Summary Basis of Decision for Tegsedi

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 Tegsedi is located below.

Recent Activity for Tegsedi

SBDs written for eligible drugs (as outlined in Frequently Asked Questions: Summary Basis of Decision [SBD] Project: Phase II) 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. The PAATs will be updated regularly with post-authorization activity throughout the product life cycle.

Post-Authorization Activity Table (PAAT) for Tegsedi

Updated: 2025-03-26

The following table describes post-authorization activity for Tegsedi, a product which contains the medicinal ingredient inotersen (supplied as inotersen sodium). For more information on the type of information found in PAATs, please refer to the Frequently Asked Questions: Summary Basis of Decision (SBD) Project: Phase II and to the List of abbreviations found in Post-Authorization Activity Tables (PAATs).

For additional information about the drug submission process, refer to the Guidance Document: The Management of Drug Submissions and Applications.

Drug Identification Number (DIN):

  • DIN 02481383 - 284 mg/1.5 mL inotersen, solution, subcutaneous administration

Post-Authorization Activity Table (PAAT)

Activity/submission type, control number Date submitted Decision and date Summary of activities
DIN 02481383 cancelled (post market) Not applicable Discontinuation date 2024-10-24 The manufacturer notified Health Canada that sale of the drug has been discontinued post market. Health Canada cancelled the DIN pursuant to section C.01.014.6(1)(a) of the Food and Drug Regulations.
SNDS # 284567 2024-03-08 Issued NOC 2024-09-25 Submission filed as a Level II – Supplement (Safety) to update the PM with new safety information. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Serious Warnings and Precautions Box, Warnings and Precautions, Adverse Reactions, and Dosage and Administration sections of the PM. Corresponding changes were made to Part III: Patient Medication Information and to the package insert. An NOC was issued.
SNDS # 256844 2021-09-22 Issued NOC 2022-03-02 Submission filed as Level II – Supplement (Safety) to update the PM with new safety information. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Warnings and Precautions and Adverse Reactions sections of the PM, and corresponding changes were made to Part III: Patient Medication Information. An NOC was issued.
NC # 234581 2020-01-02 Issued NOL
2020-06-22		 Submission filed as a Level II (90 day) Notifiable Change to update the PM with new safety information. As a result of the NC, modifications were made to the Warnings and Precautions and Clinical Trials sections of the PM. Corresponding changes were made to the PM Part III: Consumer Information/Patient Medication Information. The submission was reviewed and considered acceptable, and an NOL was issued.
Drug product (DIN 02481383) market notification Not applicable Date of first sale 2019-01-07 The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
NDS # 214274 2018-03-07 Issued NOC
2018-10-03		 Notice of Compliance issued for New Drug Submission.
Summary Basis of Decision (SBD) for Tegsedi

Date SBD issued: 2019-03-11

The following information relates to the New Drug Submission for Tegsedi.

Inotersen (supplied as inotersen sodium)
284 mg/1.5 mL, solution, subcutaneous

Drug Identification Number (DIN):

  • 02481383

Akcea Therapeutics, Inc.

New Drug Submission Control Number: 214274

 

On October 3, 2018, Health Canada issued a Notice of Compliance to Akcea Therapeutics, Inc. for the drug product Tegsedi.

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 Tegsedi is favourable for the treatment of stage 1 or stage 2 polyneuropathy in adult patients with hereditary transthyretin amyloidosis (hATTR).

1 What was approved?

 

Tegsedi, an antisense oligonucleotide, was authorized for the treatment of stage 1 or stage 2 polyneuropathy in adult patients with hereditary transthyretin amyloidosis (hATTR).

No data are available to Health Canada regarding the use of Tegsedi in patients younger than 18 years of age. Therefore, an indication for pediatric use has not been authorized.

Evidence from the pivotal clinical study suggests that use of Tegsedi in the geriatric population (patients aged 65 years and over) is not associated with major differences in safety or efficacy in comparison to younger patients. However, caution should be exercised in these patients, especially with respect to thrombocytopenia.

