Summary Basis of Decision for Vyndaqel

Review decision

The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.


Product type:

Drug

Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Vyndaqel is located below.

Recent Activity for Vyndaqel

SBDs written for eligible drugs approved after September 1, 2012 will be updated to include post-authorization information. This information will be compiled in a Post-Authorization Activity Table (PAAT). The PAAT will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. PAATs will be updated regularly with post-authorization activity throughout the product's life cycle.

Summary Basis of Decision (SBD) for Vyndaqel

Date SBD issued: 2020-05-21

The following information relates to the new drug submission for Vyndaqel.

Tafamidis meglumine

Drug Identification Number (DIN):

  • DIN 02495732 ‑ 20 mg capsule, oral administration

Pfizer Canada ULC

New Drug Submission Control Number: 228368

On January 20, 2020, Health Canada issued a Notice of Compliance to Pfizer Canada ULC for the drug product, Vyndaqel.

The market authorization was based on quality (chemistry and manufacturing), non‑clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and efficacy) information submitted. Based on Health Canada's review, the benefit‑harm‑uncertainty profile of Vyndaqel is favourable for the treatment of adult patients with cardiomyopathy due to transthyretin‑mediated amyloidosis, wild type or hereditary, to reduce cardiovascular mortality and cardiovascular‑related hospitalization.

1 What was approved?

Vyndaqel, a transthyretin stabilizer, was authorized for the treatment of adult patients with cardiomyopathy due to transthyretin‑mediated amyloidosis, wild‑type or hereditary, to reduce cardiovascular mortality and cardiovascular‑related hospitalization.

No data in patients under the age of 18 are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use.

The safety and efficacy of Vyndaqel was demonstrated in the geriatric population, with more than 90% of patients in the pivotal trial being 65 years of age or older. No dosage adjustment is required for this population.

Vyndaqel is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container.

Vyndaqel was approved for use under the conditions stated in its Product Monograph, taking into consideration the potential risks associated with the administration of this drug product.

Vyndaqel (20 mg tafamidis meglumine) is presented as a capsule. In addition to the medicinal ingredient, the capsule contains ammonium hydroxide 28%, brilliant blue FCF, carmine, gelatin, glycerin, iron oxide (yellow), polyethylene glycol 400, polysorbate 80, polyvinyl acetate phthalate, propylene glycol, sorbitan monooleate, sorbitol, and titanium dioxide.

For more information, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

Additional information may be found in the Vyndaqel Product Monograph, approved by Health Canada and available through the Drug Product Database.

2 Why was Vyndaqel approved?

Health Canada considers that the benefit‑harm‑uncertainty profile of Vyndaqel is favourable for the treatment of adult patients with cardiomyopathy due to transthyretin‑mediated amyloidosis, wild‑type or hereditary, to reduce cardiovascular mortality and cardiovascular‑related hospitalization.

Transthyretin amyloidosis (ATTR) is a rare, progressive fatal disorder caused by defects in transthyretin (TTR), a carrier protein for thyroxine and vitamin A. The condition is characterized by destabilization of the TTR tetramer transport protein, leading to its dissociation into free monomers. This initial and rate‑limiting step in amyloidogenesis results in misfolded proteins that aggregate into TTR amyloid fibrils and deposit in the nervous system, gastrointestinal tract, kidney, and heart.

Transthyretin amyloidosis is classified as either wild‑type or hereditary. In wild‑type ATTR, TTR becomes structurally unstable due to age; approximately 12,700 Canadians are estimated to be affected and are primarily men over 65 years of age. Hereditary ATTR is inherited as an autosomal dominant trait, is caused by over 120 mutations in the TTR gene, and is mostly seen in patients over 55 years of age. In North America, hereditary ATTR affects primarily Afro‑Caribbean males carrying a Val122Ile mutation, with an estimated prevalence of up to 3.3% in this population and a total of about 500 Canadians.

