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Replagal scientific evidence

Replagal is indicated for long-term enzyme replacement therapy in patients with a confirmed diagnosis of Fabry disease (α-galactosidase A deficiency).1

THE FABRY OUTCOME SURVEY

Fabry Outcome Survey LogoThe Fabry Outcome Survey or FOS is a registry that was started more than 15 years ago in 2001, and is a global registry of patients with Fabry disease.1

The aims of this Fabry registry are to:1

  1. Broaden our understanding of the nature of Fabry disease
  2. Improve clinical management of affected patients

The FOS database includes data from more than 2962* patients in 24 countries around the world, and has resulted in at least 47 published manuscripts on Fabry disease to date.1

*As of 1 June 2016.
Reference:
1. Giugliani R, et al. J Inborn Err Metab. 2016;4:1-12
CARDIAC OUTCOMES

Studies

(Please click the links below to read more about each study):

Kampmann C, et al.
Orphanet J Rare Dis.
2015;10:125
Beck M, et al.
Eur J Clin Invest.
2004;34:838-844
Mehta A, et al.
Lancet.
2009;374:1986-1996
Ries M, et al.
Pediatrics
2006;118:924-932
Whybra C, et al.
Genet Med.
2009;11:441-449
Hughes DA, et al.
Heart.
2008;94:153-158
Schiffmann R, et al.
J Pediatr.
2010;156:832-837

Replagal demonstrated 10-year benefits across cardiac function, structure and symptoms, in addition to renal function1

  • Replagal preserved cardiac function2-6
  • Replagal improved or stabilised* heart failure and angina symptoms over 10 years6
  • Replagal demonstrated a long-term benefit on cardiac structure, regardless of LVMI at baseline6
  • Replagal largely stabilised cardiac function in male patients over 10 years6
*Improved defined as a move to a lower classification compared with baseline; stabilisation defined as no move in classification compared with baseline; 98% based on n=41/42.
LVMI, left ventricular mass index

References:
1. Kampmann C, et al. Orphanet J Rare Dis. 2015;10:125
2. Mehta A, et al. Lancet. 2009;374:1986-1996
3. Whybra C, et al. Genet Med. 2009;11:441-449
4. Ries M, et al. Pediatrics. 2006;118:924-932
5. Schiffmann R, et al. J Pediatr. 2010;156:832-837
6. Hughes DA, et al. Heart. 2008;94:153-158

Graph showing LVMI during 10 yeas of Replagal

Figure adapted from Kampmann C et al 2015.

LVMI during 10 years1 Replagal treatment for male and female patients stratified by LVMI <50 g/m2-7 or ≥50 g/m2-7 before treatment. Data points are means with standard deviations
‡Statistically significant (P<0.05) change from baseline among females with LVMI ≥50 g/m2-7 before treatment

RENAL OUTCOMES

Studies

(Please click the links below to read more about each study):

Kampmann C, et al.
Orphanet J Rare Dis. 2015;10:125
Beck M, et al.
Mol Genet Metab Rep. 2015;3:21-27
Whybra C, et al.
Genet Med. 2009;11:441-449
West M, et al.
J Am Soc Nephrol. 2009;20:1132-1139
Ries M, et al.
Pediatrics. 2006;118:924-932
Schiffmann R, et al.
J Pediatr. 2010;156:832-837
Mehta A, et al.
Lancet. 2009;374:1986-1996
Feriozzi S, et al.
Clin J Am Soc Nephrol. 2012;7:60-69

Replagal demonstrated 10-year benefits across cardiac function, structure and symptoms, in addition to renal function1

  • Replagal preserved renal function1
  • Replagal stabilised renal function1-8
  • Replagal stabilised renal function over 10 years1
*Improved defined as a move to a lower classification compared with baseline; stabilisation defined as no move in classification compared with baseline; 98% based on n=41/42.

