fact book on surfactants for nrds

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Surfactants for Neonatal Respiratory Distress Syndrome

© 2009 SmithStreetSolutions All rights reserved

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Table of Contents

Neonatal Respiratory Distress Syndrome

– Definition

– Pathology

– Epidemiology

Management of Neonatal Respiratory Distress Syndrome

Brief History of Surfactant Research

Surfactants

Exogenous Surfactants for Clinical Use

Important Clinical Trials

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Definition

Neonatal Respiratory distress syndrome is a breathing disorder of premature newborns, which commences at, or soon after the birth

The air sacs (alveoli) in these newbornʹs lungs collapse and do not remain open because of absence of or insufficient production of surfactant

Respiratory distress syndrome (RDS) is a life threatening lung disorder that commonly affects premature infants

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Pathology

Pathogenesis of RDS is a “vicious cycle”

http://www.lungusa.org/site/pp.asp?c=dvLUK9O0E&b=35693http://bmj.bmjjournals.com/cgi/content/full/329/7472/962?etoc

Pathogenesis

– NRDS is caused by a lack of pulmonary surfactant, a foamy fluid substance produced by the body between the 34th and 37th week of pregnancy

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Pathology

Clinical Signs and Symptoms

– Labored breathing (the ʺrespiratory distressʺ of RDS) may begin as soon as the infant is born, or within a few hours

– Grunting sounds

– Nasal flaring

– Bluish color of the skin and mucus membranes (Cyanosis) resulting from drop of O2 level in blood

– Brief stop in breathing (Apnea)

– Rapid, shallow breathing (Tachypnoea)

– Retraction of thoracic cage: The ribs move inwards each time a breath is taken

– Two major complications of RDS:

Pneumothorax

Intraventricular hemorrhage

http://www.nhlbi.nih.gov/health/dci/Diseases/rds/rds_signsandsymptoms.html

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Epidemiology

High Risk Factors for Neonatal RDS

– Prematurity

– Diabetic mother

– Delivery by Cesarean section

– Perinatal asphyxia

– Hypothermia

– Multiple pregnancy

– Male sex

http://www.patient.co.uk/showdoc/40000462/

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Epidemiology

Occurrence

– RDS nearly always occurs in premature infants, and the more premature the infants are at birth, the less developed the lungs are, and the greater is the chance that RDS will develop. Most cases are seen in babies born before 28 weeks. It is very uncommon in infants born full‐term (at 40 weeks)

Prevalence

– In the US: RDS affected 16,268 infants born alive in the United States in 2005. Generally, RDS occurs in approximately 20,000‐30,000 infants each year and is a complication in about 1% pregnancies. Approximately 50% of the neonates born at 26‐28 weeks of gestation develop RDS, whereas <30% of premature neonates born at 30 to 30‐31 weeks develop RDS. Fanaroff et al reported results of the National Institute of Child Health and Human Development (NICHD) Neonatal Research Network study. Rates of RDS were 42% in infants weighing 501‐1500 g, 71% in those 501‐750 g, 54% in those 751‐1000 g, 36% in those 1001‐1250 g, and 22% in those 1251‐1500g

– Internationally: RDS has been reported in all races worldwide, occurring most often in premature infants of Caucasian ancestry. RDS is encountered less frequently in the developing countries than elsewhere, primarily because of malnutrition or pregnancy‐induced hypertension

http://www.lungusa.org/site/pp.asp?c=dvLUK9O0E&b=35693http://www.emedicine.com/ped/topic1993.htm

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Table of Contents



– Antenatal Steroids to Prevent RDS

– Breathing Support

– Surfactant Replacement Therapy


Surfactants



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Management of NRDS

http://www.phac‐aspc.gc.ca/publicat/2007/lbrdc‐vsmrc/rds‐sdr‐eng.phphttp://www.rain.org/~medmall/resources/medmall_pubs/steroids.htmlhttp://www.nhlbi.nih.gov/health/dci/Diseases/rds/rds_prevent.htmlhttp://bmj.bmjjournals.com/cgi/content/full/329/7472/962?etochttp://www.patient.co.uk/showdoc/40000462/

