Source: European Medicines Agency (EU) Revision Year: 2023 Publisher: Chiesi Farmaceutici S.p.A., Via Palermo 26/A, 43122 Parma, Italy
Pharmacotherapeutic group: Other alimentary tract and metabolism products, enzymes
ATC code: A16AB20
The active substance of Elfabrio is pegunigalsidase alfa. Pegunigalsidase alfa is a pegylated recombinant form of human α-galactosidase-A. The amino acid sequence of the recombinant form is similar to the naturally occurring human enzyme.
Pegunigalsidase alfa supplements or replaces α-galactosidase-A, the enzyme that catalyses the hydrolysis of the terminal α-galactosyl moieties of oligosaccharides and polysaccharides in the lysosome, reducing the amount of accumulation of globotriaosylceramide (Gb3) and globotriaosylsphingosine (Lyso-Gb3).
The efficacy and safety of pegunigalsidase alfa were evaluated in 142 patients (94 males and 48 females), of which 112 receiving pegunigalsidase alfa 1 mg/kg every other week (EOW).
Analyses of kidney biopsies from naïve patients treated with pegunigalsidase alfa in a phase ½ study exhibited a reduction of the globotriaosylceramide (Gb3) substrate from the renal peritubular capillaries, measured with BLISS (Barisoni Lipid Inclusion Scoring System) of 68% in the overall population (including females, classic males and non-classic males exposed to different tested doses; n=13) after 6 months of treatment. Additionally, 11 out of 13 subjects with available biopsies had substantial reduction (≥50%) in their BLISS score following 6 months of treatment. Plasma Lyso-Gb3 decreased by 49% after 12 months of treatment (n=16) and by 83% after 60 months of treatment (n=10). In a phase 3 study, where patients were switching from agalsidase beta to pegunigalsidase alfa, plasma Lyso-Gb3 values stayed stable after 24 months of treatment (+3.3 nM mean value, n=48).
The renal function was evaluated through the estimated glomerular filtration rate (eGFR – CKD-EPI equation) and its annualised measurement slope was the primary endpoint for efficacy in two phase 3 studies in previously ERT-treated adult Fabry patients: BALANCE (main study), a randomized, double blinded, head-to-head comparison with agalsidase beta, after switch from agalsidase beta at month 12 (primary analysis) and month 24, and an open label single arm study, after switch from agalsidase alfa, both followed by a long-term extension study.
No final conclusion on non-inferiority over agalsidase beta as measured by the annualised eGFR can be retrieved from the main study given that the data for the primary endpoint comparison at month 12 was not on its own sufficiently informative due to the design and size of the trial. Nevertheless, the median eGFR slopes from baseline to month 24 of pegunigalsidase and the comparator agalsidase beta appeared close. At month 12, the mean slopes for eGFR were -2.507 mL/min/1.73 m²/year for the pegunigalsidase alfa arm and -1.748 for the agalsidase beta arm (difference -0.749 [-3.026, 1.507]. At month 24, the median slopes for eGFR were -2.514 [-3.788; -1.240] mL/min/1.73 m²/year for the pegunigalsidase alfa arm and -2.155 [-3.805; -0.505] for the agalsidase beta arm (difference -0.359 [-2.444; 1.726]).
The European Medicines Agency has deferred the obligation to submit the results of studies with Elfabrio in one or more subsets of the paediatric population in the treatment of Fabry disease (see section 4.2 for information on paediatric use).
Plasma pharmacokinetic (PK) profiles of pegunigalsidase alfa were characterized during the course of the clinical development at 0.2, 1, and 2 mg/kg administered every two weeks in adult patients with Fabry disease. The pharmacokinetic results for all three dose levels demonstrated that the enzyme was available throughout the 2-week intervals with a plasma half-life (t1/2) ranging from 53-134 hours across dose groups and visit day. The mean value for AUC0-∞ increased with increasing dose on Day 1 and throughout the study. Mean values for dose-normalized AUC0-2wk were similar for all dose levels, indicating linear dose-proportionality. For patients who received 1 and 2 mg/kg Elfabrio, there were increases in mean t1/2 and AUC0-∞ with increasing duration of treatment and corresponding decreases in Cl and Vz, suggesting a saturated clearance.
Pegunigalsidase alfa is a protein and is expected to be metabolically degraded through peptide hydrolysis. Consequently, impaired liver function is not expected to affect the pharmacokinetics of Elfabrio in a clinically significant way. The molecular weight of pegunigalsidase alfa is ~116 KDa, which is twice the cut-off value for glomerular filtration, thus excluding filtration and/or proteolytic degradation in kidneys.
There are no animal studies to assess the carcinogenic or mutagenic potential of Elfabrio.
In the 6-month chronic toxicity study in mice, an increased incidence and/or mean severity of multifocal nephropathy and interstitial lymphocytic infiltration in the kidneys, hepatocytic vacuolation and hepatocyte necrosis in the liver, were confined to males and females administered the high-dose of 40 mg/kg/injection (3.2-fold human exposure, in terms of AUC, following a dose of 1 mg/kg); in monkeys, an increased incidence of Kupffer cell hypertrophy was noted in the liver (7.6-fold above AUC reached in humans following a dose of 1 mg/kg); all findings resolved during the recovery period.
Animal studies demonstrated low systemic exposure in foetus (between 0.005 and 0.025% of dams' systemic exposure) and suckling pups (maximum 0.014% compared to mother’s systemic exposure) following repeated treatment of the dams or mothers with pegunigalsidase alfa. Fertility and embryofoetal developmental toxicity studies did not show evidence of impaired fertility, embryotoxicity or teratogenicity. However, prenatal and postnatal developmental toxicity studies were not performed with pegunigalsidase alfa and the risks for foetus and pups during the late pregnancy and lactation are unknown.
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