Pregnancy Outcome After Exposure to Migalastat: A Case Study · Pregnancy Outcome After Exposure to...
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Pregnancy Outcome Aſter Exposure to Migalastat: A Case Study Haninger-Vacariu N, 1 El-Hadi S, 1 Pauler U, 2 Foretnik M, 1 Kain R, 3 Schmidt A, 1 Skuban N, 4 Barth JA, 4 Sunder-Plassmann G 1 1 Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria; 2 Department of Medicine I, University Hospital St. Pölten, Lower Austria, Austria; 3 Clinical Instute of Pathology, Medical University of Vienna, Vienna, Austria; 4 Amicus Therapeucs, Inc., Cranbury, NJ, USA Supported by Amicus Therapeucs, Inc. Presented at the 14th Annual WORLDSymposium TM ; February 5-9, 2018; San Diego, CA 129 INTRODUCTION • Fabry disease is a rare X-linked lysosomal storage disorder caused by deficiency of α-galactosidase A (α-Gal A), encoded by the GLA gene 1 • The resulng accumulaon of globotriaosylceramide (GL-3) produces a wide variety of debilitang signs and symptoms, including cardiomyopathy, renal failure, cerebrovascular events, and gastrointesnal manifestaons 2 • The first clinical symptoms of Fabry disease typically occur during childhood, and, if leſt untreated, the burden of disease increases over me 3 • Unl recently, enzyme replacement therapy (ERT), consisng of infusions of agalsidase alfa or agalsidase beta, was the standard treatment approach for paents with Fabry disease 4 • Migalastat is a small-molecule pharmacological chaperone designed to bind selecvely and reversibly to the acve sites of amenable mutant forms of α-Gal A 5,6 ◦ It is esmated that approximately 35-50% of Fabry paents worldwide have amenable mutaons 5 ◦ Migalastat binding stabilizes the mutant forms of α-Gal A and facilitates their proper trafficking to lysosomes, where dissociaon of migalastat then restores endogenous α-Gal A acvity, leading to the catabolism of GL-3 and other disease substrates 6 • In the phase 3 FACETS (NCT00925301) and ATTRACT (NCT01218659) trials, migalastat was shown to provide clinical benefits for paents with Fabry disease and amenable mutaons and was generally well tolerated 7,8 • Migalastat is now approved for long-term treatment of Fabry disease in paents ≥16 years old in the European Union, Switzerland, Israel, Australia, and Republic of Korea and in adult paents in Canada 6 • In rabbits, developmental toxicity was observed at maternally toxic doses 6 ◦ As a result, migalastat is not recommended during pregnancy OBJECTIVE AND METHODS • To describe the medical history and outcome of a Caucasian woman with Fabry disease who became pregnant, despite hormonal contracepves, while being treated with migalastat during the phase 3 ATTRACT trial • The 18-month, randomized, acve-controlled study aimed to assess the effects of migalastat on renal funcon in paents with Fabry disease previously treated with ERT 8 • Paents of reproducve potenal agreed to use medically accepted methods of contracepon throughout the duraon of the study and for up to 30 days aſter the last dose of migalastat CASE REPORT Paent History • The paent was a Caucasian woman with Fabry disease aged 35 years at the me of migalastat iniaon and 37 years at the me of pregnancy • Her family history is shown in Figure 1 ◦ Her father was had Fabry disease (generaon II), and all 3 surviving siblings (all females) also have Fabry disease (generaon III) Figure 1. Family Tree I II III IV The paent is indicated by the arrow. Black boxes represent males with Fabry disease; circles with black dots represent females with Fabry disease. Slash indicates deceased. • The paent’s medical history prior to migalastat treatment is shown in Figure 2 Figure 2. Paent History Second pregnancy Emergency cesarean delivery at 38+ weeks of gestaon due to preeclampsia (BP ≥140 and/or 90 mm Hg), proteinuria (≥300 mg/24 h), and pelvic abnormalies Fabry diagnosis October 2005, 1 month postpartum Medical history 1989, age 12 – first onset of symptoms: recurrent headache Delivery of a healthy male infant • 50 cm, 3.4 kg, GLA WT ERT iniaon 2009 – agalsidase alfa iniated • No progression of renal, cardiac, or neurological symptoms September 2005, age 28 Increase of proteinuria (1.4 g/24 h), hypertension (210/130 mm Hg), severe neck pain, headache, and edema during the postpartum period Diagnosis based on kidney