Antenatal Steroids to Prevent RDS

– Corticosteroids that cross the placenta (dexamethasone or betamethasone) given to women at risk of preterm delivery accelerate fetal surfactant production and lung maturation

– According to Liggins, steroids should be used at 26 to 34 weeks gestation and beyond 34 weeks only if the L/S ratio is immature. (Liggins et al reported the potential benefits of giving antenatal steroids to mothers expecting pre‐term babies)

– Tocolytics, e.g., atosiban, nifedipine or ritodrine, may delay delivery by 48 hours and therefore enable time for antenatal corticosteroids to be given

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Management of NRDS

http://www.hmc.psu.edu/childrens/healthinfo/r/respiratorydistress.htmhttp://www.nhlbi.nih.gov/health/dci/Diseases/rds/rds_treatments.htmlhttp://www.nhlbi.nih.gov/health/dci/Diseases/rds/rds_treatments.html

Breathing Support

– O2 Hood: Infants born with mild RDS may need nothing more than an oxygen hood for a short time to assist with breathing

– Mechanical ventilators: Babies with RDS often are put on a machine that helps them breathe until their lungs have developed enough to start making their own surfactant. Until recently, these babies usually were put on a mechanical ventilator that was connected to a breathing tube that ran through the babyʹs mouth or nose into the windpipe

– CPAP: Today, more and more babies are receiving breathing support from a nasal continuous positive airway pressure (NCPAP) machine, which pushes air into the babyʹs lungs through prongs in the nostrils

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Management of NRDS

Surfactant Replacement Therapy

– The baby is given exogenous surfactant until his or her lungs have developed enough to start making their own endogenous surfactant. Surfactant usually is given through a tube thatʹs attached to a breathing machine. The machine pushes the surfactant directly into the babyʹs lungs

– Surfactant may be given right after birth in the delivery room to try to prevent or treat RDS. It can be given two to four more times over the next few days, until the baby is able to breathe on his or her own

http://www.nhlbi.nih.gov/health/dci/Diseases/rds/rds_treatments.htmlhttp://bmj.bmjjournals.com/cgi/content/full/329/7472/962?etoc

Meta‐analysis of prophylactic versus selective use of surfactant to prevent mortality in preterm infants. Adapted from Soll et al. Cochrane Database Syst Rev 2003;(4): CD000510

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Table of Contents




– Famous Victim

– Highlights in Surfactant Research

Surfactants



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Famous VictimPatrick Bouvier Kennedy, son of President John F. Kennedy and First Lady Jacqueline Kennedy, died of RDS two days after his premature birth at 34 weeks gestation in 1963.

President John F. Kennedy and First Lady Jacqueline Kennedy

http://en.wikipedia.org/wiki/Infant_respiratory_distress_syndrome

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Highlights in Surfactant Research

Name EventDiscovery & Early Knowledge

Von Neergaard Demonstrated that surface tension was responsible for a greater part of lung elastic recoil than was tissue elasticity (1929)

Gruenwald Described surface tension as a major factor in the “resistance to the expansion of RDS lungs during inspiration” (1947)

Pattle Inferred the presence and importance of surface active substance in the lung (1955)

Clements Discovered and described mammalian surfactant (1957)

Avery & Mead Found that surfactant deficiency was the cause of neonatal respiratory distress syndrome (1959)

Tierney First described surfactant inactivation (1965)

Clements Identification of DPPC (1962)

King & Clements Characterized biochemistry and surface behavior of surfactant. Identification and importance of Surfactant proteins (1972)

Gluck Amniotic fluid constituents reflects risk of RDS

Gregory & Tooley CPAP splints the surfactant deficient lung and improves survival (1970)

Liggins Induction of lung maturity with glucocorticoids (1972)

Jobe & Ikegami Extensive studies on surfactant turnover

http://www.chinaphar.com/1671‐4083/23/11s.pdf

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Highlights in Surfactant Research (Contd.)

