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Biologic use in pregnancy in Severe AsthmaDr Adel Mansur

Heart of England NHS Foundation Trust, Birmingham

UK/REZ/17/0047at Date of Preparation: June 2018

Pregnancy in Severe Asthma; the role of biological

treatments

Dr Adel H Mansur PhD FRCP

Consultant Physician and Honorary Reader

Birmingham Regional Severe Asthma Service (BRSAS)

Heartlands Hospital, Birmingham UK

www.severeasthma-birmingham.co.uk

Twitter: BRSAS@BRSAS1

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Disclosures

• Adel Mansur has received funds for talks and advisory group

meetings and was sponsored to attend national and international

conferences from various pharmaceutical companies that include:

GlaxoSmithKline, AstraZeneca UK, Novartis, Chiesi Limited, Teva UK

Limited, Boehringer Ingelheim, NAPP Pharmaceuticals Limited.

Topics

• Case history

• Outcomes of pregnancy in asthma

• Biological treatments and pregnancy

• The need for a national consensus on biological treatment in pregnancy

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Case presentation

• 34 year old female, allergic asthma and eczema from childhood

• Frequent admissions, OCS requirements despite treatment at step 4 leading to

consideration for omalizumab treatment in 2008

• 2008-2012 on omalizumab, discontinued in 2012 when found to be pregnant

Pre omalizumab Post omalizumab

OCS requiring

exacerbations

per annum

8 2

ACQ 6 4.9 2.9

FEV1 108% 91%

OCS: oral corticosteroids

ACQ6: asthma control questionnaire of 6 items

FEV1: forced expiratory volume in 1 second

Serial FEV1 (L) & FeNO (ppb)

012345

01

/09

/20

12

01

/07

/20

13

01

/05

/20

14

01

/03

/20

15

01

/01

/20

16

01

/11

/20

16

01

/09

/20

17

FEV1

FEV1 050

100150200250300

01

/09

/20

12

01

/03

/20

13

01

/09

/20

13

01

/03

/20

14

01

/09

/20

14

01

/03

/20

15

01

/09

/20

15

01

/03

/20

16

01

/09

/20

16

01

/03

/20

17

01

/09

/20

17

01

/03

/20

18

FeNO

FeNO

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Case history continued

• 2012: first pregnancy; asthma stable, but eczema flare up

• 2015: second pregnancy: struggled with allergies and asthma

requiring maintenance 5-10mg prednisolone (question raised on

treatment adherence)

• Both pregnancies were full term

• No asthma issues during delivery

BRSAS case series

Case number Treatment Pregnancy Action Outcome

1- omalizumab On treatment Stopped but recommenced after

birth

Full term delivery

(asthma ok)

2- omalizumab On treatment Stopped but recommenced Full term delivery

(asthma was difficult to

control)

3- omalizumab On treatment Stopped

(did not need to go back on it)

Miscarriage

(asthma remained stable)

4- omalizumab On treatment Stopped Full term delivery

(asthma ok)

5- mepolizumab On treatment Stopped Miscarriage

6- mepolizumab On treatment Stopped

7- mepolizumab On treatment Stopped

BRSAS: Birmingham Regional Severe Asthma Service. This case series is inclusive of patients treated at BRSAS over last 10 years.

Dr Mansur personal data (unpublished)

Pregnancy on treatment: omalizumab 4/150 (2.7%), mepolizumab▼ 3/60 (3%)

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Changes in asthma during pregnancy

Murphy VE et al. Eur Respir J 2005;25:731-750

© 2005 by European Respiratory Society

Pregnancy in Severe Asthma

• Due to female predominance and the reproductive age of Severe

Asthma patients, the challenges of pregnancy management is

arguably more of an issue than in any other chronic disease

• 45% of females experience asthma exacerbation in pregnancy

• Exacerbations are associated with adverse outcomes

Murphy VE et al. Thorax. 2006;61(2):169-176

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Frequency of acute asthma attacks

during pregnancy

0

45 5

89

6

4 4

2

0

2

4

6

8

10

1-4

weeks

5-8

weeks

9-12

weeks

13-16

weeks

17-20

weeks

21-24

weeks

25-28

weeks

29-32

weeks

33-36

weeks

37-40

weeks

Gestation (week)

Nu

mb

er

of

acu

te a

sth

ma a

ttacks

Acute asthma attacks were most frequent between weeks 17 and 24 of gestation

Stenius-Aarniala BS, Hedman J, Teramo KA. Acute asthma during pregnancy. Thorax. 1996;51:411-414

