Impact of New Biologics and Tofacitinib on Pregnancy and … · 2019. 11. 22. · Development in the Cynomolgus Macaque Following Administration of Ustekinumab, a Human Anti -IL-12/23p40

www.danielbaumgart.ca

Impact of New Biologics and Tofacitinib on Pregnancy and

Breastfeeding

Daniel C. Baumgart, MD PhD MBA FRCP (London) AGAFProfessor and Director, Division of Gastroenterology

Director, Inflammatory Bowel Disease UnitUniversity of Alberta

Edmonton, AB, Canada

www.danielbaumgart.ca.

New Biologics & Tofacitinib and Pregnancy

New Biologics & Tofacitinib and Breastfeeding

Recommendations of Professional Societies

Agenda


Ustekinumab

IL-12 IL-23


Development in the Cynomolgus Macaque Following Administration of Ustekinumab, a Human Anti-IL-12/23p40

Monoclonal Antibody, During Pregnancy and Lactation

Martin PL et al. Birth Defects Research (Part B) 89:351–363 (2010)

Ustekinumab treatmentproduced no maternaltoxicity and no toxicity in thefetuses or infants, includingno effects on the TDAR orDTH responses.

Ustekinumab was present inserum from GD100 fetusesand was present in infantserum through day 120post-birth. Low levels ofustekinumab were presentin breast milk.


Ustekinumab Exposed Psoriaris Patients in Pregnancy Case Series

Galluzo M et al. The Journal of Dermatological Treatment 2019;30:40-4.


Ustekinumab exposure during conception andpregnancy in patients with chronic plaque psoriasis: a case

series of 10 pregnancies

Watson N et al. Br J Dermatol 2019;180:195-6.


Sixty-seven pregnancies in 62 IBD females (43 for Crohn's disease and 19for ulcerative colitis) were reported among 19 centers of the GETAID group.Median age at conception was 29 years. Median time between introductionof ustekinumab or vedolizumab treatment and pregnancy was 12 months.

Twenty-five pregnancies occurred on ustekinumab: 7 received ustekinumabin the last 2 months before conception, 11 received 1 injection afterconception, and 7 stopped ustekinumab in the 2nd trimester.Among the 25pregnancies occurred on ustekinumab, there were 22 (88%) live births, 1elective termination and 2 spontaneous abortions.

Maternal complications were reported in 2 women (one gestational diabetesand one threat of premature labor).

Fetal complications were reported in 3 pregnancies (intra uterine growthrestriction). Four newborns presented a non severe neonatal complication(3 preterm deliveries, one low birth weight) and one a Tetralogy of Fallot.

Concerning IBD activity, 65% of women were in remission at conception.Among them, only 2 patients flared during pregnancy.

No Severe Neonatal And Maternal Complications in Female Patients With Inflammatory Bowel Diseases Treated With

Ustekinumab or Vedolizumab During Pregnancy

Wils P et al. UEGW 2019.


Maternal Serum, Cord Bloodand Breast Milk Ustekinumab Drug Levels in a

Patient with Crohn’s Disease

Klenske E et al. Crohns Colitis 2019;13:267-9.1–363

24-year-old woman with refractoryCrohn’s disease, who was treatedwith UST until Week 30 ofpregnancy and successfullydelivered a healthy baby boy, whohad normal development in thefollow-up period of one year. Thecord blood UST level was markedlyhigher than the measured maternalserum drug level. The trough levelin the breast milk after re-initiatingpostpartum UST therapy wasinitially in the same range as thecorresponding serum trough level,and then decreased duringmaintenance therapy.

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Baumgart et al. Inflammopharmacology. 2012 Feb;20(1):1-18.


Evaluation of the Developmental Toxicityof Vedolizumab in Rabbit and Cynomolgus Monkeys

Crawford D et al. nt J Toxicol 2019;38:395-404.


In rabbits, vedolizumab did not affect maternal net bodyweight or net gains, gravid uterine weights, or meanmaternal food consumption, nor did it affect intrauterinegrowth or fetal survival. There were also no vedolizumabeffects on embryo–fetal development compared to controls.In cynomolgus monkeys, there was no increase in prenatalloss/death or stillbirth and no maternal toxicity associatedwith vedolizumab. On day 28 postpartum, low levels ofvedolizumab were detected in the breast milk of 3 of 11monkeys in the 100 mg/kg group. No vedolizumab-relatedeffects on the number of infants born, infant development, oranimal hematology or clinical chemistry were noted.Administration of vedolizumab to pregnant rabbits andcynomolgus monkeys did not show any potential formaternal or developmental effects.

Evaluation of the Developmental Toxicityof Vedolizumab in Rabbit and Cynomolgus Monkeys

Crawford D et al. nt J Toxicol 2019;38:395-404.


Pregnancy outcomes in inflammatory bowel disease patientstreated with vedolizumab, anti‐TNF or conventional therapy:

results of the European CONCEIVE study

Moens et al. Aliment Pharmacol Ther. 2019;00:1–10.