Name EventAttempts in clinical field

Enhorning Along with Fujiwara, Robertson, and Adams showed that surfactant replacement improved lung function of immature Rabbits (1972)

Fujiwara First successful use of surfactant treatment of human infants (1980)

Hallman Characterized surfactant in adult RDS

Shapiro & Notter Developed antecedent of bLES and Infasurf

Clements Invented Exosurf

Bangham & Morley Developed synthetic surfactant

Curstedt Along with Johannsen and Robertson developed Curosurf

Whitsett Molecular biology of surfactant proteins

Hawgood Mechanisms of surfactant function

http://www.chinaphar.com/1671‐4083/23/11s.pdf

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Table of Contents




Surfactants

– Surfactant

– Pulmonary Surfactant

– Function

– Composition



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SurfactantSurfactantʹ is a blend of ʺsurface acting agentʺ. Surfactants are usually organic compounds that are amphiphilic, meaning they contain both hydrophobic groups (their ʺtailsʺ) and hydrophilic groups (their ʺheadsʺ). Therefore, they are soluble in both organic solvents and inorganic liquids.

http://en.wikipedia.org/wiki/Surfactant

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Pulmonary SurfactantPulmonary surfactant is a surface‐active lipoprotein complex formed by type II alveolar cells. Theproteins and lipids that comprise surfactant have both a hydrophilic region and a hydrophobic region. By adsorbing to the air‐water interface of alveoli with the hydrophilic headgroups in the water and the hydrophobic tails facing towards the air, the main lipid component of surfactant, dipalmitoylphosphatidylcholine, reduces surface tension.

Diagram of the alveoli with both cross‐section and external view

Alveolar type II cell, the lamellar bodies can be seen leaving the surface of the cell

http://en.wikipedia.org/wiki/Pulmonary_surfactant

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Function

http://en.wikipedia.org/wiki/Pulmonary_surfactanthttp://www.ias.ac.in/resonance/Aug2005/pdf/Aug2005p91‐96.pdf

Surfactant reduces surface tension throughout the lung

To increase pulmonary compliance

To prevent the lung from collapsing at the end of expiration

To keep alveoli dry

To help mucociliary transport

Host Defense

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CompositionHuman surfactant consists of approximately 80% phospholipids, 8% neutral lipids and 12% proteins and its composition is fairly constant across mammalian species

Phospholipids, 80%

Proteins, 12%

Neutral Lipids, 8%

Human Surfactant Composition

http://www.curoservice.com/health_professionals/rds_therapies/curosurf/monograph.pdf

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Composition

http://www.curoservice.com/health_professionals/rds_therapies/curosurf/monograph.pdf

Lipids

– Half of the lipid is dipalmitoylphosphatidylcholine (DPPC). This is a phospholipid with two 16‐carbon saturated chains and a phosphate group with quaternary amine group attached

– Phosphatidylglycerol (PG) forms about 11% of the lipids in surfactant, it has unsaturated fatty acid chains that fluidize the lipid monolayer at the interface. Phosphatidylglycerol (PG) is another important phospholipid that helps to stabilize the surfactant complex

– Neutral lipids and cholesterol are also present. The components for these lipids diffuse from the blood into type II alveolar cells where they are assembled and packaged for secretion into secretory organelles called lamellar bodies

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Composition

Proteins Solubility Functions

SP‐A(Apoprotein A) Hydrophilic

SP‐A is important in the organization and function of the surfactant complex regulating surfactant recycling and secretionProtect surfactant fSP‐A is necessary for the production of tubular myelin, a lipid transport structure unique to the lungs. Tubular myelin consists of square tubes of lipid lined with proteinImmune system (host‐defense mechanisms)Protect surfactant from negative effects of serum proteins

SP‐B(Apoprotein B) Hydrophobic

Tubular myelin component Enhance adsorption and spreading (interact with surfactant phospholipids to optimize surface tension lowering function)

SP‐C(Apoprotein C) Hydrophobic Enhance the rate of adsorption (Accelerates the adsorption and spreading of

phospholipids)SP‐D

(Apoprotein D) Hydrophilic Immune system (host‐defense mechanisms) Regulate surfactant balance

SP‐B(Apoprotein B) Hydrophobic

Tubular myelin component Enhance adsorption and spreading (interact with surfactant phospholipids to optimize surface tension lowering function)