Tegsedi is contraindicated in patients who are hypersensitive to inotersen or to any ingredient in the formulation, including any non-medicinal ingredient or component of the container. Tegsedi is also contraindicated in patients that have any of the following before the start of treatment:

  • a platelet count below 100×109/L
  • urine protein to creatinine ratio (UPCR) ≥113 mg/mmol (1 g/g)
  • an estimated glomerular filtration rate (eGFR) <45 ml/min/1.73m2
  • severe liver impairment

Tegsedi 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.

Tegsedi (284 mg/1.5 mL inotersen, supplied as 300 mg inotersen sodium) is presented as a solution for subcutaneous injection. In addition to the medicinal ingredient, the solution contains hydrochloric acid, sodium hydroxide, and water for injection. Tegsedi is provided in a single-dose, prefilled syringe with a safety syringe device.

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 Tegsedi Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

2 Why was Tegsedi approved?

 

Health Canada considers that the benefit-harm-uncertainty profile of Tegsedi is favourable for the treatment of stage 1 or stage 2 polyneuropathy in adult patients with hereditary transthyretin amyloidosis (hATTR).

Hereditary transthyretin amyloidosis, also known as familial amyloidotic polyneuropathy (TTR-FAP), is a progressive, fatal disease related to mutations in the transthyretin (TTR) protein. These proteins usually assemble into a tetramer. The mutations that cause hATTR prevent the proteins from folding into the correct conformation, which destabilizes the tetramer. The misfolded proteins then accumulate as amyloid fibrils in many tissues and organs. This causes cellular degeneration and death, ultimately resulting in organ dysfunction.

Hereditary transthyretin amyloidosis is a rare disease with an estimated prevalence of 10,000 patients worldwide. There are several known mutations of the TTR protein associated with amyloidosis, of which Val30Met is the most common.

Historically, hATTR has been phenotypically divided into hATTR with polyneuropathy (hATTR-PN) and hATTR with cardiomyopathy (hATTR-CM). Some mutations have been predominantly associated with one phenotype. For example, Val30Met is associated mainly with polyneuropathy, while other mutations are more strongly associated with cardiomyopathy. However, patients usually develop multiple organ dysfunctions simultaneously and present with a wide spectrum of clinical manifestations.

The age of onset of symptoms varies widely, from early onset in the third or fourth decade to late onset in the sixth to eighth decade. Life expectancy after diagnosis is three to 15 years. The ultimate cause of death is typically cachexia, heart disease or kidney disease.

There are no medications currently approved for the treatment of hATTR in Canada. Since the liver is the main producer of TTR, liver transplant is the best treatment available at this time. However, it is associated with better outcomes in early phases of the disease in younger patients. Additionally, the wild type (normal) TTR produced by the transplanted liver can continue to contribute to the amyloid fibrils.

Inotersen, the medicinal ingredient in Tegsedi, is an antisense oligonucleotide (ASO) complementary to the molecular target TTR messenger RNA (mRNA). The selective binding of Tegsedi to the TTR mRNA causes the degradation of both mutant and wild type (normal) TTR mRNA.

For the clinical studies conducted with Tegsedi and included in this submission, the sponsor used a three-stage classification system based on the mobility of patients:

  • In stage 1, patients present with weaknesses in the lower limbs and do not require assistance with ambulation.
  • In stage 2, patients show gait dysfunctions, distal amyotrophies and hand involvement, and depend on assistance with ambulation.
  • In Stage 3, patients are either wheelchair-bound or bedridden with generalized weakness and areflexia.

The market authorization was based primarily on the outcomes of one pivotal trial, NEURO-TTR, which demonstrated the safety and efficacy of Tegsedi in treating the symptoms of stage 1 or 2 polyneuropathy in adult patients with hATTR. This was a randomized, double-blind, Phase II/III trial in 172 hATTR patients with stage 1 or 2 polyneuropathy, and who had a Neuropathy Impairment Scale (NIS) composite score between 10 and 130. Patients were randomized in a 2:1 ratio to receive weekly treatment with either Tegsedi (n = 112) or a placebo (n = 60), and were monitored for 15 months. Patients treated with Tegsedi received a 284 mg dose three times during the first week of the trial, and then once per week until the end of the trial. Patients in the placebo group followed the same administration schedule.

