Summary Basis of Decision for Vimizim

 

Clinical Pharmacology

The clinical pharmacological data provided supports the use of Vimizim for the specified indication.

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

Clinical Efficacy

The efficacy of Vimizim was assessed in a 24-week, Phase III, randomized, double-blind, placebo-controlled study (MOR-004). A total of 176 patients with Mucopolysaccharidosis IVA (MPS IVA) were enrolled and randomized to one of three treatment regimens: Vimizim 2 mg/kg once per week [number of patients (n) = 58]; Vimizim 2 mg/kg once every other week (n = 59); or  placebo (n = 59).

Most patients had a medical history of musculoskeletal conditions (82%), including knee deformity (52%), kyphosis (31%), hip dysplasia (22%), prior spinal fusion surgery (22%) and arthralgia (20%). Patients ranged in age from 5 to 57 years and half were 5 to 11 years old. At baseline, all patients could walk >30 m, but <325 m in six minutes.

The primary objective of the study was to evaluate the impact of Vimizim treatment upon endurance in patients with MPS IVA, as measured by the change from baseline in the number of meters walked in six minutes [6 Minute Walk Test (6-MWT)] at week 24 as compared with placebo. Secondary efficacy endpoints were the change from baseline in the rate of stair climbing in three minutes [3-minute stair climb test (3-MSCT)] compared with placebo at Week 24, and the percent change from baseline in the urine KS level compared with placebo.

The primary efficacy endpoint was achieved in the group receiving Vimizim once per week: a statistically significant improvement in 6-MWT distance was demonstrated compared with placebo. The estimated mean treatment effect at Week 24, compared with placebo, was 22.5 meters [95% confidence interval (CI), 4.0, 40.9; p = 0.0174] for the Vimizim 2 mg/kg once per week regimen. There was no difference in 6-MWT results between the group receiving Vimizim once every other week and the placebo group. Per protocol, supportive, subgroup, and sensitivity analyses of the primary endpoint were consistent with the primary analysis, and beneficial trends were observed in supportive responder analysis of the Vimizim once per week group. Overall, the results of the primary efficacy analysis were considered adequately robust in the Vimizim once per week group.

In secondary efficacy endpoint analysis, the mean difference in 3-MSCT was not statistically significant for the comparison of the Vimizim 2mg/kg once per week regimen with placebo, and no difference was observed between the group receiving Vimizim once every other week and the placebo group. A trend was observed for numerically greater reduction in mean urinary KS levels from baseline in both Vimizim treatment groups compared to the placebo group. The relationship between urinary KS levels and other measures of clinical response has not been established.

Patients who completed the MOR-004 study were eligible to continue treatment in an extension study, MOR-005 [Number of patients (n) = 173]. In Part 1 of MOR-005, all subjects received double-blinded treatment with Vimizim: those who received Vimizim in MOR-004 continued with the same treatment, while those who received placebo in MOR-004 were re-randomized (1:1) to treatment with Vimizim 2 mg/kg given either once per week or once every other week.  Completion of the MOR-004 analysis triggered Part 2 of MOR-005, in which all subjects transitioned to open-label treatment with Vimizim 2 mg/kg given once per week. No further improvement in walking ability was observed in those patients who continued to receive 2 mg/kg once per week for an additional 24 weeks of extension study (for a total exposure of 48-weeks including the placebo-controlled study).

For this New Drug Submission, the sponsor initially sought approval for the following indication: Vimizim (elosulfase alfa) is indicated for patients with Mucopoly-saccharidosis IVA (Morquio A syndrome, or MPS IVA). Health Canada has revised this indication to: Vimizim (elosulfase alfa) is indicated for long-term enzyme replacement therapy in patients with a confirmed diagnosis of Mucopolysaccharidosis IVA (Morquio A syndrome, or MPS IVA). The revised indication is to specify that Vimizim should only be used in patients with a confirmed diagnosis of MPS IVA. Vimizim has also been approved for long-term use.