SP‐C(Apoprotein C) Hydrophobic Enhance the rate of adsorption (Accelerates the adsorption and spreading of

phospholipids)SP‐D

(Apoprotein D) Hydrophilic Immune system (host‐defense mechanisms) Regulate surfactant balance

http://ising.cwru.edu/surfactants/proteins.html

Proteins

– Approximately half of the proteins consist of protein from plasma or lung tissue (Jobe 1993). In addition, there are four surfactant proteins (SPs) expressed by respiratory epithelial cells, designated as SP‐A, SP‐B, SP‐C and SP‐D

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Table of Contents




Surfactants


– Introduction

– FDA approved surfactantsSurvantaCurosurfInfasurfExosurf Neonatal

– Other surfactants in marketSurfaxinAerosurfBLESALEC


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IntroductionSurfactants and their compositions

Name Event

ExosurfA mixture of DPPC with Cetyl alcohol and Tyloxapol added as spreading agents; suspension contains 13.5 mg/ml colfosceril palmitate, 1.5 mg/ml cetyl alcohol, and 1 mg/ml tyloxapol in 0.1 N NaCl

Pumactant (ALEC) A mixture of DPPC and PG; Protein‐Free

KL‐4Composed of DPPC, palmitoyl‐oleoyl phosphatidylglycerol, and palmitic acid, combined with a 21 amino acid synthetic peptide that mimics the structural characteristics of SP‐B

Venticute DPPC, PG, palmitic acid and recombinant SP‐C

SurvantaExtracted from minced cow lung with additional DPPC, palmitic acid and tripalmitin; 25 mg phospholipids/ml

Curosurf Extracted from minced pig lung ; 80 mg phospholipids/ml

Infasurf Extracted from calf lung lavage fluid; 35 mg phospholipids/ml

BLES Extracted from cow lung lavage fluid; 27 mg phospholipids/ml

ExosurfA mixture of DPPC with Cetyl alcohol and Tyloxapol added as spreading agents; suspension contains 13.5 mg/ml colfosceril palmitate, 1.5 mg/ml cetyl alcohol, and 1 mg/ml tyloxapol in 0.1 N NaCl

http://en.wikipedia.org/wiki/Pulmonary_surfactant

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IntroductionSurfactants and their compositions

http://www.chestjournal.org/cgi/reprint/131/5/1577.pdf?ck=nck

Preparation Animal Source Brand Name Generic Name Manufacturing Co. and Location

Animal Derived surfactants

Lung Lavage Bovine Alveofact BovactantBoehringer Ingleheim; Bilberach,

Germany

Lung Lavage Bovine BLESBovine Lipid Extract

Surfactant

BLES Biochemicals; London, ON, Canada

Lung Lavage Bovine Infasurf Calfactant ONY, Inc; Amherst, NY

Processed Animal Lung Tissue

Porcine Curosurf Poractant Chiesi Farmaceutici SpA; Parma, Italy

Supplemented, Processed Animal Lung Tissue

Bovine Surfacten Surfactant TA Mitsubishi; Tokyo, Japan

Supplemented, Processed Animal Lung Tissue

Bovine Survanta Beractant Abbott Laboratories; Abbott Park, IL

Synthetic and Recombinant Lung Surfactants

Protein‐free ‐ ALEC Pumactant Britannia Pharmaceuticals; Crawley, UK

Protein‐free ‐ ExosurfColfosceril palmitate

Glaxo Wellcome; Uxbridge, Middlesex, UK

Peptide ‐Containing ‐ Surfaxin Lucinactant DiscoveryLabs; Warrington, PA

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FDA Approved Surfactants

http://www.ll.georgetown.edu/federal/judicial/fed/opinions/03opinions/03‐1067.html http://survanta.com/pdf/packageinsert.pdf

SURVANTA® (Beractant)

– Manufacturer: Abbott Laboratories Ltd.