The primary endpoints used to evaluate efficacy in this trial were the changes in patients' scores in two assessments, from study initiation to week 66:

  • The modified NIS+7 (mNIS+7) composite score, which consists of the NIS composite score and the modified SUM7 Test (+7) composite score, additionally modified to include a greater sensory component and assesses both large and small nerve fiber function. These measure the extent of impairment due to neuropathy.
  • The Norfolk Quality of Life-Diabetic Neuropathy (QoL-DN) questionnaire, which is a patient-reported assessment of quality of life in relation to symptoms of neuropathy.

Both scores were also assessed at week 35. The two endpoints were analyzed hierarchically, starting with the mNIS+7 results. If the difference in mNIS+7 composite score between the two time points met the criteria for statistical significance (p≤0.05), the QoL-DN scores were analyzed. Statistically significant improvements were observed at week 35 and week 66 in both assessments.

The effects of Tegsedi on certain cardiac parameters were studied as a secondary objective, as approximately 40% of NEURO-TTR patients were also diagnosed with hATTR-CM at entry. However, the results did not demonstrate consistent differences in efficacy between Tegsedi and the placebo in treating the symptoms of cardiomyopathy.

Thrombocytopenia, glomerulonephritis, and ocular toxicity related to vitamin A deficiency were identified as adverse events of special interest. Instructions on safe use and risk minimization in connection with thrombocytopenia and glomerulonephritis are included in the Tegsedi Product Monograph. Safety information related to vitamin A deficiency has also been included.

In NEURO-TTR, 35 cases of thrombocytopenia were experienced by 27 patients receiving Tegsedi. One of these cases was associated with intracranial haemorrhage, which caused the death of a patient. The trial protocol was changed to monitor platelet levels weekly and to allow for dose reduction at the discretion of the investigator. Doses could be reduced more than once if necessary.

Renal issues are considered adverse events of special interest, as they have been associated with treatment with antisense oligonucleotides. Severe and serious renal impairment were observed more often in patients treated with Tegsedi than in patients in the placebo group. Glomerulonephritis was detected in four NEURO-TTR patients, and led to the withdrawal of two patients. Close monitoring is recommended to detect signs of renal impairment as soon as possible.

Relevant contraindications have been specified in the Tegsedi Product Monograph. In addition, the risks of thrombocytopenia and glomerulonephritis are specifically addressed in a Serious Warnings and Precautions box. Monitoring and dose reduction recommendations have also been included in the Product Monograph.

Ocular toxicity due to vitamin A deficiency is considered a risk, because Tegsedi reduces TTR levels, which in turn can reduce vitamin A levels and cause ocular damage. Although signs of increased ocular toxicity were not observed in NEURO-TTR, decreased levels of vitamin A were detected. Patients were therefore given vitamin A supplements (3,000 IU/day). However, as overly high or low vitamin A levels can affect fetal development, precautions should be taken during pregnancy. Recommendations for monitoring, supplementation, and pregnancy-related precautions are included in the Product Monograph.

Liver abnormalities were detected in a higher percentage of patients receiving Tegsedi (12.5%) than patients in the placebo group (6.7%). Although inotersen accumulates in the liver, Tegsedi was not associated with hepatotoxicity in clinical or non-clinical studies. Monitoring for hepatic impairment is advised in the Product Monograph, and Tegsedi is contraindicated in patients with severe liver impairment.

A Risk Management Plan (RMP) for Tegsedi was submitted by Akcea Therapeutics, Inc. to Health Canada, and was considered acceptable upon review. The RMP 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, package insert and Patient Medication Information section of the Tegsedi 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 Tegsedi was accepted.

Tegsedi 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 Tegsedi 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 Tegsedi?

 

The drug submission for Tegsedi was reviewed under the Priority Review Policy. At the time of the request for Priority Review, there were no drugs authorized for the treatment of hereditary transthyretin amyloidosis (hATTR) in Canada, and sufficient evidence was provided to demonstrate the efficacy of Tegsedi.

