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Division: Worldwide DevelopmentInformation Type: Worldwide Epidemiology Interim Study ReportControl: Non-Interventional.

Title: The Belimumab Pregnancy Registry

Phase: Late Phase

CompoundNumber:

Not Applicable

Effective Date: 16 November 2015

Description: A Post-Authorization Safety Study Conducted by GlaxoSmithKline

The purpose of the Belimumab Pregnancy Registry (BPR) is to evaluate pregnancy andinfant outcomes for pregnancies in women with systemic lupus erythematosus (SLE)exposed to commercially supplied belimumab within the four months prior to and/orduring pregnancy.

Subject: Pregnancy Registry

This study was performed in compliance with Good Clinical Practices, GoodPharmacoepidemiology, and GlaxoSmithKline Standard Operating Procedures for allprocesses involved, including the archiving of essential documents.

Copyright 2014 the GlaxoSmithKline group of companies. All rights reserved.Unauthorized copying or use of this information is prohibited.

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CONFIDENTIAL 2010N108011_00GlaxoSmithKline group of companies WWEpi Project # BEL114256

BPR Steering CommitteeName TitleMichelle Petri, MD,MPH1, Chair

Professor, Department of Medicine, Director, Lupus Center, Division ofRheumatology, Johns Hopkins University, Baltimore, MD

Helain Landy, MD1 Professor and Chair, Department of Obstetrics and Gynecology,Georgetown University Hospital, Department of Obstetrics &Gynecology, Washington, DC

Carl Laskin, MD1 Professor, Department of Medicine (Rheumatology) and Obstetrics &Gynecology, University of Toronto, Toronto, ON

Richard Miller, PhD1 Professor, Department of Obstetrics and Gynecology, University ofRochester School of Medicine and Dentistry

M. Anthony Moody,MD1

Assistant Professor of Pediatrics and Assistant Professor ofImmunology, Duke Human Vaccine Institute, Duke University School ofMedicine, Durham, NC

Hugh Tilson, MD,DrPH1

Adjunct Professor, Public Health Leadership, University of NorthCarolina, Gillings School of Global Public Health, Chapel Hill, NC

Jeanne Pimenta, PhD GSK Belimumab Pregnancy Registry Clinical Investigation Lead,Director, Worldwide Epidemiology

Tracie Pickler GSK Operational Science LeadLisa Edwards Associate Director, Biostatistics at PAREXELJames Groark, MD GSK Director Clinical DevelopmentTodd Rudo, MD, FACC GSK Medical Director, Safety Evaluation & Risk Management

Global Clinical Safety and PharmacovigilanceAshlyn Bassiri GSK Director, Safety Evaluation and Risk Management, Global Clinical

Safety and PharmacovigilanceAnn Mallard, MPH PPD EpidemiologistDeborah Covington,DrPH

PPD Global Head, Observational Studies & Pregnancy Registries

Laura McKain, MD PPD Principal InvestigatorPaige Churchill, BA PPD Director, Global Late Stage ResearchTammy Moore PPD Global Project Manager1Member of the Scientific Advisory Committee (SAC)

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Belimumab (Benlysta™) Pregnancy Registry: Interim Report including data up to 28th September 2015

The purpose of the Belimumab (Benlysta™) Pregnancy Registry (BPR) is to evaluate pregnancy and infant

outcomes for pregnancies in women with systemic lupus erythematosus (SLE) exposed to commercially

supplied belimumab within the four months prior to and/or during pregnancy. The primary endpoint is

birth defects, and secondary endpoints include spontaneous miscarriage, live births (including preterm

birth and birth of infants classified as small for gestational age), stillbirth, elective termination, and

serious and/or clinically significant infections in infants through one year of age.

The BPR is a global, multi-center, prospective cohort study with voluntary participant registration

following informed consent. Data are collected at registration, at the end of the second trimester of

pregnancy (approximately 26 weeks’ gestation), and at pregnancy outcome (delivery or early

termination). For live births, infant data are collected at pregnancy outcome and at four and 12 months

of age.

Since BPR started on 16 July 2012 through 28 September 2015, 30 participants consented to the BPR of

which 19 participants were deemed evaluable with a confirmed outcome (three pure prospective; 13

traditional prospective; three retrospective; see Glossary for definitions). Of the other 11 consented

participants, three participants had an ongoing pregnancy, six participants were deemed invalid or

ineligible, one participant had an unconfirmed pregnancy and exposure, and one participant was

considered lost to follow-up prior to pregnancy outcome (see Table 1.0).

The pregnancy outcomes reported in the BPR were: live birth (n=15) [includes one participant classified

as lost to follow-up after outcome which was a live birth], spontaneous miscarriage (n=3), and elective

termination (n=1) (see Table 2.0). Of all pregnancy outcomes except elective termination, seventeen

participants (three pure prospective, 13 traditional prospective; one retrospective) were exposed to

belimumab within four months prior to conception, and one retrospective participant was exposed

during the first trimester (see Tables 3.1-3.3). Of the three live pure prospective infant births, two were

full term (born at 381/7 and 383/7 weeks gestational age [GA]) and one was preterm (366/7 weeks GA)

(Table 4.0). Of the 12 live traditional prospective infant births, nine were full term (ranging from 375/7 to

404/7 weeks GA) and three were preterm (ranging from 325/7to 366/7weeks). Of the four preterm births,

the last belimumab exposure occurred during the 1st or 2nd trimester of pregnancy.

Per assessments done by the birth defect evaluator (BDE) through 28 September 2015, there was one

confirmed report of a congenital anomaly for one pure prospective participant and four reports of

congenital anomalies for three traditional prospective participants. Three additional events (non-

descending testis; patent ductus arteriosus and patent foramen ovale) were reported by health care

professionals (HCPs) for two traditional prospective participants. However, these events are still pending

BDE assessment (see Listing 1 and Listing 2). The pure prospective participant had a bilateral club foot

considered by the HCP not to be attributed to the use of belimumab and the temporality was

considered irrelevant by the evaluator. The traditional prospective participants reported the following:

A very mild Ebstein’s anomaly of the cardiac tricuspid valve considered by the HCP to be attributed to

the use of belimumab and considered by the BDE that a possible temporal association cannot be ruled

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out; one case of congenital heart block, one case of congenital hydronephrosis and one case of

ventricular septal defect all were considered by reporting HCPs to have an unknown relationship to the

use of belimumab and were considered by the BDE that a possible association cannot be ruled out. The

Scientific Advisory committee confirmed there is no known common association between the three

different heart defect events and also considered that the heart block case was unrelated to belimumab

as there was a known mechanism of anti-Ro and anti-La antibodies in the pregnancy.

There were 11 maternal serious adverse events (SAEs) reported among nine women and 17 infant SAEs

from 11 infants; these events did not indicate a trend or safety signal with Benlysta™ (see Tables 5.1-

5.2). Infant infection or fever was reported for one full-term pure prospective infant at the 4-Month

follow-up visit and one full-term pure prospective infant at the 12-Month follow-up visit. The reporting

HCPs indicated that the infections were not attributed to exposure to belimumab (Table 6.1). Infant

infection or fever was reported for one full-term traditional prospective infant at outcome and one

preterm pure prospective infant at the 12-Month follow-up visit. The HCP indicated that the attribution

of the event was unknown to exposure to belimumab for the full-term event. Attribution was not

reported for the event experienced by the preterm infant (Table 6.2).

The BPR is unique from routine pharmacovigilance pregnancy follow-up in that it collects detailed

maternal clinical characteristics at multiple time points during pregnancy and also live birth infant

outcomes through one year of age. Through 28 September 2015, there were three pure prospective

infants (two full-term infants; one preterm infant) and 10 traditional prospective infants (seven full-term

infants; three preterm infants) with completed data at the 4-Month follow-up visit (see Tables 6.1-6.2):

Eight full-term infants (two pure prospective; six traditional prospective) had no other birth

defects noted at the 4-Month follow-up visit. One traditional prospective infant had a

pending/missing birth defect status recorded at this visit. All full-term infants (two pure

prospective; seven traditional prospective) met age-appropriate developmental milestones for

gross motor skills, fine motor skills, language, cognitive, and social/emotional stages.

Four preterm infants (one pure prospective and three traditional prospective) had no other birth

defects noted at the 4-Month follow-up visits. All four preterm infants met age-appropriate

developmental milestones for fine motor skills, cognitive, and social/emotional stages. The gross

motor skill was not met for one traditional prospective infant, and the language milestone was

missing for the pure prospective infant.

Through 28 September 2015, there were three pure prospective infants (two full-term infants; one

preterm infant) and five traditional prospective infants (two full-term infants; three preterm infants)

with completed data at the 12-Month follow-up visit. No new birth defects were noted beyond what

was already reported at Outcome or the 4-Month time point. The gross motor skill, language skill, and

the social/emotional skill were each reported as not met for one traditional prospective preterm

infant.No cases of lactation exposure were received for the pure prospective participants during the

reporting period. However, one traditional prospective participant reported lactation exposure during

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the 12-month follow-up visit. No new important safety information regarding administration during

lactation has been identified during the time period.

In conclusion, overall, the types and distribution of maternal outcomes reported in the BPR are

consistent with pregnancy outcomes reported from all clinical trials and other spontaneous reports for

belimumab. No new important safety information regarding use in pregnancy has been identified from

the registry or other cases received in the reporting period.

Data from Other Sources:

Other non-registry reports of belimumab-exposed pregnancies

A cumulative summary of pregnancy outcomes from pregnancies in clinical trials, spontaneous reports

and post-marketing surveillance studies is presented in Table A. Through 22 July 2015 , the total number

of spontaneous abortions plus stillbirths / (total pregnancies with known outcomes excluding elective

terminations) in subjects treated with belimumab outside of the BPR was 37.7% (46/122) which is

consistent with the background estimated rate in patients with SLE (25-52%) [Andrade, 2008 ; Clowse,

2005; Rahman , 1998; YanYuen 2008].

A cumulative summary of live births and congenital anomalies (CA) incidence among live births is

presented in Table A. Five cases of congenital anomaly were reported as part of the BPR and are

detailed above. Four cases of congenital anomaly were reported in clinical trials outside of the BPR and

included: unbalanced translocation involving chromosomes 11 & 13 with microencephaly and

atrioventricular canal defect, Dandy Walker syndrome, oligohydramnios with bilateral enlarged severely

abnormal functioning kidneys, and a case reported as pulmonic stenosis. An in-depth review of these

cases in terms of embryological or biological considerations did not identify multiple defects of a

common nature or type that would suggest an unusual pattern of birth defects. At this time, the total

number of live births with known outcomes is not yet sufficient to make quantitative comparison of the

total occurrence of congenital anomalies compared to the SLE population (not exposed to belimumab)

or the general population.

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TABLE A Cumulative Pregnancy Outcomes from Clinical trials, Spontaneous reports, and Post-marketing Surveillance Studies through 22 July 2015

IV Completed Clinical Trialsc

SC Completed Clinical Trialsc

IV Completed or Ongoing Open-

label Clinical Trials

SC Completed or Ongoing Open-label

Clinical Trials

IV Ongoing Blinded

Clinical Trials

Outcomea,b Belimumab Placebo Belimumab Placebo Belimumab Belimumab Blinded

Total pregnancies 26 6 8 3 60 10 44

Lost to follow up or unknown 3 0 0 1 1 1 3

Pregnancy ongoing 0 0 1 1 4 1 11

Total pregnancies with known outcomes

23 6 7 1 55 8 30

Elective termination No apparent CA 6 2 1 1 15 3 17

Total pregnancies with known outcomes excluding elective terminations

17 4 6 0 40 5 13

Ectopic pregnancy 0 0 0 0 0 0 1

Spontaneous abortion No Apparent CA (<22wk)

7 3 2 0 11 0 4

Spontaneous abortion CA (<22wks) 0 0 0 0 0 0 1

Stillbirth No Apparent CA (>22wks) 1 1 0 0 0 0 1

Spontaneous abortions plus Stillbirths / (Total Pregnancies with known Outcomes excluding Elective Terminations)

8/17 (47.06) 4/4 (100.00)

2/6 (33.33) 0 11/40 (27.50) 0/5 (0.00) 6/13 (46.15)

Total Live Births (Infants) 9 0 4 0 29 5 6

Live Infant No apparent CA 8 0 4 0 27 4 6

Live Infant CA 1 0 0 0 2 1 0

CA Incidence among Live Birth 1/9 (11.11) 0 0/4 (0.00) 0 2/29 (6.90) 1/5 (20.00) 0/6 (0.00)

a. Table does not include outcomes from an egg donor exposure, or four partner pregnancies. b. Changes in the numbers of the cumulative outcomes since the previous safety update reflect the addition and follow-up obtained on previously received cases. c. Includes the completed double-blind, placebo controlled phase of BEL112341 d. Other includes spontaneous pregnancy reports and post-marketing surveillance reports outside of the belimumab pregnancy registry.