In conclusion, the efficacy of Vimizim (2 mg/kg/week) has been adequately demonstrated in the pivotal MOR-004 study. The treatment benefit in 6-MWT results was statistically significant and robust. It is unknown, whether Vimizim treatment will benefit patients with better than average mobility or who are confined to a wheelchair. Long term benefit in growth, mobility, fatigue, premature death and other meaningful endpoints is yet to be established.

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

Clinical Safety

The safety of Vimizim was evaluated in a pooled analysis of six studies in which 235 MPS IVA patients were exposed to Vimizim. A total of 222 patients received the recommended dose of Vimizim (2 mg/kg once per week) with a mean exposure of 30 weeks (range 1 - 100 weeks). The six studies are:

• The pivotal Phase III study (MOR-004) and its extension (MOR-005);
• A Phase I-II study (MOR-002) and its extension (MOR-100);
• Two ancillary Phase II studies (MOR-007 and MOR-008).

The MOR-004 and MOR-005 studies have been previously described in the Clinical Efficacy section of this Summary Basis of Decision.

MOR-002 was a Phase I-II, multicentre, open-label, dose-escalation study designed to evaluate the use of Vimizim in 20 patients with MPS IVA who were 4 to 16 years of age. Patients who completed the 36-week dose escalation period (consisting of three consecutive 12-week dosing periods of 0.1, 1.0, and 2.0 mg/kg/week), had the option to continue Vimizim treatment with weekly doses of 1.0 mg/kg for an additional 36 to 48 weeks.

MOR-100 was an ongoing Phase I-II extension study designed to evaluate the long-term safety and efficacy of Vimizim 2.0 mg/kg/week administered for up to 240 weeks in 17 patients with MPS IVA who completed the MOR-002 study.

MOR-007  was an ongoing Phase II, open-label, multinational study designed to evaluate Vimizim 2.0 mg/kg/week administered for an initial treatment period of 52 consecutive weeks in 15 patients with MPS IVA who were <5 years of age at the time of first study-drug infusion. It is anticipated that there will be an extension treatment phase of up to an additional 157 weeks.

MOR-008 was an ongoing Phase II, randomized, double-blind, multicentre study designed to evaluate Vimizim 2.0 mg/kg/week and 4.0 mg/kg/week administered for an initial treatment period of 27 consecutive weeks in 25 patients with MPS IVA who were ≥7 years of age and able to walk ≥200 meters in the 6-MWT. It is anticipated that there will be an extension treatment phase of up to an additional 130 weeks.

An additional ongoing study (MOR-006) is evaluating the safety and efficacy of Vimizim in patients with limited ambulation.

In pooled safety data derived from the above six studies, the most common adverse events (AEs) were infusion-associated events, reported in 93% (218/235) of patients and including: headache; vomiting; pyrexia; nausea; and cough. Despite routine pre-treatment with antihistamines, serious adverse events during infusion have included anaphylactic reaction, hypersensitivity, status asthmaticus and vomiting. Severe adverse events during infusion have included anaphylactic reaction, rash, chills, hypersensitivity and status asthmaticus. Infusion reactions did not increase with prolonged use of Vimizim and were generally tolerated. Infusion reactions leading to interruption or discontinuation of Vimizim administration occurred in 49% of patients, with 23% (54/235) requiring medical intervention including antihistamines (16%) and/or corticosteroids (13%). There were no deaths.

Anaphylactic reactions were identified in 7.7% (18/235) of patients based on the National Institute of Allergy and Infectious Diseases (NIAID) and Food Allergy and Anaphylaxis Network (FAAN) criteria. These 18 patients experienced a total of 26 anaphylactic events, 13 patients experienced a single event, 4 patients experienced two events, 1 experienced five events. Twenty of the 26 anaphylactic events were mild or moderate in severity, four were severe, and two were life-threatening. Five anaphylactic events were reported as serious and 21 were non-serious. There were no fatal anaphylaxis events. Anaphylaxis occurred as early as 30 minutes from the start of infusion and up to three hours after infusion. Anaphylaxis occurred as late into treatment as the 47th infusion. All of the anaphylactic events were self-limited; none required intubation or cardiopulmonary resuscitation; two required hospitalization; and all were treated successfully with supportive care [e.g. antihistamines, corticosteroids and/or epinephrine]. Of the five patients who experienced a recurrent anaphylactic reaction following re-challenge, three continued Vimizim after the recurrences, and two permanently discontinued Vimizim.