 

Submission Milestones: Tegsedi

Submission Milestone Date
Pre-submission meeting: 2018-02-14
Request for priority status  
Filed: 2018-01-19
Approval issued by Director, Bureau of Medical Sciences: 2018-02-21
Submission filed: 2018-03-07
Screening  
Screening Acceptance Letter issued: 2018-04-06
Review  
Quality Evaluation complete: 2018-10-02
Clinical Evaluation complete: 2018-10-02
Biostatistics Evaluation complete: 2018-10-03
Review of Risk Management Plan complete: 2018-09-21
Labelling Review complete, including Look-alike Sound-alike brand name assessment: 2018-10-02
Notice of Compliance issued by Director General, Therapeutic Products Directorate: 2018-10-03

 

The Canadian regulatory decision on the quality, non-clinical and clinical review of Tegsedi was based on a critical assessment of the data package submitted to Health Canada. Review reports from the European Medicines Agency (EMA) were consulted during the review of Tegsedi for relevant supplementary information.

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. In addition to these commitments, the sponsor has agreed to implement a patient registry to monitor long-term effects of treatment with Tegsedi. The registry data are also expected to contribute to the existing knowledge of the risks associated with Tegsedi and the effectiveness of the current risk minimization strategies. A long-term, open-label trial is also in progress to further develop the safety profile of Tegsedi.

The sponsor has additionally committed to distributing educational materials to healthcare professionals, patients, and caregivers regarding the risks of thrombocytopenia, glomerulonephritis, and ocular toxicity due to vitamin A deficiency. Patient alert cards will be made available as well.

 

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

 

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's life cycle.

The PAAT for Tegsedi is found above.

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

Hereditary transthyretin amyloidosis (hATTR) is caused by mutations in the gene that encodes the protein transthyretin (TTR). To carry out their function as protein transporters, four TTR proteins assemble to form a tetramer. Mutations in the gene are translated into the protein sequence. This prevents the proteins from folding into the correct structure and compromises their ability to form stable tetramers. The misfolded proteins aggregate and form amyloid fibrils that are deposited in various organs and tissues, including the peripheral neurons, the gastrointestinal tract, and the heart. This promotes the development of lesions, leading to organ damage and failure.

Inotersen, the medicinal ingredient in Tegsedi, is an antisense oligonucleotide. Its sequence is complementary to the TTR messenger RNA (mRNA), from which the TTR protein is translated. The complementarity of the sequence allows inotersen to bind to both mutant and wild type (normal) TTR mRNA, which promotes the degradation of the TTR mRNA. The synthesis of TTR is thereby inhibited, reducing the level of mutated and wild type TTR in the body that could potentially form amyloid fibrils.

The major pharmacokinetic aspects of absorption, distribution, metabolism, and elimination of Tegsedi are well-characterized in patients and healthy volunteers. Overall, the pharmacokinetic data support the use of Tegsedi for the approved indication.

The efficacy of Tegsedi in reducing TTR mRNA levels was initially observed in non-clinical studies. Considerable decreases in TTR mRNA levels were seen in human and cynomolgus monkey hepatocytes in vitro. Reductions in TTR mRNA and protein levels were measured in transgenic mice carrying human TTR, as well as in cynomolgus monkeys. These results were later shown to be predictive of efficacy in treating patients with hATTR.

Thrombocytopenia was first identified as a safety concern in a non-clinical study in monkeys. This was later confirmed in clinical trials. Other important properties of inotersen were also identified in non-clinical studies, and not investigated further in clinical trials. Inotersen does not readily cross the blood-brain barrier or the placental barrier, and is not readily transferred into breast milk.

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

Clinical Efficacy

The efficacy of Tegsedi was mainly established in the pivotal clinical trial, NEURO-TTR. This was a double-blind, placebo-controlled Phase III trial in 172 adult hATTR patients with polyneuropathy (hATTR-PN). All patients included in the trial had stage 1 or 2 polyneuropathy, and a Neuropathy Impairment Scale (NIS) composite score of 10 to 130. Patients were randomized in a 2:1 ratio to receive either Tegsedi or a placebo. Both were administered subcutaneously, three times in the first week and then once weekly from weeks 2 to 65.

