Summary Basis of Decision for Xenpozyme

Clinical Pharmacology

Clinical pharmacology data supporting the use of Xenpozyme (olipudase alfa) in adult and pediatric patients with acid sphingomyelinase deficiency were derived from five clinical studies, population pharmacokinetic and pharmacodynamic models, a quantitative system pharmacology model, and exposure-response analyses.

Olipudase alfa is a recombinant form of the human acid sphingomyelinase, an enzyme that catalyzes the hydrolysis of sphingomyelin to ceramide and phosphocholine.

Olipudase alfa exhibited linear pharmacokinetics, with plasma exposures increasing in a dose-proportional manner over the dose range of 0.03 to 3 mg/kg. Its mean terminal half-life ranged from 31.9 to 37.6 hours in adult patients. Minimal accumulation of the compound was observed after repeated administration at a dose of 3.0 mg/kg every 2 weeks.

The population pharmacokinetic analysis identified body weight as a significant intrinsic factor affecting the pharmacokinetics of olipudase alfa. Consequently, the recommended treatment regimen is based on the patient’s body weight.

Across clinical studies, plasma ceramide, a major product of olipudase alfa-mediated metabolism of sphingomyelin, increased transiently following each olipudase alfa infusion in both adult and pediatric patients. A consistent decrease in plasma ceramide, plasma lyso-sphingomyelin (a deacylated form of sphingomyelin) and other pharmacodynamic markers was observed with continued olipudase alfa treatment, consistent with the debulking of sphingomyelin and reflecting the mechanism of action of olipudase alfa.

The exposure-response and the population pharmacokinetic and pharmacodynamic analyses demonstrated that olipudase alfa exposures achieved with the maintenance dose of 3.0 mg/kg every 2 weeks resulted in a near-maximal reduction in plasma lyso-sphingomyelin and led to marked improvements in clinical efficacy endpoints in both adult and pediatric patients. The quantitative systems pharmacology model demonstrated that the only clinically meaningful difference between adult and pediatric patients with acid sphingomyelinase deficiency was disease severity, given that pediatric patients were predicted to exhibit a larger degree of acid sphingomyelinase enzymatic deficiency; there were no age-related differences in disease pathophysiology.

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). Overall, 48.3% (29 of 60) of patients with acid sphingomyelinase deficiency developed treatment-emergent ADAs while receiving olipudase alfa (40.0% [16 of 40] of adult patients and 65.0% [13 of 20] of pediatric patients). Fifteen percent of the olipudase alfa-treated patients developed neutralizing ADAs that inhibited the activity of olipudase alfa. The majority of patients who developed ADAs had low antibody titers. No clinically significant effects of ADAs were observed on the pharmacokinetics and efficacy of olipudase alfa in adult and pediatric patients.

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

Clinical Efficacy

The efficacy of Xenpozyme for the long-term treatment of non-central nervous manifestations of acid sphingomyelinase deficiency was primarily evaluated in the DFI12712/ASCEND study in adult patients and the DFI13803/ASCEND-Peds study in pediatric patients.

Study DFI12712/ASCEND

Study DFI12712/ASCEND was a Phase II/III, multicentre, randomized, double-blind, placebo-controlled study in 36 adult patients with acid sphingomyelinase deficiency type B. The study consisted of a 52-week, placebo-controlled, double-blind treatment period, which was the primary analysis period, and a subsequent, 4-year, open-label, extension treatment period (ongoing at the time of data cut-off). In the primary analysis period, patients were randomized in a ratio of 1:1 to receive Xenpozyme (18 patients) or placebo (18 patients) via intravenous infusion every 2 weeks over 52 weeks. Initially, a 14-week dose escalation was employed, with a starting dose of 0.1 mg/kg that was gradually increased to a target maintenance dose of 3 mg/kg every 2 weeks. In the extension treatment period, 17 of the 18 placebo-treated patients crossed over to treatment with Xenpozyme and underwent dose escalation to a target dose of 3 mg/kg every 2 weeks, whereas all 18 Xenpozyme-treated patients continued treatment with Xenpozyme.

Overall, 61% of the study patients were female and the mean age was 34.8 years. Eighty-nine percent of the patients were White, 6% were Asian, and 6% were categorized as “other”. Among all patients, the mean time since diagnosis of acid sphingomyelinase deficiency was 16.8 years. At the time of data cut-off, cumulative duration of exposure to Xenpozyme was 144.8 weeks for patients who received Xenpozyme from the beginning of the study and 118.3 weeks for patients who received placebo over 52 weeks and switched to Xenpozyme in the extension treatment period.

