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Pregnancy outcomes and postpartum relapse rates in women with RRMS treated with alemtuzumab in the phase 2 and 3 clinical development program over 16 years.
Mult Scler Relat Disord. 2020 Aug; 43:102146.MS

Abstract

BACKGROUND

Relapsing-remitting multiple sclerosis (RRMS) is frequently diagnosed in women of reproductive age. Because the use of disease-modifying therapies (DMTs) early in the disease course is increasing, it is important to evaluate the safety of DMTs in pregnant women and their developing fetuses. Alemtuzumab, approved for the treatment of relapsing forms of MS, is administered as 2 courses of 12 mg/day on 5 consecutive days at baseline and on 3 consecutive days 12 months later. Alemtuzumab is eliminated from the body within approximately 30 days after administration; it is recommended that women of childbearing potential use effective contraception during and for 4 months after treatment. Here, we report pregnancy outcomes in alemtuzumab-treated women from the phase 2 and 3 clinical development program over 16 years.

METHODS

We followed 972 women who had alemtuzumab in phase 2 (CAMMS223 [NCT00050778]) and phase 3 (CARE-MS I [NCT00530348], CARE-MS II [NCT00548405]) studies, and/or in 2 consecutive extension studies (NCT00930553; NCT02255656 [TOPAZ]). In the extension studies, patients could receive additional alemtuzumab (12 mg/day on 3 days; ≥12 months apart) as needed for disease activity. All women who received alemtuzumab in the clinical development program were included. Pregnant or lactating patients were followed up for safety.

RESULTS

As of November 26, 2018, 264 pregnancies occurred in 160 alemtuzumab-treated women, with a mean age at conception of 32.6 years, and mean time from last alemtuzumab dose to conception of 35.9 months. Of the 264 pregnancies, 233 (88%) were completed, 11 (4%) were ongoing, and 20 (8%) had unknown outcomes; 16 (6%) conceptions occurred within 4 months, and 5 conceptions within 1 month of the last alemtuzumab dose. Of the 233 completed pregnancies with known outcomes, there were 155 (67%) live births with no congenital abnormalities or birth defects, 52 (22%) spontaneous abortions, 25 (11%) elective abortions, and 1 (0.4%) stillbirth. Maternal age was associated with an increased risk of spontaneous abortion in alemtuzumab-treated patients (<35 years: 15%; ≥35 years: 37%; relative risk [RR], 2.46 [95% CI: 1.53-3.95], p=0.0002). Risk of spontaneous abortion was not increased in patients becoming pregnant ≤4 months versus >4 months since alemtuzumab exposure (19% vs 23%; RR, 1.08 [95% CI: 0.41-2.85], p=0.88). Autoimmune thyroid adverse events did not increase risk for spontaneous abortion (patients with vs without thyroid adverse events, 23.7% vs 21.3%; RR, 1.11 [95% CI: 0.69-1.80], p=0.75). Annualized relapse rate was 0.10 and 0.12 in the 2 years prior to pregnancy (post alemtuzumab), and was 0.22, 0.12, and 0.12 in each of the first 3 years postpartum, respectively.

CONCLUSION

Normal live births were the most common outcome in women exposed to alemtuzumab 12 mg or 24 mg in clinical studies. Spontaneous abortion rate in alemtuzumab-treated patients was comparable with rates in the general population and treatment-naive MS patients, and was not increased in women with pregnancy onset within 4 months of alemtuzumab exposure. There was a minimal increase in postpartum relapses.

