TEGSEDI Solution for injection Ref.[116635] Active ingredients: Inotersen

Pharmacotherapeutic group: Other Nervous System Drugs
ATC code: N07XX15

Mechanism of action

Inotersen is a 2′-O-2-methoxyethyl (2′-MOE) phosphorothioate antisense oligonucleotide (ASO) inhibitor of human transthyretin (TTR) production. The selective binding of inotersen to the TTR messenger RNA (mRNA) causes the degradation of both mutant and wild type (normal) TTR mRNA. This prevents the synthesis of TTR protein in the liver, resulting in significant reductions in the levels of mutated and wild type TTR protein secreted by the liver into the circulation.

TTR is a carrier protein for retinol binding protein 4 (RBP4) which is the principal carrier of vitamin A (retinol). Therefore, reduction in plasma TTR is expected to result in reduction of plasma retinol levels to below the lower limit of normal.

Pharmacodynamic effects

In the pivotal study, a phase ⅔ randomized, double-blind, placebo-controlled study to assess the efficacy and safety of ISIS 420915 in patients with Familial Amyloid Polyneuropathy (NEURO-TTR Study), in the inotersen treatment group, robust reduction in circulating TTR levels was observed throughout the 15-month treatment period, with mean percent changes from baseline in serum TTR ranging from 68.41% to 74.03% (median range: 74.64% to 78.98%) from Week 13 to Week 65 (Figure 1). In the placebo group, mean serum TTR concentration decreased by 8.50% at Week 3 and then remained fairly constant throughout the treatment period.

Figure 1. Percent change from baseline in serum TTR over time:

Transthyretin (TTR)
Least Squares Mean (LSM)
Standard Error (SE)

Clinical efficacy and safety

The NEURO-TTR multicentre, double-blind, placebo-controlled trial was comprised of 172 treated patients with hereditary transthyretin amyloidosis with polyneuropathy (hATTR-PN). The disease hATTR-PN is classified into 3 stages such that i) Stage 1 patients do not require assistance with ambulation, ii) Stage 2 patients do require assistance with ambulation, and iii) Stage 3 patients are bound to wheelchair. Subjects with Stage 1 and Stage 2 hATTR-PN and a Neuropathy Impairment Score (NIS) ≥ 10 and ≤ 130 were recruited in the pivotal NEURO-TTR study. The study evaluated 284 mg inotersen administered as one subcutaneous injection once per week, for 65 weeks of treatment. Patients were randomised 2:1 to receive either inotersen or placebo. The primary efficacy endpoints were the change from baseline to Week 66 in the modified Neuropathy Impairment Score + 7 tests (mNIS+7) composite score and in the Norfolk Quality of Life – Diabetic Neuropathy (QoL-DN) questionnaire total score. Patients were stratified for stage of disease (Stage 1 versus Stage 2), TTR mutation (V30M versus non-V30M) and previous treatment with either tafamidis or diflunisal (yes versus no). Baseline demographic and disease characteristics are shown in Table 3.

Table 3. Baseline demographics:

¹ Based on clinical database.
² Defined as all patients with a diagnosis of hereditary transthyretin amyloidosis with cardiomyopathy (hATTR-CM) at study entry or left ventricular wall thickness >1.3 cm on echocardiogram without a known history of persistent hypertension.
³ Duration from symptom onset to informed consent date.
modified Neuropathy Impairment Score (mNIS)
Quality of Life-Diabetic Neuropathy (QoL-DN)
hereditary transthyretin amyloidosis-polyneuropathy (hATTR-PN)
Standard deviation (SD)

The changes from baseline in both primary endpoints (mNIS+7 and Norfolk QoL-DN) demonstrated statistically significant benefit in favour of inotersen treatment at Week 66 (Table 4). Results across multiple disease characteristics [TTR mutation (V30M, non-V30M)], disease stage (Stage 1, Stage 2), previous treatment with tafamidis or diflunisal (yes, no), presence of hATTR-CM (yes, no) at Week 66 showed statistically significant benefit in all subgroups based on mNIS+7 composite score and all but one of these subgroups (CM-Echo Set; p=0.067) based on Norfolk QoL-DN total score (Table 5). Furthermore, results across the components of mNIS+7 and domains of Norfolk QoL-DN composite scores were consistent with the primary endpoint analysis, showing benefit in motor, sensory and autonomic neuropathies (Figure 2).

Table 4. Primary endpoint analysis mNIS+7 and Norfolk QoL-DN:

Quality of Life-Diabetic Neuropathy (QoL-DN)
Standard deviation (SD)
Least squares mean (LSM)

Table 5. Subgroup analysis of mNIS+7 and Norfolk QoL-DN:

Figure 2. Difference in least squares mean (LSM) change from baseline between treatment groups in mNIS+7 and components:

Least squares mean (LSM)
Quality of Life-Diabetic Neuropathy (QoL-DN)
modified Neuropathy Impairment Score (mNIS)
NIS-W – sub-score for weakness
NIS-R – sub-score for muscle stretch reflexes
NIS-S – sub-score for clinical sensation
Heart Rate during Deep Breathing (HRDB)

A responder analysis of mNIS+7 using thresholds ranging from a 0-point to 30-point increase from baseline (using the safety set), showed the inotersen group had approximately a 2-fold higher response rate than the placebo group at each threshold tested, demonstrating consistency of response. A responder was defined as a subject who had a change from baseline that was less than or equal to the threshold value. Subjects that terminate the treatment early irrespective of the reason or have missing week 66 data are considered as non-responders. Statistical significance in favour of inotersen was demonstrated at all thresholds beyond a 0-point change.

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with Tegsedi in all subsets of the paediatric population in transthyretin amyloidosis (see section 4.2 for information on paediatric use).