Summary Basis of Decision for Aubagio

Clinical Pharmacology

Multiple sclerosis (MS) is a serious and severely debilitating chronic autoimmune and neurodegenerative disease of the central nervous system (CNS). Aubagio (teriflunomide) is an immunomodulatory agent with anti-inflammatory properties that selectively and reversibly inhibits the mitochondrial enzyme dihydroorotate dehydrogenase (DHO-DH), required for the de novo pyrimidine synthesis. As a consequence teriflunomide blocks the proliferation of stimulated lymphocytes, which need the de novo synthesis of pyrimidine to expand, and may diminish the numbers of activated lymphocytes in peripheral blood. The exact mechanism by which teriflunomide exerts its therapeutic effect in MS is not known, but may involve reduced numbers of activated lymphocytes available for migration into the CNS.

The sponsor conducted a study to support a change in the formulation [that is (i.e.,) removal of colloidal anhydrous silica] and a study to compare the bioavailability of milled and unmilled batches of teriflunomide tablets. The design of the studies and the data submitted were considered acceptable to support the formulation change and the use of unmilled tablets for the manufacturing of the drug substance.

The clinical pharmacological data support the use of Aubagio for the specified indication. Extensive labelling revisions were proposed to address the many safety concerns associated with the use of Aubagio and the proposed revisions were accepted. Appropriate warnings and precautions are in place in the approved Aubagio Product Monograph to address the identified safety concerns.

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

Clinical Efficacy

The efficacy of Aubagio (teriflunomide) as monotherapy in the treatment of relapsing remitting multiple sclerosis (RRMS) was demonstrated in two pivotal Phase III studies: TEMSO and TOWER.

The study TEMSO was a randomized, multicentre, double-blind, placebo-controlled, parallel-group study that evaluated the efficacy and safety of Aubagio in patients with MS exhibiting a relapsing remitting clinical course. The study was conducted in 1,088 patients, of which 1,086 were treated. The study was stratified by centre and by baseline score of the expanded disability status scale (EDSS) [≤3.5 versus (vs.) >3.5]. The patients were randomized (1:1:1) to 1 of the 3 treatment groups (placebo, Aubagio 7 mg or 14 mg daily) and treated for approximately 2 years. The primary efficacy variable in TEMSO was the Annualized Relapse Rate (ARR), defined as the number of confirmed relapses per patient-year. The key secondary variable was confirmed progression of disability for at least 12 weeks, as assessed by the EDSS.

Results from study TEMSO demonstrated that Aubagio 14 mg administered for 2 years significantly reduced the rate of relapse in patients with relapsing remitting MS, by 31.5%(p = 0.0005) relative to the placebo group. Aubagio reduced the risk of 12 week-sustained disability progression by 29.8% (p = 0.0279) at the 14 mg dose. An effect of Aubagio on various magnetic resonance imaging (MRI) parameters was shown, including burden of disease, percentage of change from baseline in T1-hypointense lesion volume, number of Gadolinium (Gd)-enhancing T1 lesions per scan, number of unique active lesions per scan, and proportion of patients free from Gd-enhancing T1 lesions.

The second pivotal study, TOWER, was a randomized, multicentre, double-blind, parallel-group, placebo-controlled study that evaluated once daily doses of Aubagio 7 mg and 14 mg in patients with RRMS with mean treatment duration of approximately 18 months. The study was conducted in 1,169 patients, of which 1,165 were treated. Patients were randomly assigned to receive either placebo, Aubagio 7 mg or Aubagio 14 mg, in a ratio of 1:1:1.

Results from study TOWER demonstrated that Aubagio 14 mg significantly reduced the rate of relapse compared to placebo by 36.3% (p = 0.0001) and the risk of sustained disability progression by 31.5% (p = 0.0442). A beneficial effect was observed on the annualized rate of relapses with sequelae and on the adjusted annualized rates of relapses leading to hospitalization.

Based on the efficacy results from the TOWER study, the key secondary variable has failed for the 7 mg dose. Therefore, the sponsor's proposed indications and proposed dosing regimen were restricted to only the 14 mg tablet strength, reflecting the positive, clinically-meaningful results relating to the annualized rate of relapse and disability progression. These results were consistent with the results obtained in the TEMSO study and support not authorizing the 7 mg dose for the proposed indication.

Overall, the efficacy of Aubagio for the treatment of RRMS was demonstrated in the two Phase III clinical studies. The results showed significant reduction in relapse rates and delayed the accumulation of physical disability with Aubagio 14 mg as compared to placebo.

The original proposed indication by the sponsor for Aubagio in the New Drug Submission (NDS) was: "Aubagio (teriflunomide) is indicated for the treatment of patients with relapsing forms of multiple sclerosis (RMS) to reduce the frequency of clinical exacerbations, to delay the accumulation of physical disability and to decrease the number and volume of active brain lesions identified on magnetic resonance imaging (MRI) scans".

Following the review of the submission, Health Canada revised the indication to: "Aubagio (teriflunomide) is indicated as monotherapy for the treatment of adult patients with relapsing remitting multiple sclerosis (RRMS) to reduce the frequency of clinical exacerbations and to delay the accumulation of physical disability".