biopsy (Figure 3A) and mutaonal analysis (GLA p.R112H) 1994, age 17 – onset of psoriasis 1995, age 18 – onset of nausea, voming, and vergo First pregnancy Miscarriage at 18 weeks gestaon due to traffic accident September 2002, age 25 Postdiagnosis symptoms Since 2005 – occasional occurrence of leg edema and moderate swelling of the face and eyelids 2009 – inial diagnosis of depression 2009 – increase of proteinuria and headaches 2011 – chronic pharyngis due to tobacco use 2011 – euthyroid goiter (thyroid volume 31.8 mL) New symptoms 2011 – PUVA phototherapy used to treat psoriasis 2003, age 26 – in-paent hospital stay: strong headache and neck pain New symptoms BP=blood pressure; ERT=enzyme replacement therapy; PUVA=psoralen and ultraviolet A; WT=wild type. Figure 3. Images From Kidney Biopsy Showing Fabry Disease and C3 Deposits A B AFOG=acid fuchsin orange G; IgA=immunoglobulin A; IgG=immunoglobulin G; PAS=periodic acid-Schiff; TEM=transmission electron microscopy. (A) The first renal biopsy (2005) shows in >50% of the glomeruli a diffuse, segmentally accentuated mesangial matrix and cell increase (PAS and AFOG), and segmentally obliterated capillary loops adherent to the Bowman’s capsule (AFOG). There is dominant segmental C3 deposion (C3) in the absence of IgG and IgA. Podocytes show characterisc lamellar and zebroid bodies by TEM; however, the classical appearance of “foamy” podocytes was less dominant by light microscopy (PAS) due to the segmental nature of the pathological changes. (B) The second renal biopsy (2014) shows characterisc foamy macrophages (PAS and AFOG, >) as well as segmental mesangial matrix and cell increase. Dominant C3 deposits (C3) correspond to mesangial electron dense deposits (*) by TEM (right) while almost all podocytes contain lamellar and zebroid inclusion bodies (leſt). Treatment With Migalastat • Details of migalastat treatment and of the third pregnancy are shown in Figure 4 Figure 4. Migalastat Treatment and Pregnancy April 2012 – 187 mg/24 h Third pregnancy September 2015 – ongoing • Agalsidase alfa, home infusion Enrolled in ATTRACT May 2012, age 35 – iniaon of migalastat therapy Restarted ERT therapy June 2014 – proteinuria (>1000 mg/24 h) prompted kidney biopsy (Figure 3B); posive serum pregnancy test result Paent taking hormonal contracepves (Diane mite; ovulaon inhibitor) May 2014 – negave urine pregnancy test result September 2014 – fetal MRI performed • Normal findings (Figure 5) June 2014 – confirmaon of pregnancy by ultrasound examinaon • 18+0 weeks of gestaon • Despite taking hormonal contracepves • Migalastat and hormonal contracepves stopped October 2014 – birth of second child • • Via cesarean delivery at 37+ weeks of gestaon Female, 45 cm, 2.29 kg, GLA WT Proteinuria May 2012 – 83 mg/24 h May 2014 – proteinuria 2166 mg/24 h (without hypertension; 131/68 mm Hg) February 2014 – proteinuria 78 mg/24 h MRI=magnec resonance imaging. • During the pregnancy, fetal magnec resonance imaging indicated normal development (Figure 5) • Although the pregnancy was unevenul, the birth weight was low Figure 5. Fetal MRI (Coronal Plane) During Pregnancy CONCLUSIONS • Except for low birth weight, pregnancy outcome in this case was normal despite exposure to migalastat for 18 weeks during the pregnancy • Migalastat therapy during pregnancy is not advised REFERENCES 1. Ishii S et al. Biochem J. 2007;406(2):285-295. 2. Schiffmann R et al. Kidney Int. 2017;91(2):284-293. 3. Germain DP. Orphanet J Rare Dis. 2010;5:30. 4. Schiffmann R, Ries M. Pediatr Neurol. 2016;64:10-20. 5. Benjamin ER et al. Genet Med. 2017;19(4):430-438. 6. Migalastat [summary of product characteriscs]. Buckinghamshire, UK: Amicus Therapeucs, UK Ltd. 7. Germain DP et al. N Eng J Med. 2016;375(6):545-555. 8. Hughes DA et al. J Med Genet. 2017;54(4):288-296. ACKNOWLEDGMENTS The authors thank the paent and her family. Third-party medical wring assistance was provided by ApotheCom (Yardley, PA) and was supported by Amicus Therapeucs, Inc. DISCLOSURE Conflicts of Interest NH-V has received a travel grant from Amicus Therapeucs and Shire. SE-H, UP, MF, RK, and AS have nothing to disclose. NS and JAB are employees of and hold stock in Amicus Therapeucs. GS-P has served on advisory boards and received honoraria and research funding from Amicus Therapeucs, Shire, and Sanofi.