– Approval date: July 1991, Abbott received both FDA approval and orphan drug status (providing seven years’ market exclusivity) for Survanta®

– A sterile, non‐pyrogenic pulmonary surfactant intended for intratracheal use only

– 25 mg/ml phospholipids, 0.5‐1.75 mg/ml triglycerides, 1.4‐3.5 mg/ml free fatty acids, and less than 1.0 mg/ml protein

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CUROSURF® (Poractant alfa)

– Manufacturer: Chiesi Farmaceutici S.p.A

– Approval date: Curosurf® has been marketed in Europe since 1992 by Chiesi Farmaceutici S.p.A of Italy

– Dey licensed Curosurf® from Chiesi Farmaceutici, S.p.A and received U.S. Food & Drug Administration approval in November 1999

– A white to yellow sterile suspension for endotracheopulmonary instillation in single dose vials

– Phospholipid fraction from porcine lung is 80 mg/ml

http://www.chiesigroup.com/2007/eng/chiesi_informa/news_detail.asp?id=22; http://www.curoservice.com/health_professionals/rds_therapies/curosurf/monograph.pdf

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http://www.infasurf.com/

INFASURF® (Calfactant)

– Manufacturer: ONY, Inc.

– Marketer: Forest Pharmaceuticals, Inc.

– Approval date: July, 1998

– A sterile, non‐pyrogenic lung surfactant intended for intratracheal instillation only

– Each milliliter of Infasurf contains 35 mg total phospholipids (including 26 mg phosphatidylcholine of which 16 mg is disaturated phosphatidylcholine) and 0.65 mg proteins including 0.26 mg of SP‐B

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EXOSURF NEONATAL® (Colfosceril palmitate, cetyl alcohol, tyloxapol)

– Manufacturer: Burroughs Wellcome Co. (Now GlaxoSmithKline)

– Approval date: July 1990

– A protein‐free synthetic lung surfactant stored under vacuum as a sterile lyophilized powder

– Each 10‐ml vial contains 108 mg colfosceril palmitate, commonly known asdipalmitoylphosphatidylcholine (DPPC), 12 mg cetyl alcohol, 8 mg tyloxapol, and 47 mg sodium chloride

http://findarticles.com/p/articles/mi_m1370/is_n9_v24/ai_9146244http://www.drugdigest.org/DD/PrintablePages/Monograph/0,7765,7961%7C,00.html

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Other Surfactants in Market

SURFAXIN® (Lucinactant)

– Manufacturer: Discovery Labs

– Orphan Drug Status from FDA

– The first available synthetic surfactant containing a peptide (sinapultide; KL4) that mimics human SP‐B

– A synthetic surfactant composed of DPPC, palmitoyl‐oleoyl phosphatidylglycerol, and palmitic acid combined with a 21 amino acid synthetic peptide

http://www.discoverylabs.com/2008pr/052908‐PR.pdf http://www.discoverylabs.com

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http://www.discoverylabs.com/aerosurf.html

AEROSURF® (Lucinactant for inhalation)

– Manufacturer: Discovery Labs

– Investigational drug product not approved for use

– Discovery Labsʹ second product based on KL4 technology

– An aerosolized SRT formulation

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http://www.pmprb‐cepmb.gc.ca/english/View.asp?x=325&mp=572&pf=1http://www.emedicine.com/ped/topic1993.htm

BLES (Bovine Lipid Extract Surfactant)

– Manufacturer: BLES Biochemicals Inc.

– A mixture of proteins and phospholipids obtained from bovine lung lavage

– Each ml of suspension contains 27 mg phospholipid and 176‐500 mcg Surfactant associated proteins SP‐ B and SP‐C with sodium chloride and calcium chloride

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ALEC/ADSURF (Pumactant)

– Artificial lung expanding compound (ALEC)

– The marketing of pumactant (ALEC) has been suspended by Britannia Pharmaceuticals

– 70% DPPC and 30% unsaturated phosphatidylglycerol

http://www.emedicine.com/ped/topic1993.htmhttp://www.pjonline.com/Editorial/20000429/clinical/pumactant.html

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Table of Contents




Surfactants



– Survanta

– Curosurf

– Infasurf

– Exosurf Neonatal

– Surfaxin

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Prevention Studies

– Study 1243 infants of 600‐1,250 g birth weight and 23 to 29 weeks estimated gestational age enrolledSurvanta (multiple‐dose) versus control

