Clinical & preclinical data with Fabrazyme®

Two placebo-controlled, double-blind trials have been conducted as part of the clinical development program. A first study to evaluate the efficacy on a biomarker (decreased microvascular deposits of GL-3).^[1] and a second to prove that such efficacy correlates with major clinical endpoints (renal, cardiac, or cerebrovascular events, or death)^[2].

These two studies have shown that biweekly infusions of Fabrazyme^® in a dose of 1 mg/kg resulted in near complete clearance of vascular endothelium in the kidney (the primary endpoint in the first study) as well as significantly reduces the time to a first clinical event (the primary endpoint used in the second study)(see table I).

Table I: Placebo-controlled Fabrazyme^® studies

* Fabrazyme 1 mg/kg every other week

This study – a multinational, multicentre, double-blind, placebo-controlled trial – is the largest ever conducted among Fabry patients, and measured the efficacy of enzyme replacement therapy on patients’ clinical symptoms and disease progression ^[2]. It was initiated by Genzyme in January 2001, and enrolled 82 male and female patients with mild to moderate Fabry disease. The participants were randomized in a 2:1 ratio to receive Fabrazyme^® at a dose of 1 mg/kg of body weight given every 2 weeks, or a placebo. None of the patients had previously received targeted therapy for Fabry disease. The trial’s primary endpoint sought to determine whether Fabrazyme^® would reduce the rate of occurrence of certain clinically significant events that mark the progression of Fabry disease.

Detailed results of the three-year study were presented at the Warsaw meeting by the trial’s principal investigator, Dr Stephen Waldek of Hope Hospital in Manchester, UK. The data show that Fabrazyme^® therapy slows the rate of progression of Fabry disease, as measured by the occurrence of clinically significant complications involving the kidneys, heart or cerebrovascular system (for example, stroke).

Subgroup analysis revealed that these clinical benefits of Fabrazyme^® therapy were most obvious among patients who started receiving the drug when their disease was at an early stage. “This underscores the importance of early diagnosis and prompt initiation of enzyme replacement therapy”, Dr Waldek said in his concluding remarks.

Results:

Analysis of the data for all 82 patients enrolled in the Phase IV study (the ‘intent-to-treat population’) showed that those who received Fabrazyme^® were 53% less likely to experience a clinically significant event compared to those with placebo, when adjusted for baseline proteinuria. A statistically significant 61% reduction in risk was achieved in the 74 patients who met the predefined study requirements (the per-protocol population corrected for differences in baseline proteinuria). There was no difference among the Fabrazyme^® and placebo-treated groups in the incidence of serious adverse events during the study. As expected, infusion reactions occurred at a higher rate in the treatment group and most frequently consisted of mild fever and chills.

A. Placebo-controlled study

A double-blind, randomised, placebo-controlled Phase III clinical trial was conducted in eight centers in the United States and Europe ^[1]. The 58 participants (56 men and 2 women) had classical Fabry disease with α-GAL activity <1.5 nmol/hr/ml in plasma, and ranged in age from 16 to 61, with an average age of 28-32. Patients were randomised to receive an infusion of Fabrazyme^® (n=29) or placebo (n=29) every 2 weeks for 20 weeks (11 doses).

Since accumulation of GL-3 in the kidney vasculature is a fundamental cause of the most common, devastating feature of classical Fabry disease – kidney failure – clearance of GL-3 in the vascular endothelium of the kidney was chosen prospectively (in collaboration with regulatory authorities) as the primary efficacy endpoint.

Clearance of GL-3 was evaluated by light microscopic examination of tissue biopsy samples obtained before and after 20 weeks of treatment. Three independent expert pathologists, who were blinded to treatment assignment and time of biopsy, examined an average of 223 capillaries in each specimen and assigned a composite score of 0 (no or trace vessel inclusions with a maximum of 5% of vessels scored as 1, 2, or 3) to 3 (severe vessel inclusions). On the basis of pathophysiologic considerations, treatment success was defined as a score of 0 at week 20, a clinically important measurement that represents restoration of blood vessels to a near-normal state, predictive of halting further kidney deterioration.

Three secondary endpoints were also evaluated from baseline to week 20: the composite score of GL-3 clearance in the vascular endothelium of the heart, kidney and skin; reduction of GL-3 in urinary sediment and kidney tissue; and pain reduction as determined by the McGill Pain Questionnaire (Short Form).

