Summary Basis of Decision for Elfabrio

Clinical Pharmacology

Pegunigalsidase alfa, the medicinal ingredient in Elfabrio, is a pegylated recombinant form of human α-galactosidase A, the enzyme that catalyses the hydrolysis of the terminal α-galactosyl moieties of oligosaccharides and polysaccharides in the lysosome. This action reduces accumulated globotriaosylceramide (Gb3) and globotriaosylsphingosine (lyso-Gb3; a metabolite of Gb3) caused by α-galactosidase A deficiency in Fabry disease.

The clinical pharmacology supporting the proposed dosing regimen of Elfabrio in adults with Fabry disease is based on the pharmacokinetic, pharmacodynamic, and immunogenicity results of studies PB-102-F01/F02 and PB-102-F03 where Elfabrio was administered to enzyme replacement therapy (ERT)-naïve patients, as well as the results of Study PB-102-F20 where Elfabrio was administered to ERT-experienced patients (i.e., previously treated with agalsidase beta).

Pharmacokinetics

In ERT-naïve patients, pegunigalsidase alfa exhibited non-linear, time-dependent pharmacokinetics with clearance decreasing as the dose increased. The exposure of pegunigalsidase alfa, as measured by the maximum concentration (C_max) and the area under the concentration-time curve (AUC), increased in a more than dose-proportional manner following the intravenous administration of 0.2 mg/kg, 1.0 mg/kg, and 2.0 mg/kg pegunigalsidase alfa. At 1.0 mg/kg, the mean elimination half-life (t_1/2) was 79 hours after a single dose and 86 to 121 hours following dosing every two weeks for up to 12 months. When administered at a dose of 1.0 mg/kg every two weeks, the mean AUC from time zero to the last measurable concentration (AUC_0-t) and C_max increased with treatment duration. In a subset of ERT-experienced patients with Fabry disease who were treated for 2 years (17 patients), the mean t_1/2 ranged from 82.6 to 97 hours and the mean AUC_0-t was generally consistent over the duration of treatment.

Pharmacodynamics

The pharmacodynamic effect of pegunigalsidase alfa was assessed by the reduction from baseline in plasma lyso-Gb3 levels. For ERT-naïve patients with Fabry disease, following 12 months of treatment, the overall mean reduction from baseline in plasma Gb3 concentration was 43%, 60%, and 40% in the 0.2 mg/kg, 1.0 mg/kg, and 2.0 mg/kg groups, respectively. Over the course of up to 60 months at a dose of 1.0 mg/kg every two weeks, there was a trend in plasma lyso-Gb3 reduction over time.

Immunogenicity

Treatment with any therapeutic protein is accompanied by the risk of immunogenicity (the development of anti-drug antibodies [ADAs], which have the potential to neutralize the biological activity of the drug). Among patients with Fabry disease, pre-existing ADAs were detected in 2 out of 18 (11.1%) ERT-naïve patients and in 18 out of 52 (34.6%) ERT-experienced patients. Following 24 months of treatment, 20 out of 52 ERT-experienced patients (38.5%) were ADA positive after treatment with pegunigalsidase alfa and 11 out of 25 patients (44.4%) were ADA positive after treatment with agalsidase beta.

In ERT-experienced patients, pegunigalsidase alfa exposures (as measured by AUC and C_max) were significantly decreased in 3 out of 17 patients (17.6%) who were ADA positive at baseline and who had a high titer of ADAs during treatment. Based on the pharmacodynamic data from 52 patients, plasma lyso-Gb3 levels at baseline and during treatment were higher in ADA-positive patients compared with ADA-negative patients. The presence of ADAs did not appear to have an effect on efficacy, as measured by the estimated glomerular filtration rate (eGFR) slope. However, treatment-emergent adverse events and infusion-associated reactions occurred at a higher rate in ADA-positive patients than in ADA-negative patients.

Only one ERT-naïve patient was ADA positive following treatment, therefore, the impact of ADAs on the pharmacokinetics, pharmacodynamics, efficacy, and safety of pegunigalsidase alfa for this group could not be fully characterized due to the limited data available.

Overall, the pharmacokinetic, pharmacodynamic, and immunogenicity profile of pegunigalsidase alfa is considered acceptable and supports the use of Elfabrio for the recommended indication and dosage regimen of 1.0 mg/kg every two weeks.

For further details, please refer to the Product Monograph for Elfabrio, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The clinical benefit of Elfabrio for the treatment of adults with Fabry disease is supported by evidence demonstrating substantial reductions in Gb3 accumulation within renal peritubular capillaries, together with data indicating a renal effect comparable to agalsidase beta, an approved ERT that has the same mechanism of action as Elfabrio. Reducing Gb3 inclusions in renal tissue is expected to beneficially modify the pathophysiology of Fabry disease, including slowing the decline in renal function as assessed by the eGFR.