The proposed revisions to include "adult" in the indication, followed by statements with regards to pediatric and geriatric populations were made to reflect the fact that only MS patients aged 18 to 55 were included in the clinical studies (TEMSO and TOWER). It was requested that "monotherapy" be added to the proposed indication, since the efficacy and safety data from the clinical trials were obtained by administering Aubagio alone, and not concomitantly with other MS drugs.

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

Clinical Safety

The clinical safety evaluation was based primarily on data from the two Phase III pivotal studies (TEMSO and TOWER) and the two supportive studies (Study 2001 and TENERE).

The most common adverse events (AEs) reported with a frequency of ≥10% in the Aubagio14 mg group with a difference of ≥1% compared to placebo were alopecia, diarrhea, increased alanine aminotransferase (ALT), and nausea.

The cumulative exposure to the product in the monotherapy studies was over 6,200 patient-years up to the data cut-off for this submission. In the pooled analysis of the Phase II and Phase III placebo-controlled studies (Pool I), 2,430 patients with relapsing forms of MS were randomized to receive Aubagio 7 mg (838 patients), Aubagio 14 mg (786 patients) or placebo (806 patients). The median treatment exposure was approximately 680 days across treatment groups. In Pool II (non-controlled including long-term extension studies), 2,284 patients were exposed to Aubagio 7 mg and 14 mg with a maximum exposure of up to 11.1 years. The median duration of study treatment was 2.1 years in the 7 mg and 14 mg Aubagio groups in Pool II.

Teriflunomide is the active metabolite of leflunomide (Arava), approved by Health Canada for the treatment of active rheumatoid arthritis. Therefore it is expected to share some of the adverse reactions previously identified for leflunomide. The known important identified and potential risks with teriflunomide are hepatic effects, teratogenicity, hypertension, hematologic effects and infections.

Hepatic Effects

In Pool I, the proportion of patients with treatment-emergent adverse events (TEAEs) for hepatic disorders was higher in the Aubagio treatment groups (19.5% and 21.0% on Aubagio 7 mg and 14 mg, respectively) compared to the placebo group (14.6%). The main hepatic AE was an increase in alanine aminotransferase (ALT). The percentages of patients with ALT >1 to ≤3 times the upper limit of normal (ULN) in the on-treatment period were higher in the Aubagio treatment groups compared to the placebo group with no dose-effect relationship. However, the percentages of patients with ALT >3 to ≤5 times the ULN, ALT >5 to ≤20 times the ULN, or ALT >20 times the ULN were balanced across treatment groups.

Teratogenicity

Toxicologic studies have shown that Aubagio is teratogenic in animals. There are no adequate and well-controlled studies evaluating Aubagio in pregnant women. Pregnant women or women of child bearing potential not taking appropriate contraception method were excluded from the clinical studies and an accelerated elimination procedure to quickly decrease plasma concentration of Aubagio is recommended in case of pregnancy. Therefore, the teratogenic risk of Aubagio in humans remains uncertain.

Hypertension

Hypertension was reported as an AE in 4.2% of patients treated with 14 mg of Aubagio, compared with 2% on placebo. Blood pressure should be verified before the initiation of treatment with Aubagio and periodically thereafter. Elevated blood pressure should be appropriately managed during treatment with Aubagio. There were no reports of hypertensive emergency, e.g., malignant hypertension, hypertensive encephalopathy and no other acute life-threatening complications secondary to increases in blood pressure. In patients who developed hypertension, the introduction or modification of antihypertensive treatment usually led to adequate control of blood pressure.

Bone marrow disorders

In Pool I, the proportion of patients with TEAEs for bone marrow disorders was higher in both Aubagio groups (10.3% and 11.1% in the Aubagio7 mg and 14 mg groups, respectively) compared to the placebo group (3.7%). The main bone marrow related adverse events (AE) were neutrophil and white blood cell (WBC) count decreases.

Regarding laboratory data, an average decrease affecting primarily the WBC count (mainly neutrophil and lymphocyte count decreases) was observed with a small dose effect. The decrease in the mean change occurred during the first 6 weeks followed by stabilization over time while on-treatment. The magnitude did not exceed 15% on average.

Other potential risks

In addition to the identified risks, there are also known important potential risks with Aubagio: hypersensitivity reactions (including severe skin reactions); serious opportunistic infections; cardiovascular effects; malignancies (including lymphoproliferative disorders); peripheral neuropathy; renal failure; interaction with cytochrome P450 (CYP) enzyme CYP2C8 substrates; interaction with CYP1A2 substrates; interaction with organic anion transporter 3 (OAT3); breast cancer resistant protein (BCRP) transporter and organic anion transporter protein B1(OATP1B1) substrates (especially rosuvastatin); interaction with warfarin; interaction with oral contraceptives; osteoporosis associated with hypophosphatemia; and pancreatic disorders.

To address the known concerns related to the safety of Aubagio, Health Canada has recommended revisions to the sponsor's proposed Product Monograph. These revisions were generally aligned with the approved labelling in the United States and Europe and with labelling for important safety issues observed with the related compound leflunomide (ARAVA). The major safety concerns are clearly highlighted for prescribers and patients.

A Serious Warnings and Precautions Box describing the risk of hepatotoxicity and teratogenicity has been included in the Product Monograph for Aubagio.

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