Disclosures United Therapeutics Not approved by the FDA for use - - PowerPoint PPT Presentation

3/11/2017 1

Prostanoids

Stephanie Handler, MD Children’s Hospital of Wisconsin Medical College of Wisconsin

Disclosures

• United Therapeutics
• Not approved by the FDA for use in children

Other Disclosures

• Limited “best practice” data in children
• Treatment decisions based on:

√ Adult PAH data √ Pediatric off-label experience › predominantly retrospective case series √ AHA/ATS Guidelines

Definition

• Prostanoids- subclass of eicosanoids

√ Prostaglandins √ Thromboxanes √ Prostacyclins

• Synthesized from arachidonic acid by cyclooxygenase
• PGH2

Thromboxane Prostacyclin (PGI2)

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Therapy for PAH

Lang I et Gaine S. Eur Respir Rev 2015;24:630-41.

Prostacyclin Pathway

Medications Target Receptors

Epoprostenol

• Approved by FDA in 1995 for FC III/IV PAH
• Rapidly hydrolyzed with very short half life (~3 min)
• Requires continuous intravenous infusion
• Flolan requires ice pack (unstable at room temperature)

√ Newer IV formulation Veletri thermostable

Yung D et al. Circulation 2004;110:660-5.

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Treprostinil

• Remodulin approved by FDA in 2002 (SC) & 2004 (IV)
• Longer half life (~3-4 hours)
• Local site reactions have limited SC delivery in adults but

seems to be better tolerated in children

Ferdman et al. Pediatrics 2014. Levy M et al. J Pediatr 2011;158:584-8.

Pediatric Survival

Circ 2004;110:660-665. JHLT 2013;32(5):546-52.

EPOPROSTENOL ERA EPOPROSTENOL & TREPROSTINIL ERA

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Pharmacokinetics Parenteral Prostacyclin Therapy

• Epoprostenol – “gold standard”

√ Use limited by risk of indwelling central venous catheter, short half life and complexity with delivery √ Can be used for rapid up-titration

• Treprostinil – available as SC/ IV

√ Similar risk of infection with indwelling central venous catheter but longer half life √ Monitor for site pain in SC route

Bourge R et al. Chest 2016;150(1):27-35.

Inhaled Prostacyclin

• Epoprostenol (reserved for ICU)
• Iloprost

√ Approved by FDA in 2004 √ Requires patient cooperation (10 minute delivery) and 6-9x/day administration limiting use in children

• Treprostinil (Tyvaso)

√ Approved by FDA in 2009 √ Administered 4x/day via nebulizer

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Ivy D et al. JACC 2008;51:161-9. Krishnan U et al. JACC 2010;55:1915-22. Abman S et al. Circulation 2015;132. Abman S et al. Circulation 2015;132.

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Parenteral Therapy- Are we too late?

Farber H et al. J Heart Lung Transplant 2013;32:1114-1122.

FDA Reported Pediatric Mortality

Maxey D, et al. Pediatr Cardiol 2013;34:1628-36.

Oral Therapy

• Selexipag (Uptravi)

√ Selective IP prostacyclin receptor agonist √ Approved by FDA in 2015 √ Administered 2x/day (tablet only)

• Treprostinil (Orinetram)

√ Approved by FDA in 2013 √ Administered 3-4x/day (tablet only)

Sitbon O et al. NEJM 2015;373:2522-33.

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Chest 2013;144(3):952-8. Circulation 2013;127:624-33

Oral Treprostinil – Pediatric PAH

• Multi-center, open-label, 24-week trial in pediatric

patients aged 7-17 years with PAH

• Primary objective

√ Assess the safety and tolerability of oral treprostinil

• Secondary objectives

√ Assess effect of oral treprostinil √ Describe treprostinil pharmacokinetics

Oral Treprostinil Pediatric Trial

• 32 subjects enrolled

√ Cohort 1 (Remodulin) - 10 √ Cohort 2 (Tyvaso) - 10 √ Cohort 3 (de novo) – 12

• RESULTS… STAY TUNED!!

Expanded Use

• Beyond Group 1 PAH…
• Neonatal/infant pulmonary hypertension
• Single ventricle congenital heart disease

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Neonate/Infant Congenital Diaphragmatic Hernia

Skarda D et al. Eur J Pediatr Surg 2015;25(5):454-9.

Treprostinil PPHN Trial

• Randomized, placebo-controlled, multi-center clinical trial in

neonates with PPHN with inadequate response to iNO √ Study drug administered IV or SC for up to 28 days

• Hypothesis: Remodulin will reduce rate of clinical worsening defined

as death, ECMO, or use of additional pulmonary vasodilator therapy

• Primary objective (assessed at day 14)

√ Explore safety and treatment effect of Remodulin as add on therapy in neonates with PPHN compared to placebo

• Secondary objectives

√ Assess the effect of Remodulin √ Evaluate pharmacokinetics

Treprostinil PPHN Trial

• 23 sites participating
• 9 subjects enrolled & dosed

√ 4 CDH, 5 PPHN › 2 MAS, 1 birth hypoxia, 1 sepsis, 1 idiopathic √ 3 IV, 6 SC

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Summary

• Pediatric use of treprostinil SC/IV de novo or in transition

continues to increase (including new populations)

• Inhaled/ oral agents considered in low risk patients

√ Need to have caution to not delay institution of SC/IV therapy if novel agents considered

• Combination with other PAH therapy not well understood

Thank You