The clinical efficacy of Elfabrio as an ERT for the long-term treatment of adult patients with a confirmed diagnosis of Fabry disease was primarily supported by data from Study PB-102-F01/F02, a Phase I/II, open-label, single-arm, dose-finding study. This study enrolled 18 patients with Fabry disease who were ERT-naïve or who had not received ERT for more than 26 weeks and had a negative test for anti-pegunigalsidase alfa IgG antibodies prior to enrollment. Patients received pegunigalsidase alfa at 0.2 mg/kg, 1.0 mg/kg, or 2.0 mg/kg (6 to 8 patients per group) administered by intravenous infusion every two weeks for 52 weeks. Among the 16 patients who completed the study, 9 (56%) were male and 7 (44%) were female. Patients ranged in age from 17 to 54 years with a median age of 30 years. Twelve (75%) patients were White, 3 (19%) were Black or African American, and 1 (6%) where the race/ethnicity had not been reported. Three (19%) were Hispanic/Latino and 13 (81%) were not Hispanic/Latino.

Fourteen of the 16 patients who completed the study had evaluable renal biopsies at baseline and at Week 26. Treatment with Elfabrio produced substantial and sustained reductions in Gb3 inclusions in renal peritubular capillaries, as assessed by the Barisoni Lipid Inclusion Scoring System (BLISS). At Week 26, the median percent reduction from baseline in the number of Gb3 inclusions per renal peritubular capillary was -78% (95% confidence interval [CI]: -86%, -53%) and the mean absolute reduction from baseline in the number of Gb3 inclusions per renal peritubular capillary was -3.1 (95% CI: -4.8, -1.4). Patient-level analyses showed that 11 out of 14 patients (79%) achieved a reduction of at least 50% from baseline (range: -53% to -95%).

Additional data were provided from Study PB-102-F20, a pivotal, Phase III, multicentre, randomized, double-blind, head-to-head study in ERT-experienced adults with Fabry disease. The effect of Elfabrio on the annualized eGFR slope, a recognized clinical endpoint, was evaluated in comparison with agalsidase beta. Eligible patients were treated with agalsidase beta for at least one year prior to study entry (mean: 5.7 years). In total, 77 patients were randomized 2:1 to receive Elfabrio (1.0 mg/kg; 52 patients) or agalsidase beta (1.0 mg/kg; 25 patients) by intravenous infusion every two weeks for 104 weeks. Forty-seven (61%) patients were male and 30 (39%) were female. Patients ranged in age from 18 to 60 years with a median age of 46 years at baseline. Seventy-two (94%) patients were White, 3 (4%) were Black or African American, and 2 (3%) were Asian. Two (3%) patients were Hispanic/Latino and 75 (97%) were not Hispanic/Latino. The median baseline eGFR was 75 mL/min/1.73 m².

The primary efficacy endpoint of the study was the annualized change in eGFR over 104 weeks (eGFR slope). The annualized eGFR slope was comparable between treatment groups. Mean slopes were -2.4 mL/min/1.73 m²/year (95% CI: -3.6, -1.1) in the Elfabrio group and -2.3 mL/min/1.73 m²/year (95% CI: -4.1, -0.5) in the agalsidase beta group. The estimated treatment difference was -0.1 mL/min/1.73 m²/year (95% CI: -2.3, 2.1). While limitations of the study preclude establishing non-inferiority of Elfabrio to agalsidase beta, the results are supportive of a comparable effect on renal function. Sensitivity analyses were consistent with the primary analysis.

Indication

The New Drug Submission for Elfabrio was filed by the sponsor with the following proposed indication:

Elfabrio (pegunigalsidase alfa for injection) is indicated for long-term enzyme replacement therapy in adult patients with a confirmed diagnosis of Fabry disease (deficiency of alpha-galactosidase).

Health Canada approved the following indication:

Elfabrio (pegunigalsidase alfa for injection) is an enzyme replacement therapy indicated for the long-term treatment of adult patients with a confirmed diagnosis of Fabry disease (deficiency of α-galactosidase A).

For more information, refer to the Product Monograph for Elfabrio, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The clinical safety of Elfabrio as an ERT for the long-term treatment of adult patients with a confirmed diagnosis of Fabry disease was primarily derived from the results of the pivotal Phase III Study PB-102-F20 described in the Clinical Efficacy section. This data was supplemented by safety information from 7 additional clinical studies, resulting in a total safety population of 141 patients (17 ERT-naïve patients and 124 ERT-experienced patients), with exposure durations of up to 91 months. The interpretation of safety findings from open-label extension studies is limited by the absence of a comparator arm, making attribution of adverse events to treatment uncertain.