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Committee Consensus

On 16 Nov 2015, the SAC independently reviewed all data reported to the BPR as well as supplemental

data and concluded that there is insufficient information at this time to reach a conclusion about the risk

for birth defects and the secondary endpoints of interest for pregnancies exposed to commercially

supplied belimumab.

Glossary of Terms:

Term Registry Definition

Pure prospective report Pure prospective reports of pregnancy are a subset of

traditional prospective reports and include those where (a)

the enrollee did not know at the time of enrollment

whether the fetus had a malformation, and (b) no prenatal

testing was completed prior to enrollment.

Retrospective report

Retrospective reports of pregnancy are those in which the

pregnancy ended before enrollment or at the time of first

contact with the registry.

Traditional prospective report Traditional prospective reports of pregnancy will include all

women who enroll in the registry before the end of

pregnancy (live birth, fetal loss, etc), regardless of known

normal or abnormal prenatal test results.

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Protocol: BEL114256 Population: All Registry Participants Page 1 of 2

Table 1.0 Enrollment Status

Source: \\wilbtib\wilbtib07\GSK GSKBEL114256\GSK new database TL delivery\TLF\T0100 BEL114256 Interim Analysis: Generated: 02NOV2015 15:52

Note: Denominator is the total number of participants in each column (N). [1]Includes retrospective patients and/or patients with insufficient dosing data. Therefore trimester of enrollment is not defined, and columns may not add up to all registry participants. [2]Includes participants who meet the enrollment criteria and consent but commercial belimumab exposure is never confirmed. [3]Includes eligible participants where critical data remains pending, resulting in a temporary pending status. [4]Evaluable cases are cases with confirmed exposure to commercial belimumab administered within the four months preconception and/or during pregnancy and that are confirmed pregnant by any HCP [5]Pure Prospective cases are a subset of traditional prospective reports and include those where (a) the enrollee did not know at the time of enrollment whether the fetus had a malformation, and (b) no prenatal testing was completed prior to enrollment. [6]Traditional prospective cases are pregnant participants who enroll in the registry before the end of pregnancy, regardless of known normal or abnormal prenatal test results. [7]Non SLE cases are any evaluable cases where the participant has not been diagnosed with SLE upon entry into the registry. [8]Retrospective cases are reports of pregnancy in which the pregnancy ended before enrollment or at the time of the first contact with the registry. [9]Includes evaluable participants without a medically confirmed outcome, resulting in a temporary pending status.

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Table 1.0 Enrollment Status

Note: See footnotes on Page 1. Source: \\wilbtib\wilbtib07\GSK GSKBEL114256\GSK new database TL delivery\TLF\T0100 BEL114256 Interim Analysis: Generated: 02NOV2015 15:52

Trimester of Enrollment

All Registry Participants[1]

(N=30) 1st Trimester

(N=13) 2nd Trimester

(N=7) 3rd Trimester

(N=6)

All registry participants Participants previously enrolled in belimumab clinical trial

1 (3.3%) 0 1 (14.3%) 0

Participants previously enrolled in belimumab pregnancy registry

0 0 0 0

Invalid/ineligible participants[2] 6 (20.0%) 2 (15.4%) 1 (14.3%) 2 (33.3%)

Eligible participants with an unconfirmed pregnancy and exposure[3]

1 (3.3%) 0 0 1 (16.7%)

Evaluable patients with an on-going pregnancy[4] 3 (10.0%) 2 (15.4%) 1 (14.3%) 0

Evaluable participants with a confirmed outcome[4] 19 (63.3%) 8 (61.5%) 5 (71.4%) 3 (50.0%) Pure prospective cohort[5] 3 (10.0%) 2 (15.4%) 0 1 (16.7%) Traditional prospective cohort[6] 13 (43.3%) 6 (46.2%) 5 (71.4%) 2 (33.3%) Non SLE cohort[7] 0 0 0 0 Retrospective cohort[8] 3 (10.0%) NA NA NA

Evaluable participants with a medically unconfirmed outcome[9]

0 0 0 0

Participants considered lost to follow-up before pregnancy outcome

1 (3.3%) 1 (7.7%) 0 0

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Table 2.0 Registry Status

(Evaluable Participants with a Confirmed Outcome)

Source: \\wilbtib\wilbtib07\GSK GSKBEL114256\GSK new database TL delivery\TLF\T0200 BEL114256 Interim Analysis: Generated: 30OCT2015 11:40

Note: Denominator is the total number of participants in each column (N) unless otherwise noted. Live birth: the birth of a living fetus at 200/7 weeks' gestational age or greater (>=20 weeks), or, if gestational age is unknown, a fetus weighing 500 g or more (>=500 g); Neonatal death: an infant who after live birth expired within the first 28 days (<= 28 days) of life; Stillbirth: a fetal death occurring at 200/7 weeks' gestational age or greater (>=20 weeks), or, if gestational age is unknown, a fetus weighing 500 g or more (>=500 g); Spontaneous miscarriage: fetal death or expulsion of products of conception prior to 20 weeks' ( < 20 weeks) gestation Elective termination: voluntary interruption of pregnancy, including pregnancy termination that occurs electively, to preserve maternal health, or due to fetal abnormalities; Ectopic pregnancy: implantation of a conception outside of the uterus; Molar pregnancy: a conception that results in a gestational trophoblastic tumor. [1]Completed registry participation is defined as pregnancy outcome is known and if a live birth, follow-up has been completed through month 12. [2]Denominator is the number of participants completing the belimumab registry. [3]Pediatric follow-up time points are not mutually exclusive. Therefore, percentages may add up to more than 100%. [4]Denominator is the number of live births, pediatric follow-up pending.

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Table 2.0 Registry Status

(Evaluable Participants with a Confirmed Outcome)

Note: See footnotes on Page 1. Source: \\wilbtib\wilbtib07\GSK GSKBEL114256\GSK new database TL delivery\TLF\T0200 BEL114256 Interim Analysis: Generated: 30OCT2015 11:40

Pure Prospective

(N=3)

Traditional Prospective

(N=13) Non SLE (N=0)

Retrospective(N=3)

Registry participation complete[1] 3 (100.0%) 6 (46.2%) 0 3 (100.0%) Live birth, pediatric follow-up complete[2] 3 (100.0%) 5 (83.3%) 0 0 Neonatal death[2] 0 0 0 0 Stillbirth[2] 0 0 0 0 Spontaneous miscarriage[2] 0 1 (16.7%) 0 2 (66.7%) Elective termination[2] 0 0 0 1 (33.3%) Ectopic pregnancy[2] 0 0 0 0 Molar pregnancy[2] 0 0 0 0

Live birth, pediatric follow-up pending[3] 0 6 (46.2%) 0 0 Pediatric outcome pending[4] 0 1 (16.7%) 0 0 4 month follow-up pending[4] 0 1 (16.7%) 0 0 12 month follow-up pending[4] 0 6 (100.0%) 0 0

Lost to follow-up after pregnancy outcome/incomplete pediatric follow-up

0 1 (7.7%) 0 0

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Table 3.1 Exposures of Participants with Known Pregnancy Outcome

(Pure Prospective Cohort)


Note: Denominator is the total number of participants in each column (N). Exposure is defined as at least one dose during the period of observation (6 months prior to/during pregnancy for concomitant medications and 4 months prior to/during pregnancy for commercial belimumab) and does not imply continued use throughout the period of observation. Preconception is defined as six months prior to pregnancy for concomitant medications and 4 months prior to/during pregnancy for commercial belimumab). Participants may be presented in one or several time points and may be exposed to one or several medications; therefore, percentages may not add to 100%. For Rituximab and Anti-Malarials half-lives are assessed to determine the trimester of exposure. ACE inhibitors=angiotensin-converting-enzyme inhibitors; NSAIDs=non-steroidal anti-inflammatory drugs. SAB=spontaneous miscarriage. SGA=small for gestational age. [1]Total includes spontaneous miscarriages, stillbirths and live births. [2]Small for gestational age is defined as live births whose birth weight lies below the 10th percentile for that gestational age based on WHO reference data [Williams]. [3]Small for gestational age is defined as live births whose birth weight lies below the 10th percentile for that gestational age based on reference data [Alexander]. [4]Preconception occurs within 4 months prior to conception. The first trimester begins the day after date of conception, the second trimester begins at week 140/7 after the date of conception, and the third trimester begins at week 280/7. [5]Defined by the first or last recorded exposure with a non-missing treatment date. [6]Includes azathioprine, cyclophosphamide, methotrexate, mycophenolate, cyclosporin, and rituximab.

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Total[1] (N=3)

SAB (N=0)

Still- births (N=0)

Live Births (N=3)

Preterm (N=1)

SGA[2] (N=0)

SGA[3] (N=0)

Birth Defects (N=1)

Earliest Belimumab exposure [4,5] Preconception 3(100.0%) 0 0 3(100.0%) 1(100.0%) 0 0 1(100.0%) 1st trimester 0 0 0 0 0 0 0 0 2nd trimester 0 0 0 0 0 0 0 0 3rd trimester 0 0 0 0 0 0 0 0

Last Belimumab exposure [4,5] Preconception 0 0 0 0 0 0 0 0 1st trimester 0 0 0 0 0 0 0 0 2nd trimester 2(66.7%) 0 0 2(66.7%) 1(100.0%) 0 0 1(100.0%) 3rd trimester 0 0 0 0 0 0 0 0

Postpartum 1(33.3%) 0 0 1(33.3%) 0 0 0 0

Total Belimumab doses (preconception through outcome) n 3 0 0 3 1 0 0 1 Mean (SD) 4.0

(2.00) - - 4.0

(2.00) 6.0 ( - )

- - 4.0 ( - )

Median 4.0 - - 4.0 6.0 - - 4.0 Min - Max 2 - 6 - - 2 - 6 6 - 6 - - 4 - 4 Q1, Q3 2.0,

6.0 - - 2.0,

6.0 6.0, 6.0

- - 4.0, 4.0

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Total[1] (N=3)

SAB (N=0)

Still- births (N=0)

Live Births (N=3)

Preterm (N=1)

SGA[2] (N=0)

SGA[3] (N=0)

Birth Defects (N=1)

Cumulative exposure, days n 3 0 0 3 1 0 0 1 Mean (SD) 324.0

(205.67) - - 324.0

(205.67) 264.0 ( - )

- - 155.0 ( - )

Median 264.0 - - 264.0 264.0 - - 155.0 Min - Max 155 - 553 - - 155 - 553 264 - 264 - - 155 - 155 Q1, Q3 155.0,

553.0 - - 155.0,

553.0 264.0, 264.0

- - 155.0, 155.0

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Total[1] (N=3)

SAB (N=0)

Still- births (N=0)

Live Births (N=3)

Preterm (N=1)

SGA[2] (N=0)

SGA[3] (N=0)

Birth Defects (N=1)

Other exposures during pregnancy Corticosteroids (FOR SLE ONLY)

3(100.0%) 0 0 3(100.0%) 1(100.0%) 0 0 1(100.0%)

Preconception 3(100.0%) 0 0 3(100.0%) 1(100.0%) 0 0 1(100.0%) During pregnancy 3(100.0%) 0 0 3(100.0%) 1(100.0%) 0 0 1(100.0%)

1st Trimester 3(100.0%) 0 0 3(100.0%) 1(100.0%) 0 0 1(100.0%) 2nd Trimester 3(100.0%) 0 0 3(100.0%) 1(100.0%) 0 0 1(100.0%) 3rd Trimester 3(100.0%) 0 0 3(100.0%) 1(100.0%) 0 0 1(100.0%)

NSAIDS 0 0 0 0 0 0 0 0 Preconception 0 0 0 0 0 0 0 0 During pregnancy 0 0 0 0 0 0 0 0

1st Trimester 0 0 0 0 0 0 0 0 2nd Trimester 0 0 0 0 0 0 0 0 3rd Trimester 0 0 0 0 0 0 0 0

Anti-malarials 2(66.7%) 0 0 2(66.7%) 0 0 0 1(100.0%) Preconception 2(66.7%) 0 0 2(66.7%) 0 0 0 1(100.0%) During pregnancy 2(66.7%) 0 0 2(66.7%) 0 0 0 1(100.0%)