Use of concomitant medication in vedolizumab‐exposedpregnancies. Trimester 1: exclusion of 12 earlymiscarriages and three elective terminations. Trimester2: exclusion of one late miscarriages, one electiveterminations and one stillbirth. Patients at conceptionon anti‐TNF therapy where not yet on VDZ therapy

Use of concomitant medication in anti‐tumour necrosisfactorexposed pregnancies. Trimester 1‐3: exclusion of 24early miscarriages and one elective terminations


Sixty-seven pregnancies in 62 IBD females (43 for Crohn's disease and 19 for ulcerativecolitis) were reported among 19 centers of the GETAID group. Median age atconception was 29 years. Median time between introduction of ustekinumab orvedolizumab treatment and pregnancy was 12 months.

Forty-two pregnancies occurred on vedolizumab: 15 received vedolizumab in the last 2months before conception, 16 received 1 injection after conception, and 11 stoppedvedolizumab (6 during the 2nd trimester and 5 during the 3rd trimester). Among the 42pregnancies occurred on vedolizumab, there were 36 (86%) live births, 1 electivetermination (for Down Syndrom) and 5 (12%) spontaneous abortions.

Maternal complications were reported in 5 women (one cholestasis and 4 pre-eclampsia).

Fetal complications were reported in one pregnancy (intra uterine growth restriction)and 13 newborns developed a neonatal complication (6 preterm deliveries, 6 low birthweight and one congenital corpus callosum hypoplasia).

Concerning IBD activity, 65% of women were in remission at conception. Among them,only 2 patients flared during pregnancy.

No Severe Neonatal And Maternal Complications in Female Patients With Inflammatory Bowel Diseases Treated With

Ustekinumab or Vedolizumab During Pregnancy

Wils P et al. UEGW 2019.


Exposure to Vedolizumab in IBD Pregnant WomenAppears of Low Risk for Mother and Neonate: A First

Prospective Comparison Study

Bar-Gil Shitrit A et al. Am J Gastroenterol 2019;114:1172-5


Exposure to Vedolizumab in IBD Pregnant WomenAppears of Low Risk for Mother and Neonate: A First

Prospective Comparison Study

Bar-Gil Shitrit A et al. Am J Gastroenterol 2019;114:1172-5

In total, 5 spontaneous abortions (20.8%) were documented. Of these, 3 presented with active disease at conception, and 2 were invitro fertilization-achieved pregnancies in a 45-year old woman with an active CD. However, all

pregnancies that continued after the first trimester successfully resulted in live births.


Vedolizumab Drug Levels in Cord Blood lower than and maternal blood. Longer half-life than (25 days) infliximab (9

days) and adalimumab (14 days)

Julsgaard M and Baumgart DC et al. Aliment Pharmacol Ther 2018;48:386-8.


Cytokine Signaling of Janus Kinase (JAK)

22

Ig, immunoglobulin; IL, interleukin; JAK, Janus kinase; NK, natural killer; STAT, signal transducer and activator of transcription; Th, T helper; Tc , cytotoxic T cell 1ADIS. Drugs 2010; 10(4): 271-274; 2Coombs J et al. Ann Rheum Dis 2007; 66: 257; 3Li X et al. Presented at the 15th IIRA Conference, Chantilly, Virginia, September 21-24, 2008; 4Rochman Y et al. Nat Rev Immunol 2009; 9(7): 480-490

Tofacitinib blocks

phosphorylation of STAT and downstream

activationJAK

α

STAT

STAT

mRNA

JAKPP

STAT

STAT

P

P

P

β γCytokine

Abstract: 1029156

Cytokine Effects on the immune system

IL-2 Stimulate the proliferation and differentiation of Th, Tc, B, and NK cells

IL-4 Induce the differentiation of Th0 to Th2Induce Ig switching

IL-7 Promote the development, proliferation and survival of T, B, and NK cells

IL-9 Stimulate intrathymic T cell development

IL-15 Promote the proliferation, cytotoxicity and cytokine production of NK cells

IL-21 Enhance T and B cell function

Tofacitinib (CP-690,550) is a novel, small-molecule, oral JAK inhibitor that is being investigated as a targeted immunomodulatorfor several inflammatory diseases including ulcerative colitis and Crohn’s disease1,2

Tofacitinib inhibits JAK1, JAK2, and JAK3 in vitro with functional cellular specificity for JAK1 and JAK3 over JAK2.3 Importantly, tofacitinib directly or indirectly modulates signaling for an important subset of pro-inflammatory cytokines including IL-2, -4, -7, -9, -15, and -214


Pregnancy Outcomes in the Tofacitinib Safety Databases for Rheumatoid Arthritis and Psoriasis

Clowse MEB et al. Drug Saf (2016) 39:755–762


Outcomes of Pregnancies With Maternal/Paternal Exposure in the Tofacitinib Safety Databases for Ulcerative Colitis

Mahadevan U and Baumgart DC et al. Inflamm Bowel Dis 2018 doi: 10.1093/ibd/izy160


Tofacitinib likely crosses the placenta

Tofacitinib was found to be teratogenic andfetocidal in rats at 146 times the 5-mg BID humandose and 73 times the 10-mg BID human dose aswell as in rabbits at 13 times the 5-mg BID humandose and 6.3 times the human 10-mg BID dose

The current manufacturer recommendations are touse effective contraception during treatment andfor 4 to 6 weeks after the last dose

Tofacitinib - Overview

https ://www.acces sdata .fda.gov/drugs atfda docs/label/2018/20321 4s018 lbl.pdf





Agenda


Exposure Concentrations of Infants Breastfed by WomenReceiving Biologic Therapies for Inflammatory Bowel Diseases and

Effects of Breastfeeding on Infections and Development

Matro A et al. Gastroenterology 2018;155:696-704.





