension and Inhaled Iloprost: Good Night Rebound Effects?

Duration of action (30–120 min)

??Risk of rebound pulmonary hypertension (RPH) at night during treatment free period.

5 IPAH patients (NYHA III) on chronic iloprost treatment .

Hemodynamics by a Swan-Ganzcatheter during day and night

No significant RPH during the

off-medication time at night

PAP and PVR did not exceed the maximal day time values.

Respiration 2007;74:498–502

Lack of desensitization

• Inhaled iloprost avoids continuous receptor activation and desensitization of acute vasodilatation response does not occur

• Acute hemodynamic response is maintained for many months

1. Schermuly RT et al. Respir Res 2007;8:4;2. 2. Nilius SM et al. FEBS Lett 2000;484:211–16;

3. Olschewski H et al. Intensive Care Med 1998;24:631–4.

Pre-inhalationPost-inhalation

0

mP

AP

(m

mH

g)

1

20

40

180

Day

60

3600

PV

R (

dyn

•s•

cm

-5)

1

500

1500

180

Day

2000

360

1000

2500

Overview of published clinical studies

1. Olschewski H et al. N Engl J Med 2002;347:322–9; 2. Olschewski H et al. Respir Med 2010;104:731–40; 3. Hoeper MM et al. N Engl J Med 2000;342:1866–70; 4. McLaughlin VV et al. Am J Respir Crit Care Med 2006;174:1257–63; 5. Ghofrani HA et al. Ann Intern Med 2002;136:515–22; 6. Ghofrani HA et al. J Am Coll Cardiol 2003;42:158–64.

Study name Patients Duration Key result

Monotherapy

AIR FC III/IV (n=203)

12 weeksSignificant treatment benefit with

iloprost in patients with severe PAH

AIR-2 FC II/III/IV (n=63)

2 yearsSustained inhaled iloprost improves

predicted 2 year survival

Long-term3 FC III/IV (n=24)

1 year Clinical benefits of inhaled iloprost are sustained over 1 year of therapy

Combination therapy

STEP (bosentan + iloprost)

FC II/III/IV (n=67)

12 weeks Inhaled iloprost + bosentan is well tolerated and effective

Acute iloprost + sildenafil

FC III/IV (n=30)

Acute dose Inhaled iloprost + sildenafil acts synergistically to induce

strong pulmonary vasodilation

Iloprost + sildenafil

FC III/IV (n=14)

1 year Inhaled iloprost + sildenafil improves outcomes in patients with severe PAH

-40

-20

0

20

40

1 2 3 4

Inhaled

Iloprost

Placebo

AIR study

Olschewski H et al. N Engl J Med 2002;347:322–9.

Improvement in 6MWD

Mean

ch

an

ge in

dis

tan

ce w

alk

ed

(m

)

Baseline Week 4 Week 8 Week 12

• In IPAH patients on inhaled iloprost, average increase in 6MWD was 58.8 m longer than for placebo-treated patients

Δ6MWD =36 mp=0.004

STEP study

Inhalediloprost

50

25

Mean

ch

an

ge i

n

dis

tan

ce w

alk

ed

(m

)

Baseline

Week 4

Week 8

Week 12

Placebo0

-25

Δ6MWD =26 mp=0.051

McLaughlin VV et al. Am J Respir Crit Care Med 2006;174:1257–63.

(Bosentan + inhaled iloprost)

AIR study: Aerosilized Iloprost Randomized study

Olschewski H et al. N Engl J Med 2002;347:322–9.

Combined primary endpoint:• Improvement by ≥1 NYHA FC • ≥10% improvement in 6MWD • no deterioration or death

0

5

10

15

20

Inhaled Iloprost

Pati

en

ts (

%)

Placebo

5%

p=0.007

17%

Significant improvement in the combined primary endpoint with inhaled iloprost vs placebo

Efficacy (time to clinical worsening)

• No patients receiving bosentan + inhaled iloprost experienced clinical worsening, compared with 15% of patients receiving bosentan + placebo (p=0.02)

McLaughlin VV et al. Am J Respir Crit Care Med 2006;174:1257–63.

