FEMALES WITH FABRY HAVE HISTORICALLY BEEN UNDERTREATED1,2
IN THE MULTICENTER FEMALE FABRY STUDY (n=224)3:
OF FEMALES WERE
EVEN THOUGH CRITERIA FOR TREATMENT INITIATION WERE FULFILLED
- Elevated plasma Lyso-GL-3 levels in treatment-naive females can be a marker of disease burden. These women showed a higher frequency of pain than women ~8 years older with normal Lyso-GL-3
- Mapping disease progression over time can help you identify a decline in organ function
IN THE FABRY REGISTRY (n=1077)4,*:
ONLY 47% OF FEMALES WITH CKD > STAGE 3 ARE TREATED VS 88% OF MALES
CKD=chronic kidney disease.
*Data as of January 2007 including 1077 women enrolled in the Fabry Registry.
FEMALES WITH FABRY DISEASE ARE NOT JUST “CARRIERS”4
DUE TO X-INACTIVATION, FEMALES ARE DESCRIBED AS “MOSAIC” BECAUSE THEIR BODIES CONSIST OF A MIXTURE OF FABRY-AFFECTED CELLS AND NON-AFFECTED, “NORMAL” CELLS5
HOW X-INACTIVATION RESULTS IN MOSAICISM6
- XY males have a single X chromosome in each somatic cell, while XX females have two X chromosomes. One of the two X chromosomes is active and the other is inactive6
- The process for X-inactivation is typically random. If there are more cells in an organ whose active X chromosome contains the mutant allele, then those cells may have deficient levels of alpha-GAL A, resulting in an accumulation of substrate in that organ5
- Females with near-normal levels of alpha-GAL A in plasma or leukocytes can still present with clinical manifestations7
X-inactivation can lead to females with Fabry having a range of symptoms.7
FEMALES WITH FABRY CAN SUFFER FROM LIFE-ALTERING SYMPTOMS
Females with Fabry have higher occurrence of serious complications than females in the general population4:
In the Fabry Registry, ~70% of females reported having signs and symptoms.4,*
HAVE ABDOMINAL PAIN15
HAVE NEUROPATHIC PAIN4
*Data as of January 2007, including 1077 women enrolled in the Fabry Registry.
Neuropathic pain could be a red flag suggesting underlying organ damage.15
FABRY IS PROGRESSIVE, AND ERT SHOULD BE CONSIDERED UPON EARLY SIGNS OF DISEASE IN FEMALES16,17
International Panel Consensus Guidelines16,17
*Data as of January 2007, including 1077 women enrolled in the Fabry Registry.
Recommendations apply to patients with classic and later-onset variants.
CNS=central nervous system; GI=gastrointestinal; ERT=enzyme replacement therapy; GL-3=globotriaosylceramide; MRI=magnetic resonance imaging; TIA=transient ischemic attack; GFR=glomerular filtration rate.
Don’t wait until she’s had her first stroke or has severe CKD. When you map disease progression over time and see decline in organ function, start FABRAZYME for appropriate patients.
A LONG-TERM OBSERVATIONAL STUDY
EVALUATING THE USE OF FABRAZYME IN FEMALES2
Large cohort of female patients
Female patients in the Fabry Registry* (NCT00196742), using records from 1998 to 2018, who were ≥18 years at treatment initiation and had pre- and post- treatment data available as required by the study.18
Long-term FABRAZYME outcomes
Patients had ≥2 pre-treatment and ≥2 post-treatment outcome measurements ≥2 years apart during the 5 years before and 5 years after treatment initiation.2
Self-controlled pre- and post-treatment comparison
Kidney function (eGFR) as surrogate clinical endpoint of Fabry disease progression. eGFR was assessed and renal patient data were stratified into low renal involvement (LRI) or high renal involvement at baseline (HRI).2,†,‡
†LRI defined as urine protein-to-creatinine ratio (UPCR) <0.5 g/g or urine albumin-to-creatinine ratio (UACR) <0.3 g/g. HRI defined as UPCR >0.5 g/g or UACR >0.3 g/g.2
Characteristics of the adult female patients in the Fabry Registry included in the pre- vs post-FABRAZYME treatment analysis2
Baseline characteristics (median)
eGFR analysis (N=86)
Age at symptom onset (years)
15.4 (9.7–30.6) (n=56)
Age at diagnosis (years)
35.1 (28.3-45.1) (n=81)
Age at first FABRAZYME (years)
46.3 (38.8-56.2) in=86)
Time from diagnosis to first FABRAZYME (years)
5.8 (2.6-13.6) (n=81)
Pre-FABRAZYME follow-up time (years)
3.6 (2.8-4.2) (n=86)
Post-FABRAZYME follow-up time (years)
4.1 (3.2-4.5) (n=86)
Low renal involvement
53 (70.7) (n=86)
High renal involvement
22 (29.3) (n=86)