Authors+Show Affiliations

St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada. Electronic address: ohjiw@smh.ca.The Chaim Sheba Medical Center, Tel Hashomer, Israel; Tel Aviv University, Tel Aviv, Israel. Electronic address: anat.achiron@sheba.health.gov.il.Oslo University Hospital Ullevål and Institute of Clinical Medicine, University of Oslo, Oslo, Norway. Electronic address: uxelgu@ous-hf.no.University of California San Diego, La Jolla, CA, United States. Electronic address: chchambers@ucsd.edu.Murfreesboro Medical Clinic and SurgiCenter, Murfreesboro, TN, United States.University of British Columbia, Vancouver, British Columbia, Canada. Electronic address: jderwenskus@mmclinic.com.St. Josef Hospital, Ruhr University Bochum, Bochum, Germany. Electronic address: k.hellwig@klinikum-bochum.de.Baylor College of Medicine, Houston, TX, United States. Electronic address: ghutton@bcm.edu.The University of Queensland, Brisbane, Australia. Electronic address: pamela.mccombe@uq.edu.au.Carolinas Health MS Center, Charlotte, NC, United States. Electronic address: marie.m.moore@carolinashealthcare.org.Manchester Centre for Clinical Neurosciences, Salford Royal NHS Foundation Trust, Salford, United Kingdom. Electronic address: david.rog@srft.nhs.uk.MS and Neuromuscular Center of Excellence, Clearwater, FL, United States. Electronic address: jeanraphaelschneider@gmail.com.Universidade de São Paulo, São Paulo, Brazil. Electronic address: rfsimm@gmail.com.Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal. Electronic address: liviadiogosousa@gmail.com.Idaho Falls MS Center, Idaho Falls, ID, United States. Electronic address: svincentmd@gmail.com.Sanofi, Cambridge, MA, United States. Electronic address: luke.chung@sanofi.com.Sanofi, Cambridge, MA, United States. Electronic address: nadia.daizadeh@sanofi.com.Sanofi, Cambridge, MA, United States. Electronic address: colin.mitchell@sanofi.com.University of Cambridge, Cambridge, United Kingdom. Electronic address: alastair.compston@medschl.cam.ac.uk.No affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32498033

