Postnatal development in cynomolgus monkeys following prenatal exposure to natalizumab, an α4 integrin inhibitor

Wehner, Nancy; Shopp, George M.; Osterburg, Ingrid; Fuchs, Antje; Buse, Eberhard; Clarke, Jessica L.

doi:10.1002/bdrb.20193

Cited by 53 publications

(49 citation statements)

References 25 publications

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“…Based on animal studies of embryonic and post-natal development it has been deemed that prolonged, high dose natalizumab treatment caused no developmental defects 85-87. These results cannot be extrapolated to other α4 antagnoists.…”

Section: α4 Integrinsmentioning

confidence: 99%

Integrin Targeted Therapeutics

Millard¹,

Odde²,

Neamati³

2011

Theranostics

224

197

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Integrins are heterodimeric, transmembrane receptors that function as mechanosensors, adhesion molecules and signal transduction platforms in a multitude of biological processes. As such, integrins are central to the etiology and pathology of many disease states. Therefore, pharmacological inhibition of integrins is of great interest for the treatment and prevention of disease. In the last two decades several integrin-targeted drugs have made their way into clinical use, many others are in clinical trials and still more are showing promise as they advance through preclinical development. Herein, this review examines and evaluates the various drugs and compounds targeting integrins and the disease states in which they are implicated.

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Section: α4 Integrinsmentioning

confidence: 99%

Integrin Targeted Therapeutics

Millard¹,

Odde²,

Neamati³

2011

Theranostics

224

197

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“…Studies of natalizumab in MS have shown reduced relapse rates and disability progression, but less is known about its effects on pregnancy outcomes [10, 11]. Natalizumab is classified as a pregnancy category C drug, as potential fetal effects have been reported in animal studies [12–14] and there is a paucity of well-controlled human studies [6]. Although some animal studies have shown that natalizumab can cross the placental barrier and produce hematologic effects on fetal guinea pigs and primates [6, 12, 14, 15], others have not shown fetal interaction [16].…”

Section: Introductionmentioning

confidence: 99%

“…Natalizumab is classified as a pregnancy category C drug, as potential fetal effects have been reported in animal studies [12–14] and there is a paucity of well-controlled human studies [6]. Although some animal studies have shown that natalizumab can cross the placental barrier and produce hematologic effects on fetal guinea pigs and primates [6, 12, 14, 15], others have not shown fetal interaction [16]. Human studies and case reports have not shown increases in spontaneous abortions or birth defects; however, results are limited by small sample sizes [17–20].…”

Section: Introductionmentioning

confidence: 99%

Evaluation of pregnancy outcomes from the Tysabri® (natalizumab) pregnancy exposure registry: a global, observational, follow-up study

et al. 2016

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BackgroundPatients with multiple sclerosis (MS) or Crohn’s disease (CD) being treated with natalizumab (Tysabri®, Biogen) who are planning to become pregnant or discover they are pregnant after exposure to natalizumab are currently advised to balance the potential benefits and potential risks of exposure when considering treatment options. This study was undertaken to evaluate pregnancy outcomes of women with MS or CD who were exposed to natalizumab at any time within 3 months prior to conception or during pregnancy. A pregnancy registry was created to better understand the effect of natalizumab exposure on pregnancy outcomes.MethodsThe Tysabri Pregnancy Exposure Registry was a global, observational exposure registration and follow-up study. Evaluations included spontaneous abortions (<22 weeks gestational age), fetal losses (≥22 weeks gestational age), ectopic pregnancies, elective or therapeutic terminations, stillbirths, birth defects, and live births. Birth defects were reviewed and coded in accordance with the Metropolitan Atlanta Congenital Defects Program (MACDP) classification of birth defects.ResultsA total of 369 patients with MS and 7 patients with CD were enrolled prospectively, of whom 355 patients (99.4 %; 349 MS and 6 CD) had known pregnancy outcomes (including 8 twin sets). The spontaneous abortion rate was 9.0 % (n = 32; 95 % confidence interval [C. I.], 6.3–12.5 %). An independent advisory committee review determined the major birth defect rate to be 5.05 % (16 of 316 live births + 1 elective abortion; 95 % C. I., 2.9–8.1 %). The mean gestational age of the live-born infants was 38.3 weeks, and the mean birth weight was 3158.3 g.ConclusionsAlthough the overall rate of birth defects was higher than that observed by the MACDP, these registry outcomes showed no specific pattern of malformations that would suggest a drug effect, and the spontaneous abortion rate was consistent with that of the general population.Trial registrationClinicalTrials.gov NCT00472992 (11 May 2007).

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“…Few dams had measurable natalizumab in the breast milk, and IgG antibodies are not subject to significant transport out of the gut and into the circulation of primates. 6 …”

mentioning

confidence: 99%

Transfer of Natalizumab into Breast Milk in a Mother with Multiple Sclerosis

et al. 2015

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Natalizumab (Tysabri) is a recombinant humanized antibody to α4-integrin that is approved by the Food and Drug Administration for the treatment of multiple sclerosis (MS) and Crohn disease. This is a case report of a 28-year-old woman with MS who was taking natalizumab (300 mg intravenously infused over 1 hour every 4 weeks) while breastfeeding her 11.5-month-old daughter 3 times a day. Breast milk samples were collected over a 50-day period after the patient's first drug infusion. The average concentration of natalizumab was 0.93 µg/mL/d, and the relative infant dose was 1.74% of the weight-adjusted maternal dose. Transfer of natalizumab into human milk increased over time and with subsequent injections, with the highest concentration of 2.83 µg/mL at day 50 with a relative infant dose of 5.3%. Because these data suggest continued accumulation of natalizumab in milk, and because we cannot provide an accurate assessment of levels of this drug at 24 weeks (steady state), we are unable to determine safety at this time.

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Postnatal development in cynomolgus monkeys following prenatal exposure to natalizumab, an α4 integrin inhibitor

Abstract: Natalizumab had no adverse effects on the general health, survival, development, or immunological structure and function of infants born to dams treated with natalizumab during pregnancy.

Cited by 53 publications

References 25 publications

Integrin Targeted Therapeutics

Integrin Targeted Therapeutics

Evaluation of pregnancy outcomes from the Tysabri® (natalizumab) pregnancy exposure registry: a global, observational, follow-up study

Transfer of Natalizumab into Breast Milk in a Mother with Multiple Sclerosis

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