1st Trimester 2(66.7%) 0 0 2(66.7%) 0 0 0 1(100.0%) 2nd Trimester 2(66.7%) 0 0 2(66.7%) 0 0 0 1(100.0%) 3rd Trimester 2(66.7%) 0 0 2(66.7%) 0 0 0 1(100.0%)

Folate 2(66.7%) 0 0 2(66.7%) 0 0 0 1(100.0%) Preconception 2(66.7%) 0 0 2(66.7%) 0 0 0 1(100.0%) During pregnancy 2(66.7%) 0 0 2(66.7%) 0 0 0 1(100.0%)

1st Trimester 2(66.7%) 0 0 2(66.7%) 0 0 0 1(100.0%)

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Total[1] (N=3)

SAB (N=0)

Still- births (N=0)

Live Births (N=3)

Preterm (N=1)

SGA[2] (N=0)

SGA[3] (N=0)

Birth Defects (N=1)

2nd Trimester 2(66.7%) 0 0 2(66.7%) 0 0 0 1(100.0%) 3rd Trimester 2(66.7%) 0 0 2(66.7%) 0 0 0 1(100.0%)

Ace Inhibitors 0 0 0 0 0 0 0 0 Preconception 0 0 0 0 0 0 0 0 During pregnancy 0 0 0 0 0 0 0 0


Calcium Channel Blockers

0 0 0 0 0 0 0 0

Preconception 0 0 0 0 0 0 0 0 During pregnancy 0 0 0 0 0 0 0 0


Beta Blockers 0 0 0 0 0 0 0 0 Preconception 0 0 0 0 0 0 0 0 During pregnancy 0 0 0 0 0 0 0 0


Angiotensin II Receptor Antagonists

0 0 0 0 0 0 0 0

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Total[1] (N=3)

SAB (N=0)

Still- births (N=0)

Live Births (N=3)

Preterm (N=1)

SGA[2] (N=0)

SGA[3] (N=0)

Birth Defects (N=1)



Insulin 0 0 0 0 0 0 0 0 Preconception 0 0 0 0 0 0 0 0 During pregnancy 0 0 0 0 0 0 0 0


Heparin 0 0 0 0 0 0 0 0 Preconception 0 0 0 0 0 0 0 0 During pregnancy 0 0 0 0 0 0 0 0


Aspirin 0 0 0 0 0 0 0 0 Preconception 0 0 0 0 0 0 0 0 During pregnancy 0 0 0 0 0 0 0 0


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Total[1] (N=3)

SAB (N=0)

Still- births (N=0)

Live Births (N=3)

Preterm (N=1)

SGA[2] (N=0)

SGA[3] (N=0)

Birth Defects (N=1)

Epilepsy Medication

0 0 0 0 0 0 0 0



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Total[1] (N=3)

SAB (N=0)

Still- births (N=0)

Live Births (N=3)

Preterm (N=1)

SGA[2] (N=0)

SGA[3] (N=0)

Birth Defects (N=1)

Other Immunosuppressants[6]

0 0 0 0 0 0 0 0



Azathioprine 0 0 0 0 0 0 0 0 Preconception 0 0 0 0 0 0 0 0 During pregnancy 0 0 0 0 0 0 0 0


Cyclophosphamide 0 0 0 0 0 0 0 0 Preconception 0 0 0 0 0 0 0 0 During pregnancy 0 0 0 0 0 0 0 0


Methotrexate 0 0 0 0 0 0 0 0 Preconception 0 0 0 0 0 0 0 0 During pregnancy 0 0 0 0 0 0 0 0


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Total[1] (N=3)

SAB (N=0)

Still- births (N=0)

Live Births (N=3)

Preterm (N=1)

SGA[2] (N=0)

SGA[3] (N=0)

Birth Defects (N=1)

Mycophenolate 0 0 0 0 0 0 0 0 Preconception 0 0 0 0 0 0 0 0 During pregnancy 0 0 0 0 0 0 0 0


Cyclosporin 0 0 0 0 0 0 0 0 Preconception 0 0 0 0 0 0 0 0 During pregnancy 0 0 0 0 0 0 0 0


Rituximab 0 0 0 0 0 0 0 0 Preconception 0 0 0 0 0 0 0 0 During pregnancy 0 0 0 0 0 0 0 0


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(Traditional Prospective Cohort)


Note: Denominator is the total number of participants in each column (N). Exposure is defined as at least one dose during the period of observation (6 months prior to/during pregnancy for concomitant medications and 4 months prior to/during pregnancy for commercial belimumab) and does not imply continued use throughout the period of observation. Preconception is defined as six months prior to pregnancy for concomitant medications and 4 months prior to/during pregnancy for commercial belimumab). Participants may be presented in one or several time points and may be exposed to one or several medications; therefore, percentages may not add to 100%. For Rituximab and Anti-Malarials half-lives are assessed to determine the trimester of exposure. ACE inhibitors=angiotensin-converting-enzyme inhibitors; NSAIDs=non-steroidal anti-inflammatory drugs. SAB=spontaneous miscarriage. SGA=small for gestational age. [1]Total includes spontaneous miscarriages, stillbirths and live births. [2]Small for gestational age is defined as live births whose birth weight lies below the 10th percentile for that gestational age based on WHO reference data [Williams]. [3]Small for gestational age is defined as live births whose birth weight lies below the 10th percentile for that gestational age based on reference data [Alexander]. [4]Preconception occurs within 4 months prior to conception. The first trimester begins the day after date of conception, the second trimester begins at week 140/7 after the date of conception, and the third trimester begins at week 280/7. [5]Defined by the last recorded exposure with a non-missing treatment date. [6]Includes azathioprine, cyclophosphamide, methotrexate, mycophenolate, cyclosporin, and rituximab.

23






Total[1] (N=13)

SAB (N=1)

Still- births (N=0)

Live Births (N=12)

Preterm (N=3)

SGA[2] (N=2)

SGA[3] (N=3)

Birth Defects (N=3)

Earliest Belimumab exposure [4,5] Preconception 13(100.0%) 1(100.0%) 0 12(100.0%) 3(100.0%) 2(100.0%) 3(100.0%) 3(100.0%) 1st trimester 0 0 0 0 0 0 0 0 2nd trimester 0 0 0 0 0 0 0 0 3rd trimester 0 0 0 0 0 0 0 0

Last Belimumab exposure [4,5] Preconception 0 0 0 0 0 0 0 0 1st trimester 1(7.7%) 0 0 1(8.3%) 1(33.3%) 0 0 0 2nd trimester 8(61.5%) 0 0 8(66.7%) 1(33.3%) 2(100.0%) 2(66.7%) 2(66.7%) 3rd trimester 1(7.7%) 0 0 1(8.3%) 0 0 0 0

Postpartum 3(23.1%) 1(100.0%) 0 2(16.7%) 1(33.3%) 0 1(33.3%) 1(33.3%)


(4.32) 8.0 ( - )

- 6.9 (4.50)

7.3 (7.57)

4.5 (0.71)

7.7 (5.51)

8.3 (6.66)

Median 6.0 8.0 - 5.5 4.0 4.5 5.0 5.0 Min - Max 2 - 16 8 - 8 - 2 - 16 2 - 16 4 - 5 4 - 14 4 - 16 Q1, Q3 4.0,

9.0 8.0, 8.0

- 3.5, 9.5

2.0, 16.0

4.0, 5.0

4.0, 14.0

4.0, 16.0

24






Total[1] (N=13)

SAB (N=1)

Still- births (N=0)

Live Births (N=12)

Preterm (N=3)

SGA[2] (N=2)

SGA[3] (N=3)

Birth Defects (N=3)


(126.20) 306.0 ( - )

- 272.9 (131.46)

284.7 (220.01)

204.0 (11.31)

290.7 (150.32)

315.0 (192.42)

Median 254.0 306.0 - 233.0 184.0 204.0 212.0 212.0 Min - Max 129 - 537 306 - 306 - 129 - 537 133 - 537 196 - 212 196 - 464 196 - 537 Q1, Q3 184.0,

348.0 306.0, 306.0

- 173.5, 353.5

133.0, 537.0

196.0, 212.0

196.0, 464.0

196.0, 537.0

25






Total[1] (N=13)

SAB (N=1)

Still- births (N=0)

Live Births (N=12)

Preterm (N=3)

SGA[2] (N=2)

SGA[3] (N=3)

Birth Defects (N=3)


13(100.0%) 1(100.0%) 0 12(100.0%) 3(100.0%) 2(100.0%) 3(100.0%) 3(100.0%)

Preconception 13(100.0%) 1(100.0%) 0 12(100.0%) 3(100.0%) 2(100.0%) 3(100.0%) 3(100.0%) During pregnancy 12(92.3%) 0 0 12(100.0%) 3(100.0%) 2(100.0%) 3(100.0%) 3(100.0%)

1st Trimester 12(92.3%) 0 0 12(100.0%) 3(100.0%) 2(100.0%) 3(100.0%) 3(100.0%) 2nd Trimester 11(84.6%) 0 0 11(91.7%) 3(100.0%) 2(100.0%) 3(100.0%) 3(100.0%) 3rd Trimester 10(76.9%) 0 0 10(83.3%) 3(100.0%) 2(100.0%) 3(100.0%) 3(100.0%)

NSAIDS 8(61.5%) 0 0 8(66.7%) 2(66.7%) 2(100.0%) 3(100.0%) 2(66.7%) Preconception 7(53.8%) 0 0 7(58.3%) 1(33.3%) 2(100.0%) 3(100.0%) 2(66.7%) During pregnancy 7(53.8%) 0 0 7(58.3%) 1(33.3%) 2(100.0%) 3(100.0%) 2(66.7%)


Anti-malarials 12(92.3%) 1(100.0%) 0 11(91.7%) 3(100.0%) 2(100.0%) 3(100.0%) 3(100.0%) Preconception 12(92.3%) 1(100.0%) 0 11(91.7%) 3(100.0%) 2(100.0%) 3(100.0%) 3(100.0%) During pregnancy 12(92.3%) 1(100.0%) 0 11(91.7%) 3(100.0%) 2(100.0%) 3(100.0%) 3(100.0%)

1st Trimester 12(92.3%) 1(100.0%) 0 11(91.7%) 3(100.0%) 2(100.0%) 3(100.0%) 3(100.0%) 2nd Trimester 12(92.3%) 1(100.0%) 0 11(91.7%) 3(100.0%) 2(100.0%) 3(100.0%) 3(100.0%) 3rd Trimester 12(92.3%) 1(100.0%) 0 11(91.7%) 3(100.0%) 2(100.0%) 3(100.0%) 3(100.0%)

Folate 9(69.2%) 1(100.0%) 0 8(66.7%) 1(33.3%) 2(100.0%) 3(100.0%) 2(66.7%) Preconception 7(53.8%) 1(100.0%) 0 6(50.0%) 1(33.3%) 1(50.0%) 2(66.7%) 1(33.3%) During pregnancy 8(61.5%) 0 0 8(66.7%) 1(33.3%) 2(100.0%) 3(100.0%) 2(66.7%)

1st Trimester 8(61.5%) 0 0 8(66.7%) 1(33.3%) 2(100.0%) 3(100.0%) 2(66.7%)

26






Total[1] (N=13)

SAB (N=1)

Still- births (N=0)

Live Births (N=12)

Preterm (N=3)

SGA[2] (N=2)

SGA[3] (N=3)

Birth Defects (N=3)

2nd Trimester 8(61.5%) 0 0 8(66.7%) 1(33.3%) 2(100.0%) 3(100.0%) 2(66.7%) 3rd Trimester 8(61.5%) 0 0 8(66.7%) 1(33.3%) 2(100.0%) 3(100.0%) 2(66.7%)

Ace Inhibitors 1(7.7%) 0 0 1(8.3%) 1(33.3%) 0 0 1(33.3%) Preconception 1(7.7%) 0 0 1(8.3%) 1(33.3%) 0 0 1(33.3%) During pregnancy 0 0 0 0 0 0 0 0



1(7.7%) 0 0 1(8.3%) 0 0 0 0

Preconception 1(7.7%) 0 0 1(8.3%) 0 0 0 0 During pregnancy 1(7.7%) 0 0 1(8.3%) 0 0 0 0

1st Trimester 1(7.7%) 0 0 1(8.3%) 0 0 0 0 2nd Trimester 1(7.7%) 0 0 1(8.3%) 0 0 0 0 3rd Trimester 0 0 0 0 0 0 0 0