In ATTR with cardiomyopathy (ATTR-CM), which chiefly involves the heart, TTR amyloid fibrils are deposited between myocardial cells, producing a thickening and stiffening of the myocardium and affecting the conduction system and/or aortic valves. This results in diastolic dysfunction progressing to restrictive cardiomyopathy and heart failure with preserved left ventricular function, which can result in arrhythmias and/or aortic stenosis. Symptoms include exertional dyspnea, orthostatic hypotension, syncope and peripheral edema, as well as signs of chronic right ventricular failure, including peripheral, gastrointestinal, and hepatic congestion/edema, leading to cardiovascular-related hospitalization and, ultimately, death. Median survival is approximately 43 months for wild‑type ATTR-CM, and 30 months for hereditary ATTR-CM. Over 90% of ATTR-CM cases are caused by wild‑type ATTR.

At the time of authorization, there were no approved therapies in Canada for ATTR-CM. Treatments are symptomatic, with use of diuretics for symptoms of heart failure, pacemaker implantation for cardiac arrhythmias, and cardiac transplantation or cardiac and/or liver transplantation for some hereditary cases. Liver transplantation eliminates the primary production site of the defective TTR protein, but must be performed early for benefit, in some cases before cardiomyopathy has been diagnosed.

Tafamidis meglumine, generally referred to as tafamidis throughout this Summary Basis of Decision, is the medicinal ingredient in Vyndaqel. It is an orally administered small molecule which selectively binds to the thyroxine binding sites of TTR, stabilizing the native tetramer state of TTR and preventing its dissociation into amyloidogenic monomers.

The market authorization for Vyndaqel was based on a single double-blind, placebo‑controlled Phase III trial, known as B3461028 (also known as ATTR‑ACT). In this trial, patients with cardiomyopathy due to hereditary or wild-type ATTR were randomized in a 1:2:2 ratio to receive 20 mg Vyndaqel, 80 mg Vyndaqel, or placebo over a period of 30 months. At randomization, patients were stratified by TTR gene status and New York Heart Association (NYHA) classification. The NYHA classification, ranging from least severe (Class I) to most severe (Class IV), provides a simple way of classifying the extent of heart failure based on a patient's symptoms and limitations during physical activity.

Results from the B3461028 trial demonstrated a reduction in the primary efficacy endpoint, a hierarchical combination of all‑cause mortality and frequency of cardiovascular‑related hospitalization, in the pooled Vyndaqel group compared to placebo (29.5% vs 42.9%, respectively). The difference in mortality between groups was attributable to cardiovascular‑related deaths.

Differences favouring Vyndaqel over placebo were also seen for both key secondary endpoints: distance walked during the 6‑minute walk test (6MWT) and Kansas City Cardiomyopathy Questionnaire‑Overall Summary (KCCQ‑OS) scores.

Overall, the efficacy was similar between 20 mg and 80 mg Vyndaqel doses, however, the trial was not powered to distinguish between doses. The potential benefit of the 80 mg dose over the 20 mg dose was suggested based on post‑hoc exploratory subgroup analyses. Therefore, the recommended dose of Vyndaqel is 80 mg tafamidis meglumine (administered as four 20 mg capsules) orally once daily.

The safety profile of Vyndaqel was comparable to placebo and did not differ significantly according to dose. The most commonly reported Treatment‑emergent Adverse Events (≥10%) in the Vyndaqel groups that occurred at rates higher than placebo are as follows: atrial fibrillation, cardiac failure, cardiac failure acute, cardiac failure congestive, asthenia, edema peripheral, bronchitis, pneumonia, fall, muscle spasms, pain in extremity, insomnia, hematuria, cough, and hypotension. Incidence of hypothyroidism was reported in 6.8%, 5.7% and 5.6% of patients in the Vyndaqel 80 mg, 20 mg and placebo groups, respectively. The most frequently reported events leading to discontinuation in any treatment group were cardiac failure, congestive cardiac failure, and cardiac amyloidosis.