The study had two co-primary efficacy endpoints:

• the percentage change from baseline to Week 52 in diffusing capacity of the lung for carbon monoxide (DLco), as measured in percent predicted of normal (and adjusted for hemoglobin and ambient barometric pressure), and

• the percentage change from baseline to Week 52 in spleen volume (in multiples of normal [MN]).

The co-primary efficacy endpoints were analyzed in the modified intention-to-treat population (i.e., randomized patients who received at least one infusion, partial or total) using a mixed model for repeated measures.

After 52 weeks of treatment, statistically significant improvements in both co-primary efficacy endpoints were reported for Xenpozyme-treated patients compared to those who received placebo. At baseline, the mean DLco (percent predicted) was 49.44% in the Xenpozyme group and 48.45% in the placebo group. The least squares mean percentage change in DLco (percent predicted) from baseline to Week 52 was greater in the Xenpozyme group (21.97%) compared to the placebo group (2.96%), resulting in a statistically significant treatment difference of 19.01% (95% confidence interval [CI]: 9.23, 28.70; p = 0.0004). The mean spleen volume at baseline was 11.70 MN in the Xenpozyme group and 11.21 MN in the placebo group. At Week 52, the least squares mean percentage change in spleen volume from baseline was -39.45% in the Xenpozyme group and 0.48% in the placebo group, resulting in a statistically significant treatment difference of -39.93% (95% CI: -47.05, -32.80; p < 0.0001).

In addition, the study demonstrated statistically significant improvements in the secondary endpoints of percentage change in liver volume from baseline to Week 52 and percentage change in platelet count from baseline to Week 52 for Xenpozyme-treated patients compared to those who received placebo. There were no clinically meaningful and statistically significant differences between the groups in other secondary endpoints, which were related to patient-reported outcomes.

In the extension treatment period, patients in the Xenpozyme/Xenpozyme group continued to show improvements in DLco and spleen volume. Patients in the placebo/Xenpozyme group demonstrated similar responses to those observed in patients treated with Xenpozyme during the 52-week primary analysis period. By Week 132, the improvements in both parameters were similar in the placebo/Xenpozyme group and the Xenpozyme/Xenpozyme group.

The reductions in liver volume were maintained among patients who continued to receive Xenpozyme in the extension treatment period. Similar reductions over time were observed in the placebo/Xenpozyme group.

Study DFI13803/ASCEND-Peds

Study DFI13803/ASCEND-Peds was a Phase I/II, multicentre, open-label study of Xenpozyme in pediatric patients with acid sphingomyelinase deficiency type B or type A/B. The study enrolled 20 pediatric patients: 4 patients aged 12 to 17 years (adolescent cohort), 9 patients aged 6 to 11 years (child cohort), and 7 patients aged 1 to 5 years (infant/early child cohort). Fifty percent of the study patients were female, and mean age at symptom onset was 1.4 years. Patients received Xenpozyme via intravenous infusion every 2 weeks over a period of 64 weeks. A starting dose of 0.03 mg/kg was gradually increased according to a dose-escalation protocol to a target maintenance dose of 3 mg/kg every 2 weeks. Nine of the 20 patients completed dose escalation by Week 16 as scheduled; ultimately, all the patients reached the target dose. After completion of the 64-week treatment period, all 20 patients continued treatment with Xenpozyme in the long-term study LTS13632.

Study DFI13803/ASCEND-Peds was intended to evaluate the safety and tolerability of Xenpozyme in pediatric patients. In addition, the study evaluated exploratory efficacy endpoints related to organomegaly, pulmonary and liver functions, and linear growth.

The mean spleen volume at baseline was 19.0 MN in the overall pediatric population, 16.6 MN in the adolescent cohort, 19.4 MN in the child cohort, and 19.9 MN in the infant/early child cohort. A substantial decrease in spleen volume from baseline of approximately 40% was observed by Week 26. By Week 52, there was a mean percentage decrease in spleen volume from baseline of 49.2% (46.9% in the adolescent cohort, 46.0% in the child cohort, and 54.6% in the infant/early child cohort). Therefore, the mean spleen volume values at Week 52 were 8.7 MN in the adolescent cohort, 9.8 MN in the child cohort, and 8.9 MN in the infant/early child cohort.