Bosentan + inhaled iloprost1.00

0.75

0.50

0.25

0.00

Wit

ho

ut

cli

nic

al

dete

rio

rati

on

(p

ercen

tag

e o

f p

ati

en

ts)

Bosentan + placebo

Baseline Week 4 Week 8 Week 12

Clinical worsening defined as: death due to PAH, worsening PAH leading to hospitalization or early elimination from the study, necessary additional PAH-specific therapy, lung transplant or atrial septostomy

STEP study

STEP open-label extension: Clinical worsening

• A 3-month delay in adding prostacyclin therapy may negatively affect the clinical result

Olschewski H et al. Eur Resp Rev 2009;18:29–34.

Placebo+ Inhaled iloprost

Bosentan

0 3 6 9 12

Inhaled iloprost

Bosentan

43%

23%

Patients withclinical worseningafter one year

Patients withclinical worseningafter one year

Months

Addition of sildenafil to inhaled iloprost further increased exercise capacity

inhaled iloprost+ oral sildenafil

sil-ilo9-12 mo

treatment interval18 + 4 months

sil-ilo6 mo

sil-ilo3 mo

pre-sililo3 mo

Baseline

180

200

220

240

260

280

300

320

340

360

380

400

6-m

inu

te w

alk

dis

tan

ce (

m)

p=0.002p=0.014

p=0.002+

++

Ghofrani HA et al. J Am Coll Cardiol 2003;42:158–64.

• Inhaled iloprost alone and oral sildenafil alone showed similar efficacy (pulmonary vasodilatory potency)

• Inhaled iloprost and oral sildenafil together acted synergistically to cause strong pulmonary vasodilatation

Acute use study (sildenafil + inhaled iloprost): Hemodynamic outcomes

Ghofrani HA et al. Ann Intern Med 2002;136:515–22.

PVR

(% c

hange f

rom

baseline)

60

NO Iloprost Sildenafil 50 mg

0 60 0 120

-30

-20

-10

0

-50

-40

Time (min)

n = 8

180

NO

0 60 0 60 120

Time (min)

n = 8

Iloprost Sildenafil 50 mg

Iloprost

Inhaled Iloprost in acute right heart failure due to PAH

Age (y) 72 59 52 65 55 48 63

Baseline PH therapy

SC treprostinil

Bosentan SC treprostinil

SC treprostinil

SC treprostinil

Sitaxentan Sitaxentan

NT-proBNP

9,690 10,636 9,340 8,964 1,265 20,239 35,000

J Card Fail. 2011 October; 17(10): 813–818

(7 patients) Hourly inhaled iloprost for 12 hours

Open-label extension of the AIR study – 71 patients

NYHA FC improved in 41% at 1 year & 76% at 3 year

Survival rate:

83% at 1 yr

78% at 2 yrs

58% at 5 yrs (Estimated survival without treatment 32%)

www.clinicalstudyresults.org/ drugdetails/?company_id573&indication_id5854&sort5c.company_name&page51&drug_id52423 December 16, 2008

Long term efficacy of IloprostSurvival

Transition from Parenteral prostacyclin toinhaled Iloprost (n=37)

Pulmonary circulation April-Iune 2013

iloprost is not approved for use in childrenData on its use in the pediatric PAH population is limited.

22 children median age 11.5 years (range, 4.5–17 i PAH & PAH-CHD19 On background PAH-specific therapyDuration 6 months WHO FC improved in 35% , decreased in 15% and unchanged in 50% Bronchopasm and compliance issue were major limitations

Ivy et al. (2008)

.