References:
1. Kampmann C, et al. Orphanet J Rare Dis. 2015;10:125
2. Mehta A, et al. Lancet. 2009;374:1986-1996
3. Whybra C, et al. Genet Med. 2009;11:441-449
4. West M, et al. J Am Soc Nephrol. 2009;20:1132-1139
5. Ries M, et al. Pediatrics. 2006;118:924-932
6. Schiffmann R, et al. J Pediatr. 2010;156:832-837
7. Beck M, et al. Mol Genet Metab Rep. 2015;3:21-27
8. Feriozzi S, et al. Clin J Am Soc Nephrol. 2012;7:60-69

eGFR during 10 year Replagal ERT Treatment

Figure adapted from Kampmann C et al 2015.

eGFR during 10 years1 Replagal treatment in male and female patients stratified by eGFR <90 or ≥90 mL/min/1.73 m2 before treatment. Data points are means with standard deviations
‡Statistically significant (P<0.05) change from baseline among females with eGFR <90  mL/min/1.73 m2 before treatment
eGFR, estimated glomerular filtration rate

REDUCTION OF EVENTS WITH REPLAGAL
Beck M, et al.
Mol Genet Metab Rep. 2015;3:21-27

Long-term morbidity outcomes with Replagal

Replagal reduced the risk of cardiac, cerebrovascular or renal events1*

  • After 2 years of Replagal therapy, the probability of a cardiac, cerebrovascular or renal morbidity event was approximately 16% (FOS Evaluable Treated Morbidity cohort, n=79; 48% males) compared with approximately 45% in a cross-study control population who had not received ERT1
    • The probability of a composite morbidity event for males only (n=38) was approximately 26% in the FOS Evaluable Treated Morbidity cohort ¹

 

Replagal delayed the time to first event by 7 years for male and approximately 4 years for female Fabry disease patients1

  • Median age at first event was 48 years for Replagal-treated males and ~41 years in the untreated male population, and 56.9 years for Replagal-treated females and ~53 years in the untreated female population.
*To compare with untreated patients from Banikazemi, et al.2 the endpoint comprised myocardial infarction, any serious cardiac event indicative of coronary artery disease, heart failure, valvular disease or arrhythmia; any event resulting in or reported as percutaneous transluminal coronary angioplasty or coronary artery bypass graft; any serious heart failure event; serious events requiring valvular surgery; serious adverse events stating or indicating renal transplant, dialysis or indicative of chronic dialysis; an increase in serum creatinine by 33% from baseline (two consecutive values); cerebrovascular accident, stroke or transient ischaemic attack, or death.
ERT, enzyme replacement therapy; FOS, Fabry Outcome Survey.
References:
1. Beck M, et al. Mol Genet Metab Rep. 2015;3:21-27
2. Banikazemi M, et al. Ann Intern Med. 2007;146:77-86

Reference:
1. Replagal (agalsidase alfa), EMA Summary of Product Characteristics, August  2016.
Available here.

QUALITY OF LIFE OUTCOMES

Studies

(Please click the links below to read more about each study):

Mehta A, et al.
Lancet. 2009;374:1986-1996
Schiffmann R, et al.
JAMA. 2001;285:2743-2749.
Baehner F, et al.
J Inherit Metab Dis. 2003;26:617-627.
Beck M, et al.
Eur J Clin Invest. 2004;34:838-844.
Whybra C, et al.
Clin Genet. 2004;65:299-307.