Similarly, substantial decreases were observed for liver volume. At baseline, the mean liver volume was 2.65 MN in the overall pediatric population, ranging from 2.28 MN in the adolescent cohort to 2.76 MN in the infant/early child cohort. By Week 26, there was a mean percentage decrease in liver volume from baseline of approximately 33%. By Week 52, the mean percentage decrease in liver volume from baseline was 40.6% among all patients (41.3% in the adolescent cohort, 36.7% in the child cohort, and 45.1% in the infant/early child cohort). Therefore, the mean liver volume values at Week 52 were 1.3 MN in the adolescent cohort, 1.7 MN in the child cohort, and 1.5 MN in the infant/early child cohort.

Overall, continued treatment with Xenpozyme resulted in substantial improvements in spleen and liver volumes that were similar across the three pediatric age cohorts and were greater than those reported in adult patients. There were also marked improvements in mean percent change in DLco (percent predicted), platelet counts, and linear growth progression (as measured by height z-scores) at Week 52 as compared to baseline.

Given that Xenpozyme is not intended for the treatment of central nervous system manifestations of the disease, the drug was not studied in patients with acid sphingomyelinase deficiency type A, in whom the dominant disease manifestation is rapidly progressive neurological degeneration, with ultimately fatal outcome before the age of 3 years. Health Canada, however, did not exclude patients with acid sphingomyelinase deficiency type A from the recommended target population for Xenpozyme, but it did acknowledge the lack of data regarding the use of Xenpozyme for the treatment of non-central nervous system manifestations in patients with this form of the disease, allowing for informed clinical decision-making.

Indication

The New Drug Submission for Xenpozyme was filed by the sponsor with the following proposed indication, which was subsequently approved by Health Canada:

Xenpozyme (olipudase alfa) is an enzyme replacement therapy indicated for long-term treatment of non-central nervous system manifestations of acid sphingomyelinase deficiency in pediatric and adult patients.

The approved indication is accompanied by a sentence clarifying that there is no clinical trial experience with Xenpozyme in patients with acid sphingomyelinase deficiency type A.

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

Clinical Safety

In four clinical studies of Xenpozyme, 60 patients with acid sphingomyelinase deficiency were exposed to the drug for a median of 3.11 years (range: 0.4 to 7.8 years). The median exposure to Xenpozyme was 2.95 years (range: 0.4 to 7.8 years) in 40 adult patients and 4.15 years (range: 2.5 to 5.7 years) in 20 pediatric patients.

In adult patients who received Xenpozyme, the most frequently reported treatment-emergent adverse events were headache, nausea, nasopharyngitis, upper respiratory tract infection, back pain, abdominal pain, and arthralgia. Infusion-associated reactions (events reported within 24 hours from the start of the infusion and considered related or possibly related to Xenpozyme treatment by the investigator) were experienced by 22 of the 40 adult patients (55%) and included headache, nausea, urticaria, arthralgia, myalgia, pyrexia, pruritus, vomiting, and abdominal pain. There was one serious event of extrasystoles reported in an adult patient with a history of cardiomyopathy that was not considered related to the treatment. No fatal events were reported during the clinical studies.

In pediatric patients treated with Xenpozyme, the most frequently reported treatment-emergent adverse events were pyrexia, cough, nasopharyngitis, nasal congestion, vomiting, contusion, rhinitis, and upper respiratory infection. Serious events included anaphylaxis, urticaria, rash, hypersensitivity, and elevation in liver transaminases. Infusion-associated reactions occurred in 13 of the 20 patients (65%) and included pyrexia, urticaria, vomiting, headache, nausea, increased C-reactive protein, increased serum ferritin, and rash. No fatal events were reported during the clinical studies; however, one pediatric patient in the Xenpozyme programs for compassionate use or managed access died of an acute phase reaction (cause of death: respiratory failure) within 24 hours of an overdose of Xenpozyme during treatment initiation.

The identified safety concerns have been addressed in the Xenpozyme Product Monograph. A Serious Warnings And Precautions box highlights the risk of life-threatening infusion-associated reactions, including hypersensitivity (anaphylaxis) and acute phase reactions, along with recommendations for access to appropriate medical monitoring and support measures. Dosing considerations and the recommended dose-escalation regimens for adult and pediatric patients are detailed in the Xenpozyme Product Monograph. In addition, the sponsor has prepared and will disseminate to patients, caregivers and health care professionals educational materials related to fetal toxicity, infusion-related reactions, and medication errors/overdose.

Additional safety data will be provided from the ongoing DFI12712/ASCEND study, the long-term LTS13632 study, and a 5-year observational study (PMR 4291-1) that was required by the United States Food and Drug Administration to evaluate the long-term safety of Xenpozyme in pediatric patients under 2 years of age with acid sphingomyelinase deficiency and patients with acid sphingomyelinase deficiency type A.