A review of 28 studies (most case series) 195 childrenInhaled iloprost has acute effects similar to those of inhaled NO and might have a role in the short-term treatment of pediatric PH, including neonates.This application of inhaled Iloprost is useful especially in countries where inhaled NO is not available

Mulligan and Beghetti,2011

Inhaled Iloprost in Children

Cost effectiveness of inhaled Iloprost (3 year analysis)

Appl Health Econ Health Policy 2012; 10 (3): 175-188

Inhaled Treprostinil (Tyvaso)Administered 4 times daily with Optineb

Maximum 9 breaths 4 times a day

Each breath 6 microgram

1 ampule of inhaled treprostinil enough for the day

whether 3 breaths or 9 breaths 4 times a day.

Discard the remaining dose after last dose of the day

Needs washing of optineb accessories everyday.

%

0

3.0

5.0

10

TRIUMPH[TReprostinil sodium Inhalation Used in the Management of Pulmonary Hypertension]

• 6-minute walk distance (6MWD) ↑ in treprostinil vs. placebo at 12 weeks (21.6 vs. 3.0 m, p = 0.0004); noted as early as 6 weeks (p = 0.0001)

• No difference in Borg dyspnea score, NYHA class, PAH signs and symptoms (p = NS)

• Clinical worsening similar (3% vs. 5%, p = NS)

Trial design: Patients with pulmonary arterial hypertension (PAH) who were symptomatic on bosentan or sildenafil were randomized to either inhaled treprostinil or placebo. Clinical outcomes were assessed at 12 weeks.

Results

Conclusions

•Inhaled treprostinil was associated with improved 6MWD as compared with placebo in symptomatic patients with PAH already on bosentan or sildenafil

McLaughlin W, et al. J Am Coll Cardiol 2010;55:1915-22

Treprostinil(n = 115)

Placebo(n = 120)

(p = NS)

15

30

21.6

3.0

m

06MWD Clinical worsening

5

(p = 0.0004)

Rapid transition from Inhaled Iloprost to Inhaled Treprostinil (n-73)

Cardiovascular Therapeutics 31 (1), 38-44 (Feb 2013)

Treatment satisfaction is associated with improved quality of life in patients transitioned to inhaled treprostinil from iloprost

Chen et al. Health and Quality of Life Outcomes 2013, 11:31http://www.hqlo.com/content/11/1/31

66 subjects with PAH in a single-arm, open-labelMulticenter trial of iTRE following transition from iILO

Treatment Satisfaction Questionnaire for Medication (TSQM)

MDI-Treprostenol vs Nebulized

Pulmonary Pharmacology & Therapeutics 22 (2009) 50–56

39 consecutive patients with moderate to severe PAH were enrolled in anopen label, placebo controlled trial

Treatment of inhaled Treprostinil induced cough

Inhaled anticholinergic

Inhaled steroids

Oral phenol-based analgesic sprays (eg,Chlorasept)

Drinking very cold or warm water before a treatment

Reducing number of breaths per treatment

• Cough

• Flushing

• Headache

• Trismus

• Insomnia

• Nausea

Side Effects of inahled Prostacyclin

• Hypersensitivity to the drug

• Patients with an increased risk of hemorrhage

• Severe IHD or unstable angina

• Myocardial infarction within the last 6 months

• CVA (TIA or stroke) in the previous 3 months

• Veno-occlusive disease

Relative contraindications to inhaled prostacyclins

Summary

• Inhaled Prostacyclin is an effective treatment of pulmonary arterial hypertension

• Inhaled Prostacyclin causes rapid improvement of pulmonary hemodynamic which is maintained even after long duration due to lack of desensitization

• Inhaled Prostacyclin causes vasodilatation of the well ventilated parts of lung so results in better oxygenation

• Few systemic adverse effects due to selective action • Avoids infection and localized site pain of parenteral

therapy • No involvement of CYP450 so minimal potential for

interaction with drugs metabolized by the liver• Frequent dosaging and preparation time is a major

disadvantage • Cough and facial flushing are the commonest side effects

Thanks

43