The primary endpoints used to evaluate efficacy in this trial were the changes in patients' scores in two assessments, from study initiation to week 66:

  • The modified NIS+7 (mNIS+7) composite score, which consists of the NIS composite score and the modified SUM7 Test (+7) composite score, additionally modified to include a greater sensory component and assesses both large and small nerve fiber function. These measure the extent of impairment due to neuropathy.
  • The Norfolk Quality of Life-Diabetic Neuropathy (QoL-DN) questionnaire, which is a patient-reported assessment of quality of life in relation to symptoms of neuropathy.

Together, these enabled monitoring of the effects of Tegsedi on the progression of neuropathy due to hATTR.

The change in both scores was also evaluated at week 35. The two scores were analyzed hierarchically. The difference in the mNIS+7 score was calculated first. If it was statistically significant (p≤0.05), then the difference in the QoL-DN score was calculated. Statistically significant differences for both tests were apparent at week 35. The differences in least squares means (LSMs) between treatment groups were -8.69 for the mNIS+7 (p = 0.0005), and -6.14 for the QoL-DN score (p = 0.032). At week 66, statistically significant differences were again observed for both primary endpoints, indicating that treatment with Tegsedi hinders the progression of neuropathy and enhances the patients' quality of life. The differences in LSMs between treatment groups were -19.73 for the mNIS+7 score (p = 0.00000004), and -11.68 for the QoL-DN score (p = 0.0006). Thirteen sensitivity analyses were conducted, all of which were consistent with the results from the primary analysis. The results from one of these sensitivity analyses were retained and included in the labelling (analysis number 6 - multiple imputation assuming jump to reference) as it addresses the uneven sizes of the two treatment groups.

Indication

Sponsor's proposed indication Health Canada-approved indication
Tegsedi (inotersen solution for subcutaneous injection) is indicated for the treatment of patients with hereditary transthyretin amyloidosis with symptoms of polyneuropathy to delay disease progression and improve quality of life. Tegsedi (inotersen solution for subcutaneous injection) is indicated for the treatment of stage 1 or stage 2 polyneuropathy in adult patients with hereditary transthyretin amyloidosis (hATTR).

The indication of Tegsedi was limited to treatment of stage 1 or stage 2 polyneuropathy in hATTR-PN patients, as its efficacy in connection with cardiomyopathy and stage 3 polyneuropathy could not be established in clinical trials.

Some secondary endpoints were included in the trial design to examine the effects of Tegsedi on cardiomyopathy. Forty percent (40%) of NEURO-TTR patients had hATTR with cardiomyopathy (hATTR-CM) in addition to polyneuropathy. However, the results did not consistently show differences in efficacy between Tegsedi and the placebo.

Additionally, all patients had either stage 1 or 2 polyneuropathy at the beginning of the study, and six patients receiving the placebo progressed to stage 3 during the course of treatment. They were switched to Tegsedi treatment in the CS3 clinical trial (an extension of NEURO-TTR), which was ongoing at the time of review. Conclusions could not be made regarding the efficacy of Tegsedi in patients with stage 3 polyneuropathy.

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

Clinical Safety

The safety of Tegsedi was demonstrated primarily in the pivotal clinical trial, NEURO-TTR. A total of 112 adult patients with polyneuropathy caused by hATTR received Tegsedi in this study, and 60 patients received a placebo. The study design and results are described in the Clinical Efficacy section.

The three adverse events of special interest associated with Tegsedi are thrombocytopenia, glomerulonephritis, and ocular toxicity related to vitamin A deficiency.

Reductions in platelet count may lead to thrombocytopenia, and were observed at various levels of severity in patients receiving Tegsedi. Platelet counts dropped below the normal level (140×109/L) in 54% of Tegsedi-treated patients, and in 13% of patients receiving the placebo. A platelet reduction to below 100×109/L was observed in 23% of patients receiving Tegsedi, and 2% of patients receiving the placebo. Levels below 75×109/L were detected in 10.7% of patients receiving Tegsedi. Three patients (3%) receiving Tegsedi developed sudden severe thrombocytopenia (platelet counts below 25×109/L), which led to a fatal intracranial haemorrhage in one of these patients. The protocol was changed during the course of the trial to increase monitoring of platelet count and to allow for dose reductions as necessary. Accordingly, Tegsedi is contraindicated in patients with a platelet count below 100×109/L, and the risk of thrombocytopenia has been highlighted in a Serious Warnings and Precautions box of the Tegsedi Product Monograph. In addition, the Product Monograph provides recommendations for monitoring platelet count and for dose adjustment in case of thrombocytopenia.