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

Olipudase alfa, the medicinal ingredient in Xenpozyme, is a recombinant form of the human acid sphingomyelinase, an enzyme that catalyzes the hydrolysis of sphingomyelin to ceramide and phosphocholine. Non-clinical data submitted for olipudase alfa consisted of pharmacodynamic, pharmacokinetic, safety pharmacology, and toxicology studies in several species, including acid sphingomyelinase knockout (ASMKO) mice, a mouse model of acid sphingomyelinase deficiency.

Tissue sphingomyelin levels were reduced in ASMKO mice administered intravenously a single dose (up to 5 mg/kg) of olipudase alfa. Sphingomyelin began to reaccumulate or returned to background levels between 2 to 4 weeks post dose.

In a safety pharmacology study in cynomolgus monkeys, olipudase alfa was well tolerated up to a dose of 30 mg/kg. Transient changes in blood pressure and heart rate were observed in a safety pharmacology study in ASMKO mice after one dose of 3 mg/kg or two doses of 3 mg/kg administered 4 days apart.

In single and repeat-dose toxicity studies conducted in rats, dogs, and monkeys, olipudase alfa was well tolerated. No adverse findings related to olipudase alfa were observed in Sprague-Dawley rats or cynomolgus monkey at doses of up to 30 mg/kg administered intravenously every other week for 26 weeks. However, signs of hypersensitivity were observed in rats at all doses. The no-observed-adverse-effect level (NOAEL) was considered to be 30 mg/kg, resulting in exposures that were 2.3-fold (in rats) to 3.9-fold (in monkeys) the human exposure at the recommended clinical dose, based on the area under the concentration-time curve (AUC) values.

In ASMKO mice, single doses of olipudase alfa greater than or equal to 10 mg/kg administered as an intravenous bolus injection resulted in mortality. Clinical observations of lethargy, coolness to touch, and unwillingness to move were accompanied by elevations of serum aspartate aminotransferase, alanine aminotransferase, cholesterol, catabolites of accumulated sphingomyelin (ceramide, sphingosine, and sphingosine 1-phosphate), as well as elevations in the serum concentrations of inflammatory mediators, such as cytokines and acute phase proteins. In addition, there were dose-related microscopic findings consisting of focal areas of necrosis, ballooning degeneration, inflammation, and apoptosis in the liver and adrenal glands, and hemorrhage in the adrenal glands. Repeat-dose toxicity studies in ASMKO mice demonstrated that administration of olipudase alfa via a dose-escalation regimen did not result in olipudase alfa-related mortality and reduced the severity of other toxicity findings. The dose-escalation regimen consisted of four administrations of olipudase alfa at a dose of 3 mg/kg intravenously every other day, followed by a repeat doses of up to 30 mg/kg intravenously every 2 weeks. Such regimen allowed a gradual “debulking” of sphingomyelin and gradual release of ceramide, thereby decreasing the potential for toxicity observed after single-dose administration of olipudase alfa in these animals.

In two pivotal repeat-dose toxicity studies in ASMKO mice administered olipudase alfa at doses of 0.3, 1, and 3 mg/kg by intravenous bolus injection every 2 weeks for 12 or 13 weeks, the NOAEL was determined to be 3 mg/kg.

Four pivotal reproductive and developmental toxicity studies were conducted. In a fertility and early embryo-fetal development study in CD-1 mice, a prenatal and postnatal development study in CD-1 mice, and an embryo-fetal development study in NZW rabbits, the NOAEL for reproductive, maternal, and developmental toxicity, respectively, was determined to be 30 mg/kg (the highest dose tested).

Notably, in an embryo-fetal development study in CD-1 mice, an increased incidence of exencephaly (a neural tube defect) was observed when pregnant mice were treated with olipudase alfa at a dose grater than or equal to 10 mg/kg/day. This incidence was slightly higher compared to that noted in historical control data. Therefore, in this study, the developmental NOAEL for olipudase alfa in CD-1 mice was determined to be 3 mg/kg/day, which produced exposure levels that corresponded to 0.14-fold the human exposure at the recommended clinical dose, based on the AUC values.

Unscheduled deaths occurred disproportionately in the low-dose (3 mg/kg) groups in rodent studies and were attributed to hypersensitivity responses.

Olipudase alfa was detected in the milk of lactating CD-1 mice 2 days after the mice were administered 3 mg/kg olipudase alfa intravenously on Day 7 post partum.

