OM-85 Applicability in routine clinical practice - Professor Susanna Esposito

OM ‐85: are the clinical trial results applicable in routine clinical practice?

Prof Susanna EspositoPediatric Highly Intensive Care Unit

Fondazione IRCCS Ca’ Granda Ospedale Maggiore PoliclinicoMilan, Italy

DEFINITION OF RECCURENT RESPIRATORY TRACT INFECTIONS (RTIs)

«THE FIRST CAUSE OF RECURRENT INFECTIONS IN CHILDREN IS...CHILDHOOD ITSELF»2

Absence of any pathological underlying condition that may justify that may justify the recurrence of infections1

1. Gruppo di studio di immunologia della società Italiana di pediatria. Le infezioni ricorrenti nel bambino: definizione ed approccio diagnostico. Riv Immunol Allergol Pediatrica 1988; 2: 127–34. 2. J. Gary Wheeler Evaluating the child with recurrent infections - includes patient information sheet. Nov 15, 1996.

Savitha MR, Nandeeshwara SB, Pradeep Kumar MJ, ul-Haque F, Raju CK. Modifiable risk factors for acute lower respiratory tract infections. Indian J Pediatr. 2007 May;74(5):477-82.

EPIDEMIOLOGY AND ETIOLOGY OF RRTIs

• RRTIs affect up to 25% of children aged <1 year and 18% of children aged 1-4 years in developed countries1

• Bacteria such as Streptococcus pneumoniae, Mycoplasma pneumoniae, Haemophilus influenzae and Streptococcus pyogenes may play a role3

• Viruses (mainly respiratory syncytial virus, rhinovirus and influenza viruses) are the main etiological agents of RRTIs2

1. Bellanti et al. Drugs 1997 2. Esposito et al. Eur J Clin Microbiol Infect Dis 2012 3. Purushothama V. Et al. Chapter 93. Infections of the Respiratory System. Medical Microbiology. 4th edition. Baron S, editor. Galveston (TX): University of TexasMedical Branch at Galveston; 1996.

VIRUSES ARE THE MAIN CAUSES OF RTIS

• ≥80% of RTIs are caused by viruses1

• Viruses that commonly cause RTIs include2:

• Secondary bacterial infection (bacterial superinfection)is common following viral RTIs3

1. Esposito et al. Eur J Clin Microbiol Infect Dis 2012; 2. Heikkinen T, Järvinen A. The common cold. Lancet. 2003 Jan 4;361(9351):51-9. 3. Hament et al. FEMS Immunol Med Microbiol 1999

1. Jackson et al. Am J Respir Crit Care Med 2008; 2. Kusel et al. Eur Respir J 2012; 3. von Mutius et al. Eur Respir J 1999

RECURRENT RTIs IN EARLY CHILDHOOD ARE ASSOCIATED WITH SUBSEQUENT

ASTHMA• Virus-induced wheezing episodes during the first 3 years of life are

significant predictors of the development of asthma by 6 years of age1

• These observations are consistent with findings of other prospective studies reporting associations between RTIs and subsequent asthma2,3

What can be done?

• Treatment controversial role of antibiotics role of symptomatic measures

• PREVENTION Firstly, based on risk factors Secondly, based on past history

• PARENT EDUCATION• ACTIVE IMMUNIZATION• Non specific IMMUNOSTIMULATION

PREVENTIVE Measures

RRTIs

I M M U N I Z A T I O N

• ACTIVE efective IMMUNIZATION ultimate objective

• Viral vaccines: Influenza, measles(RSV, rhinovirus)

• Bacterial vaccines: Pneumococcus (PCV),Haemophilus influenzae type b, Bordetellapertussis (Staph. aureus)

Non specific IMMUNOSTIMULATION

• Stimulation – Modulation – Improvementof the immune system

• Fundaments: correlation between the RTIs and immaturity / defects in the immune system

• Bacterial IMMUNOSTIMULATION, for example OM - 85 BV (Broncho-Vaxom), a bacterial lysate extract of 8 respiratory bacteria