Survanta

Results of Study 1Percentage of infants

Efficacy Parameter Survanta (N=119) Control (N=124) p‐Value

Incidence of RDS 27.6 63.5 <0.001

Death due to RDS 2.5 19.5 <0.001

Death or BPD due to RDS 48.7 52.8 0.536

Death due to any cause 7.6 22.8 0.001

Air Leaka 5.9 21.7 0.001

Pulmonary interstitial emphysema 20.8 40.0 0.001

a. Pneumothorax or pneumopericardium

http://survanta.com/pdf/packageinsert.pdf

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Prevention Studies

– Study 2187 infants of 600‐1,250 g birth weight and 23 to 29 weeks estimated gestational age enrolledSurvanta (multiple‐dose) versus control

Survanta

Results of Study 2 (Study 2 discontinued when Treatment IND initiated)Percentage of infants


Incidence of RDS 28.6 48.3 0.007

Death due to RDS 1.1 10.5 0.006

Death or BPD due to RDS 27.5 44.2 0.018

Death due to any causec 16.5 13.7 0.633

Air Leaksa 14.5 19.6 0.374

Pulmonary interstitial emphysema 26.5 33.2 0.298

a. Pneumothorax or pneumopericardiumb. No cause of death in the SURVANTA group was significantly increased; the higher number of deaths in this group was due to the sum of all causes


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Rescue Studies

– Study 3391 infants of 600‐1,750 g birth weight with RDS enrolledSurvanta (multiple‐dose) versus control

Survanta

Results of Study 3 (Study 3 discontinued when Treatment IND initiated)Percentage of infants


Death due to RDS 12 18 0.071

Death or BPD due to RDS 59 67 0.102

Death due to any cause 22 26 0.285

Air Leaksa 12 30 <0.001

Pulmonary interstitial emphysema 16 34 <0.001



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Rescue Studies

– Study4407 infants of 600‐1,750 g birth weight with RDS enrolledSurvanta (multiple‐dose) versus control

Survanta



Death due to RDS 6 22 <0.001

Death or BPD due to RDS 44 63 <0.001

Death due to any cause 15 28 0.001

Air Leaksa 11 2 0.005

Pulmonary interstitial emphysema 21 44 <0.001



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Single‐dose study (Study 1)

– Infants 700‐2,000g birth weight with RDS enrolled

– Curosurf 2.5 ml/kg single dose (200 mg/kg) versus control (disconnection from the ventilator and manual ventilation for two minutes)

Curosurf


Efficacy Parameter Single‐dose Curosurf (N=78) Control (N=67) p‐Value

Any death to 28 days 27 71 ≤0.05

Bronchopulmonary Dysplasiaa 23 33 N.S.b

Pneumothorax 27 54 ≤0.05

Pulmonary Interstitial Emphysema 27 57 ≤0.05

a. Bronchopulmonary dysplasia (BPD) diagnosed by positive x‐ray and supplemental oxygen dependence at 28 days of life

b. not statistically significant

http://www.dey.com/Curosurf/ClinicalStudies.htm

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CurosurfMultiple‐dose study (Study 2)

– Infants 700‐2,000g birthweight with RDS enrolled

– Single‐dose arm (Curosurf 2.5 ml/kg ) versus multiple‐dose arm (2.5 ml/kg and a subsequent dose of 1.25 ml/kg )


Efficacy Parameter Single‐dose Curosurf (N=184) Control (N=173) p‐Value

Any death to 28 days 11 8 0.048

Bronchopulmonary Dysplasiaa 10 10 N.S.b

Pneumothorax 9 5 0.03

Pulmonary Interstitial Emphysema 15 13 N.S.b

a. Bronchopulmonary dysplasia (BPD) diagnosed by positive x‐ray and supplemental oxygen dependence at 28 days of life

b. not statistically significant


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CurosurfAdverse Reaction


Complications of PrematurityPercentage of infants

Type of Adverse Reaction Curosurf 2.5 ml/kg (200 mg/kg) (N=78) Controla (N=66)

Acquired Pneumonia 17 21

Acquired Septicemia 14 18

Bronchopulmonary Dysplasia 18 22

Intracranial Hemorrhage 51 64

Patent Ductus Arteriosus 60 48

Pneumothorax 21 36

Pulmonary Interstitial Emphysema 21 38

a. Control patients were disconnected from the ventilator and manually ventilated for two minutes. No surfactant was instilled

