Akcea — Tegsedi EMA EPAR public assessment report (EMEA/H/C/004782, 2018)
Akcea · 2018 · EMA EPAR public assessment report · company profile →
Report summary
This report summarizes the EMA's 2018 assessment of Tegsedi (inotersen) for hereditary transthyretin amyloidosis (hATTR). Inotersen, an antisense oligonucleotide, received accelerated assessment due to unmet medical need. Manufacturing, quality control, and non-clinical studies (pharmacology, pharmacokinetics, toxicology) are detailed, highlighting kidney, liver, and dose-dependent platelet toxicities. Clinical pharmacokinetic and pharmacodynamic properties, including bioanalytical assay validation and anti-drug antibody impact, are also covered. Pivotal Phase 2/3 study (CS2) and open-label extension (CS3) demonstrated statistically significant improvements in mNIS+7 and Norfolk QoL-DN scores for hATTR-PN patients (Stage 1 and 2) at Week 66. However, efficacy in advanced hATTR-PN (Stage 3) and cardiomyopathy was limited. Safety concerns include high rates of thrombocytopenia (24.1% vs 1.7% placebo), renal impairment (20.5% vs 10.0% placebo), and injection site reactions. One death was attributed to intracranial hemorrhage due to severe thrombocytopenia. The benefit-risk assessment concluded a positive profile for Stage 1 and 2 hATTR-PN, with stringent risk minimization for identified risks like immune-mediated thrombocytopenia and glomerulonephritis.
Key findings — cited to the page
| Death due to intracranial haemorrhage as a consequence of Grade 4 thrombocytopenia | 1 subject | · p.112 |
| Incidence of CTCAE Grade 3 or 4 thrombocytopenia | 7.1 % | · p.128 |
| Number of subjects with Grade 4 thrombocytopenia in CS2 | 3 subjects | ISIS 420915-CS2 · p.92 |
| Number of additional subjects with Grade 4 thrombocytopenia in CS3 | 1 subject | ISIS 420915-CS3 · p.92 |
| Additional subjects with Grade 3 or Grade 4 thrombocytopenia in CS3 | 5 subjects | CS3 · p.112 |
| Total patients with Grade 3 or 4 thrombocytopenia from longitudinal safety set | 7.1 % | · p.112 |
| Platelet count range for Grade 3 TEAEs (CTCAE criteria) | 25 to 50 x 10^9/L | · p.92 |
| Platelet count range for Grade 4 TEAEs (CTCAE criteria) | <25 x 10^9/L | · p.92 |
| Percentage of subjects with Grade 4 thrombocytopenia in CS2 | 2.7 % | ISIS 420915-CS2 · p.92 |
| Number of additional subjects with Grade 3 thrombocytopenia in CS3 | 4 subjects | ISIS 420915-CS3 · p.92 |
| Grade 3 or Grade 4 thrombocytopenia in inotersen-treated subjects in CS2 | 2.7 % | CS2 · p.112 |
| Incidence of thrombocytopenia (all grades) | 24.1 % | Inotersen · p.133 |
Source: Akcea ↗ · License: EMA - reuse permitted with acknowledgement. Summary and findings are extracted from the published document; every figure cites its page. Informational only — not investment advice. Explore the Neurology library →