Results:

Fabrazyme^® infusions resulted in highly significant clearance of GL-3 from the renal capillary endothelium. Twenty of the 29 Fabrazyme^® treated patients (69%) reached the 0 endpoint (no or trace vessel inclusions). Of the remaining nine Fabrazyme^® treated patients, eight had scores of 1 (including six who improved and two who had a score of 1 at baseline) and the remaining patient had a missing biopsy and was assigned a score of 3. In contrast, none of the 29 patients treated with placebo had a 0 score (P < 0.001).

Plasma GL-3 levels decreased significantly in the treated patients, and these decreases correlated with histological findings in the kidney vasculature.

GL-3 was cleared from the vascular endothelium in the major organs of pathology (kidney, heart, skin) to normal or near-normal levels.

Pain and quality of life scores improved significantly in both treatment groups but since there was no statistically significant difference between the groups, an actual effect cannot be separated from a placebo effect.

Seroconversion had no effect on treatment efficacy.

69% of the Fabrazyme^®-treated patients (N=29) and none of the placebo patients (N=29) achieved clearance of GL-3 from the vascular endothelium (see figure 1) and other cell types of the kidney and skin to normal or near normal levels (a score of 0 in a histologic scoring system) (P <0.001).

Figure 1: GL-3 is cleared from the endothelial cells of the peritubular (interstitial) capillaries ^[3]

(A) baseline biopsy, pre-treatment. GL-3 is present near endothelial nuclei and around the perimeter of the capillaries. (B)Post-treatment biopsy. Capillaries are clear of GL-3

B. Open-label extension study (54 months)

To determine the long-term safety and efficacy of recombinant human α-galactosidase A, an open-label, phase III extension study was conducted ^[4]. All 58 patients who were enrolled in the 20-wk phase III double-blind, randomized, and placebo-controlled study received subsequently 1 mg/kg of rh-aGalA (agalsidase beta, Fabrazyme^®, Genzyme Corporation).

GL-3 accumulation was evaluated in the capillary endothelia of the skin, kidney, and heart. Renal function was assessed. By month 54, all patients with optional kidney biopsies (n=8) maintained complete GL-3 clearance in renal capillary endothelial cell types. Continued, complete clearance of skin (31 of 36) and heart (six of eight) capillary endothelium was demonstrated. Mean plasma GL-3 levels remained decreased in the normal range. Median serum creatinine and estimated GFR remained stable (normal) in patients with renal data at month 54 (n=41). Six patients had renal disease progression; most (four of six) were older than 40 yr and had significant proteinuria at baseline and evidence of sclerotic glomeruli pretreatment. Adverse events were generally mild and unrelated to treatment. The most common treatment-related adverse events were infusion-associated reactions, which decreased over time.

Results: Long-term agalsidase beta therapy stabilizes renal function in patients without renal involvement at baseline, maintains reduction of plasma GL-3, and sustains GL-3 clearance in capillary endothelial cells and multiple renal cell types.

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References

1. Eng CM, Guffon N, Wilcox WR, Germain DP, Lee P, Waldek S, Caplan L, Linthorst GE, Desnick RJ. Sagety and efficacy of recombinant human α-galactosidase A-replacement therapy in Fabry’s disease. N. Engl J Med 2001b; 345(1):9-16

2. Banikazemi M, Bulta J, Waldek S, Wilcox W, Withley C, McDonald M, Finkel R, Packman S, Bichet D, Warnock D, Desnick R. Agalsidase-Beta Therapy for Advanced Fabry Disease – A Randomized Trial. Ann Intern Med. 2007; 146; 77-86

3. Thurberg BL, Rennke H, Colvin RB, Dikman S, Gordon RE, Collins AB, Desnick RJ, O’Callaghan M. Globotriaosylceramide accumulation in the Fabry kidney is cleared from the multiple cell types after enzyme replacement therapy. Kidney International, Vol 62 (2002), pp 1933-1946

4. Germain DP, Waldek S, Banikazemi M, Bushinsky DA, Charrow J, Desnick RJ, Lee P, Loew T, Vedder AC, Abichandani R, Wilcox WR, Guffon N. Sustained, long-term renal stabilization after 54 month of agalsidase beta therapy in patients with Fabry disease. J Am Soc Nephrol 18:1547-1557,2007