Beta Blockers 1(7.7%) 0 0 1(8.3%) 0 0 0 0 Preconception 1(7.7%) 0 0 1(8.3%) 0 0 0 0 During pregnancy 1(7.7%) 0 0 1(8.3%) 0 0 0 0

1st Trimester 0 0 0 0 0 0 0 0 2nd Trimester 1(7.7%) 0 0 1(8.3%) 0 0 0 0 3rd Trimester 1(7.7%) 0 0 1(8.3%) 0 0 0 0


0 0 0 0 0 0 0 0

27






Total[1] (N=13)

SAB (N=1)

Still- births (N=0)

Live Births (N=12)

Preterm (N=3)

SGA[2] (N=2)

SGA[3] (N=3)

Birth Defects (N=3)





Heparin 3(23.1%) 0 0 3(25.0%) 1(33.3%) 1(50.0%) 1(33.3%) 2(66.7%) Preconception 2(15.4%) 0 0 2(16.7%) 1(33.3%) 1(50.0%) 1(33.3%) 2(66.7%) During pregnancy 3(23.1%) 0 0 3(25.0%) 1(33.3%) 1(50.0%) 1(33.3%) 2(66.7%)


Aspirin 6(46.2%) 0 0 6(50.0%) 1(33.3%) 1(50.0%) 2(66.7%) 2(66.7%) Preconception 3(23.1%) 0 0 3(25.0%) 1(33.3%) 0 1(33.3%) 1(33.3%) During pregnancy 6(46.2%) 0 0 6(50.0%) 1(33.3%) 1(50.0%) 2(66.7%) 2(66.7%)


28






Total[1] (N=13)

SAB (N=1)

Still- births (N=0)

Live Births (N=12)

Preterm (N=3)

SGA[2] (N=2)

SGA[3] (N=3)

Birth Defects (N=3)

Epilepsy Medication

1(7.7%) 0 0 1(8.3%) 0 0 0 0

Preconception 1(7.7%) 0 0 1(8.3%) 0 0 0 0 During pregnancy 1(7.7%) 0 0 1(8.3%) 0 0 0 0

1st Trimester 1(7.7%) 0 0 1(8.3%) 0 0 0 0 2nd Trimester 0 0 0 0 0 0 0 0 3rd Trimester 0 0 0 0 0 0 0 0

29






Total[1] (N=13)

SAB (N=1)

Still- births (N=0)

Live Births (N=12)

Preterm (N=3)

SGA[2] (N=2)

SGA[3] (N=3)

Birth Defects (N=3)


8(61.5%) 1(100.0%) 0 7(58.3%) 2(66.7%) 1(50.0%) 2(66.7%) 1(33.3%)

Preconception 7(53.8%) 1(100.0%) 0 6(50.0%) 1(33.3%) 1(50.0%) 2(66.7%) 1(33.3%) During pregnancy 5(38.5%) 0 0 5(41.7%) 1(33.3%) 1(50.0%) 1(33.3%) 1(33.3%)


Azathioprine 5(38.5%) 0 0 5(41.7%) 2(66.7%) 1(50.0%) 1(33.3%) 1(33.3%) Preconception 3(23.1%) 0 0 3(25.0%) 1(33.3%) 1(50.0%) 1(33.3%) 1(33.3%) During pregnancy 3(23.1%) 0 0 3(25.0%) 1(33.3%) 1(50.0%) 1(33.3%) 1(33.3%)




Methotrexate 3(23.1%) 1(100.0%) 0 2(16.7%) 1(33.3%) 0 0 0 Preconception 3(23.1%) 1(100.0%) 0 2(16.7%) 1(33.3%) 0 0 0 During pregnancy 2(15.4%) 0 0 2(16.7%) 1(33.3%) 0 0 0

1st Trimester 2(15.4%) 0 0 2(16.7%) 1(33.3%) 0 0 0 2nd Trimester 1(7.7%) 0 0 1(8.3%) 0 0 0 0 3rd Trimester 0 0 0 0 0 0 0 0

30






Total[1] (N=13)

SAB (N=1)

Still- births (N=0)

Live Births (N=12)

Preterm (N=3)

SGA[2] (N=2)

SGA[3] (N=3)

Birth Defects (N=3)

Mycophenolate 1(7.7%) 0 0 1(8.3%) 0 0 1(33.3%) 0 Preconception 1(7.7%) 0 0 1(8.3%) 0 0 1(33.3%) 0 During pregnancy 0 0 0 0 0 0 0 0


Cyclosporin 1(7.7%) 0 0 1(8.3%) 0 0 0 0 Preconception 1(7.7%) 0 0 1(8.3%) 0 0 0 0 During pregnancy 1(7.7%) 0 0 1(8.3%) 0 0 0 0

1st Trimester 1(7.7%) 0 0 1(8.3%) 0 0 0 0 2nd Trimester 1(7.7%) 0 0 1(8.3%) 0 0 0 0 3rd Trimester 1(7.7%) 0 0 1(8.3%) 0 0 0 0



31




(Retrospective Cohort)


Note: Denominator is the total number of participants in each column (N). Exposure is defined as at least one dose during the period of observation (6 months prior to/during pregnancy for concomitant medications and 4 months prior to/during pregnancy for commercial belimumab) and does not imply continued use throughout the period of observation. Preconception is defined as six months prior to pregnancy for concomitant medications and 4 months prior to/during pregnancy for commercial belimumab). Participants may be presented in one or several time points and may be exposed to one or several medications; therefore, percentages may not add to 100%. For Rituximab and Anti-Malarials half-lives are assessed to determine the trimester of exposure. Reports of pregnancy in which the pregnancy outcome or anticipated outcome is already known before enrollment can be biased toward the reporting of more unusual or severe cases compared to women whose pregnancy outcome is not yet known at the time of enrollment into the pregnancy registry. Therefore, rates of outcomes cannot be calculated from these data. However, a series of reported birth defects can be evaluated to detect patterns of specific birth defects and can assist with identification of potential early signals of therapy risks. ACE inhibitors=angiotensin-converting-enzyme inhibitors; NSAIDs=non-steroidal anti-inflammatory drugs. SAB=spontaneous miscarriage. SGA=small for gestational age. [1]Total includes spontaneous miscarriages, stillbirths and live births. [2]Small for gestational age is defined as live births whose birth weight lies below the 10th percentile for that gestational age based on WHO reference data [Williams]. [3]Small for gestational age is defined as live births whose birth weight lies below the 10th percentile for that gestational age based on reference data [Alexander]. [4]Preconception occurs within 4 months prior to conception. The first trimester begins the day after date of conception, the second trimester begins at week 140/7 after the date of conception, and the third trimester begins at week 280/7. [5]Defined by the last recorded exposure with a non-missing treatment date. [6]Includes azathioprine, cyclophosphamide, methotrexate, mycophenolate, cyclosporin, and rituximab.

32






Total[1] (N=2)

SAB (N=2)

Still- births (N=0)

Live Births (N=0)

Preterm (N=0)

SGA[2] (N=0)

SGA[3] (N=0)

Birth Defects (N=0)

Earliest Belimumab exposure [4,5] Preconception 1(50.0%) 1(50.0%) 0 0 0 0 0 0 1st trimester 1(50.0%) 1(50.0%) 0 0 0 0 0 0 2nd trimester 0 0 0 0 0 0 0 0 3rd trimester 0 0 0 0 0 0 0 0

Last Belimumab exposure [4,5] Preconception 0 0 0 0 0 0 0 0 1st trimester 0 0 0 0 0 0 0 0 2nd trimester 0 0 0 0 0 0 0 0 3rd trimester 0 0 0 0 0 0 0 0

Postpartum 2(100.0%) 2(100.0%) 0 0 0 0 0 0


(2.12) 1.5 (2.12)

- - - - - -

Median 1.5 1.5 - - - - - - Min - Max 0 - 3 0 - 3 - - - - - - Q1, Q3 0.0,

3.0 0.0, 3.0

- - - - - -

33






Total[1] (N=2)

SAB (N=2)

Still- births (N=0)

Live Births (N=0)

Preterm (N=0)

SGA[2] (N=0)

SGA[3] (N=0)

Birth Defects (N=0)


(94.05) 194.5 (94.05)

- - - - - -

Median 194.5 194.5 - - - - - - Min - Max 128 - 261 128 - 261 - - - - - - Q1, Q3 128.0,

261.0 128.0, 261.0

- - - - - -

34






Total[1] (N=2)

SAB (N=2)

Still- births (N=0)

Live Births (N=0)

Preterm (N=0)

SGA[2] (N=0)

SGA[3] (N=0)

Birth Defects (N=0)


2(100.0%) 2(100.0%) 0 0 0 0 0 0

Preconception 2(100.0%) 2(100.0%) 0 0 0 0 0 0 During pregnancy 2(100.0%) 2(100.0%) 0 0 0 0 0 0

1st Trimester 2(100.0%) 2(100.0%) 0 0 0 0 0 0 2nd Trimester 2(100.0%) 2(100.0%) 0 0 0 0 0 0 3rd Trimester 2(100.0%) 2(100.0%) 0 0 0 0 0 0

NSAIDS 1(50.0%) 1(50.0%) 0 0 0 0 0 0 Preconception 1(50.0%) 1(50.0%) 0 0 0 0 0 0 During pregnancy 0 0 0 0 0 0 0 0


Anti-malarials 1(50.0%) 1(50.0%) 0 0 0 0 0 0 Preconception 1(50.0%) 1(50.0%) 0 0 0 0 0 0 During pregnancy 1(50.0%) 1(50.0%) 0 0 0 0 0 0


Folate 0 0 0 0 0 0 0 0 Preconception 0 0 0 0 0 0 0 0 During pregnancy 0 0 0 0 0 0 0 0

1st Trimester 0 0 0 0 0 0 0 0

35






Total[1] (N=2)

SAB (N=2)

Still- births (N=0)

Live Births (N=0)

Preterm (N=0)

SGA[2] (N=0)

SGA[3] (N=0)

Birth Defects (N=0)

2nd Trimester 0 0 0 0 0 0 0 0 3rd Trimester 0 0 0 0 0 0 0 0

Ace Inhibitors 0 0 0 0 0 0 0 0 Preconception 0 0 0 0 0 0 0 0 During pregnancy 0 0 0 0 0 0 0 0



0 0 0 0 0 0 0 0



Beta Blockers 1(50.0%) 1(50.0%) 0 0 0 0 0 0 Preconception 1(50.0%) 1(50.0%) 0 0 0 0 0 0 During pregnancy 1(50.0%) 1(50.0%) 0 0 0 0 0 0

1st Trimester 1(50.0%) 1(50.0%) 0 0 0 0 0 0 2nd Trimester 0 0 0 0 0 0 0 0 3rd Trimester 0 0 0 0 0 0 0 0


0 0 0 0 0 0 0 0

36






Total[1] (N=2)

SAB (N=2)

Still- births (N=0)

Live Births (N=0)

Preterm (N=0)

SGA[2] (N=0)

SGA[3] (N=0)

Birth Defects (N=0)





Heparin 0 0 0 0 0 0 0 0 Preconception 0 0 0 0 0 0 0 0 During pregnancy 0 0 0 0 0 0 0 0


Aspirin 0 0 0 0 0 0 0 0 Preconception 0 0 0 0 0 0 0 0 During pregnancy 0 0 0 0 0 0 0 0


37






Total[1] (N=2)

SAB (N=2)

Still- births (N=0)

Live Births (N=0)

Preterm (N=0)

SGA[2] (N=0)

SGA[3] (N=0)

Birth Defects (N=0)

Epilepsy Medication

0 0 0 0 0 0 0 0



38






Total[1] (N=2)

SAB (N=2)

Still- births (N=0)

Live Births (N=0)

Preterm (N=0)

SGA[2] (N=0)

SGA[3] (N=0)

Birth Defects (N=0)


2(100.0%) 2(100.0%) 0 0 0 0 0 0

Preconception 2(100.0%) 2(100.0%) 0 0 0 0 0 0 During pregnancy 2(100.0%) 2(100.0%) 0 0 0 0 0 0


Azathioprine 0 0 0 0 0 0 0 0 Preconception 0 0 0 0 0 0 0 0 During pregnancy 0 0 0 0 0 0 0 0




Methotrexate 1(50.0%) 1(50.0%) 0 0 0 0 0 0 Preconception 1(50.0%) 1(50.0%) 0 0 0 0 0 0 During pregnancy 1(50.0%) 1(50.0%) 0 0 0 0 0 0