*This retrospective subanalysis used data from the Fabry registry, a multicenter, international, longitudinal, observational program designed to monitor the natural history and treatment outcomes of patients with Fabry disease. It included adult female patients enrolled in the Fabry Registry who had initiated treatment with FABRAZYME as first ERT and had received an average dose at or near the licensed dose of 1 mg/kg every other week (EOW) (0.9–1.1 mg/kg EOW) for >2 years. The outcomes assessed were end-diastolic left ventricular posterior wall thickness and intraventricular septal thickness, both using standard echocardiography measurements (either 2-dimensional or M-mode), and eGFR using the Chronic Kidney Disease Epidemiology Collaboration equation based on reported serum creatinine. Treating physicians determined assessment frequency according to each patient’s individual need for medical care and follow-up.2
‡Patients with end-stage kidney failure were excluded (eGFR <15 mL/min/1.73m2/year) at the first pre- or first post-treatment assessment or chronic dialysis or kidney transplant prior to treatment initiation.2
IN A LONG-TERM STUDY OF 86 FEMALES,
FABRAZYME MAINTAINED NORMAL EGFR DECLINE2
Mean rate of yearly eGFR decline post treatment remained. The difference between the 2 slopes was not significant and remained within the normal range of a healthy population: -0.13 mL/min/1.73m2/year (-1.15, 0.89; P=0.80)2
Adapted from Wanner C et al. 20202 and CKD Work Group 2012.19
- In healthy individuals, renal function, as measured by eGFR, declines with age at a rate of approximately -1mL/min/1.73m2/year starting in the 4th decade of life19
In a long-term study of females on FABRAZYME:
- eGFR decline during the pre-treatment period: -0.83 mL/min/1.73m2/year (95% CI: -1.52, -0.13; P=0.02)2
- eGFR decline in the post-treatment period: -0.95 mL/min/1.73m2/year (95% CI: -1.59, -0.32; P<0.01)2
- Overall stability of eGFR slope during sustained treatment with FABRAZYME (median 4.1 years) suggests that treatment maintained the normal decline in kidney function reported for females in a healthy population2
Most common adverse reactions (≥20%) are: upper respiratory tract infection, chills, pyrexia, headache, cough, paresthesia, fatigue, peripheral edema, dizziness, and rash.
IMPORTANT SAFETY INFORMATION
IMPORTANT SAFETY INFORMATION
WARNINGS AND PRECAUTIONS
Anaphylaxis and Hypersensitivity Reactions
In clinical trials and postmarketing safety experience with Fabrazyme, approximately 1% of patients developed anaphylactic or severe hypersensitivity reactions during Fabrazyme infusion. Life-threatening anaphylactic and severe hypersensitivity reactions have been observed in patients during Fabrazyme infusions.
- Reactions have included localized angioedema (including swelling of the face, mouth, and throat), bronchospasm, hypotension, generalized urticaria, dysphagia, rash, dyspnea, flushing, chest discomfort, pruritus, and nasal congestion.
- Interventions have included cardiopulmonary resuscitation, oxygen supplementation, IV fluids, hospitalization, and treatment with inhaled beta-adrenergic agonists, antihistamines, epinephrine, and IV corticosteroids.
- If anaphylactic or severe hypersensitivity reactions occur, immediately discontinue administration of Fabrazyme and provide necessary emergency treatment. Because of the potential for severe hypersensitivity reactions, appropriate medical support measures should be readily available when Fabrazyme is administered.
In clinical trials with Fabrazyme, some patients developed IgE antibodies or skin test reactivity specific to Fabrazyme.
- Higher incidences of hypersensitivity reactions were observed in adult patients with persistent anti-Fabrazyme antibodies and in adult patients with high antibody titer compared to that in antibody negative adult patients.
- Physicians should consider testing for IgE antibodies in patients who experienced suspected hypersensitivity reactions and consider the risks and benefits of continued treatment in patients with anti-Fabrazyme IgE antibodies. Rechallenge of these patients should only occur under the direct supervision of qualified personnel, with appropriate medical support measures readily available.