Fabry patients experienced significantly improved quality of life after Replagal treatment

  • The benefit of Replagal has been demonstrated across different instruments measuring health status including QoL1-6*
*QoL, (EuroQol, Short Form 36 and EQ-5D), pain (Brief Pain Inventory) and severity (Mainz Severity Score Index)
QoL, quality of life
References:
1. Mehta A, et al. Lancet. 2009;374:1986-1996
2. Schiffmann R, et al. JAMA. 2001;285:2743-2749.
3. Baehner F, et al. J Inherit Metab Dis. 2003;26:617-627.
4. Beck M, et al. Eur J Clin Invest. 2004;34:838-844.
5. Whybra C, et al. Clin Genet. 2004;65:299-307.
6. Replagal (agalsidase alfa), EMA Summary of Product Characteristics, August 2016. Available here.
NEUROPATHIC PAIN: OVERALL FABRY POPULATION

Studies

(Please click the links below to read more about each study):

Mehta A, et al.
Lancet. 2009;374:1986-1996
Schiffmann R, et al.
J Pediatr. 2010;156:832-837
Hoffmann B, et al.
Clin Gastroenterol Hepatol. 2007;5:1147-1153

Replagal significantly reduced average pain and worst pain scores after 5 years of treatment1-3

  • Replagal significantly reduced average pain and worst pain scores after 5 years of treatment1,2
  • Replagal reduced both the prevalence of abdominal pain and diarrhoea in paediatric patients3
  • Replagal significantly relieved the burden of pain in patients with Fabry disease by reducing the severity of mean BPI ‘pain on average’ scores by -1.2 ±2.7 points after 5 years of treatment (P=0.0023) (Figure 1).1
  • Replagal significantly reduced the severity of ‘pain at its worst’ with a reduction in the mean BPI score of -1.3 ±3.5 points after 5 years of treatment (P=0.0137).1
  • Replagal significantly relieved the burden of pain in children aged ≥7 years by reducing the severity of mean BPI ‘pain on average’ scores from 2.96 ±2.16 points at baseline to 1.70 ±1.87 points at 1 year with a significant benefit remaining at up to 4 years (P<0.05).3
BPI, Brief Pain Inventory

 

Average pain measured by BPI score. Patient numbers are shown in parentheses. Horizontal line represents baseline
*P<0.05 versus baseline
Figure adapted from Mehta A, et al. 2009
References:
1. Mehta  A, et al. Lancet. 2009;374:1986-1996.
2. Schiffmann  R, et al. J Pediatr. 2010;156:832-837.
3. Hoffmann B, et al. Clin Gastroenterol Hepatol. 2007;5:1147-1153.
SWITCHING TO REPLAGAL

Impact of switching from agalsidase beta to Replagal

Pisani A, et al.
Genet Med. 2017;19:275-282

Switching to Replagal maintains clinical stability. A systematic review and meta-analysis of the available data on patients switched from agalsidase beta to Replagal after viral contamination in the manufacturing process of agalsidase beta (1.0 mg/kg EOW)  led to a global shortage.1

Meta-analysis: Changes from baseline eGFR in patients switched from agalsidase beta (1.0 mg/kg EOW)  to Replagal1

Baseline LVMI changes in Replagal patients

Figure adapted from Pisani, et al. 20171

CI, confidence interval; eGFR, estimated glomerular filtration rate; EOW, every other week

There was no significant modification in glomerular filtration rate at the end of follow-up (mean change from baseline: ˆ’0.52 mL/min/1.73 m2; 95% CI: ˆ’3.22, 2.19; P=0.708)1

  • The urine albumin-creatinine ratio was in agreement with eGFR rate data and did not change

 

Meta-analysis: Changes from baseline LVMI in patients switched from agalsidase beta (1.0 mg/kg EOW)  to Replagal1

Figure adapted from Pisani, et al. 20171

EOW, Every other week
Outcome measures: Clinical events (cardiac events, renal events and death); changes in organ function and structure at the cardiac, renal and neurologic level; changes in Fabry disease-related symptoms and questionnaires; adverse events.
Safety: Five studies (n=121 patients) reported on this outcome. A total of 30  patients experienced at least one adverse event after the switch (24.8% of patients). The pooled incidence rate of major adverse events was reported in five studies including 150 patients, and was equal to 0.04 events per person-year (95% CI: 0.01, 0.19).
Limitations: Low number of patients, the short observation period (only 11 patients had a 3-year follow-up), the heterogeneity of the study population, and, in particular, the low number of clinical events that demonstrate the slow progression of the disease with enzyme replacement therapy, thus reflecting the intrinsic nature of rare genetic diseases. The possibility that the incidence of clinical events or symptoms may increase over a longer observation period can therefore not be excluded, nor can the degree to which the incidence of adverse events is conditioned by the baseline conditions of the single patients or by the duration of the disease and patient’s age (both increased during the follow-up) be understood.
  • Data showed a significant reduction in LVMI after the switch (mean change from baseline: ˆ’4.2 g/m2; 95% CI: ˆ’8.66, -0.25; P<0.034)1*