Consistent with the overall study population, a reduction in combined all‑cause mortality and cardiovascular‑related hospitalization was seen with Vyndaqel treatment for NYHA Class I, II, and III patients, as well as individual reductions in all‑cause mortality, cardiovascular mortality, and cardiovascular‑related hospitalization. The only exception was an increased rate of cardiovascular‑related hospitalizations in Class III patients, with 76.9% of Vyndaqel treated patients hospitalized compared to 58.7% of placebo patients. For Class III patients, the rate of cardiovascular‑related deaths was 47.4% vs 49.2% for the pooled Vyndaqel and placebo treatment groups, respectively. In light of the consistent benefit seen across functional classes for all endpoints other than cardiovascular‑related hospitalization, it was considered appropriate to include Class III patients along with Class I and II patients in the Vyndaqel indication. No NYHA Class IV patients were enrolled in the pivotal study.

Based on animal (non‑clinical) data, tafamidis is associated with a potential risk of reproductive and developmental toxicity, and is secreted in the milk of lactating rats. Limited clinical data are available, and a risk to children born to women exposed to tafamidis during pregnancy or during lactation cannot be excluded. Therefore, Vyndaqel should not be administered to pregnant or nursing women. In addition, Vyndaqel has not been studied in patients with severe hepatic impairment, and data are limited in patients with severe renal impairment. These issues have been addressed through appropriate labelling in the Vyndaqel Product Monograph.

A Risk Management Plan for Vyndaqel was submitted by Pfizer Canada ULC to Health Canada. Upon review, it was considered to be acceptable. The Risk Management Plan is designed to describe known and potential safety issues, to present the monitoring scheme and, when needed, to describe measures that will be put in place to minimize risks associated with the product.

The submitted inner and outer labels and Patient Medication Information section of the Vyndaqel Product Monograph meet the necessary regulatory labelling, plain language and design element requirements.

A Look‑alike Sound‑alike brand name assessment was performed and the proposed name, Vyndaqel, was accepted.

Overall, the benefits of Vyndaqel seen in the pivotal B3461028 trial are considered to outweigh the potential risks. Vyndaqel has an acceptable safety profile based on the non‑clinical data and clinical studies. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Vyndaqel Product Monograph to address the identified safety concerns.

This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations. For more information, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

3 What steps led to the approval of Vyndaqel?

The drug submission for Vyndaqel was reviewed under the Priority Review Policy on the basis that Vyndaqel demonstrated a significant reduction in the incidence of death and cardiovascular‑related hospitalizations in patients with transthyretin amyloidosis cardiomyopathy, a fatal disease for which no drug is presently marketed in Canada.

Submission Milestones: Vyndaqel

Submission MilestoneDate
Pre-submission meeting:2019-02-27
Request for priority status
Filed:2019-04-26
Approval issued by Director, Bureau of Medical Sciences:2019-05-28
Submission filed:2019-06-03
Screening
Screening Deficiency Notice issued:2019-06-28
Response filed:2019-07-12
Screening Acceptance Letter issued:2019-07-24
Review
Quality Evaluation complete:2020-01-09
Clinical/Medical Evaluation complete:2020-01-20
Biostatistics Evaluation complete:2020-01-17
Review of Risk Management Plan complete:2019-12-20
Labelling Review complete, including Look-alike Sound-alike brand name assessment:2020-01-15
Notice of Compliance issued by Director General, Therapeutic Products Directorate:2020-01-20

The Canadian regulatory decision on the review of Vyndaqel was based on a critical assessment of the data package submitted to Health Canada. The foreign reviews completed by the European Medicines Agency and the United States Food and Drug Administration were used as added references.

For additional information about the drug submission process, refer to the Management of Drug Submissions Guidance.

4 What follow-up measures will the company take?

Requirements for post‑market commitments are outlined in the Food and Drugs Act and Regulations.

5 What post-authorization activity has taken place for Vyndaqel?

Summary Basis of Decision documents (SBDs) for eligible drugs authorized after September 1, 2012 will include post‑authorization information in a table format. The Post-Authorization Activity Table (PAAT) will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. The PAAT will continue to be updated during the product life cycle.