The effects of maternal asthma on

pregnancy outcome

Murphy VE et al. Eur Respir J 2005;25:731-750

© 2005 by European Respiratory Society

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Outcomes of pregnancy in asthma versus

control in large population study, presented

as odds ratio (95% CI)

Outcome All subjects

Number= 36,985

Asthma most severe

Number= 1,396

Perinatal mortality 1.21 (1.08-1.35) 1.28 (0.76-2.17)

Pre-eclampsia 1.15 (1.08-1.22) 1.42 (1.09-1.86)

Preterm birth (<37 weeks) 1.15 (1.09-1.22) 1.56 (1.27-1.90)

Low birth weight (<2500gm) 1.21 (1.14-1.29) 1.98 (1.52-2.59)

Congenital malformations 1.05 (0.99-1.10) 1.08 (0.83-1.40)

Källén B, Rydhstroem H, Aberg A. Asthma during pregnancy--a population based study. Eur J Epidemiol. 2000 ;16:167-71

Meta-analysis of cohort studies for

low birth weight

Meta-analysis of cohort studies for low birth weight. Increased risk indicates that the outcome was more likely in subjects with a history of asthma

exacerbation during pregnancy. Data are presented as relative risk (95% CI). Heterogeneity: p=0.75, I2=0%; effect: p<0.00001. #: RR 3.02 (95%

CI 1.87–4.89).

Jennifer A. Namazy et al. Eur Respir J 2013;41:1082-1090

© 2013 by European Respiratory Society

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Rates per 100 person-months of follow-up for a) hospitalisations, b)

emergency department (ED) visits and c) physician office visits for asthma,

asthma-related conditions and non-pregnancy-related conditions during the

three time periods in this study.

Teresa To et al. Eur Respir J 2018;51:1800209

© 2018 by European Respiratory Society

FDA pregnancy risk categories

prior to 2015

Category A: controlled human studies showed no risk

(e.g. levothyroxine)

Category B: animal reproduction studies no risk

No adequate human data, benefit outweighs risk (e.g. amoxicillin)

Category C: risk cannot be ruled out

Animal studies showing risk, no human data, benefit outweighs risk (e.g. amlodipine)

Category D: positive evidence of risk

Benefit may warrant use in pregnancy despite risk (e.g. lisinopril)

Category X: contraindicated in pregnancy

Studies showing foetal abnormalities, risks outweighs benefit (e.g. warfarin)

FDA 1979

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Pregnancy and lactation labelling

rule “PLLR”

FDA 2015 • Use of categories were over simplistic and led to wrong interpretation

• Did not capture the evidence behind labelling

• Advocate narrative structure for pregnancy labelling*

• Summary of risk (maternal “pregnancy and labour”, lactation,

reproductive organs)

• Discussion of data supporting that summary

• Relevant information to health care professionals to:

• Make decision on drug use in pregnancy

• Counsel patients re benefit vs risk

*https://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/SmallBusinessAssistance/UCM431132.pdf.

Accessed 3rd June 2018

1. Known or potential maternal and

foetal adverse reaction

2. Dose adjustment needed in

pregnancy and postpartum

US FDA pregnancy categories of

common asthma medicationsMedicine Category Risk Recommendation Comments

Salbutamol C Teratogenic in

animals

Benefit vs risk Cleft lip formation

Inhaled fluticasone Not assigned

B3 (TGA)

Hypoadrenalism in

neonates

Benefit vs risk Hypo-adrenalism in

neonates

Formeterol/

budesonide

(Symbicort®)

C Teratogenic in

animals

Benefit vs risk Embryocidal

Montelukast B No teratogenic

effect in animals

Harm not excluded

only use if indicated

Theophylline C Teratogenic in

animals

Benefit vs risk

Tiotropium

(Respimat®)

C Teratogenic in mice Benefit vs risk C

Prednisolone*

plain/slow release

C/D Teratogenic in

animals/and harm in

humans

Benefit vs risk Cleft palate, low

birth weight, adrenal

suppression

Methotrexate X Teratogenic in

animals and harm in

humans

Contraindicated in

pregnancy

Major defects and

stillbirth

*Not specifically licensed for the treatment of asthma

TGA: Therapeutic Goods Administration, Australian Government

https://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/SmallBusinessAssistance/UCM431132.pdf.