Data from 296 patients across 16 studies have shown that patients switched from agalsidase beta (1.0 mg/kg EOW)  to Replagal maintained clinical stability‡, including:2

  • Clinical events
  • Cardiac parameters
  • Renal parameters
  • Neurological parameters

 

*The significant improvements in LVMI and left ventricular posterior wall diameter combined with slight worsening in ejection fraction were interpreted by the authors as a sign for clinical stability after switch.
‡With the exception of two observational studies.

LVMI, left ventricular mass index.

References:
1. Pisani A, et al. Genet Med. 2017;19:275-2
2. Total number of patients (n=296) obtained from the following 16 studies: Tsuboi K & Yamamoto H. Genet Med. 2014;16:766-772: observational study, full publication (n=11); Pisani A, et al. JIMD Rep. 2013;9:41-48: observational study, full publication (n=10); West M & LeMoine K. Acta Paediatr. 2006;451:136: retrospective review, abstract (n=5); Eyskens FJ. Mol Genet Metab. 2009;98:39-88: case report, abstract (n=1); Thompson L, et al. J Inherit Metab Dis. 2010;33(Suppl 1):S153 (abstract 492-P): nursing perspective review, abstract (n=64); Eyskens FJM & De Boeck K. J Inherit Metab Dis. 2011;34(Suppl 3):S228 (abstract P-444): case report (n=4); West M, et al. Mol Genet Metab. 2012;105:S15-S69: prospective study, abstract (n=36); Goker-Alpan O, et al. JIMD Rep. 2015;23:7-15: open-label study, full publication (n=71); Wakabayashi T, et al. J Inherit Metab Dis. 2013;36(Suppl 2):S282: retrospective review (n=18); Lin HY, et al. J Chin Med Assoc. 2014;77:190-197: retrospective review, full publication (n=9); Smid BE, et al. Orphanet J Rare Dis. 2011;6:69: observational study, full publication (n=20); Tanaka A, et al. J Inherit Metab Dis. 2010;33(Suppl 3):S249-S252: case report, full publication (n=1); Reidt S, et al. Int Med J. 2014;44:205-207: case study, letter to editor (n=5); Politei J, et al. Clin Genet. 2016;89:88-92: observational study, full publication (n=2); Tsuboi K, et al. JIMD Rep. 2015; 15:105-111: case report, full publication (n=2); Lenders M, et al. J Am Soc Nephrol. 2016;27:952-962: observational study, full publication (n=37) [follow-up to Weidemann F, et al. J Am Soc Nephrol. 2014;25:837-849].
REPLAGAL REGISTRATION TRIALS

The safety and efficacy of Replagal was assessed in two randomised, double-blind, placebo-controlled studies and open-label extension studies, in a total of 40 patients with a diagnosis of Fabry disease based on clinical and biochemical evidence.*1-5

*As included in SmPC
References:
1. Replagal (agalsidase alfa), EMA Summary of Product Characteristics, August 2016. Available here.
2. Schiffmann R, et al. JAMA. 2001;285:2743-2749.
3. Hughes DA, et al. Heart. 2008;94:153-158
4. Schiffmann R, et al. Nephrol Dial Transplant. 2006;21:345-354.
5. Replagal: EPAR – scientific discussion. EMEA 2004.

TKT003

Schiffmann R, et al.
JAMA. 2001;285:2743-2749.