At this time, no PAAT is available for Vyndaqel. When available, the PAAT will be incorporated into this SBD.

For the latest advisories, warnings and recalls for marketed products, see MedEffect Canada.

6 What other information is available about drugs?

Up to date information on drug products can be found at the following links:

7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical basis for decision

Clinical Pharmacology

Tafamidis meglumine, generally referred to as tafamidis throughout this Summary Basis of Decision, is the medicinal ingredient in Vyndaqel. As a selective stabilizer of transthyretin (TTR), tafamidis binds to TTR at the thyroxine binding sites, stabilizing the tetramer and slowing dissociation into monomers, the rate limiting step in the amyloidogenic process. The relationship between tafamidis concentration and stabilization of the TTR tetramer was characterized by using a population pharmacokinetic-pharmacodynamic analysis of pooled data from 11 clinical studies in which TTR stabilization was measured. The 80 mg dose of tafamidis meglumine is expected to reach the peak percentage stabilization of the TTR tetramer.

The major pharmacokinetic aspects of absorption, distribution, metabolism, and elimination of tafamidis have been well characterized in patients and healthy volunteers.

At a single dose of 400 mg, approximately 2.2 times the steady-state peak plasma concentration (Cmax) at the recommended dose of 80 mg, tafamidis does not prolong the corrected QT interval (QTc) to any clinically relevant extent. Tafamidis may decrease serum concentrations of total thyroxine, without an accompanying change in free thyroxine (T4) or thyroid stimulating hormone (TSH).

The Cmax for tafamidis is achieved within 4 hours. Exposure increased dose proportionally between 15 and 30 mg but increases were less than proportional from 30 to 60 mg. Tafamidis is highly protein bound (>99%) in plasma and the apparent steady-state volume of distribution is 16 L. The mean half-life of tafamidis is approximately 49 hours and the apparent oral clearance is 0.228 L/h. The degree of drug accumulation at steady-state after repeated tafamidis daily dosing is approximately 2.5-fold greater than that observed after a single dose.

Steady-state pharmacokinetic parameters in transthyretin amyloidosis cardiomyopathy (ATTR-CM) patients showed tafamidis clearance was affected by age and body weight. Over the range of 57.5 to 93 kg (corresponding to the 10th and 90th percentile of the observed body weights), the clearance changed from 0.85-fold to 1.14-fold relative to the median body weight. Clearance decreased by 14.5% in patients ≥65 years of age compared to younger patients. While there is no explicit evidence of biliary excretion of tafamidis in humans, non-clinical data suggests that tafamidis is metabolized by glucuronidation and excreted via the bile.

For patients with moderate hepatic impairment (Child-Pugh Class B), pharmacokinetic data indicated that systemic exposure decreased by approximately 40% and apparent oral clearance increased by approximately 68% compared to healthy volunteers. Transthyretin levels are lower in patients with moderate hepatic impairment compared to healthy volunteers. The exposure of tafamidis relative to the amount of TTR would therefore be sufficient for stabilization of the TTR tetramer in these patients. Exposure to tafamidis was similar between patients with mild hepatic impairment (Child-Pugh Class A) and healthy volunteers. The pharmacokinetics of tafamidis in patients with severe hepatic impairment (Child-Pugh Class C) is unknown.

Tafamidis has not been evaluated in patients with renal impairment. Limited data are available in patients with severe renal impairment (creatinine clearance ≤30 mL/min).

