Regulatory Decision Summary for Tegsedi

Review decision

The Regulatory Decision Summary explains Health Canada’s decision for the product seeking market authorization. The Regulatory Decision Summary includes the purpose of the submission and the reason for the decision.

Product type:


Medicinal ingredient(s):

inotersen sodium

Therapeutic area:

Other Nervous System Drugs

Type of submission:

Priority New Drug Submission (New Active Substance)

Control number:

What was the purpose of this submission?


This New Drug Submission is seeking marketing authorisation for Tegsedi (inotersen) for the treatment of patients with hereditary transthyretin amyloidosis with symptoms of polyneuropathy to delay disease progression and improve quality of life.

Following review by Health Canada, the approved indication was the treatment of symptoms of stage 1 or stage 2 polyneuropathy in adult patients with hereditary transthyretin amyloidosis (hATTR).


Why was the decision issued?


Hereditary Transthyretin Amyloidosis is a rare and fatal disease for which there is no current treatment in Canada other than liver transplantation.

This New Drug Submission presented the results from a pivotal phase 2/3 study along with a phase 1dose finding/pharmaco-kinetics/pharmacodynamics study and an ongoing long-term open-label extension to the pivotal study. These studies aimed to demonstrate efficacy of Tegsedi treatment in slowing the progression of polyneuropathy in hereditary transthyretin amyloidosis (hATTR) patients.

Efficacy of inotersen was demonstrated in the pivotal study (CS2), a 15 month, multicenter, randomized, double-blind, placebo-controlled study of hATTR patients with neuropathy at stage 1 or stage 2 and a Neuropathy Impairment Score (NIS) between 10 and 130.

The efficacy was evaluated by two primary outcomes that tested the progression of neuropathy as assessed by a modified Neuropathy Impairment Score (mNIS+7) and the Norfolk Quality of Life Diabetic Neuropathy questionnaire (QoL-DN). The primary endpoints were changes in mNIS+7 and QoL-DN scores from baseline to week 66. One hundred seventy-three patients were randomized, 172 received at least one dose, 112 of those were dosed with inotersen and 60 received placebo. Both primary endpoints demonstrated statistically significant differences from baseline at week 35, as well as at week 66.

A number of patients (~40%) with a diagnosis of hATTR-CM (cardiomyopathy) at entry, (more advanced heart disease than permitted by the CS2 inclusion/exclusion criteria) were included in an ECHO-CM subgroup to assess the effects of inotersen on certain cardiac parameters as a secondary objective which failed to consistently show differences from placebo.

The safety assessment of inotersen was based on patients in the CS2 study. The safety dataset for CS2 includes 112 patients exposed to inotersen and 60 patients in the placebo group.

Serious safety concerns were reported but mitigation of risks was possible with monitoring and labelling. Cases of low platelet counts and thrombocytopenia, including a case of fatal intracranial hemorrhage were reported. Based on the profile of platelet counts of the patients in the pivotal study, a monitoring scheme with dosage recommendations were included in the label. Glomerulonephritis and kidney renal function decline were also reported. Monitoring and dosage recommendations were included in the label. Due to the role of transthyretin in retinol transport, low levels of vitamin A were expected and reported. No ocular adverse event increases were noted. Vitamin A supplementation recommendation was included in the label along with statements regarding possible ocular consequences of low vitamin A. Statements regarding the role of vitamin A in fetal development were also included with recommendations on pregnancy.

In order to better characterize the risk associated with Tegsedi a long-term safety study is ongoing (most patients in CS2 continued onto the open label CS3 study) and a patient registry will be put in place. Educational materials will be made available to Health Care Providers and Alert cards to patients to highlight the risk mitigation measures for thrombocytopenia, glomerulonephritis and ocular toxicity to vitamin A deficiency.

Based on the results from the pivotal study and the measures put in place to mitigate the risks, the benefit-harm-uncertainty profile of Tegsedi was found to be favourable.


Decision issued

Approved; issued a Notice of Compliance in accordance with the Food and Drug Regulations.