The safety database indicated that Elfabrio has an acceptable safety profile that is consistent with other ERTs. In Study PB-102-F20, the proportion of patients who experienced a treatment-emergent adverse event (TEAE) was similar between treatment groups (88.5% in the Elfabrio group and 96.0% in the agalsidase beta group). The primary safety concern was severe hypersensitivity, including anaphylaxis, and infusion-associated reactions.

Across the clinical program, the most frequently reported (occurring in more than 15% of patients) TEAEs included nasopharyngitis, fatigue, headache, back pain, cough, diarrhea, pain in the extremity, nausea, upper respiratory tract infection, pyrexia, and sinusitis. Related events, which occurred in 41.1% of patients overall, were mostly considered infusion-associated reactions. Five serious infusion-associated reactions were attributed to Elfabrio; four of these were immunoglobulin E (IgE)-mediated hypersensitivity reactions meeting the criteria for anaphylaxis, all of which occurred during or shortly after the first infusion and led to treatment discontinuation. One additional related serious adverse event of membranoproliferative glomerulonephritis with immune deposits was reported in an ERT-experienced patient. Four deaths occurred during the program; none were considered related to Elfabrio.

A numerically higher number of Fabry clinical events (a composite of cardiac, cerebrovascular, and renal events and non-cardiac-related deaths) were observed in the Elfabrio group; however, interpretation is limited by the small number of events, prior ERT exposure, and disease progression. Additional uncertainties remain in treatment-naïve patients; although few were enrolled, available data suggest a potentially higher rate of related infusion-associated reactions or hypersensitivity adverse events compared with ERT-experienced patients.

Appropriate warnings and precautions are in place in the approved Product Monograph for Elfabrio to address the identified safety concerns. The following warnings have been included in a Serious Warnings and Precautions box in the Product Monograph for Elfabrio: Patients treated with Elfabrio have experienced severe hypersensitivity reactions, including anaphylaxis. Appropriate medical support measures, including cardiopulmonary resuscitation equipment, should be readily available during Elfabrio administration. Patients should be monitored during and after infusions. If a severe hypersensitivity reaction (e.g., anaphylaxis) occurs, infusion should be immediately paused, appropriate medical treatment initiated, and the benefits and risks of the re-administration of Elfabrio should be considered.

For more information, refer to the Product Monograph for Elfabrio, approved by Health Canada and available through the Drug Product Database.

Proof of concept for the use of pegunigalsidase alfa as an enzyme replacement therapy was demonstrated in in vitro and in vivo studies.

In repeat-dose toxicity studies, the intravenous administration of pegunigalsidase alfa in mice resulted in mortalities and clinical signs due to allergic reactions and adverse effects on the kidneys (nephropathy) and liver (hepatocellular necrosis). Adverse clinical signs due to allergic reactions were also observed in monkeys. No-observed-adverse-effect levels (NOAELs) for general toxicity could not be established in either species. In addition, all adverse effects were observed at exposures that were lower than or only slightly greater than the human exposure at the maximum recommended human dose (MRHD).

The intravenous administration of pegunigalsidase alfa to pregnant rabbits in an embryo-fetal development study resulted in maternal toxicity (deaths and body weight loss) and embryo-fetal toxicity (increases in abortions, late resorptions, post-implantation loss, small fetuses, and reduced fetal weights). Exposure at the NOAEL for maternal toxicity and embryo-fetal toxicity was lower than the human exposure at the MRHD. No adverse effects on fertility or embryonic or fetal development were observed in rats. A pre- and postnatal development study was not conducted, and therefore, the risks to the fetus and offspring as a result of exposure during late pregnancy and lactation are unknown. However, hazards for developmental toxicity have been identified and mitigated through labelling in the Product Monograph for Elfabrio.

In view of the intended use of Elfabrio, there are no pharmacological or toxicological issues within this submission which preclude authorization of the product.

For more information, refer to the Product Monograph for Elfabrio, approved by Health Canada and available through the Drug Product Database.

Characterization of the Drug Substance

Pegunigalsidase alfa, the medicinal ingredient in Elfabrio, is produced using recombinant deoxyribonucleic acid technology. It is a PEGylated, covalently cross-linked recombinant human protein α-galactosidase A enzyme expressed in plant (Nicotiana tabacum, Bright Yellow 2) cells with a total molecular weight of approximately 116 kDa.