Tafamidis induces cytochrome P450 (CYP) 3A4 in vitro. A 20 mg dose of tafamidis did not affect the pharmacokinetics of midazolam, a CYP3A4 substrate, in healthy volunteers. However, the effect of 80 mg tafamidis has not been studied and may decrease exposure of CYP3A4 substrates (e.g., midazolam, triazolam). Based on in vitro studies, tafamidis inhibits breast cancer resistant protein (BCRP), both systemically and in the gastrointestinal tract, and may increase exposure of BCRP substrates (e.g., methotrexate, rosuvastatin, imatinib). Tafamidis has a potential to inhibit organic anion transporters (OAT) 1 and OAT3 (e.g., antiretroviral agents, diuretics, methotrexate, nonsteroidal anti-inflammatory drugs [NSAIDs], olmesartan, pravastatin) and may therefore decrease exposure of substrates of these transporters. Therefore, caution should be exercised when tafamidis is co-administered with CYP3A4 substrates, BCRP substrates, OAT1 substrates, or OAT3 substrates. Dose adjustment may be needed if Vyndaqel is administered concomitantly with these substrates.

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

Clinical Efficacy

The efficacy of Vyndaqel (tafamidis meglumine) for the treatment of adult patients with cardiomyopathy due to transthyretin-mediated amyloidosis (ATTR-CM), wild-type or hereditary, to reduce cardiovascular mortality and cardiovascular-related hospitalization was based on evidence from a sole pivotal trial known as B3461028.

The B3461028 trial was a Phase III, multicenter, international, double-blind, placebo-controlled, randomized trial in which 441 patients with hereditary or wild-type ATTR-CM were enrolled. Baseline demographics and disease characteristics were balanced across treatment arms. Patients were randomized to receive 20 mg Vyndaqel, 80 mg Vyndaqel, or placebo (88, 176, 177 patients, respectively) for 30 months. Patients were stratified at baseline by TTR gene status (wild-type or variant) and New York Heart Association (NYHA) classification. The NYHA classification, ranging from least severe (Class I) to most severe (Class IV), provides a simple way of classifying the extent of heart failure based on a patient's symptoms and limitations during physical activity.

Of the patients in the pooled Vyndaqel group and the placebo group, the mean age was 74.5 and 74.1 years, 91.3% and 88.7% were male, 9.1% and 7.3% were NYHA Class I (no limitation of physical activity), 61.4% and 57.1% were Class II (slight limitation of physical activity), and 29.5% and 35.6% were Class III (marked limitation of physical activity), respectively. Across groups, 76% of patients had wild-type ATTR and 24% had hereditary ATTR. There were no patients with severe hepatic impairment, and few patients with severe renal impairment. In the pooled Vyndaqel group, mean exposure duration was 24 months, with 69% of patients treated for ≥24 months. Overall, 170 patients receiving Vyndaqel and 84 patients receiving the placebo remained on treatment at Month 30.

The Vyndaqel 80 mg/day dose was emphasized in the trial design based on greater TTR stabilization observed at this dose compared to the 20 mg dose in pharmacokinetic studies. The sponsor hypothesized that the greater TTR stabilization at this dose might result in increased clinical efficacy; however, the clinical relevance of a higher TTR tetramer stabilization with respect to cardiovascular outcome is not known.

The primary efficacy endpoint was a Finkelstein-Schoenfeld analysis of the hierarchical combination of all-cause mortality and frequency of cardiovascular-related hospitalizations. In exploratory analyses, results were compared by dose, TTR genotype, and baseline NYHA classification (Classes I and II were combined).

Overall, all-cause mortality and cardiovascular-related hospitalizations were lower in the pooled Vyndaqel group than in the placebo group. The primary endpoint showed a statistically significant reduction in mortality with Vyndaqel after 18 months of treatment. All-cause mortality was 29.5% in the pooled Vyndaqel group and 42.9% in the placebo group, resulting in a 30% reduction compared to placebo. The difference in mortality between groups was attributable to cardiovascular-related mortality, which was 20.8% in the pooled Vyndaqel group and 33.3% in the placebo group. These findings were reflected in the approved indication found in the Vyndaqel Product Monograph. Of note, non-cardiovascular-related deaths were reported in 5.3% of the pooled Vyndaqel group compared to 4.7% in the placebo group.