Agenda


The EULAR points to consider for use ofantirheumatic drugs before pregnancy, and during

pregnancy and lactation

Götestam Skorpen C, et al. Ann Rheum Dis 2016;75:795–810

www.danielbaumgart.ca.Mahadevan U et al. Gastroenterology 2019;156:1508–1524

Summary: PreconceptionPregnancy Planning

www.danielbaumgart.ca.Mahadevan U et al. Gastroenterology 2019;156:1508–1524

Summary: Pregnancy – ManagementRemession / Flare Medication Choices

Slide Number 1AgendaAgendaUstekinumabDevelopment in the Cynomolgus Macaque Following Administration of Ustekinumab, a Human Anti-IL-12/23p40 Monoclonal Antibody, During Pregnancy and LactationUstekinumab Exposed Psoriaris Patients in Pregnancy Case SeriesUstekinumab exposure during conception and�pregnancy in patients with chronic plaque psoriasis: a case series of 10 pregnanciesNo Severe Neonatal And Maternal Complications in Female Patients With Inflammatory Bowel Diseases Treated With Ustekinumab or Vedolizumab During PregnancyMaternal Serum, Cord Blood�and Breast Milk Ustekinumab Drug Levels in a�Patient with Crohn’s DiseaseVedolizumab and other Leukocyte Anti-Trafficking AgentsEvaluation of the Developmental Toxicity�of Vedolizumab in Rabbit and Cynomolgus MonkeysEvaluation of the Developmental Toxicity�of Vedolizumab in Rabbit and Cynomolgus Monkeys Evaluation of the Developmental Toxicity�of Vedolizumab in Rabbit and Cynomolgus Monkeys Pregnancy outcomes in inflammatory bowel disease patients�treated with vedolizumab, anti‐TNF or conventional therapy:�results of the European CONCEIVE studyPregnancy outcomes in inflammatory bowel disease patients�treated with vedolizumab, anti‐TNF or conventional therapy:�results of the European CONCEIVE studyPregnancy outcomes in inflammatory bowel disease patients�treated with vedolizumab, anti‐TNF or conventional therapy:�results of the European CONCEIVE studyPregnancy outcomes in inflammatory bowel disease patients�treated with vedolizumab, anti‐TNF or conventional therapy:�results of the European CONCEIVE studyNo Severe Neonatal And Maternal Complications in Female Patients With Inflammatory Bowel Diseases Treated With Ustekinumab or Vedolizumab During PregnancyExposure to Vedolizumab in IBD Pregnant Women�Appears of Low Risk for Mother and Neonate: A First�Prospective Comparison StudyExposure to Vedolizumab in IBD Pregnant Women�Appears of Low Risk for Mother and Neonate: A First�Prospective Comparison Study Vedolizumab Drug Levels in Cord Blood lower than and maternal blood. Longer half-life than (25 days) infliximab (9 days) and adalimumab (14 days)�Cytokine Signaling of Janus Kinase (JAK)Pregnancy Outcomes in the Tofacitinib Safety Databases for Rheumatoid Arthritis and PsoriasisOutcomes of Pregnancies With Maternal/Paternal Exposure in the Tofacitinib Safety Databases for Ulcerative ColitisTofacitinib - OverviewAgendaExposure Concentrations of Infants Breastfed by Women�Receiving Biologic Therapies for Inflammatory Bowel Diseases and Effects of Breastfeeding on Infections and DevelopmentExposure Concentrations of Infants Breastfed by Women�Receiving Biologic Therapies for Inflammatory Bowel Diseases and Effects of Breastfeeding on Infections and DevelopmentExposure Concentrations of Infants Breastfed by Women�Receiving Biologic Therapies for Inflammatory Bowel Diseases and Effects of Breastfeeding on Infections and DevelopmentExposure Concentrations of Infants Breastfed by Women�Receiving Biologic Therapies for Inflammatory Bowel Diseases and Effects of Breastfeeding on Infections and DevelopmentAgendaThe EULAR points to consider for use of�antirheumatic drugs before pregnancy, and during�pregnancy and lactationSummary: Preconception�Pregnancy PlanningSummary: Pregnancy – Management�Remession / Flare Medication Choices

Documents

Impact of New Biologics and Tofacitinib on Pregnancy and … · 2019. 11. 22. · Development in the Cynomolgus Macaque Following Administration of Ustekinumab, a Human Anti -IL-12/23p40