Pegunigalsidase alfa is well characterized in terms of primary and secondary structure, post-translational modifications, and biological activity. Product-related substances and impurities and process-related impurities were also well characterized and are adequately controlled. A risk assessment for the potential presence of nitrosamine impurities was conducted according to requirements outlined in Health Canada’s Guidance on Nitrosamine Impurities in Medications. The risks relating to the potential presence of nitrosamine impurities in the drug substance and/or drug product are considered negligible or have been adequately addressed (e.g., with qualified limits and a suitable control strategy.)

Manufacturing Process of the Drug Substance and Drug Product and Process Controls

The drug substance manufacturing process begins with the thawing of a single vial of the working cell bank. The cells are initially grown on solid growth media and then transferred to liquid media in flasks, followed by further expansion using increasingly larger bioreactors. Next, an induction bioreactor is used for the expression of the plant recombinant human-α-galactosidase A protein. Cells from several induction bioreactors are harvested via disc stack centrifugation and then pooled prior to forward processing into a single drug substance intermediate batch. The pooled harvest is cooled and then protein is extracted and clarified, purified via a series of chromatography steps, and filtered prior to being filled into bottles and stored frozen.

The drug substance manufacturing process continues with the thawing and pooling of the drug substance intermediate. After pooling, the drug substance intermediate is PEGylated, purified using strong cation exchange chromatography, compounded, filtered, and filled into bottles and stored frozen.

The Elfabrio drug product is a sterile, preservative-free, single-dose solution for intravenous infusion available in two different fill volumes: 2.5 mL/vial (5 mg/2.5 mL [2 mg/mL]) and 10 mL/vial (20 mg/10 mL [2 mg/mL]).

The Elfabrio drug product manufacturing process consists of thawing the drug substance, pooling, and mixing. The bulk drug substance solution undergoes bioburden reduction filtration, followed by two sequential sterile filtrations and aseptic filling into vials. Vials are stoppered, sealed, 100% visually inspected, and stored at 2 °C to 8 °C prior to secondary packaging. None of the non-medicinal ingredients (excipients) in the drug product are prohibited for use in drug products by the Food and Drug Regulations. The compatibility of the medicinal ingredient with the excipients is supported by the stability data provided.

Changes to the manufacturing process made throughout the pharmaceutical development are considered acceptable upon review.

The method of manufacturing and the controls used during the manufacturing process for both the drug substance and drug product are validated and considered to be adequately controlled within justified limits.

Control of the Drug Substance and Drug Product

The control strategy for the drug substance intermediate, drug substance, and drug product involves control of materials, in-process controls of product quality attributes, control of process parameters, release and stability specifications, and facility and equipment controls. Both master and working cell banks have been appropriately established and tested to support their use as cell substrate for the manufacture of the drug substance. The in-process and specification acceptance criteria were suitably justified and ensure the safety, identity, strength, potency, and purity of the drug substance and drug product. A two-tier reference standard program has been established, and the in-house analytical methods were appropriately validated.

Elfabrio is a Schedule D (biologic) drug and is, therefore, subject to Health Canada's Lot Release Program before sale as per the Guidance for Sponsors: Lot Release Program for Schedule D (Biologic) Drugs.

Stability of the Drug Substance and Drug Product

Based on the stability data submitted, the proposed shelf life and storage conditions for the drug substance and drug product were adequately supported and are considered to be satisfactory. The proposed 48-month shelf life for Elfabrio is considered acceptable when stored at 2 °C to 8 °C. The in-use shelf life of the diluted product is 24 hours when stored at 2 °C to 8 °C and up to 8 hours when stored at room temperature.

The compatibility of the drug product with the container closure system was demonstrated through compendial testing and stability studies. The container closure system met all validation test acceptance criteria.

The proposed packaging and components are considered acceptable.

Facilities and Equipment

The design, operations, and controls of all facilities and equipment involved in the production are considered suitable.

Taking into consideration the risk assessment score determined by Health Canada and mitigating factors, an on-site evaluation of the drug substance manufacturing facility was not recommended. Furthermore, based on a risk assessment score determined by Health Canada, an on-site evaluation of the drug product manufacturing facility was not deemed necessary.

Adventitious Agents Safety Evaluation

The drug substance manufacturing process incorporates adequate control measures to prevent contamination and maintain microbial control. Pre-harvest culture fluid from each lot is tested to ensure absence of adventitious microorganisms (bioburden, mycoplasma, and fungal contaminants) and appropriate limits are set.

One raw material of indirect animal origin that is manufactured using an animal-sourced pancreatic enzyme (soy peptone) is used in the manufacture of the drug substance. The soy peptone used is properly sourced and tested to ensure absence of adventitious agents. The excipients used in the drug product formulation are not of animal or human origin.