JESENAK M et al. Chapter 8 – Infectious Diseases open accessDOI: 10.5772/19422

Alterations in immune system observed in children with RRTI

MoA

Tratto da Rossi GA. Opinioni a confronto 2012

Increase the ability of APC to stimulate T cells specific for Ag in order to induce the maturation of B cells to plasma cells

To activate T cells and NK cells as well as stimulation of phagocytosis by macrophages and neutrophils against pathogens with IgG

OM‐85 Overview of the clinical data in children

Concept of the "ideal" time window with the largest absolute efficacy of OM‐85 in the Pediatric RTIs

Partial Partial ImmunologicalImmunological

immaturity

immaturityimmaturity"Refractory"Period

Day CareCenters, etc.

N RTIs

Age

Placebo

BronchoVaxom

SCHOOL-SCHOOL-AGEAGE

Epidemiology of Viral Infections and Evaluation of the PotentialBenefit of OM‐85 BV on the Virologic Status of Children

Attending Day‐Care Centers

• Statistically significant differences in the prevalence of Virus carriers in favor of children treated with OM-85 BV.

• VSR: 10 placebo vs 5 BV (p < 0.05)

• Influenza A: 4 placebo vs 1 BV (p < 0.05)• These results corroborate the clinical

findings.

M. Aymarda et al., Respiration 1994;6 l(suppl 1):24‐3 ILaboratoire de Virologie, Centre Hospitalo‐Universitaire de Lyon,

Broncho-Vaxom® (OM-85 BV)

Objective:

Investigate further the therapeutic benefit of OM-85 in children with recurrent URTIs

OM-85 en las IRTR en los niñosVisión General ClínicaSchaad et al. – Chest 2002

•Double blind, randomized, controlled trial with placebo•220 patients (ITT) aged between 36 and 96 months with URTIs (3 + / 12

months)

•OM‐85 or placebo 1 capsule/day

OM-85 - URTIs in children

Schaad et al. Chest 2002 – Study design

In children 3-8 years of age, with upper respiratory tract infections

OM-85 : URTIs in children

OM-85 significantly reduces the rate of URTIs in children

‐16%• The average cumulative rate

reduction from 2.5 to 2.1 = ‐ 0.4 URTIs / 6 months

• Less Risk to develop infecctionswith Broncho‐Vaxom vs placebo:

at 4 months 15% vs 36%, at 6 months 26% vs 40%

• Good safety and tolerability comparable to placebo

Pediatric studies of BV double blind and placebo controlled

L.P. Nicod. Eur Respir Rev 2005; 14: 95, 43–44

Objective

Assess the safety and efficacy of OM-85 in the prevention of the ARTIs in children (Mexico)

OM- 85 ARTIs in children (Mexico)

Gutiérrez-Tarango y Berber, Chest 2001

• Double blind, randomized, controlled trial with placebo• 54 patients aged 1 to 12 years old with acute recurrent ARTIs during the past 12

months: average of 12 ARTIs in both groups OM‐85 or placebo 1 caps /day : two courses of 3 months in 12 months

OM-85 . ARTIs in children (Mexico)

Gutiérrez-Tarango y Berber, Chest 2001 – Study design

Percentage of patients with less than six ARTIs over 12 consecutive months

OM-85 - ARTIs in children

OM-85 reduces the burden of ARTIs in children

OM-85

Placebo

Gutiérrez‐Tarango et al. Chest 2011;119:1742‐1748

• reduces the number of ARTIs (up to 5/12 months 8/ 12 months ≤ 37%)• reduces the duration of disease

• reduce the use of antibiotics and absenteeism

ARTIs in children (Mexico)

OM-85 reduce the burden of ARTIs in children


BV–OM85 decreases antibiotic treatments with in 1 year


Study Objectives:

Investigate the effect of OM-85 BV in the total number of wheezing attacks induced by the ITRA for the period of 12 months.

Secondary objectives: the duration of episodes of wheezing, the use of beta2‐agonists and steroids, the rate of hospitalization and the number/type of RTIs for the period of 12 months.

OM85- Prevention of Wheezing attacks

Razi et al. 2010 – J Allergy Clin Immunol

• A randomized, double blind, controlled study with placebo was performed between August 2007 and September 2008.