1st Trimester 1(50.0%) 1(50.0%) 0 0 0 0 0 0 2nd Trimester 0 0 0 0 0 0 0 0 3rd Trimester 0 0 0 0 0 0 0 0

39






Total[1] (N=2)

SAB (N=2)

Still- births (N=0)

Live Births (N=0)

Preterm (N=0)

SGA[2] (N=0)

SGA[3] (N=0)

Birth Defects (N=0)

Mycophenolate 0 0 0 0 0 0 0 0 Preconception 0 0 0 0 0 0 0 0 During pregnancy 0 0 0 0 0 0 0 0


Cyclosporin 1(50.0%) 1(50.0%) 0 0 0 0 0 0 Preconception 1(50.0%) 1(50.0%) 0 0 0 0 0 0 During pregnancy 1(50.0%) 1(50.0%) 0 0 0 0 0 0




40



Table 4.0 Live Birth Outcome Characteristics

(Pure Prospective, Traditional Prospective, Retrospective Cohorts


Note: Each infant of a multiple live birth is counted separately. n is the total number of non-missing responses. Anti-ds=anti-double-stranded; LAC=lupus anticoagulant; max=maximum; min=minimum; Q=quartile; NSAIDs=non-steroidal anti-inflammatory drugs; SD= standard deviation. [1]Small for gestational age is defined as live births whose birth weight lies below the 10th percentile for that gestational age based on WHO reference data [Williams]. [2]Small for gestational age is defined as live births whose birth weight lies below the 10th percentile for that gestational age based on reference data [Alexander]. [3]Denominator is the number of live births per cohort. Each infant of a multiple live birth will be counted separately. [4]Not all preterm births will be classified as early or late preterm. Therefore, percentages for early and late preterm will not add up to 100.0% [5]Low birth weight is defined as a birth weight less than 2500 grams among infants. Full-Term low birth weight defined as infants born at >=370/7 weeks'gestational age weighing less than 2500 grams. Preterm low birth weight is defined as infants born at <370/7 weeks'gestational age weighing less than 2500 grams. Multiple gestations are excluded. [6]Defined by the last recorded exposure with a non-missing treatment date.

41






Live Births All Live Births Full-Term Preterm SGA[1] SGA[2]

Pure Prospective Cohort 3 2 1 0 0 Delivery method[3] Normal vaginal 0 0 0 0 0 Cesarean 3 (100.0%) 2 (100.0%) 1 (100.0%) 0 0

Live births[3] Singleton 3 (100.0%) 2 (100.0%) 1 (100.0%) 0 0 Twin 0 0 0 0 0 Triplet 0 0 0 0 0 Other 0 0 0 0 0

Gender[3] Male 3 (100.0%) 2 (100.0%) 1 (100.0%) 0 0 Female 0 0 0 0 0 Ambiguous Gender 0 0 0 0 0

Gestational age at birth (weeks) n 3 2 1 0 0 Mean (SD) 37.81 (0.837) 38.29 (0.202) 36.86 ( - ) - - Median 38.14 38.29 36.86 - - Min - Max 36.9 - 38.4 38.1 - 38.4 36.9 - 36.9 - - Q1, Q3 36.86, 38.43 38.14, 38.43 36.86, 36.86 - -

42







Pure Prospective Cohort 3 2 1 0 0 Preterm[4] 1 (33.3%) NA 1 (100.0%) 0 0 Early preterm (<280/7 weeks) 0 0 0 0 Late preterm (340/7 weeks - 366/7 weeks)

1 (33.3%) 1 (100.0%) 0 0

Full-Term 2 (66.7%) 2 (100.0%) NA 0 0 Early term (370/7 weeks – 386/7 weeks)

2 (66.7%) 2 (100.0%) 0 0

Full term (390/7 weeks – 406/7 weeks)

0 0 0 0

Late term (410/7 weeks – 416/7 weeks)

0 0 0 0

Post term (>=420/7 weeks) 0 0 0 0

Low birth weight[5] 0 0 0 0 0 Male 0 0 0 0 0 Female 0 0 0 0 0

43







Pure Prospective Cohort 3 2 1 0 0 Earliest trimester of belimumab exposure by infusion date Preconception (within 4 months prior to conception)

3 (100.0%) 2 (100.0%) 1 (100.0%) 0 0

1st trimester 0 0 0 0 0 2nd trimester 0 0 0 0 0 3rd trimester 0 0 0 0 0

Last belimumab exposure by infusion date[6] Preconception (within 4 months prior to conception)

0 0 0 0 0

1st trimester 0 0 0 0 0 2nd trimester 2 (66.7%) 1 (50.0%) 1 (100.0%) 0 0 3rd trimester 0 0 0 0 0

Other exposures during pregnancy 3 (100.0%) 2 (100.0%) 1 (100.0%) 0 0 Corticosteroids 3 (100.0%) 2 (100.0%) 1 (100.0%) 0 0 NSAIDs 0 0 0 0 0 Other immunosuppressants 2 (66.7%) 2 (100.0%) 0 0 0 Anti-malarial drugs 2 (66.7%) 2 (100.0%) 0 0 0

44







Traditional Prospective Cohort 12 9 3 2 3 Delivery method[3] Normal vaginal 4 (33.3%) 4 (44.4%) 0 0 0 Cesarean 8 (66.7%) 5 (55.6%) 3 (100.0%) 2 (100.0%) 3 (100.0%)

Live births[3] Singleton 12 (100.0%) 9 (100.0%) 3 (100.0%) 2 (100.0%) 3 (100.0%) Twin 0 0 0 0 0 Triplet 0 0 0 0 0 Other 0 0 0 0 0

Gender[3] Male 5 (41.7%) 4 (44.4%) 1 (33.3%) 2 (100.0%) 2 (66.7%) Female 6 (50.0%) 4 (44.4%) 2 (66.7%) 0 1 (33.3%) Ambiguous Gender 0 0 0 0 0

Gestational age at birth (weeks) n 12 9 3 2 3 Mean (SD) 37.98 (2.121) 38.94 (0.945) 35.10 (2.140) 38.43 (1.010) 38.38 (0.719) Median 38.43 39.14 35.71 38.43 38.29 Min - Max 32.7 - 40.6 37.7 - 40.6 32.7 - 36.9 37.7 - 39.1 37.7 - 39.1 Q1, Q3 37.29, 39.14 38.29, 39.14 32.71, 36.86 37.71, 39.14 37.71, 39.14

45







Traditional Prospective Cohort 12 9 3 2 3 Preterm[4] 3 (25.0%) NA 3 (100.0%) 0 0 Early preterm (<280/7 weeks) 0 0 0 0 Late preterm (340/7 weeks - 366/7 weeks)

2 (16.7%) 2 (66.7%) 0 0

Full-Term 9 (75.0%) 9 (100.0%) NA 2 (100.0%) 3 (100.0%) Early term (370/7 weeks – 386/7 weeks)

4 (33.3%) 4 (44.4%) 1 (50.0%) 2 (66.7%)


5 (41.7%) 5 (55.6%) 1 (50.0%) 1 (33.3%)


0 0 0 0

Post term (>=420/7 weeks) 0 0 0 0

Low birth weight[5] 4 (33.3%) 2 (22.2%) 2 (66.7%) 2 (100.0%) 2 (66.7%) Male 3 (25.0%) 2 (22.2%) 1 (33.3%) 2 (100.0%) 2 (66.7%) Female 1 (8.3%) 0 1 (33.3%) 0 0

46







Traditional Prospective Cohort 12 9 3 2 3 Earliest trimester of belimumab exposure by infusion date Preconception (within 4 months prior to conception)

12 (100.0%) 9 (100.0%) 3 (100.0%) 2 (100.0%) 3 (100.0%)



0 0 0 0 0

1st trimester 1 (8.3%) 0 1 (33.3%) 0 0 2nd trimester 8 (66.7%) 7 (77.8%) 1 (33.3%) 2 (100.0%) 2 (66.7%) 3rd trimester 1 (8.3%) 1 (11.1%) 0 0 0

Other exposures during pregnancy 12 (100.0%) 9 (100.0%) 3 (100.0%) 2 (100.0%) 3 (100.0%) Corticosteroids 12 (100.0%) 9 (100.0%) 3 (100.0%) 2 (100.0%) 3 (100.0%) NSAIDs 7 (58.3%) 6 (66.7%) 1 (33.3%) 2 (100.0%) 3 (100.0%) Other immunosuppressants 10 (83.3%) 8 (88.9%) 2 (66.7%) 2 (100.0%) 3 (100.0%) Anti-malarial drugs 11 (91.7%) 8 (88.9%) 3 (100.0%) 2 (100.0%) 3 (100.0%)

47







Retrospective Cohort 0 0 0 0 0 Delivery method[3] Normal vaginal 0 0 0 0 0 Cesarean 0 0 0 0 0

Live births[3] Singleton 0 0 0 0 0 Twin 0 0 0 0 0 Triplet 0 0 0 0 0 Other 0 0 0 0 0

Gender[3] Male 0 0 0 0 0 Female 0 0 0 0 0 Ambiguous Gender 0 0 0 0 0

Gestational age at birth (weeks) n 0 0 0 0 0 Mean (SD) - - - - - Median - - - - - Min - Max - - - - - Q1, Q3 - - - - -

48







Retrospective Cohort 0 0 0 0 0 Preterm[4] 0 NA 0 0 0 Early preterm (<280/7 weeks) 0 0 0 0 Late preterm (340/7 weeks - 366/7 weeks)

0 0 0 0

Full-Term 0 0 NA 0 0 Early term (370/7 weeks – 386/7 weeks)

0 0 0 0


0 0 0 0


0 0 0 0

Post term (>=420/7 weeks) 0 0 0 0

Low birth weight[5] 0 0 0 0 0 Male 0 0 0 0 0 Female 0 0 0 0 0

49







Retrospective Cohort 0 0 0 0 0 Earliest trimester of belimumab exposure by infusion date Preconception (within 4 months prior to conception)

0 0 0 0 0



0 0 0 0 0


Other exposures during pregnancy 0 0 0 0 0 Corticosteroids 0 0 0 0 0 NSAIDs 0 0 0 0 0 Other immunosuppressants 0 0 0 0 0 Anti-malarial drugs 0 0 0 0 0

50



Table 5.1 Solicited Maternal AEs and SAEs by Cohort

(Evaluable Patients with a Confirmed Outcome)

Note: A subject with multiple occurrences of a system organ class or preferred term is counted only once. Source: \\wilbtib\wilbtib07\GSK GSKBEL114256\GSK new database TL delivery\TLF\T1301 BEL114256 Interim Analysis: Generated: 30OCT2015 11:43

Pure Prospective(N=3)



Retrospective (N=3)

Number of participants with at least one solicited maternal non-serious AE

0 3 (23.1%) 0 0

Number of participants with at least one solicited maternal SAE

2 (66.7%) 5 (38.5%) 0 2 (66.7%)

Total number of solicited maternal SAEs 2 7 0 2

Cardiac disorders 0 1 (7.7%) 0 0 Sinus tachycardia 0 1 (7.7%) 0 0

Gastrointestinal disorders 0 2 (15.4%) 0 0 Irritable bowel syndrome 0 1 (7.7%) 0 0 Nausea 0 1 (7.7%) 0 0 Vomiting 0 1 (7.7%) 0 0

Infections and infestations 0 2 (15.4%) 0 0 Cystitis 0 1 (7.7%) 0 0 Herpes zoster 0 1 (7.7%) 0 0

51









Retrospective (N=3)

Musculoskeletal and connective tissue disorders

0 1 (7.7%) 0 0

Systemic lupus erythematosus 0 1 (7.7%) 0 0

Pregnancy, puerperium and perinatal conditions

0 2 (15.4%) 0 2 (66.7%)

Abortion spontaneous 0 0 0 2 (66.7%) Foetal death 0 1 (7.7%) 0 0 Premature separation of placenta 0 1 (7.7%) 0 0

Psychiatric disorders 0 1 (7.7%) 0 0 Insomnia 0 1 (7.7%) 0 0

Renal and urinary disorders 1 (33.3%) 0 0 0 Nephrolithiasis 1 (33.3%) 0 0 0

Reproductive system and breast disorders 0 1 (7.7%) 0 0 Vaginal haemorrhage 0 1 (7.7%) 0 0

Uncoded 1 (33.3%) 2 (15.4%) 0 0 Cervix Insufficiency with e.coli infection

1 (33.3%) 0 0 0

52









Retrospective (N=3)