Accessed 4 June 2018

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Omalizumab EXPECT study

• At least one omalizumab injection within 8 weeks prior to pregnancy/

any time during pregnancy

• Rates of live births

• Elective terminations

• Stillbirths

• Congenital anomalies up to 18 months after delivery

Namazy J et al. J Allergy Clin Immunol 2015; 135:407-12

EXPECT study results

EXPECT studyΦ General populationΦPublished range (%)

Asthma populationΦ

Number studied 191 Women188 (98.4%)

exposure in 1st trimester

Exposure duration

(7.3±2.7M)

Live births 156 (160 infants)

4 twin pairs

Foetal death/stillbirth 0.6% 0.4-0.61 0-1.1Spontaneous abortion 8.6% 11-22 5.6-9.4

Elective termination 0.6%Preterm birth 14.5% 5.2-11.7 9.8-11.8

Small for gestation age 10.9% 9.2-10.5 3.9-6.1Congenital anomalies

Major defects4.4% 2.8-4.2 2.7-9.1

Conditional defect 8.8%

Ankyloglossia (6 infants)

No common pattern

*Conditional defect: common deviation from normal function. Does not require intervention

Major defects: those with cosmetic or functional significance that require intervention

Φ Namazy J et al. J Allergy Clin Immunol 2015; 135:407-12

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Omalizumab

• US FDA pregnancy category: B

No evidence of toxicity from animal studies

• Cynomolgus monkeys 75mg/kg (12 fold of MHRD)1

• No maternal or foetal toxicity 1

• Some human data (EXPECT study) demonstrating no increased harm2

• Conclusion:

• Not recommended to commence during pregnancy

• If become pregnant whilst on treatment, no need to discontinue

treatment if benefit outweighs risk

MHRD: maximum human recommended dose

1. European Public Assessment Report (EPAR): Xolair, Scientific Discussion p.11 (2005)

2. Namazy J et al. J Allergy Clin Immunol 2015; 135:407-12

Mepolizumab

• US FDA pregnancy Category: not assigned

• <300 pregnancy outcomes

• Crosses placental barrier in monkeys (no reproductive toxicity), linear

transmission worse in 2/3 trimesters (higher exposure in later

pregnancy)

• Recommendation:

• Precautionary measure: preferable to avoid use in pregnancy

• Should only be considered if expected benefit outweighs risk to

foetus

• GSK: conducting prospective study to monitor mepolizumab use and

outcomes in pregnancy*

*http://pregnancyregistry.gsk.com/mepolizumab.html Accessed 4 June 2018

MHRA: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/003860/WC500198037.pdf

Accessed 4 June 2018

FDA: https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/125526Orig1s000Lbl.pdf Accessed 4 June 2018

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Reslizumab

• US FDA pregnancy category: not assigned

• Animal study: in mice and rabbits (6 and 17 times MRHD) showed

no teratogenic effect up to 4 months after delivery

• No controlled human data

• Recommendation:

• Should only be used in pregnancy if potential benefit outweighs

risk to the foetus

https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/761033lbl.pdf Accessed 4 June 2018

Benralizumab

• Animal studies: linear transport across placenta (increases with

pregnancy progress, highest in third trimester)

• No evidence of foetal harm despite 310 times the exposure of MRHD

• Human studies: no controlled data on human pregnancy

• US FDA pregnancy category: not assigned

• Preferable to avoid use

• Risk is likely to be worse during third trimester

• Breast feeding: excretion in breast milk in animals or humans not

known

MRHD; maximum recommended human dose

http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/004433/WC500245331.pdf,

Accessed 3/06/2018

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Case for use of biologics in

pregnancy in asthma

• Other asthma treatments used despite lack of safety data

• Poor asthma control more harmful to mother and baby than the

potential of drug adverse event!

• Balance of benefit vs risk favours biologics use in pregnancy! (e.g.

risk from long-term prednisolone treatment may be worse than

biologic treatment)

Case against use of biologics in

pregnancy in asthma

• Standard good clinical care may achieve good clinical outcomes

• Unpredictable course of asthma in pregnancy (improve or worsen)

“good number of patients would improve without need for

biological treatment”

• Lack of safety data “potential harmful effect to foetus”

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Summary

• Pregnancy is a challenging period for patients with Severe Asthma

• There were no concerns overall from animal studies of biological

treatments (in contrast to many used in other asthma medications)

• However, the lack of controlled human studies is a cause of concern

(risk can not be excluded)

• In each case the potential benefit vs risk will determine the decision

to continue treatment during pregnancy or not

Way forward

• Establishment of registries to record efficacy and safety outcomes of

use of biologics in pregnancy

• The need to set up an “interest group” to inform the asthma guidelines

and establish a national unified approach

• Emphasis on pharmaceutical companies to produce the necessary

safety data for biologics use in pregnancy (e.g. ongoing GSK registry

study for mepolizumab)

• How to manage current state:

• Pregnancy testing, contraception, infertility

• Consent and disclaimer