Renal impairment was also more frequently reported among Tegsedi-treated patients, and has been associated with other antisense oligonucleotides. Adverse events related to renal impairment were observed in 20.5% of patients receiving Tegsedi, and in 10% of the placebo-treated patients. Severe and serious renal adverse events were also more often detected in patients receiving Tegsedi than in patients receiving the placebo. In the pivotal trial, four patients experienced glomerulonephritis, and two of these patients consequently withdrew from the trial. Safety information regarding glomerulonephritis was outlined in the Serious Warnings and Precautions box of the Product Monograph. In addition, relevant contraindications have been included in the Tegsedi Product Monograph.

Ocular toxicity related to vitamin A deficiency was considered an adverse event of special interest, because treatment with Tegsedi can reduce plasma levels of vitamin A. Tegsedi reduces the level of TTR, which is a carrier protein for retinol-binding protein 4 (RBP4). RBP4 is the principal carrier of vitamin A. As TTR levels decrease in response to Tegsedi, vitamin A levels are consequently expected to decrease. Although there was no evidence of increased ocular toxicity during the trial, decreased levels of vitamin A were detected. Patients were given the recommended daily allowance of vitamin A supplements (3,000 IU) to address this issue. Adverse events could not be associated with vitamin A supplementation in patients receiving the placebo, who would not be expected to have decreased vitamin A levels. However, as vitamin A levels outside the normal range can affect fetal development, precautions should be taken during pregnancy. Guidelines for monitoring, supplementation, and pregnancy-related precautions are included in the Product Monograph.

Nearly all patients in the NEURO-TTR trial experienced at least one adverse event. Withdrawals from the trial and pauses in treatment were more common among patients receiving Tegsedi than among patients in the placebo group. The majority of withdrawals were due to adverse events, and one third of these were associated with either thrombocytopenia or glomerulonephritis. Additionally, a higher percentage of patients treated with Tegsedi experienced serious adverse events than patients in the placebo group.

Liver abnormalities were observed in a larger proportion of patients receiving Tegsedi (12.5%) than patients receiving the placebo (6.7%). Although inotersen accumulates in the liver, the clinical and non-clinical data indicate that Tegsedi is not associated with hepatotoxicity. Monitoring for hepatic impairment is recommended in the Product Monograph and the use of Tegsedi is contraindicated in patients with severe liver impairment.

Five patients died during this study; all of whom had received Tegsedi. One of these deaths, due to intracranial haemorrhage following severe thrombocytopenia, was determined to be treatment-related. The deaths of the other four patients were caused by disease progression or complications of the underlying disease.

Following the review of NEURO-TTR data, it was unclear whether the three loading doses administered in the first week were needed for efficacy. They may also be associated with reduced safety. The recommended dosage frequency was therefore set to once weekly, starting from the first week of treatment.

The long-term safety of Tegsedi is being evaluated in an ongoing clinical study, CS3. This study is an open-label extension of NEURO-TTR, and is planned to continue for five years. The majority of patients from both treatment groups in NEURO-TTR continued to participate in CS3, where patients from the placebo group were switched to treatment with Tegsedi. Although the long-term safety of Tegsedi remains unclear and conclusions could not be made from the CS3 study at the time of authorization, the data suggest that efficacy is maintained.

Health Canada has determined that appropriate risk management measures are in place to address the safety concerns identified for Tegsedi, and to ensure its safe and effective use in the target patient population. Overall, the risk-benefit profile of Tegsedi is favourable. For more information, refer to the Tegsedi Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

 

 

7.2 Non-Clinical Basis for Decision

 

Substantial reductions in transthyretin (TTR) messenger RNA (mRNA) levels were observed in vivo in both human and cynomolgus monkey hepatocytes in response to Tegsedi. The results of in vivo studies in transgenic mice carrying human TTR and in cynomolgus monkeys were consistent with these findings. In these animals, subcutaneous administration of inotersen led to considerable reductions in both mutant and wild type (normal) TTR mRNA levels in the liver, as well as reduced TTR protein levels in plasma. These outcomes were predictive of the efficacy of Tegsedi in treating symptoms in patients with hereditary transthyretin amyloidosis (hATTR).