Transcript of Pregnancy Outcome After Exposure to Migalastat: A Case Study · Pregnancy Outcome After Exposure to...
Pregnancy Outcome After Exposure to Migalastat: A Case StudyHaninger-Vacariu N,1 El-Hadi S,1 Pauler U,2 Foretnik M,1 Kain R,3 Schmidt A,1 Skuban N,4 Barth JA,4 Sunder-Plassmann G1
1Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria; 2Department of Medicine I, University Hospital St. Pölten, Lower Austria, Austria; 3Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria; 4Amicus Therapeutics, Inc., Cranbury, NJ, USA
Supported by Amicus Therapeutics, Inc. Presented at the 14th Annual WORLDSymposiumTM; February 5-9, 2018; San Diego, CA
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INTRODUCTION
• Fabry disease is a rare X-linked lysosomal storage disorder caused by deficiency of α-galactosidase A (α-Gal A), encoded by the GLA gene1
• The resulting accumulation of globotriaosylceramide (GL-3) produces a wide variety of debilitating signs and symptoms, including cardiomyopathy, renal failure, cerebrovascular events, and gastrointestinal manifestations2
• The first clinical symptoms of Fabry disease typically occur during childhood, and, if left untreated, the burden of disease increases over time3
• Until recently, enzyme replacement therapy (ERT), consisting of infusions of agalsidase alfa or agalsidase beta, was the standard treatment approach for patients with Fabry disease4
• Migalastat is a small-molecule pharmacological chaperone designed to bind selectively and reversibly to the active sites of amenable mutant forms of α-Gal A5,6
◦ It is estimated that approximately 35-50% of Fabry patients worldwide have amenable mutations5
◦ Migalastat binding stabilizes the mutant forms of α-Gal A and facilitates their proper trafficking to lysosomes, where dissociation of migalastat then restores endogenous α-Gal A activity, leading to the catabolism of GL-3 and other disease substrates6
• In the phase 3 FACETS (NCT00925301) and ATTRACT (NCT01218659) trials, migalastat was shown to provide clinical benefits for patients with Fabry disease and amenable mutations and was generally well tolerated7,8
• Migalastat is now approved for long-term treatment of Fabry disease in patients ≥16 years old in the European Union, Switzerland, Israel, Australia, and Republic of Korea and in adult patients in Canada6
• In rabbits, developmental toxicity was observed at maternally toxic doses6
◦ As a result, migalastat is not recommended during pregnancy
OBJECTIVE AND METHODS
• To describe the medical history and outcome of a Caucasian woman with Fabry disease who became pregnant, despite hormonal contraceptives, while being treated with migalastat during the phase 3 ATTRACT trial
• The 18-month, randomized, active-controlled study aimed to assess the effects of migalastat on renal function in patients with Fabry disease previously treated with ERT8
• Patients of reproductive potential agreed to use medically accepted methods of contraception throughout the duration of the study and for up to 30 days after the last dose of migalastat
CASE REPORT
Patient History• The patient was a Caucasian woman with Fabry disease aged 35 years at the time of
migalastat initiation and 37 years at the time of pregnancy
• Her family history is shown in Figure 1
◦ Her father was had Fabry disease (generation II), and all 3 surviving siblings (all females) also have Fabry disease (generation III)
Figure 1. Family Tree
I
II
III
IV
The patient is indicated by the arrow. Black boxes represent males with Fabry disease; circles with black dots represent females with Fabry disease. Slash indicates deceased.
• The patient’s medical history prior to migalastat treatment is shown in Figure 2
Figure 2. Patient History
Second pregnancy
Emergency cesarean delivery at 38+ weeks of gesta�on due to preeclampsia(BP ≥140 and/or 90 mm Hg), proteinuria (≥300 mg/24 h), and pelvic abnormali�es
Fabry diagnosis
October 2005, 1 month postpartum
Medical history
1989, age 12 – first onset of symptoms: recurrent headache
Delivery of a healthy male infant• 50 cm, 3.4 kg, GLA WT
ERT ini�a�on
2009 – agalsidase alfa ini�ated• No progression of renal, cardiac, or neurological symptoms
September 2005, age 28
Increase of proteinuria (1.4 g/24 h), hypertension (210/130 mm Hg),severe neck pain, headache, and edema during the postpartum period
Diagnosis based on kidney biopsy (Figure 3A) and muta�onal analysis (GLA p.R112H)
1994, age 17 – onset of psoriasis
1995, age 18 – onset of nausea, vomi�ng, and ver�go
First pregnancy
Miscarriage at 18 weeks gesta�on due to traffic accident
September 2002, age 25
Postdiagnosis symptoms
Since 2005 – occasional occurrence of leg edema and moderate swellingof the face and eyelids
2009 – ini�al diagnosis of depression
2009 – increase of proteinuria and headaches
2011 – chronic pharyngi�s due to tobacco use
2011 – euthyroid goiter (thyroid volume 31.8 mL)
New symptoms
2011 – PUVA phototherapy used to treat psoriasis
2003, age 26 – in-pa�ent hospital stay: strong headache and neck pain
New symptoms
BP=blood pressure; ERT=enzyme replacement therapy; PUVA=psoralen and ultraviolet A; WT=wild type.