In clinical trials with Fabrazyme, 59% of patients experienced infusion-associated reactions, some of which were severe. Infusion-associated reactions are defined as adverse reactions occurring on the same day as the infusion. The incidence of infusion-associated reactions was higher in patients who were positive for anti-Fabrazyme antibodies than in patients who were negative for anti-Fabrazyme antibodies.
- In patients experiencing infusion-associated reactions, pretreatment with an antipyretic and antihistamine is recommended. Infusion-associated reactions occurred in some patients after receiving pretreatment.
- If an infusion-associated reaction occurs, decreasing the infusion rate, temporarily stopping the infusion, and/or administrating additional antipyretics, antihistamines, and/or steroids may ameliorate the symptoms.
- If severe infusion-associated reactions occur, immediate discontinuation of the administration of Fabrazyme should be considered, and appropriate medical treatment should be initiated. Severe reactions are generally managed with administration of antihistamines, corticosteroids, intravenous fluids, and/or oxygen when clinically indicated. Because of the potential for severe infusion-associated reactions, appropriate medical support measures should be readily available when Fabrazyme is administered.
- Patients with advanced Fabry disease may have compromised cardiac function, which may predispose them to a higher risk of severe complications from infusion-associated reactions. Monitor closely patients with compromised cardiac function if Fabrazyme is administered to these patients
- Common adverse reactions reported (≥20% and >2.5% compared to placebo) were upper respiratory tract infection (53% vs 42%), chills (49% vs 13%), pyrexia (39% vs 22%), headache (39% vs 28%), cough (33% vs 25%), paresthesia (31% vs 18%), fatigue (24% vs 17%), peripheral edema (21% vs 7%), dizziness (21% vs 8%), and rash (20% vs 10%).
INDICATION AND USAGE
Fabrazyme® is indicated for the treatment of adult and pediatric patients 2 years of age and older with confirmed Fabry disease.
Please see full Prescribing Information for Fabrazyme.
References: 1. Germain DP, Arad M, Burlina A, et al. Mol Genet Metab. 2019;126(3):224-235. 2. Wanner C, Feldt-Rasmussen U, Jovanovic A, et al. ESC Heart Failure. 2020;7:825-834. 3. Lenders M, Hennermann JB, Kurschat C, et al. Orphanet J Rare Dis. 2016; 11:88:1-11. 4. Wilcox WR. Mol Genet Metab. 2008;93(2):112-128. 5. Germain DP. Fabry disease. Orphanet J Rare Dis. 2010;5:30. 6. Willard HF. In: Valle D, Beaudet AL, Vogelstein B, et al, eds. The Online Metabolic and Molecular Bases of Inherited Disease; New York, NY: McGraw Hill; 2014. http://ommbid.mhmedical.com. Accessed September 18, 2018. 7. Guffon N. J Med Genet. 2003;40(4):1-2. 8. 2017 USRDS Annual Data Report. United States Renal Data System website. https://usrds. org/annual-data-report/previousadrs. Accessed June 2022. 9. MacDermot KD, Holmes A, Miners AH. J Med Gen. 2001;38(11):769-775. 10. Benjamin EJ, Blaha MJ, Chiuve SE, et al. Circulation. 2017;135(10):e146-e603. 11. Fellgiebel A, Muller MJ, Ginsberg L. Lancet Neurol. 2006;5(9):791-795. 12. Burlina A, Politei J. J Inborn Error Metab Screen. 2016;4:1-7. doi:10.1177/2326409816661361. 13. Linhart A, Kampmann C, Zamorano JL, et al; European FOS Investigators. Eur Heart J. 2007;28(10):1228-1235. 14. Schirmer H, Lunde P, Rasmussen K. Eur Heart J. 1999;20(6):429-438. 15. Wilcox WR, Feldt-Rasmussen U, Martins AM, et al. Mol Genet Metab. 2018;28:45-51. 16. Biegstraaten M, Arngrímsson R, Hollak CEM. et al. Orphanet J Rare Dis. 2015;10:36. 17. Ortiz A, Germain DP, Desnick RJ, et al. Mol Genet Metab. 2018;123(4):416-427. 18. Fabry Disease Registry & Pregnancy Sub-registry (NCT00196742). Available at: https://www.clinicaltrials.gov/ct2/show/NCT00196742. Accessed: June 2022. 19. Levin A, Stevens P, et al. Kidney Int Suppl. 2013;3(1):1-150.