Uncoded (Cont'd) Postpartum Pre-Eclampsia 0 1 (7.7%) 0 0 Worsening of Right Hip Pain resulting in Decreased Core Strength

0 1 (7.7%) 0 0

53



Table 5.2 Solicited Infant AEs and SAEs by Cohort






Retrospective (N=3)

Number of participants with at least one solicited infant non-serious AE

2 (66.7%) 2 (15.4%) 0 0

Number of participants with at least one solicited infant SAE

2 (66.7%) 8 (61.5%) 0 1 (33.3%)

Total number of solicited infant SAEs 2 14 0 1

Cardiac disorders 0 3 (23.1%) 0 0 Atrioventricular block 0 1 (7.7%) 0 0 Nonreassuring foetal heart rate pattern 0 1 (7.7%) 0 0 Supraventricular tachycardia 0 1 (7.7%) 0 0 Tricuspid valve incompetence 0 1 (7.7%) 0 0

Congenital, familial and genetic disorders

1 (33.3%) 4 (30.8%) 0 0

Atrial septal defect 0 1 (7.7%) 0 0 Cryptorchism 0 1 (7.7%) 0 0 Ebstein's anomaly 0 1 (7.7%) 0 0 Patent ductus arteriosus 0 1 (7.7%) 0 0

54









Retrospective (N=3)

Congenital, familial and genetic disorders (Cont'd) Talipes 1 (33.3%) 0 0 0 Ventricular septal defect 0 1 (7.7%) 0 0

Investigations 1 (33.3%) 0 0 0 Blood calcium increased 1 (33.3%) 0 0 0

Metabolism and nutrition disorders 1 (33.3%) 0 0 0 Hypercalcaemia 1 (33.3%) 0 0 0

Pregnancy, puerperium and perinatal conditions

0 3 (23.1%) 0 0

Hydrops foetalis 0 1 (7.7%) 0 0 Premature baby 0 2 (15.4%) 0 0

Renal and urinary disorders 0 1 (7.7%) 0 0 Hydronephrosis 0 1 (7.7%) 0 0 Pyelocaliectasis 0 1 (7.7%) 0 0

Skin and subcutaneous tissue disorders 1 (33.3%) 0 0 0 Dermatitis diaper 1 (33.3%) 0 0 0

55









Retrospective (N=3)

Uncoded 2 (66.7%) 1 (7.7%) 0 1 (33.3%) ""white spot on a prenatal scan at the infant's left heart ventricle. ""

1 (33.3%) 0 0 0

Behavioral or Benign Paroxysmal Torticollis

0 1 (7.7%) 0 0

Elective Termination 0 0 0 1 (33.3%) Non Reassuring Fetal Status 1 (33.3%) 0 0 0

56



Table 6.1 Infant Follow-up by Visit (Pure Prospective Cohort)


Note: Each infant of a multiple live birth is counted separately. n is the total number of non-missing responses. N= the number of live births with data at each time point. [1]Full-Term is defined as infants born >=370/7 weeks' gestational age. [2]Preterm is defined as delivery <370/7 weeks'gestational age; late preterm is defined as 340/7 and 366/7 weeks'gestational age; early preterm is defined as <280/7 weeks' gestational age. [3]Any infection or fever of unknown origin or of known infectious etiology that occurs through three months of age for an infant [4]Denominator is total number of infections and fevers of unknown origin or of known infectious etiology [5]An infection requiring treatment that occurs through six months of age for an infant [6]An infection that is considered an SAE and occurs through 12 months of age for an infant

57





All Live Births (N=3)

Full-Term Live Births[1] (N=2)

Preterm Live Births[2] (N=1)

Outcome (N=3)

4 Month Follow-up(N=3)


Outcome (N=2)

4 Month Follow-up (N=2)


Outcome (N=1)



Region N. America 2(66.7%) 2(66.7%) 2(66.7%) 2(100.0%) 2(100.0%) 2(100.0%) 0 0 0 Europe 1(33.3%) 1(33.3%) 1(33.3%) 0 0 0 1(100.0%) 1(100.0%) 1(100.0%)S. America 0 0 0 0 0 0 0 0 0

Length(cm) n 2 3 3 1 2 2 1 1 1 Mean (SD) 50.13

(2.645) 65.00 (1.323)

77.45 (1.938)

48.26 ( - )

64.75 (1.768)

78.42 (1.347)

52.00 ( - )

65.50 ( - )

75.50 ( - )

Median 50.13 65.50 77.47 48.26 64.75 78.42 52.00 65.50 75.50 Min - Max 48.3 -

52.0 63.5 - 66.0

75.5 - 79.4

48.3 - 48.3

63.5 - 66.0

77.5 - 79.4

52.0 - 52.0

65.5 - 65.5

75.5 - 75.5

Q1, Q3 48.26, 52.00

63.50, 66.00

75.50, 79.38

48.26, 48.26

63.50, 66.00

77.47, 79.38

52.00, 52.00

65.50, 65.50

75.50, 75.50

58








Outcome (N=3)



Outcome (N=2)



Outcome (N=1)



Weight(kg) n 3 3 3 2 2 2 1 1 1 Mean (SD) 3.17

(0.206) 6.89 (0.786)

10.38 (1.619)

3.15 (0.289)

6.69 (0.995)

10.82 (2.021)

3.20 ( - )

7.30 ( - )

9.50 ( - )

Median 3.20 7.30 9.50 3.15 6.69 10.82 3.20 7.30 9.50 Min - Max 2.9 -

3.4 6.0 - 7.4

9.4 - 12.2

2.9 - 3.4

6.0 - 7.4

9.4 - 12.2

3.2 - 3.2

7.3 - 7.3

9.5 - 9.5

Q1, Q3 2.95, 3.36

5.99, 7.39

9.39, 12.25

2.95, 3.36

5.99, 7.39

9.39, 12.25

3.20, 3.20

7.30, 7.30

9.50, 9.50

Head circumference (cm) n 2 3 3 1 2 2 1 1 1 Mean (SD) 34.46

(0.654) 42.86 (1.993)

46.91 (2.703)

34.93 ( - )

42.57 (2.729)

47.86 (3.026)

34.00 ( - )

43.43 ( - )

45.00 ( - )

Median 34.46 43.43 45.72 34.93 42.57 47.86 34.00 43.43 45.00 Min - Max 34.0 -

34.9 40.6 - 44.5

45.0 - 50.0

34.9 - 34.9

40.6 - 44.5

45.7 - 50.0

34.0 - 34.0

43.4 - 43.4

45.0 - 45.0

Q1, Q3 34.00, 34.93

40.64, 44.50

45.00, 50.00

34.93, 34.93

40.64, 44.50

45.72, 50.00

34.00, 34.00

43.43, 43.43

45.00, 45.00

59








Outcome (N=3)



Outcome (N=2)



Outcome (N=1)



Currently breastfed? Yes 0 0 0 0 0 0 0 0 0 No 2(66.7%) 3(100.0%) 3(100.0%) 2(100.0%) 2(100.0%) 2(100.0%) 0 1(100.0%) 1(100.0%)Missing/Unk 1(33.3%) 0 0 0 0 0 1(100.0%) 0 0

Ever breastfed? Yes 1(33.3%) 2(66.7%) 2(66.7%) 1(50.0%) 1(50.0%) 1(50.0%) 0 1(100.0%) 1(100.0%)No 1(33.3%) 1(33.3%) 1(33.3%) 1(50.0%) 1(50.0%) 1(50.0%) 0 0 0 Missing/Unk 1(33.3%) 0 0 0 0 0 1(100.0%) 0 0

Belimumab exposure during breast-feeding? Yes 0 0 0 0 0 0 0 0 0 No 1(33.3%) 1(33.3%) 1(33.3%) 1(50.0%) 0 0 0 1(100.0%) 1(100.0%)Missing/Unk 2(66.7%) 2(66.7%) 2(66.7%) 1(50.0%) 2(100.0%) 2(100.0%) 1(100.0%) 0 0

60








Outcome (N=3)



Outcome (N=2)



Outcome (N=1)



Birth Defect Noted Yes 1(33.3%) 0 0 1(50.0%) 0 0 0 0 0 No 1(33.3%) 3(100.0%) 3(100.0%) 1(50.0%) 2(100.0%) 2(100.0%) 0 1(100.0%) 1(100.0%)Pending/ Missing/Unk

1(33.3%) 0 0 0 0 0 1(100.0%) 0 0

Earliest Belimumab Exposure Preconception 3(100.0%) 3(100.0%) 3(100.0%) 2(100.0%) 2(100.0%) 2(100.0%) 1(100.0%) 1(100.0%) 1(100.0%)1st trimester 0 0 0 0 0 0 0 0 0 2nd trimester 0 0 0 0 0 0 0 0 0 3rd trimester 0 0 0 0 0 0 0 0 0 Postpartum 0 0 0 0 0 0 0 0 0

61








Outcome (N=3)



Outcome (N=2)



Outcome (N=1)



Last Belimumab Exposure Preconception 0 0 0 0 0 0 0 0 0 1st trimester 0 0 0 0 0 0 0 0 0 2nd trimester 2(66.7%) 2(66.7%) 2(66.7%) 1(50.0%) 1(50.0%) 1(50.0%) 1(100.0%) 1(100.0%) 1(100.0%)3rd trimester 0 0 0 0 0 0 0 0 0 Postpartum 1(33.3%) 1(33.3%) 1(33.3%) 1(50.0%) 1(50.0%) 1(50.0%) 0 0 0

Maternal Age <35 years 2(66.7%) 2(66.7%) 2(66.7%) 1(50.0%) 1(50.0%) 1(50.0%) 1(100.0%) 1(100.0%) 1(100.0%)>=35 years 1(33.3%) 1(33.3%) 1(33.3%) 1(50.0%) 1(50.0%) 1(50.0%) 0 0 0

Meeting Dev. Milestones? Gross Motor NA NA NA Yes 3(100.0%) 3(100.0%) 2(100.0%) 2(100.0%) 1(100.0%) 1(100.0%)No 0 0 0 0 0 0 Missing/Unk 0 0 0 0 0 0

62








Outcome (N=3)



Outcome (N=2)



Outcome (N=1)



Fine Motor NA NA NA Yes 3(100.0%) 3(100.0%) 2(100.0%) 2(100.0%) 1(100.0%) 1(100.0%)No 0 0 0 0 0 0 Missing/Unk 0 0 0 0 0 0

Language NA NA NA Yes 2(66.7%) 3(100.0%) 2(100.0%) 2(100.0%) 0 1(100.0%)No 0 0 0 0 0 0 Missing/Unk 1(33.3%) 0 0 0 1(100.0%) 0

Cognitive NA NA NA Yes 3(100.0%) 3(100.0%) 2(100.0%) 2(100.0%) 1(100.0%) 1(100.0%)No 0 0 0 0 0 0 Missing/Unk 0 0 0 0 0 0

Social/ Emotional

NA NA NA

Yes 3(100.0%) 3(100.0%) 2(100.0%) 2(100.0%) 1(100.0%) 1(100.0%)No 0 0 0 0 0 0 Missing/Unk 0 0 0 0 0 0

63








Outcome (N=3)



Outcome (N=2)



Outcome (N=1)



Infants experiencing at least one infection or fever[3]

0 1(33.3%) 1(33.3%) 0 1(50.0%) 1(50.0%) 0 0 0

Total number infections or fever? [3]

0 1 1 0 1 1 0 0 0

Attributable to belimumab?[4] Yes 0 0 0 0 0 0 0 0 0 No 0 1(100.0%) 1(100.0%) 0 1(100.0%) 1(100.0%) 0 0 0 Unknown 0 0 0 0 0 0 0 0 0

Requiring tmt?[4,5] Yes 0 1(100.0%) 0 0 1(100.0%) 0 0 0 0 No 0 0 1(100.0%) 0 0 1(100.0%) 0 0 0

64








Outcome (N=3)



Outcome (N=2)



Outcome (N=1)



Serious?[5,6] Yes 0 0 0 0 0 0 0 0 0 No 0 1(100.0%) 1(100.0%) 0 1(100.0%) 1(100.0%) 0 0 0

Status[5] Resolved 0 1(100.0%) 1(100.0%) 0 1(100.0%) 1(100.0%) 0 0 0 Ongoing 0 0 0 0 0 0 0 0 0 Death 0 0 0 0 0 0 0 0 0 Unknown 0 0 0 0 0 0 0 0 0