Citation

Oh, Jiwon, et al. "Pregnancy Outcomes and Postpartum Relapse Rates in Women With RRMS Treated With Alemtuzumab in the Phase 2 and 3 Clinical Development Program Over 16 Years." Multiple Sclerosis and Related Disorders, vol. 43, 2020, p. 102146.
Oh J, Achiron A, Celius EG, et al. Pregnancy outcomes and postpartum relapse rates in women with RRMS treated with alemtuzumab in the phase 2 and 3 clinical development program over 16 years. Mult Scler Relat Disord. 2020;43:102146.
Oh, J., Achiron, A., Celius, E. G., Chambers, C., Derwenskus, J., Devonshire, V., Hellwig, K., Hutton, G. J., McCombe, P., Moore, M., Rog, D., Schneider, J. R., Simm, R. F., Sousa, L., Vincent, S. G., Chung, L., Daizadeh, N., Mitchell, C., & Compston, D. A. S. (2020). Pregnancy outcomes and postpartum relapse rates in women with RRMS treated with alemtuzumab in the phase 2 and 3 clinical development program over 16 years. Multiple Sclerosis and Related Disorders, 43, 102146. https://doi.org/10.1016/j.msard.2020.102146
Oh J, et al. Pregnancy Outcomes and Postpartum Relapse Rates in Women With RRMS Treated With Alemtuzumab in the Phase 2 and 3 Clinical Development Program Over 16 Years. Mult Scler Relat Disord. 2020;43:102146. PubMed PMID: 32498033.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Pregnancy outcomes and postpartum relapse rates in women with RRMS treated with alemtuzumab in the phase 2 and 3 clinical development program over 16 years. AU - Oh,Jiwon, AU - Achiron,Anat, AU - Celius,Elisabeth G, AU - Chambers,Christina, AU - Derwenskus,Joy, AU - Devonshire,Virginia, AU - Hellwig,Kerstin, AU - Hutton,George J, AU - McCombe,Pamela, AU - Moore,Marie, AU - Rog,David, AU - Schneider,Jean-Raphael, AU - Simm,Renata Faria, AU - Sousa,Livia, AU - Vincent,Stephen G, AU - Chung,Luke, AU - Daizadeh,Nadia, AU - Mitchell,Colin, AU - Compston,D Alastair S, AU - ,, Y1 - 2020/05/06/ PY - 2019/10/02/received PY - 2020/02/28/revised PY - 2020/04/21/accepted PY - 2020/6/5/pubmed PY - 2020/6/5/medline PY - 2020/6/5/entrez KW - Alemtuzumab KW - Disease-modifying therapy KW - Multiple sclerosis KW - Pregnancy KW - Safety SP - 102146 EP - 102146 JF - Multiple sclerosis and related disorders JO - Mult Scler Relat Disord VL - 43 N2 - BACKGROUND: Relapsing-remitting multiple sclerosis (RRMS) is frequently diagnosed in women of reproductive age. Because the use of disease-modifying therapies (DMTs) early in the disease course is increasing, it is important to evaluate the safety of DMTs in pregnant women and their developing fetuses. Alemtuzumab, approved for the treatment of relapsing forms of MS, is administered as 2 courses of 12 mg/day on 5 consecutive days at baseline and on 3 consecutive days 12 months later. Alemtuzumab is eliminated from the body within approximately 30 days after administration; it is recommended that women of childbearing potential use effective contraception during and for 4 months after treatment. Here, we report pregnancy outcomes in alemtuzumab-treated women from the phase 2 and 3 clinical development program over 16 years. METHODS: We followed 972 women who had alemtuzumab in phase 2 (CAMMS223 [NCT00050778]) and phase 3 (CARE-MS I [NCT00530348], CARE-MS II [NCT00548405]) studies, and/or in 2 consecutive extension studies (NCT00930553; NCT02255656 [TOPAZ]). In the extension studies, patients could receive additional alemtuzumab (12 mg/day on 3 days; ≥12 months apart) as needed for disease activity. All women who received alemtuzumab in the clinical development program were included. Pregnant or lactating patients were followed up for safety. RESULTS: As of November 26, 2018, 264 pregnancies occurred in 160 alemtuzumab-treated women, with a mean age at conception of 32.6 years, and mean time from last alemtuzumab dose to conception of 35.9 months. Of the 264 pregnancies, 233 (88%) were completed, 11 (4%) were ongoing, and 20 (8%) had unknown outcomes; 16 (6%) conceptions occurred within 4 months, and 5 conceptions within 1 month of the last alemtuzumab dose. Of the 233 completed pregnancies with known outcomes, there were 155 (67%) live births with no congenital abnormalities or birth defects, 52 (22%) spontaneous abortions, 25 (11%) elective abortions, and 1 (0.4%) stillbirth. Maternal age was associated with an increased risk of spontaneous abortion in alemtuzumab-treated patients (<35 years: 15%; ≥35 years: 37%; relative risk [RR], 2.46 [95% CI: 1.53-3.95], p=0.0002). Risk of spontaneous abortion was not increased in patients becoming pregnant ≤4 months versus >4 months since alemtuzumab exposure (19% vs 23%; RR, 1.08 [95% CI: 0.41-2.85], p=0.88). Autoimmune thyroid adverse events did not increase risk for spontaneous abortion (patients with vs without thyroid adverse events, 23.7% vs 21.3%; RR, 1.11 [95% CI: 0.69-1.80], p=0.75). Annualized relapse rate was 0.10 and 0.12 in the 2 years prior to pregnancy (post alemtuzumab), and was 0.22, 0.12, and 0.12 in each of the first 3 years postpartum, respectively. CONCLUSION: Normal live births were the most common outcome in women exposed to alemtuzumab 12 mg or 24 mg in clinical studies. Spontaneous abortion rate in alemtuzumab-treated patients was comparable with rates in the general population and treatment-naive MS patients, and was not increased in women with pregnancy onset within 4 months of alemtuzumab exposure. There was a minimal increase in postpartum relapses. SN - 2211-0356 UR - https://www.unboundmedicine.com/medline/citation/32498033/Pregnancy_outcomes_and_postpartum_relapse_rates_in_women_with_RRMS_treated_with_alemtuzumab_in_the_phase_2_and_3_clinical_development_program_over_16_years L2 - https://linkinghub.elsevier.com/retrieve/pii/S2211-0348(20)30222-4 DB - PRIME DP - Unbound Medicine ER -
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