Carcinogenicity, genotoxicity, and juvenile toxicity studies were not conducted with olipudase alfa, based on relevant guidance and an acceptable scientific rationale.

The results of the non-clinical studies as well as the potential risks to humans have been included in the Xenpozyme Product Monograph. In view of the intended use of Xenpozyme, there are no pharmacological or toxicological issues within this submission to preclude authorization of the product.

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

Characterization of the Drug Substance

Olipudase alfa, the medicinal ingredient in Xenpozyme, is a recombinant form of the human acid sphingomyelinase. The recombinant protein contains 570 amino acid residues and has a molecular weight of approximately 76,000 Da.

Detailed characterization studies were performed to provide assurance that olipudase alfa consistently exhibits the desired characteristic structure and biological activity.

Results from process validation studies indicate that the processing steps adequately control the levels of product- and process-related impurities. The impurities that were reported and characterized were found to be within established and acceptable limits.

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

Olipudase alfa is produced using a mammalian Chinese hamster ovary (CHO) cell line that is genetically engineered to express the protein.

The commercial manufacturing process of the drug substance includes cell expansion to generate sufficient quantity of cells for inoculation of the production bioreactor, purification of the drug substance (through a series of chromatography steps, viral inactivation and viral filtration steps), formulation, and final filtration of the formulated drug substance prior to filling into storage bags.

The manufacturing process of the drug product consists of sterile filtration and filling, lyophilization, capping and inspection, followed by labelling and packaging. None of the non-medicinal ingredients (excipients) found in the drug product is prohibited by the Food and Drug Regulations. The compatibility of the medicinal ingredient with the excipients is supported by the stability data provided.

Controls of critical steps of the drug substance and drug product manufacturing processes were established during manufacturing development and were based on a risk assessment and process characterization. Comprehensive comparability studies were provided to demonstrate consistency of the drug substance and drug product throughout the development. Process validation, conducted at commercial scale, demonstrated that the manufacturing processes are capable of consistently manufacturing drug substance and drug product that meet the predefined specifications and quality attributes.

Control of the Drug Substance and Drug Product

The release and stability specifications for the drug substance and drug product were established in accordance with relevant International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines. In-house analytical methods used in the release and stability testing of the drug substance and drug product were adequately validated according to ICH guidelines. Compendial methods were compliant with relevant pharmacopeial standards.

A risk assessment for the presence of nitrosamine impurities was conducted according to requirements outlined in Health Canada’s Guidance on Nitrosamine Impurities in Medications. No risk was identified of the formation or introduction of nitrosamines during the drug substance and drug product manufacturing processes. Accordingly, no confirmatory testing is required.

Xenpozyme 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 satisfactory.

The stability data support the proposed shelf life of 24 weeks at 2 °C to 8 °C for the drug substance and 60 months at 2 °C to 8 °C for the drug product.

If immediate use is not possible after reconstitution with sterile water for injection, the reconstituted drug product may be stored for up to 24 hours at 2 °C to 8 °C or up to 6 hours at room temperature (25 °C). After dilution of the reconstituted drug product with 0.9% sodium chloride solution, the diluted drug product may be stored for no longer than 24 hours at 2 °C to 8 °C, followed by 12 hours (including infusion time) at room temperature (25 °C).

The compatibility of the drug product with the container closure system was demonstrated through stability studies and an extractables and leachables study.

Facilities and Equipment

Based on risk assessment scores determined by Health Canada, on-site evaluations of the drug substance and drug product manufacturing facilities were not deemed necessary.

The design, operations, and controls of the facility and equipment involved in the production are considered suitable for the activities and products manufactured. The sites involved in production are compliant with good manufacturing practices.

Adventitious Agents Safety Evaluation

The drug substance manufacturing process incorporates adequate control measures to prevent contamination and maintain microbial control. In-process testing is performed to monitor for bioburden, endotoxins, mycoplasma, and viruses. Purification process steps designed to inactivate and remove any potential viral contaminants from the cell culture process are adequately validated.

Animal-derived raw materials used in the manufacturing process are appropriately sourced and tested, and compliant with the Note for Guidance on Minimising the Risk of Transmitting Animal Spongiform Encephalopathy Agents via Human and Veterinary Medicinal Products [EMA/410/01, Rev.3]). The risk of contamination of the drug product with bovine spongiform encephalopathy and transmissible spongiform encephalopathy agents is considered negligible.

The excipients used in the drug product formulation are not of animal or human origin.