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InfasurfInfasurf versus Exosurf Neonatal®

– Treatment Trial1,126 infants ≤72 hours of age with RDS enrolledInfasurf (3 ml/kg) versus Exosurf Neonatal® (5 ml/kg)

Results of Infasurf vs. Exosurf Treatment TrialPercentage of infants

Efficacy Parameter Infasurf (N=570) Exosurf Neonatal (N=556) p‐Value

Incidence of air leaksa 11 22 ≤0.001

Death due to RDS 4 4 0.95


Any death before discharge 9 12 0.07

BPDb 5 6 0.41

Crossover to other surfactantc 4 4 1

a. Pneumothorax and/or pulmonary interstitial emphysemab. BPD is bronchopulmonary dysplasia, diagnosed by positive X‐ray and oxygen dependence at 28 daysc. Protocol permitted use of comparator surfactant in patients who failed to respond to therapy with the initial randomized surfactant if the infant was <96 hours of age, had received a full course of the randomized surfactant, and had an a/A PO2 ratio <0.10

http://www.fda.gov/cder/foi/label/1998/20521lbl.pdf

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InfasurfInfasurf versus Exosurf Neonatal®

– Prophylaxis Trial853 infants <29 weeks gestation enrolledInfasurf (3 ml/kg) versus Exosurf Neonatal® (5 ml/kg)

Infasurf vs. Exosurf Phophylaxis TrialPercentage of infants


Efficacy Parameter Infasurf (N=431) Exosurf Neonatal (N=422) p‐Value

Incidence of RDS 15 47 ≤0.001

Incidence of air leaksa 10 15 0.01

Death due to RDS 2 5 ≤0.01


Any death before discharge 18 19 0.56

BPDb 16 17 0.60

Crossover to other surfactantc 0.2 3 <0.001

a. Pneumothorax and/or pulmonary interstitial emphysemab. BPD is bronchopulmonary dysplasia, diagnosed by positive X‐ray and oxygen dependence at 28 daysc. Protocol permitted use of comparator surfactant in patients who failed to respond to therapy with the initial randomized surfactant if the infant was <96 hours of age, had received a full course of the randomized surfactant, and had an a/A PO2 ratio <0.10

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Infasurf

Infasurf versus Survanta®

– Treatment Trial662 infants with RDS enrolled

Infasurf (4 ml/kg of a formulation that contained 25 mg of phospholipids/ml rather than the 35 mg/ml in the marketed formulation) and Survanta® (4 ml/kg)

Results for the major efficacy parameters evaluated at 28 days or to discharge (incidence of air leaks, death due to respiratory causes or to any cause, BPD, or treatment failure) for all treated patients from this treatment trial were not significantly different between Infasurf and Survanta®


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Infasurf

Infasurf versus Survanta®

– Prophylaxis Trial457 infants <30 weeks gestation and <1,251 grams birth weight

Infasurf (4 ml/kg of a formulation that contained 25 mg of phospholipids/ml rather than the 35 mg/ml in the marketed formulation) and Survanta® (4 ml/kg)

Results for efficacy endpoints evaluated at 28 days or to discharge for all treated patients from this prophylaxis trial showed an increase in mortality from any cause at 28 days (p=0.03) and in death due to respiratory causes (p=0.005) in Infasurf‐treated infants. For evaluable patients (patients who met the protocol‐defined entry criteria), mortality from any cause and mortality due to respiratory causes were also higher in the Infasurf group (p=0.07 and 0.03, respectively)

All other efficacy outcomes (incidence of RDS, air leaks, BPD, and treatment failure) were not significantly different between Infasurf and Survanta® when analyzed for all treated patients and for evaluable patients


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Exosurf Neonatal

Results of Prophylactic Treatment TrialsPercentage of infants

http://www.rxlist.com/cgi/generic/exosurf_cp‐page2.htm

Efficacy Assessments of Prophylactic TreatmentNumber of Doses Single Dose Single Dose Single Dose 1 vs 3 DosesBirth Weight Range 500 to 700 g 700 to 1,350 g 700 to 1,100 g 700 to 1,100 g