• The study included 75 children with recurrent wheezing that had between 1 and 6 years of age: > 6 episodes per 12 months, half in both groups = 8 for 12 months.

• OM‐85 (35) or placebo (40) (1 capsule per day for 10 days each month for 3 consecutive months). It followed participants for 12 months.

OM-85 Prevention of Wheezing attacks

Razi et al. 2010 – Study Design

Cumulat

ive

numbe

r of

whe

ezing

atta

cks

per

patien

t

-37.9%p<0.001

-36%p=0.001

-34.3%p=0.003

-30.4%p=0.013

The difference in the attacks of wheezing between 2 groups was - 2.18attacks of wheezing per patient in 12 months (5.2 to 3); There was areduction of - 37.9% in the group receiving OM-85 compared to thegroup receiving placebo.

OM-85 Prevention of Wheezing attacks

Razi et al. 2010 – OM-85 reduced wheezing attacks in children

Razi CH et al. J Allergy Clin Immunol 2010 – Significant reduction in total RTIs observed with Broncho-Vaxom® vs placebo

Razi CH et al. J Allergy Clin Immunol 2010 – Significant reduction in number of cases of nasopharyngitis observed with Broncho-Vaxom® vs placebo

Razi CH et al. J Allergy Clin Immunol 2010 – Conclusions

• Cumulative number and duration of virus-induced wheezing attacks over 12 months significantly (p<0.001) reduced with OM-85 vs placebo

• Incidence of nasopharyngitis over 12 months significantly (p<0.001) reduced with OM-85 vs placebo

• Reduction in number and duration of hospitalisations with OM-85 vs placebo was not statistically significant

• Adverse events in 3 OM-85 and 2 placebo patients considered potentially treatment related; all were minor and transient

OM-85 PROTECTS CHILDREN FROM RECURRENT VIRUS-INDUCED WHEEZING

ATTACKS

SELECTIVE ACTIVATION OF HUMAN DENDRITIC CELLS BY OM-85 THROUGH NF-KB AND MAPK

DEPENDANT PATHWAY

• Aim of the study• to investigate the activation properties of Broncho-Vaxom®

(OM-85 BV) on human DC subsets.

Parola C. et al. PloS One 2013

SELECTIVE ACTIVATION OF HUMAN DENDRITIC CELLS BY OM-85 THROUGH NF-KB AND MAPK

DEPENDANT PATHWAYParola C. et al. PloS One 2013 – Significant increase in the level of IFNα with Broncho-Vaxom® vs placebo

OM-85 COULD PROTECT AGAINST VIRUS-INDUCED RTIS

• Razi CH et al. J Allergy Clin Immunol 2010Observation: Reduction in ARTI-induced wheezing attacks was paralleled by a reduction in acute nasopharyngitis (mainly caused by rhinoviruses).Hypothesis:Increase in IFN-γ production after OM-85 administrationcould mediate this benefit (reduction in virus-induced nasopharyngitis).

• Parola C et al. PloS One 2013Observation: OM-85 induced PDC to release low concentrations of IFNα, which represents the most important cytokine for the defense against viral infections.Hypothesis:OM-85 may help to set up a basal antiviral state.

Objective

The main objective of this meta-analysis was to provide a more accurate estimate of the overall effects of treatment of OM-85 from a clinical point of view. 8 randomized, placebo-controlled trials were included.

OM-85 RTIs in children

Schaad 2010 – OM-85 in children, a meta-analysis

OM-85 in the children meta-analysis– Schaad, 2010

The population treated with OM‐85 had significantly and steadily fewer cases of recurrent RTIs : ‐26% ( 3 or +/6 months ) Average reduction for 6 months from 2.9 to 1.8 = ‐1.1 RTIs ( ‐35% )The data suggest that the effect is greater in patients who are at increased risk of recurrent RTIs

OM-85 - RTIs in Children

Objective

Evaluate the efficacy of OM-85 in children with recurrent acute tonsillitis.

OM-85 acute tonsilitis

Bitar and Saade 2013 - Int J Pediatr Otorhinolaryngol

Bitar et al. Int J Pediatr Otorhinolaryngol 2013;77(5):670‐3.