Both the 20 mg and 80 mg doses of Vyndaqel appeared to be as effective; however, the trial was not powered to distinguish between doses. Hazard ratios for all-cause mortality were 0.72 (95% Confidence Interval [CI] 0.45, 1.14) and 0.69 (95% CI 0.49, 0.98) for 20 mg and 80 mg Vyndaqel relative to placebo, respectively. Relative risk ratios for cardiovascular-related hospitalization were 0.66 (95% CI 0.51, 0.86) and 0.70 (95% CI 0.57, 0.86) for 20 mg and 80 mg Vyndaqel, respectively.

Both key secondary endpoints (6-minute walk test and the Kansas City Cardiomyopathy Questionnaire-Overall Summary score) were met with a significant difference favouring the pooled Vyndaqel group vs the placebo group, observed by Month 6 and significant through to Month 30. Results were also comparable between doses on these key secondary endpoints.

Consistent with the overall study population, a reduction in combined all-cause mortality and cardiovascular-related hospitalization was seen with Vyndaqel treatment for NYHA Class I, II, and III patients, as well as individual reductions in all-cause mortality, cardiovascular mortality, and cardiovascular-related hospitalization. The only exception was an increased rate of cardiovascular-related hospitalizations in Class III patients, with 76.9% of Vyndaqel treated patients hospitalized compared to 58.7% of placebo patients. For Class III patients, the rate of cardiovascular-related deaths was 47.4% vs 49.2% for the pooled Vyndaqel and placebo treatment groups, respectively. In light of the consistent benefit seen across functional classes for all endpoints other than cardiovascular-related hospitalization, it was considered appropriate to include Class III patients along with Class I and II patients in the Vyndaqel indication. No NYHA Class IV patients were enrolled in the pivotal study.

Overall, the potential benefit of the 80 mg over 20 mg was suggested based on the post-hoc exploratory subgroup analyses which showed a greater reduction in the rate of increase in the cardiac biomarker N-terminal pro b-type natriuretic peptide (NT-proBNP) in the 80 mg group compared to the 20 mg group. The recommended dose of Vyndaqel is 80 mg tafamidis meglumine (administered as four 20 mg capsules) orally once daily.

Indication

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

  • Tafamidis is indicated for the treatment of transthyretin amyloidosis in adult patients with wild-type or hereditary cardiomyopathy to reduce all-cause mortality and cardiovascular-related hospitalization.

To ensure safe and effective use of the product, Health Canada approved the following indication:

  • Vyndaqel (tafamidis meglumine) is indicated for the treatment of adult patients with cardiomyopathy due to transthyretin-mediated amyloidosis, wild-type or hereditary, to reduce cardiovascular mortality and cardiovascular-related hospitalization.

The approved indication has been deemed by Health Canada to appropriately reflect the results of the B3461028 trial, where the difference in mortality between the Vyndaqel and placebo groups was attributable to cardiovascular-related mortality.

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

Clinical Safety

The primary source of safety data was the pivotal trial, B3461028, previously described in the Clinical Efficacy section. The safety profile was comparable across Vyndaqel and placebo treatment groups, and across doses.

During the B3461028 trial, treatment-related adverse events were reported in 45%, 39%, and 51% of patients in the 80 mg Vyndaqel, 20 mg Vyndaqel, and placebo groups, respectively. Treatment-related serious adverse events were reported in 2% of patients in each group.

Treatment-emergent adverse events with a higher incidence in the 80 mg and 20 mg treatment groups compared to placebo (≥2 times than the placebo group and reported by ≥4 patients) included cystitis (3.4%, 2.3% and 0%), sinusitis (5.7%, 5.7% and 0.6%), asthenia (10.2%, 12.5% and 6.2%), balance disorder (8.5%, 2.3% and 1.1%), and cataract (5.1%, 3.4% and 1.1%).