 

Methods

Replagal Clinical Trial 2

Figure created from Schiffmann, R, et al. 2001

EOW, every other week.

 

Objectives

To evaluate the safety and efficacy of Replagal  for Fabry disease.

Primary endpoint

Effect on neuropathic pain while without neuropathic pain medication measured by the BPI.

Other outcome measures

  • Renal function (eGFR)
  • Renal biopsy
  • Gb3 levels (plasma, urine, renal)
  • Antibody formation
  • Cardiac conduction

 

Key outcomes

  • At 6 months, Replagal stabilised renal function compared with a decline in placebo-treated patients3
    • Kidney biopsy revealed a significant increase in the fraction of normal glomeruli and a significant decrease in the fraction of glomeruli with mesangial widening in Replagal-treated patients3
  • At 6 months, there was a significant reduction in QRS interval for Replagal-treated patients (P=0.047)1
  • After 12-18 months, Replagal improved renal function (P=0.030 vs baseline)3
    • Longer-term therapy (48-54 months) resulted in stabilisation of GFR in male patients with normal baseline GFR or mild to moderate renal dysfunction (GFR 60 to <90 mL/min/1.73 m2), and in slowing of the rate of decline in male patients with more severe renal dysfunction (GFR 30-<60 mL/min/1.73 m2)

 

Replagal significantly reduced overall pain severity1

  • Treatment with Replagal resulted in a consistent and progressive reduction in overall pain severity in men with a reduction in mean BPI score from 3.8 ±0.44 points at baseline to 2.7 ±0.54 points at 6 months (P=0.02 versus placebo)1
    • Of the 11 Replagal-treated patients who were taking pain medication, four were able to discontinue these medications (P=0.03 vs placebo)

 

BPI, Brief Pain Inventory; eGFR, estimated glomerular filtration rate; EOW, every other week; Gb3, globotriaosylceramide
References:
1.  Schiffmann R, et al. JAMA. 2001;285:2743-2749
2. Schiffmann R, et al. Nephrol Dial Transplant. 2006;21:345-354
3. Replagal (agalsidase alfa), EMA Summary of Product Characteristics, August 2016. Available here.

TKT005

HUGHES
Hughes DA, et al.
Heart. 2008;94:153-158.

 

Methods

Replagal Clinical Trial

Figure created from Hughes DA, et al. 20081

Objectives

To assess the safety and efficacy of enzyme replacement therapy with Replagal on the cardiac manifestations of Fabry disease.

Primary endpoint

Myocardial Gb3 content.

Other outcome measures

  • Left ventricular mass (secondary endpoint)
  • QRS duration
  • Urine and plasma Gb3 levels

 

Key outcomes1

  • Treatment with Replagal resulted in a 20% reduction in myocardial Gb3 content compared with a 10% increase in the placebo group (P=0.42)1,2
  • Treatment with Replagal resulted in an 11.5 g decrease in LVM, while patients receiving placebo exhibited an increase in LVM of 21.8 g (P=0.041)1,2
  • Replagal was also associated with improved myocardial contractility, a mean reduction in QRS duration (P=0.8) and a concomitant decrease in septal thickness on echocardiography (P=0.01)1,2

 

Replagal reduced Gb3 levels in cardiac tissue1

Myocardial Gb3 levels after Replagal

Figure adapted from Hughes DA, et al. 20081
  • Replagal reduced accumulation of Gb3 in myocardial tissues over 6 months of double-blind treatment*1
  • Gb3 levels increased in the placebo group over the same period1
  • Lack of statistical significance (P=0.42) may reflect the small sample size and relatively short study duration1

 

EOW, every other week; Gb3, globotriaosylceramide; LV, left ventricular LVM, left ventricular mass.
References:
1. Hughes DA, et al. Heart. 2008;94:153-158
2. Replagal (agalsidase alfa), EMA Summary of Product Characteristics, August 2016. Available here.