Figure 3. Images From Kidney Biopsy Showing Fabry Disease and C3 Deposits
A B
AFOG=acid fuchsin orange G; IgA=immunoglobulin A; IgG=immunoglobulin G; PAS=periodic acid-Schiff; TEM=transmission electron microscopy. (A) The first renal biopsy (2005) shows in >50% of the glomeruli a diffuse, segmentally accentuated mesangial matrix and cell increase (PAS and AFOG), and segmentally obliterated capillary loops adherent to the Bowman’s capsule (AFOG). There is dominant segmental C3 deposition (C3) in the absence of IgG and IgA. Podocytes show characteristic lamellar and zebroid bodies by TEM; however, the classical appearance of “foamy” podocytes was less dominant by light microscopy (PAS) due to the segmental nature of the pathological changes. (B) The second renal biopsy (2014) shows characteristic foamy macrophages (PAS and AFOG, >) as well as segmental mesangial matrix and cell increase. Dominant C3 deposits (C3) correspond to mesangial electron dense deposits (*) by TEM (right) while almost all podocytes contain lamellar and zebroid inclusion bodies (left).
Treatment With Migalastat• Details of migalastat treatment and of the third pregnancy are shown in Figure 4
Figure 4. Migalastat Treatment and Pregnancy
April 2012 – 187 mg/24 h
Third pregnancy
September 2015 – ongoing• Agalsidase alfa, home infusion
Enrolled in ATTRACT
May 2012, age 35 – ini�a�on of migalastat therapy
Restarted ERT therapy
June 2014 – proteinuria (>1000 mg/24 h) prompted kidney biopsy (Figure 3B);posi�ve serum pregnancy test result
Pa�ent taking hormonal contracep�ves (Diane mite; ovula�on inhibitor)
May 2014 – nega�ve urine pregnancy test result
September 2014 – fetal MRI performed • Normal findings (Figure 5)
June 2014 – confirma�on of pregnancy by ultrasound examina�on • 18+0 weeks of gesta�on• Despite taking hormonal contracep�ves • Migalastat and hormonal contracep�ves stopped
October 2014 – birth of second child ••
Via cesarean delivery at 37+ weeks of gesta�onFemale, 45 cm, 2.29 kg, GLA WT
Proteinuria
May 2012 – 83 mg/24 h
May 2014 – proteinuria 2166 mg/24 h (without hypertension; 131/68 mm Hg)
February 2014 – proteinuria 78 mg/24 h
MRI=magnetic resonance imaging.
• During the pregnancy, fetal magnetic resonance imaging indicated normal development (Figure 5)
• Although the pregnancy was uneventful, the birth weight was low
Figure 5. Fetal MRI (Coronal Plane) During Pregnancy
CONCLUSIONS
• Except for low birth weight, pregnancy outcome in this case was normal despite exposure to migalastat for 18 weeks during the pregnancy
• Migalastat therapy during pregnancy is not advised
REFERENCES 1. Ishii S et al. Biochem J. 2007;406(2):285-295.2. Schiffmann R et al. Kidney Int. 2017;91(2):284-293.3. Germain DP. Orphanet J Rare Dis. 2010;5:30.4. Schiffmann R, Ries M. Pediatr Neurol. 2016;64:10-20.5. Benjamin ER et al. Genet Med. 2017;19(4):430-438.6. Migalastat [summary of product characteristics]. Buckinghamshire, UK: Amicus Therapeutics, UK Ltd.7. Germain DP et al. N Eng J Med. 2016;375(6):545-555.8. Hughes DA et al. J Med Genet. 2017;54(4):288-296.
ACKNOWLEDGMENTSThe authors thank the patient and her family. Third-party medical writing assistance was provided by ApotheCom (Yardley, PA) and was supported by Amicus Therapeutics, Inc.
DISCLOSURE
Conflicts of InterestNH-V has received a travel grant from Amicus Therapeutics and Shire. SE-H, UP, MF, RK, and AS have nothing to disclose. NS and JAB are employees of and hold stock in Amicus Therapeutics. GS-P has served on advisory boards and received honoraria and research funding from Amicus Therapeutics, Shire, and Sanofi.