The most commonly reported Treatment-emergent Adverse Events (≥10%) in the 80 mg and/or 20 mg Vyndaqel groups that occurred at rates higher than placebo are as follows (80 mg, 20 mg and placebo, respectively): atrial fibrillation (19.9%, 18.2% and 18.6%), cardiac failure (26.1%, 34.1% and 33.9%), cardiac failure acute (13.6%, 4.5% and 9.6%), cardiac failure congestive (12.5%, 19.3% and 18.6%), asthenia (10.2%, 12.5% and 6.2%), edema peripheral (17.0%, 19.3% and 17.5%), bronchitis (11.9%, 10.2% and 10.7%), pneumonia (13.1%, 11.4% and 9.6%), fall (24.4%, 30.7% and 23.2%), muscle spasms (8.5%, 11.4% and 7.9%), pain in extremity (15.3%, 6.8% and 11.3%), insomnia (11.4%, 13.6% and 12.4%), hematuria (5.7%, 11.4% and 9.6%), cough (11.9%, 18.2% and 16.9%), and hypotension (10.8%, 13.6% and 10.7%).

The most frequently reported treatment-emergent serious adverse events in the 80 mg Vyndaqel, 20 mg Vyndaqel and placebo groups respectively were condition aggravated (22.7%, 23.9% and 32.8%); cardiac failure (19.3%, 18.2%, and 22.6%), cardiac failure congestive (11.9%, 15.9% and 17.5%), cardiac failure acute (13.1%, 4.5% and 9.6%), fall (5.1%, 5.7% and 2.8%), and syncope (3.4%, 0%, 5.6%).

The incidence of total thyroxine <0.8 times the lower limit of normal (LLN) was greater in the 80 mg group (29.7%) than in the 20 mg (12.3%) and placebo (4.5%) groups. Adverse events of hypothyroidism were reported in 6.8%, 5.7% and 5.6% of patients in the 80 mg, 20 mg and placebo groups, respectively. Low neutrophil count (<0.8 times the LLN) was more frequent with Vyndaqel treatment than with placebo (1.9% 80 mg Vyndaqel, 1.2% 20 mg Vyndaqel, 0.6% placebo). Elevated liver function tests were more frequent in the 80 mg group (3.4%) than in the 20 mg (2.3%) and placebo (1.1%) groups.

The safety of Vyndaqel is further supported by the results of trial B3461045, considered a supportive, ongoing Phase III multicenter, double‑blind 60‑month extension trial (later amended to open‑label) to evaluate the long‑term safety of 20 mg or 80 mg Vyndaqel (or tafamidis 61 mg as the free acid) in patients who completed the pivotal trial, B3461028. The B3461045 trial had a median follow‑up of six months, with some patients followed for as long as 12 months.

In the B3461045 trial, 88 patients were assigned to the 20 mg Vyndaqel group (B3461028: 60 were in the 20 mg Vyndaqel group and 28 in the placebo group) and 164 patients were assigned to the 80 mg Vyndaqel group (B3461028: 110 patients were in the 80 mg Vyndaqel group and 54 in the placebo group). The most common reasons for discontinuation in this extension trial were death (14 patients) and withdrawal (10 patients).

Based on animal (non‑clinical) data, tafamidis is associated with a potential risk of reproductive and developmental toxicity. Limited clinical data are available and a risk to children born to women exposed to tafamidis during pregnancy cannot be excluded. Vyndaqel should not be used during pregnancy and use is not recommended in nursing women. Vyndaqel has not been studied in patients with severe hepatic impairment and use is not recommended in these patients. No dosage adjustment is required for patients with mild or moderate hepatic impairment. Data are limited in patients with severe renal impairment. No dosage adjustment is required for patients with renal impairment. Vyndaqel is not recommended in organ transplant patients, as its efficacy and safety in this patient population have not been established. Vyndaqel is not indicated and should not be prescribed in the pediatric population.

Appropriate warnings and precautions are in place in the approved Vyndaqel Product Monograph to address the identified safety concerns. It is recommended to reduce the Vyndaqel dosage to 20 mg if 80 mg is not tolerated.

Overall, the benefit‑harm‑uncertainty profile of Vyndaqel is considered favorable for the treatment of transthyretin amyloidosis in adult patients with wild‑type or hereditary cardiomyopathy to reduce cardiovascular mortality and cardiovascular‑related hospitalization.