Treatment Group:Placebo(Air)

ExosurfPlacebo(Air)

ExosurfPlacebo(Air)

ExosurfExosurf1 Dose

Exosurf3 Doses

Number of Infants: n=106 n=109 n=185 n=176 n=222 n=224 n=356 n=360Death day ≤28 53 50 11 6 21 15 16 9†Death through 1 year 59 60 14 11 30 20‡ 17 12†Death from RDS 25 13† 4 3 10 5 II 3 2Intact cardio‐pulmonary survival

29 25 69 78† 65 68 74 78

Broncho‐pulmonary dysplasia

43 44 23 18 19 21 8 12

RDS incidence 73 81 46 42 55 55 63 68† P< 0.05; ‡ P< 0.01; II P = 0.051.

Prophylactic Treatment

– 3 double‐blind, placebo‐controlled single‐dose studiesOne involving 215 infants weighing 500 to 700 gOne involving 385 infants weighing 700 to 1,350 gOne involving 446 infants weighing 700 to 1,100 g

– 1 double‐blind, placebo‐controlled multiple‐dose study: one versus three doses823 infants weighing 700 to 1,100 g

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Exosurf NeonatalRescue Treatment

– 2 double‐blind, placebo‐controlled studiesOne involving 419 infants weighing 700 to 1,350 gOne involving 1,237 infants weighing 1,250 g and above

– An initial dose (5 ml/kg) or placebo (air) between 2 and 24 hours followed by a second dose (5 ml/kg) approximately 12 hours later to infants who remained on mechanical ventilation

Results of Rescue Treatment TrialPercentage of infants

http://www.rxlist.com/cgi/generic/exosurf_cp‐page2.htm

Efficacy Assessments of Rescue TreatmentNumber of Doses 2 Doses 2 Doses

Birth Weight Range 700 to 1,350 g 1,250 g and above

Treatment Group Placebo (Air) EXOSURF Placebo (Air) EXOSURF

Number of Infants n=213 n=206 n=623 n=614

Death day ≤28 23 11† 7 4‡

Death through 1 year 27 15† 9 6§

Death from RDS II 10 3¶ 3 1‡

Intact cardio‐pulmonary survival 62 75¶ 88 93¶

Broncho‐pulmonary dysplasia 18 15 6 3‡

† P< 0.001; ‡ P< 0.05; § P = 0.067; ¶ P< 0.01.

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SurfaxinSELECT (Safety and Effectiveness of Lucinactant vs. Exosurf in a Clinical Trial)

– 1,294 very preterm infants, weighing 600 to 1,250 g and of 32 weeks gestational age enrolled– Exosurf (n = 509) versus Surfaxin (n = 527), or Survanta (n = 258)

http://pediatrics.aappublications.org/cgi/content/full/115/4/1018

Primary outcome variables: ORs (Odd Ratio) and 95% CIs (Confidence Interval) for treatment differences between lucinactant and colfosceril palmitate (top) and between lucinactant and beractant (bottom) are shown.

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SurfaxinSTAR (SURFAXIN Therapy Against RDS)

– 252 infants born between 24 and 28 weeks with birth weights between 600 and 1,250 g enrolled

– Curosurf (n = 124) versus Surfaxin (n = 128)

http://pediatrics.aappublications.org/cgi/content/full/115/4/1018

Results of STARPercentage of infants

StratumLucinactant (N=119) Poractant Alfa (N=124)

600‐1,000g (N=79) 1,001‐1,250g (N=40) 600‐1,000g (N=81) 1,001‐1,250g (N=43)

Died Day 28

36 wk PMA1623

33

2125

77

Alive without BPD

Day 2836 wk PMA

2352

6890

2156

5688

There were no statistically significant differences between groups for any of the parameters.

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The Road Ahead

The story of Surfactant has not ended.

Rigorous research on human surfactant derived from Amniotic fluid is currently going on.

Also, clinical studies on the aerosolized form of surfactant delivery, namely, Aerosurf ( Discovery Labs.) is currently on progress.

This discovery of surfactant and its new delivery systems, will help millions of babies to take second and third breath and grow up to live a healthy life.

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fact book on surfactants for nrds

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