In safety pharmacology studies, no concerns were detected with respect to effects of Tegsedi on the cardiovascular, respiratory, and central nervous systems.

Pharmacokinetic studies in mice, rats, and monkeys, showed that maximum plasma concentration (Cmax) of inotersen, the medicinal ingredient in Tegsedi, was attained between 0.5 and 2 hours after subcutaneous administration. Inotersen was rapidly distributed into various organs, with the highest concentrations detected in the kidneys, followed by the liver. Inotersen was also distributed to the mesenteric lymph nodes, bone marrow, thyroid, spleen, bones, and pancreas. Notably, it does not readily cross the blood-brain barrier. Metabolism of inotersen was primarily through nuclease activity. Elimination from the tissues, either as inotersen, or as a result of mainly nuclease-mediated metabolism was slow. Very little inotersen was present in the urine or feces. Once formed, the shortened oligonucleotide metabolites were rapidly eliminated mainly in urine and feces, with minimal amounts detected in plasma and tissues.

Inotersen is not readily transported to the embryo or fetus. No measurable quantities of inotersen were detected in the fetal liver of rabbits and mice in embryo-fetal development studies. It is also unlikely to be transferred through breast milk. Inotersen levels in mouse breast milk were lower than 0.2% of the maternal liver concentrations, and inotersen was shown to have poor oral bioavailability.

In vitro studies in human hepatocytes indicated that inotersen is not a substrate or an inhibitor of major human transporters or the cytochrome P450 (CYP 450) enzymes. Therefore, the potential for drug-drug interactions between inotersen and substrates or inhibitors of transporters, or between inotersen and CYP 450 enzymes is considered low.

Signs of oligonucleotide accumulation were observed in various tissues and at all dose levels in repeat-dose toxicology studies in mice, rats, and cynomolgus monkeys. This is also expected to occur in patients. The presence of oligonucleotides was not associated with adverse events, except at the highest doses tested in rats (15 and 40 mg/kg/week in a 26-week study) and monkeys (40 mg/kg/week in a 13-week study). Renal toxicity was observed at the highest doses administered, consistent with the highest concentrations of inotersen detected in the kidneys. Inflammation also occurred in the affected tissues, and is an anticipated class effect of oligonucleotides containing 2'-O-(2-methoxyethyl) (2'-MOE) ribonucleotides, such as inotersen.

Thrombocytopenia was initially identified as a major safety concern during non-clinical development (and was later confirmed in clinical trials). Platelet counts were considerably reduced at all dose levels in a 39-week study in monkeys. Signs of irregular or prolonged bleeding, such as bruising and petechia, were observed at the two highest dose levels (10 and 20 mg/kg/week). It was not feasible to continue the study, and the animals were euthanized. The mechanism by which the platelet counts decreased in monkeys is unclear, but is attributed to increased clearance as no evidence of bone marrow toxicity was observed. This safety concern can be mitigated to a certain degree, as the reduced platelet counts were reversible and this issue can be monitored relatively easily in patients. A dose-dependent increase in the d-dimer level, which is an indicator of blood clot degeneration, was also detected in this study. The significance of this observation is unclear, as fibrinogen concentration was not affected and there were no signs of clotting disorders.

Inotersen was not shown to be genotoxic in the standard battery of tests. Additionally, transgenic mice did not show signs of carcinogenicity in a six-month study.

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

For more information, refer to the Tegsedi 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 Tegsedi 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 eighteen months when stored at 2°C to 8 °C, with up to six weeks at 2°C to 30 °C, is acceptable when the drug product is stored in its original container.

Proposed limits of drug-related impurities are considered adequately qualified from toxicological studies.

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

All non-medicinal ingredients found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. None of the excipients used in the formulation of Tegsedi are of human or animal origin.

 

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