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

7.2 Non-Clinical Basis for Decision

Key non‑clinical findings demonstrated that tafamidis binds selectively to two thyroxine-binding sites of the tetramer, which in turn kinetically stabilizes TTR. It is suggested that TTR stabilization inhibits tetramer dissociation and formation of amyloidogenic intermediates, the rate‑limiting step of TTR amyloidogenesis. Thus, the pharmacodynamic marker used in the non‑clinical program was TTR stabilization. Tafamidis demonstrated TTR stabilization of 40 amyloidogenic TTR genotypes.

The safety pharmacology program revealed that tafamidis meglumine was unlikely to cause biologically significant undesirable effects on the cardiovascular, respiratory, or central nervous systems at clinical doses.

The pharmacokinetic profile of tafamidis in mice, rats, dogs and rabbits demonstrated that tafamidis is a well‑permeable compound with complete absorption and high oral bioavailability in rats and in dogs. After oral administration in dogs, the maximum plasma concentration was achieved within 2‑5 hours depending on the dose. Tafamidis is highly protein bound (97.1% in mice, 99.0% in rats, 99.1% in dogs and 99.2% in humans) in plasma. Based on non‑clinical data, it is suggested that tafamidis is metabolized by glucuronidation with a slow elimination rate and excreted via the bile. The predominant route of elimination of tafamidis was feces.

With respect to general toxicology and carcinogenicity, although there was no evidence of neoplasia, the liver and kidney were target organs for toxicity in the different species tested. Liver effects were observed at exposures approximately ≥0.7 times the human exposure at the dose of 80 mg tafamidis meglumine (the recommended dose of Vyndaqel). Tafamidis meglumine did not show any evidence of genotoxic activity in the in vivo rat micronucleus study at the highest tested dose of 100 mg/kg as well as when tested in vitro for induction of chromosomal damage.

Evidence of developmental toxicity was found in rats and rabbits. In rabbits, embryo‑fetal mortality and an increased incidence of malformations were observed at doses approximately nine times the human exposure of 80 mg tafamidis meglumine. Increased incidence of fetal skeletal variations was observed at doses approximately equivalent to the human exposure of 80 mg tafamidis meglumine. In rats, decreased pup survival and reduced pup weights were observed at doses approximately ≥3.4 times the human equivalent dose of 80 mg tafamidis meglumine. In males, the decrease in pup weights was associated with delayed sexual maturation (preputial separation). Impairment was also observed in a water maze test for learning and memory. In pregnant rats, radiolabelled tafamidis was present in fetal tissues and secreted in the milk of lactating rats indicating placental and milk transfer of the test compound.

In light of these safety concerns, Vyndaqel is not recommended during pregnancy and breast feeding. A contraindication in pregnancy would be warranted if the drug was intended for use in women of child bearing age. However, in this current submission, Vyndaqel is indicated for patients with ATTR‑CM with an average age of 75 years and a male predominance.

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

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

7.3 Quality Basis for Decision

The Chemistry and Manufacturing information submitted for Vyndaqel has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes. Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review. Based on the stability data submitted, the proposed shelf life of 24 months is acceptable when the drug product is stored at room temperature (15ºC to 25ºC).

Proposed limits of drug‑related impurities are considered adequately qualified (i.e. within International Council for Harmonisation [ICH] limits and/or qualified from toxicological studies).

All sites involved in production are compliant with Good Manufacturing Practices.

All non‑medicinal ingredients (described earlier) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations.

Two excipients are of animal origin. Gelatin is used in the capsule shell. Letters of attestation confirming that the materials are not from a bovine spongiform encephalopathy and transmissible spongiform encephalopathy (BSE/TSE) affected country/area have been provided for this product indicating that it is considered to be safe for human use. Purple Opacode Ink contains an ingredient (carmine) that is derived from insects; however, insects are not implicated in BSE/TSE.

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