• Retrospective cohort studies of 177 children with the diagnosis of recurrent acute tonsillitis: ≥3 episodes in 12 months

• Average age 4.5 years (range from 1 to 15 years of age)• OM‐85 was administered 1 capsule per day for 10 days each month for 3 consecutive months 131 children of cohort

• The response was defined as a decrease in the frequency of episodes of acute tonsillitis after 3 months of therapy to 6 month :– Total: >50%– Parcial: ≤50%

OM-85 acute tonsilitis

Bitar and Saade 2013 – Study design


BV‐OM85 reduces episodes of recurrent acute tonsillitis


A considerable proportion (75.6%) of children treated with OM-85 (Broncho-Vaxom) for recurrent acute tonsillitis experienced a decrease in the frequency of the episodes in the short term (6 months)

Very few finally needed tonsillectomy in the long-term follow-up(11 of 32 patients showing partial response at 6 months).

OM 85 - acute tonsilitis

Bitar et al. 2013 – OM-85 reduced acute tonsillitis in children

0 10 20 30 40 50 60 70 80 90 100

Partial response

Total response

Type of response to OM‐85 among responders(%)

100%n=99

67.67%n=67

32.32%n=32

Without tonsillectomy in this group


IMPACT OF A MIXED BACTERIAL LYSATE (OM-85 BV) ON THE IMMUNOGENICITY, SAFETY AND TOLERABILITY OF INACTIVATED

INFLUENZA VACCINE IN CHILDREN WITH RECURRENT RESPIRATORY TRACT INFECTION

• Aim of the study• To investigate the possible impact of Broncho-Vaxom® on

inactivated influenza vaccine (IIV) immunogenicity by comparing humoral and cell responses to IIV in children receiving Broncho-Vaxom® or not, as well as the safety and tolerability of the vaccine itself.



Esposito S et al. Vaccine. 2014 May 7;32(22):2546-52.







The administration of both Broncho-Vaxom® and IVV in a short periodo f time appeared to be safe and well tolerated

– model decision‐making according to the clinical progress of an are included four trials double blind, randomised, placebo‐controlled

– RTIs in children – direct and indirect costs : medications, visits, consultations, x‐rays, hospitalization... absenteeism...

– For ‐1.65 episodes de ITRS evitado /niño/6 meses

–The savings for 6 monthsfueron – Family 107 Euros (‐ 41%)– Health system 48 Euros (‐ 48%) – Society 231 Euros (‐ 45%)

OM‐85 It is profitable since the rate of prevention of 7% of the children are(Suitzerland ‐16% / México ‐37% / Metaanálisis ‐35%)

OM-85 Pharmaco-economy

Zaniolo et al 2005 – Pharmaco-economy OM-85 Pediatric RTIsFarmeconomia e Percorsi Terapeutici 2005;6(3):181-194 (Italia)

In press 2013

Safety OM‐85

A long (30 years) post‐marketing experience, many pediatric trials

3.6 million patients treated per year worldwide (adults and children)

Very low incidence of adverse events identified/observed in post‐marketing experience: approximately 3 cases per 100'000 patients treated

Good tolerance AEs mainly non serious (gastrointestinal, skin) Fuente: datos en archivo OM

DATA FROM THE POST-MARKETING SAFETY AND PEDIATRIC TRIALS

OM-85 Safety profile

CONCLUSIONS / 1

• First and always: the prevention and education of parents, active immunization, non specific interventions

The effectiveness of OM-85 BV in the recurring RTIs: OM-85 BV is particularly effective in

susceptible or overexposed children Number/severity/duration of the RTIs Consumption of antibiotics (other drugs) Absenteism

CONCLUSIONS / 2

• The effectiveness of OM-85 BV in the attacks of wheezing (rate, duration) and recurrent tonsillitis (rate, need for tonsillectomy)

SAFETY of OM-85 BV Excellent tolerance and compliance Good safety - comparable to placebo profile

OM-85 / Broncho-Vaxom is effective in children

Health & Medicine

OM-85 Applicability in routine clinical practice - Professor Susanna Esposito