65



Table 6.2 Infant Follow-up by Visit



Note: Each infant of a multiple live birth is counted separately. n is the total number of non-missing responses. N= the number of live births with data at each time point. [1]Full-Term is defined as infants born >=370/7 weeks' gestational age. [2]Preterm is defined as delivery <370/7 weeks'gestational age; late preterm is defined as 340/7 and 366/7 weeks'gestational age; early preterm is defined as <280/7 weeks' gestational age. [3]Any infection or fever of unknown origin or of known infectious etiology that occurs through three months of age for an infant [4]Denominator is total number of infections and fevers of unknown origin or of known infectious etiology [5]An infection requiring treatment that occurs through six months of age for an infant [6]An infection that is considered an SAE and occurs through 12 months of age for an infant

66









Outcome (N=12)



Outcome (N=9)



Outcome (N=3)



Region N. America 9(75.0%) 9(90.0%) 5(100.0%) 6(66.7%) 6(85.7%) 2(100.0%) 3(100.0%) 3(100.0%) 3(100.0%)Europe 3(25.0%) 1(10.0%) 0 3(33.3%) 1(14.3%) 0 0 0 0 S. America 0 0 0 0 0 0 0 0 0

Length(cm) n 10 10 5 8 7 2 2 3 3 Mean (SD) 48.41

(2.122) 61.33 (2.423)

71.78 (4.623)

48.45 (2.310)

61.31 (2.323)

68.33 (5.029)

48.25 (1.768)

61.38 (3.196)

74.08 (3.196)

Median 48.13 60.96 71.88 48.13 60.96 68.33 48.25 60.96 73.66 Min - Max 45.0 -

51.0 58.4 - 66.0

64.8 - 77.5

45.0 - 51.0

58.4 - 66.0

64.8 - 71.9

47.0 - 49.5

58.4 - 64.8

71.1 - 77.5

Q1, Q3 47.00, 50.80

60.20, 61.60

71.12, 73.66

46.86, 50.80

60.20, 61.60

64.77, 71.88

47.00, 49.50

58.42, 64.77

71.12, 77.47

67









Outcome (N=12)



Outcome (N=9)



Outcome (N=3)



Weight(kg) n 12 9 5 9 6 2 3 3 3 Mean (SD) 2.81

(0.459) 6.03 (0.529)

9.12 (0.446)

2.96 (0.390)

6.13 (0.608)

9.16 (0.706)

2.35 (0.350)

5.83 (0.325)

9.10 (0.383)

Median 2.80 5.90 9.21 3.13 5.87 9.16 2.33 5.94 9.21 Min - Max 2.0 -

3.5 5.5 - 7.3

8.7 - 9.7

2.4 - 3.5

5.7 - 7.3

8.7 - 9.7

2.0 - 2.7

5.5 - 6.1

8.7 - 9.4

Q1, Q3 2.43, 3.18

5.72, 6.08

8.67, 9.41

2.63, 3.24

5.72, 6.38

8.66, 9.66

2.00, 2.70

5.46, 6.08

8.67, 9.41

Head circumference (cm) n 9 10 5 7 7 2 2 3 3 Mean (SD) 33.81

(1.539) 41.07 (1.078)

45.62 (0.619)

34.19 (1.528)

41.27 (1.200)

45.36 (0.509)

32.50 (0.707)

40.60 (0.657)

45.80 (0.721)

Median 34.00 40.82 45.72 34.00 41.00 45.36 32.50 40.49 46.00 Min - Max 32.0 -

36.8 40.0 - 43.2

45.0 - 46.4

32.0 - 36.8

40.0 - 43.2

45.0 - 45.7

32.0 - 33.0

40.0 - 41.3

45.0 - 46.4

Q1, Q3 33.00, 34.50

40.20, 41.30

45.00, 46.00

33.00, 35.00

40.20, 42.60

45.00, 45.72

32.00, 33.00

40.00, 41.30

45.00, 46.40

68









Outcome (N=12)



Outcome (N=9)



Outcome (N=3)



Currently breastfed? Yes 5(41.7%) 7(70.0%) 3(60.0%) 4(44.4%) 5(71.4%) 2(100.0%) 1(33.3%) 2(66.7%) 1(33.3%) No 3(25.0%) 3(30.0%) 2(40.0%) 3(33.3%) 2(28.6%) 0 0 1(33.3%) 2(66.7%) Missing/Unk 4(33.3%) 0 0 2(22.2%) 0 0 2(66.7%) 0 0

Ever breastfed? Yes 1(8.3%) 2(20.0%) 2(40.0%) 1(11.1%) 1(14.3%) 0 0 1(33.3%) 2(66.7%) No 2(16.7%) 2(20.0%) 0 2(22.2%) 2(28.6%) 0 0 0 0 Missing/Unk 9(75.0%) 6(60.0%) 3(60.0%) 6(66.7%) 4(57.1%) 2(100.0%) 3(100.0%) 2(66.7%) 1(33.3%)

Belimumab exposure during breast-feeding? Yes 0 0 1(20.0%) 0 0 1(50.0%) 0 0 0 No 1(8.3%) 0 0 1(11.1%) 0 0 0 0 0 Missing/Unk 11(91.7%) 10(100.0%) 4(80.0%) 8(88.9%) 7(100.0%) 1(50.0%) 3(100.0%) 3(100.0%) 3(100.0%)

69









Outcome (N=12)



Outcome (N=9)



Outcome (N=3)



Birth Defect Noted Yes 3(25.0%) 0 0 2(22.2%) 0 0 1(33.3%) 0 0 No 6(50.0%) 9(90.0%) 5(100.0%) 6(66.7%) 6(85.7%) 2(100.0%) 0 3(100.0%) 3(100.0%)Pending/ Missing/Unk

3(25.0%) 1(10.0%) 0 1(11.1%) 1(14.3%) 0 2(66.7%) 0 0

Earliest Belimumab Exposure Preconception 12(100.0%) 10(100.0%) 5(100.0%) 9(100.0%) 7(100.0%) 2(100.0%) 3(100.0%) 3(100.0%) 3(100.0%)1st trimester 0 0 0 0 0 0 0 0 0 2nd trimester 0 0 0 0 0 0 0 0 0 3rd trimester 0 0 0 0 0 0 0 0 0 Postpartum 0 0 0 0 0 0 0 0 0

70









Outcome (N=12)



Outcome (N=9)



Outcome (N=3)



Last Belimumab Exposure Preconception 0 0 0 0 0 0 0 0 0 1st trimester 1(8.3%) 1(10.0%) 1(20.0%) 0 0 0 1(33.3%) 1(33.3%) 1(33.3%) 2nd trimester 8(66.7%) 7(70.0%) 2(40.0%) 7(77.8%) 6(85.7%) 1(50.0%) 1(33.3%) 1(33.3%) 1(33.3%) 3rd trimester 1(8.3%) 0 0 1(11.1%) 0 0 0 0 0 Postpartum 2(16.7%) 2(20.0%) 2(40.0%) 1(11.1%) 1(14.3%) 1(50.0%) 1(33.3%) 1(33.3%) 1(33.3%)

Maternal Age <35 years 10(83.3%) 8(80.0%) 4(80.0%) 8(88.9%) 6(85.7%) 2(100.0%) 2(66.7%) 2(66.7%) 2(66.7%) >=35 years 2(16.7%) 2(20.0%) 1(20.0%) 1(11.1%) 1(14.3%) 0 1(33.3%) 1(33.3%) 1(33.3%)

Meeting Dev. Milestones? Gross Motor NA NA NA Yes 9(90.0%) 4(80.0%) 7(100.0%) 2(100.0%) 2(66.7%) 2(66.7%) No 1(10.0%) 1(20.0%) 0 0 1(33.3%) 1(33.3%) Missing/Unk 0 0 0 0 0 0

71









Outcome (N=12)



Outcome (N=9)



Outcome (N=3)



Fine Motor NA NA NA Yes 10(100.0%) 5(100.0%) 7(100.0%) 2(100.0%) 3(100.0%) 3(100.0%)No 0 0 0 0 0 0 Missing/Unk 0 0 0 0 0 0

Language NA NA NA Yes 10(100.0%) 4(80.0%) 7(100.0%) 2(100.0%) 3(100.0%) 2(66.7%) No 0 1(20.0%) 0 0 0 1(33.3%) Missing/Unk 0 0 0 0 0 0

Cognitive NA NA NA Yes 10(100.0%) 5(100.0%) 7(100.0%) 2(100.0%) 3(100.0%) 3(100.0%)No 0 0 0 0 0 0 Missing/Unk 0 0 0 0 0 0

Social/ Emotional

NA NA NA

Yes 10(100.0%) 4(80.0%) 7(100.0%) 2(100.0%) 3(100.0%) 2(66.7%) No 0 1(20.0%) 0 0 0 1(33.3%) Missing/Unk 0 0 0 0 0 0

72









Outcome (N=12)



Outcome (N=9)



Outcome (N=3)



Infants experiencing at least one infection or fever[3]

1(8.3%) 0 1(20.0%) 1(11.1%) 0 0 0 0 1(33.3%)

Total number infections or fever? [3]

1 0 1 1 0 0 0 0 1

Attributable to belimumab?[4] Yes 0 0 0 0 0 0 0 0 0 No 0 0 0 0 0 0 0 0 0 Unknown 1(100.0%) 0 0 1(100.0%) 0 0 0 0 0

Requiring tmt?[4,5] Yes 1(100.0%) 0 1(100.0%) 1(100.0%) 0 0 0 0 1(100.0%)No 0 0 0 0 0 0 0 0 0

73









Outcome (N=12)



Outcome (N=9)



Outcome (N=3)



Serious?[5,6] Yes 0 0 0 0 0 0 0 0 0 No 1(100.0%) 0 1(100.0%) 1(100.0%) 0 0 0 0 1(100.0%)

Status[5] Resolved 1(100.0%) 0 0 1(100.0%) 0 0 0 0 0 Ongoing 0 0 0 0 0 0 0 0 0 Death 0 0 0 0 0 0 0 0 0 Unknown 0 0 0 0 0 0 0 0 0

74



Table 0 Pregnancy Outcome Characteristics by Earliest Period of Exposure

(Pure Prospective, Traditional Prospective and Retrospective Cohorts)


Note: Denominator is the total number of participants in each column (N) cohort by trimester of exposure unless otherwise indicated. First trimester begins day after date of conception to 136/7, second trimester begins at week 140/7 — 276/7 weeks, and the third trimester begins at week 280/7. Live birth: the birth of a living fetus at 200/7 weeks' gestational age or greater (>=20 weeks), or, if gestational age is unknown, a fetus weighing 500 g or more (>=500 g); Elective termination: voluntary interruption of pregnancy, including pregnancy termination that occurs electively, to preserve maternal health, or due to fetal abnormalities; Spontaneous miscarriage: fetal death or expulsion of products of conception prior to 20 weeks' (< 20 weeks) gestation; Neonatal death: an infant who after live birth expired within the first 28 days (<= 28 days) of life; Stillbirth: a fetal death occurring at 200/7 weeks' gestational age or greater (>=20 weeks), or, if gestational age is unknown, a fetus weighing 500 g or more (>=500 g); Ectopic pregnancy: implantation of a conception outside of the uterus; Molar pregnancy: a conception that results in a gestational trophoblastic tumor. [1]Denominator is the total number of participants with a pregnancy outcome. [2]Includes the number of participants with a pregnancy outcome of spontaneous abortion or stillbirth. [3]Denominator is the total number of participants with a pregnancy outcome minus the number of participants with an elective termination.

75



Table Pregnancy Outcome Characteristics by Earliest Period of Exposure


Note: See footnotes on Page 1.