Hypersensitivity AEs (including anaphylaxis) were identified in 18.7% (44/235) of patients. The risk of life threatening complications resulting from hypersensitivity reactions may be higher in patients with acute febrile or respiratory illness.

Serious adverse events (SAEs) were reported in 29% (69/235) of patients and treatment related SAEs were reported in 5.5% (13/235) of patients. For patients receiving the recommended dose of Vimizim, serious adverse events were reported in 4/16 (25%) of subjects less than 5 years of age, 27/117 (23%) of subjects 5 to 11 years of age, 5/50 (10%) of subjects 12 to 18 years of age and 3/39 (7.7%) of subjects 19 years of age and older.

In order to address the identified concern regarding anaphylaxis and hypersensitivity reactions, the Vimizim Product Monograph was revised to include a boxed Warning. Further revisions included a warning to describe the potential for increased risk of life threatening complications from hypersensitivity reactions in patients with acute febrile or respiratory illness at the time of the Vimizim infusion. Additional labelling recommendations were to: administer prophylactic antihistamines prior to infusion, with or without antipyretics; to assess the patient's clinical status before administering Vimizim, to consider delaying infusion in patients with acute febrile or respiratory illness, to observe patients closely during and after Vimizim infusion, to slow or stop Vimizim infusion in the event of an anaphylactic or hypersensitivity reaction and initiate treatment according to the severity of the reaction; and to assess the risk/benefit of re-administration following a severe reaction. In post-marketing commitments to the Food and Drug Administration (FDA), a clinical study will evaluate whether an immune tolerance regimen could mitigate the risk of severe hypersensitivity.

Anti-drug antibodies (immunogenicity) developed in all patients treated with Vimizim 2 mg/kg/week by Week 4 in the MOR-004 study, and were sustained through 72 weeks. Since anti-drug antibody development was rapid and universal, the impact on efficacy and safety could not be evaluated. All patients treated with Vimizim 2 mg/kg once per week in MOR-004 tested positive for neutralizing antibodies at least once during the trial.  Anti-drug antibody titers did not correlate with hypersensitivity. Neutralizing antibody was measured with a qualitative assay and titers were not measured. It is unknown if immune tolerance may develop with increased duration of exposure. In post-marketing commitments to the FDA, the sponsor will develop and validate assays for neutralising antibody titers and IgE titers.

The safety database was small [Number of patients (n) =235] which limits the ability to detect AEs that are rare, have a long latency or are due to prolonged exposure. Additionally, Vimizim exposure in children less than 5 years of age was very limited (n = 16); and the safety of Vimizim has not been assessed in the elderly (>65 years), in pregnant or lactating women, or in patients with renal or hepatic or cardiovascular impairment.

A ten-year registry is planned to collect efficacy and safety data, including the effects of treatment in children under 5 years of age; the occurrence of serious hypersensitivity reactions; immunogenicity; and pregnancy exposure data.

In conclusion, the identified safety issues are significant; but in view of the unmet need for treatment of this devastating disease, should be managed with appropriate labelling and warnings and the provisions in the Risk Management Plan, and appropriate labelling and warnings. Based on the review, it is considered that the benefit/risk ratio of Vimizim is favourable for the revised indication: Vimizim (elosulfase alfa) is indicated for long-term enzyme replacement therapy in patients with a confirmed diagnosis of Mucopolysaccharidosis IVA (Morquio A syndrome, or MPS IVA).

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