Earliest Trimester of Exposure Total Preconception Trimester 1 Trimester 2 Trimester 3

Pure Prospective Cohort 3 3 0 0 0 Number of participants with a pregnancy outcome 3 (100.0%) 3 (100.0%) 0 0 0 Live Birth[1] 3 (100.0%) 3 (100.0%) 0 0 0 Neonatal death[1] 0 0 0 0 0 Elective termination[1] 0 0 0 0 0 Fetal loss[2,3] 0 0 0 0 0 Spontaneous miscarriage[1] 0 0 0 0 0 Gestation Age at enrollment <8 weeks' gestation 0 0 0 0 0 80/7 - 116/7 weeks' gestation 0 0 0 0 0 120/7 - 136/7 weeks' gestation 0 0 0 0 0 140/7 - 196/7 weeks' gestation 0 0 0 0 0 Stillbirth[1] 0 0 0 0 0 Ectopic pregnancy[1] 0 0 0 0 0 Molar pregnancy[1] 0 0 0 0 0

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Table .0 Pregnancy Outcome Characteristics by Earliest Period of Exposure





Traditional Prospective Cohort 13 13 0 0 0 Number of participants with a pregnancy outcome 13 (100.0%) 13 (100.0%) 0 0 0 Live Birth[1] 12 (92.3%) 12 (92.3%) 0 0 0 Neonatal death[1] 0 0 0 0 0 Elective termination[1] 0 0 0 0 0 Fetal loss[2,3] 1 (7.7%) 1 (7.7%) 0 0 0 Spontaneous miscarriage[1] 1 (7.7%) 1 (7.7%) 0 0 0 Gestation Age at enrollment <8 weeks' gestation 0 0 0 0 0 80/7 - 116/7 weeks' gestation 1 (7.7%) 1 (7.7%) 0 0 0 120/7 - 136/7 weeks' gestation 0 0 0 0 0 140/7 - 196/7 weeks' gestation 0 0 0 0 0 Stillbirth[1] 0 0 0 0 0 Ectopic pregnancy[1] 0 0 0 0 0 Molar pregnancy[1] 0 0 0 0 0

77



Table 0 Pregnancy Outcome Characteristics by Earliest Period of Exposure





Retrospective Cohort 3 2 1 0 0 Number of participants with a pregnancy outcome 3 (100.0%) 2 (100.0%) 1 (100.0%) 0 0 Live Birth[1] 0 0 0 0 0 Neonatal death[1] 0 0 0 0 0 Elective termination[1] 1 (33.3%) 1 (50.0%) 0 0 0 Fetal loss[2,3] 2 (100.0%) 1 (100.0%) 1 (100.0%) 0 0 Spontaneous miscarriage[1] 2 (66.7%) 1 (50.0%) 1 (100.0%) 0 0 Stillbirth[1] 0 0 0 0 0 Ectopic pregnancy[1] 0 0 0 0 0 Molar pregnancy[1] 0 0 0 0 0

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Table 8.0 Birth Defects

(Pure and Traditional Prospective Cohorts)


Note: Reports of pregnancy in which the pregnancy outcome or anticipated outcome is already known before enrollment can be biased toward the reporting of more unusual or severe cases compared to women whose pregnancy outcome is not yet known at the time of enrollment into the pregnancy registry. Therefore, rates of outcomes cannot be calculated from these data. However, a series of reported birth defects can be evaluated to detect patterns of specific birth defects and can assist with identification of potential early signals of therapy risks. [1]Birth defects meeting the CDC Criteria only. Excludes reported defects in pregnancy losses <20 weeks. [2]MACDP birth defect prevalence (Correa, 2007) [3]EUROCAT birth defect prevalence (eurocat-network.eu) [4]Small for gestational age is defined as live births whose birth weight lies below the 10th percentile for that gestational age based on WHO reference data [Williams]. [5]Small for gestational age is defined as live births whose birth weight lies below the 10th percentile for that gestational age based on reference data [Alexander].

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Pure Prospective

(N=3) Traditional Prospective

(N=13)

Among live births and fetal deaths at or after 20 weeks gestational age, n (%) with areported birth defect[1]

1/3 (33.3%) 3/12 (25.0%)

Birth Defect Prevalence using MACDP criteriafor Earliest Belimumab Exposure[2]

Preconception 1/3 (33.3% 95%CI 0.0%-86.7%) 3/12 (25.0% 95%CI 0.5%-49.5%) First Trimester 0 0 Second/Third Trimester 0 0 Any Trimester 0 0

MACDP birth defect prevalence from most recent 5-year period

(2.78% 95% CI 2.72% – 2.84%)[3]

Birth Defect Prevalence using EUROCAT criteria for Earliest Belimumab Exposure[3]


EUROCAT birth defect prevalence for most recent 5-year period

(2.56% 95% CI 2.54% - 2.58%)[4]

80






Pure Prospective


(N=13)

Spontaneous Miscarriage Prevalence for Earliest Belimumab Exposure in

Preconception 0 1/13 (7.7% 95%CI 0.0%-22.2%) First Trimester 0 0 Second/Third Trimester 0 0 Any Trimester 0 0

Elective Termination Prevalence for EarliestBelimumab Exposure in

Preconception 0 0 First Trimester 0 0 Second/Third Trimester 0 0 Any Trimester 0 0

Stillbirth Prevalence for Earliest BelimumabExposure in

Preconception 0 0 First Trimester 0 0 Second/Third Trimester 0 0 Any Trimester 0 0

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Pure Prospective


(N=13)

Preterm Prevalence for Earliest Belimumab Exposure in


SGA[4] Prevalence for Earliest Belimumab Exposure in


SGA[5] Prevalence for Earliest Belimumab Exposure in


82






Pure Prospective


(N=13)

Infant Infection Prevalence for Earliest Belimumab Exposure in


Infant Infection Prevalence for Breastfed Infants at

Outcome 0 1/13 (7.7% 95%CI 0.0%-22.2%) Four Month Follow-up 0 0 Twelve Month Follow-up 0 0

Infant Infection Prevalence for Infants Completing Outcome

Outcome 0 1/13 (7.7% 95%CI 0.0%-22.2%) Four Month Follow-up 1/3 (33.3% 95%CI 0.0%-86.7%) 0 Twelve Month Follow-up 1/3 (33.3% 95%CI 0.0%-86.7%) 1/13 (7.7% 95%CI 0.0%-22.2%)

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Listing 1.0 Reported Birth Defects

Note: NR=Note reported; Pre=preconception [1]Days of gestational age are presented as (x/x) due to table formatting. For example, 325/7weeks is presented as 32(5/7). [2]Small for gestational age is defined as live births whose birth weight lies below the 10th percentile for that gestational age based on WHO reference data [Williams]. [3]Small for gestational age is defined as live births whose birth weight lies below the 10th percentile for that gestational age based on reference data [Alexander]. Source: \\wilbtib\wilbtib07\GSK GSKBEL114256\GSK new database TL delivery\TLF\L0400 BEL114256 Interim Analysis: Generated: 30OCT2015 11:40

Subject ID Cohort

Earliest Trim of Exp Baby ID

Gest Age at Birth[1]/

SGA[2]/SGA[3]/LBW BD Term

Attrib to TRT?

Other factors

Gest Age when

noted[1]

US0011 Pure Prosp Preconception US0011A 38(3/7)/-/-/- Bilateral Clubfoot No Other 38(3/7)

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Subject ID Cohort




Attrib to TRT?

Other factors

Gest Age when

noted[1]

DE0002 Trad Prosp Preconception DE0002A 40(4/7)/-/-/-

Testicle Left Side High Standing Unknown Other 40(4/7)

US0005 Trad Prosp Preconception US0005A 36(6/7)/-/-/-

Very Mild Ebstein Anomaly of Tricuspid Valve Yes

Maternal Age, Other 37(0/7)

US0014 Trad Prosp Preconception US0014A 39(1/7)/Y/Y/Y

Congenital Heart Block Unknown 39(1/7)

US0016 Trad Prosp Preconception US0016A 37(5/7)/Y/Y/Y hydronephrosis Unknown Other 37(5/7)

ventricular septal defect Unknown Other 37(5/7)


Closing Patent Ductus Arteriosus Unknown

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Subject ID Cohort




Attrib to TRT?

Other factors

Gest Age when

noted[1]


Small Patent Foramen Ovale Unknown

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Listing 2.0 Teratologist Evaluation Results

Source: \\wilbtib\wilbtib07\GSK GSKBEL114256\GSK new database TL delivery\TLF\L0500 BEL114256 Interim Analysis: Generated: 02NOV2015 10:15

[1]Teratologist evaluation of participant's birth defects. [2]Days of gestational age are presented as (x/x) due to table formatting. For example, 325/7weeks is presented as 32(5/7). [3]Small for gestational age is defined as live births whose birth weight lies below the 10th percentile for that gestational age based on WHO reference data [Williams]. [4]Small for gestational age is defined as live births whose birth weight lies below the 10th percentile for that gestational age based on reference data [Alexander]. [5]d=defect; nd=not a defect; ED=Exclusionary (conditional) defect; MAE=Minor Anomaly Exclusion; pend=pending defect evaluation [6]Temporal relationship between defect and exposure to belimumab therapy (1=Pending, temporality assessment awaiting results of follow-up [Prospective cases only]; 2=The development of this defect and the timing of the exposure to drug cannot rule out a possible association; 3=No temporal association; 4=Unable to assess temporality; 5=Not applicable; 6=Defect with known cause, temporality may be irrelevant; 7=Pathogenesis of this defect has yet to be defined specifically enough to assess temporality; 8=Not a EUROCAT defect; 9=Not a Metropolitan Atlanta Congenital Defects Program (MACDP) defect

87




Note: See footnotes on Page 1. Source: \\wilbtib\wilbtib07\GSK GSKBEL114256\GSK new database TL delivery\TLF\L0500 BEL114256 Interim Analysis: Generated: 02NOV2015 10:15

Subject ID Cohort Baby ID

Gest Age[2] /SGA[3] /SGA[4] /LBW

Organ System

Defect Codes MACDP

/EUROCAT[5]

Verb Term /Pref Term MACDP

/EUROCAT

Temporal Relation

[6] Confounding Factors

US0011 Pure Prosp US0011A

38(3/7) /- /- /- MS-O d/d

Bilateral Club Foot /ClubFoot, NOS /ClubFoot 6

Cigarette smoker (70 per week reported), Other maternal medications (Prednisone, Plaquenil) Advanced Maternal Age, SLE

88







Organ System

Defect Codes MACDP

/EUROCAT[5]


/EUROCAT

Temporal Relation


DE0002 Trad Prosp DE0002A

40(4/7) /- /- /- G-MALE pend/nd

non-descending Testis (Left) /Non coded /undescended testicle 2

Belimumab exposure:28Oct2013-12May2014 Axathioprine (discontinued 10/2011). Quensyl - Ongoing. Folic acid. Tobacco use (until 2008).

US0005 Trad Prosp US0005A

36(6/7) /- /- /- CV-O-HRT d/d

Very Mild Ebstein Anomaly of Tricuspid Valve /Ebstein Anomaly /Ebstein Anomaly 2

Maternal Age (38), Maternal SLE, Maternal Lupus Nephritis, Maternal Antiphospholipid Syndrome, Prednisone


39(1/7) /Y /Y /Y CV-O-HRT d/nd

Heart Block /Congenital Heart Block /Congenital Heart Block 2

Azathrioprine ( 18 DEC 2013 - ) Plaquenil (UN FEB 2014) Prednisone stopped 22 October 2014

89







Organ System

Defect Codes MACDP

/EUROCAT[5]


/EUROCAT

Temporal Relation



37(5/7) /Y /Y /Y CV-O-HRT d/d

small Ventricular Septal Defect /Ventricular Septal Defect /Ventricular Septal Defect 2

Heparin 26 SEP 14 – no stop date Aspirin 26 SEP 14 – No Stop Date Prednisone (10MG daily)– 30 SEP 14 – no stop date Deltasone 4 mg Start Date 30 May 14 Anti-malarial Start Date 30 May 14 Folic with prenatal vitamin Start Date 09 Apr 14 Lupus Anticoagulant Positive Un/Unk/2008

RENAL d/d

Hydronephrosis /Congenital Hydronephrosis /Congenital Hydronephrosis 2

90







Organ System

Defect Codes MACDP

/EUROCAT[5]


/EUROCAT

Temporal Relation



38(4/7) /- /- /- CV-O-HRT pend/Pend

Patent Ductus Arteriosus /Patent Ductus Arteriosus /Patent Ductus Arteriosus 1

SLE, Hypertension, Hypothyroidism Medications Feldene (NSAIDS), Methotrexate, Anti-malarial, Folate, Calcium Channel Blocker, Statin Aspirin, Epilepsy medications (Xyrem, Ativan, Ropinirole, Amitryptaline) Birth control pills, Prednisone, Beta blocker (Propranolol)

Patent Foramen Ovale /Patent Foramen Ovale /Patent Foramen Ovale 1

SLE, Hypertension, Hypothyroidism Medications Feldene (NSAIDS), Methotrexate, Anti-malarial, Folate, Calcium Channel Blocker, Statin Aspirin, Epilepsy medications (Xyrem, Ativan, Ropinirole, Amitryptaline) Birth control pills, Prednisone, Beta blocker (Propranolol)

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