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Also known as TEGSEDI, ISIS 420915, IONIS-TTR Rx
Inotersen · 3 trials · 6 indications
mNIS+7 composite score is a measure of neurologic impairment evaluating muscle weakness, sensation, reflexes, nerve conduction, and autonomic function. mNIS+7 consists of 2 composite scores: the NIS composite score (maximum of 244 points) \& the modified +7 composite score (maximum of 102.32 points). mNIS+7 composite total score range= -22.32 to 346.32. Higher score indicated a lower function. Least square (LS) mean \& standard error (SE) were analyzed using Mixed Effects Model with Repeated Measures (MMRM). As pre-specified in the protocol, the efficacy of eplontersen was to be assessed by comparing participants enrolled in the eplontersen arm only with the external placebo group. There was no statistical comparison planned between the inotersen arm and the eplontersen-treated/external placebo group arms.
The Norfolk QoL-DN score is a measure of physical function/large fiber neuropathy, symptoms, activities of daily living, small fiber neuropathy, and autonomic neuropathy. The Norfolk QoL-DN total score has a range of -4 to 138, and a higher score indicates poorer quality of life. LS mean and SE were analyzed using MMRM. As pre-specified in the protocol, the efficacy of eplontersen was to be assessed by comparing participants enrolled in the eplontersen arm only with the external placebo group. There was no statistical comparison planned between the inotersen arm and the eplontersen-treated/external placebo group arms.
As pre-specified in the protocol, the efficacy of eplontersen was to be assessed by comparing participants enrolled in the eplontersen arm only with the external placebo group. There was no statistical comparison planned between the inotersen arm and the eplontersen-treated/external placebo group arms. Overall number analyzed is the number of participants with data available for analysis.
As pre-specified in the protocol, the efficacy of eplontersen was to be assessed by comparing participants enrolled in the eplontersen arm only with the external placebo group. There was no statistical comparison planned between the inotersen arm and the eplontersen-treated/external placebo group arms. Overall number analyzed is the number of participants with data available for analysis.
mNIS+7 composite score is a measure of neurologic impairment evaluating muscle weakness, sensation, reflexes, nerve conduction, and autonomic function. mNIS+7 consists of 2 composite scores: NIS composite score (maximum of 244 points) \& the modified +7 composite score (maximum of 102.32 points). mNIS+7 composite total score range= -22.32 to 346.32. Higher score indicated a lower function. LS mean and SE were analyzed using MMRM. As pre-specified in the protocol, the efficacy of eplontersen was to be assessed by comparing participants enrolled in the eplontersen arm only with the external placebo group. There was no statistical comparison planned between the inotersen arm and the eplontersen-treated/external placebo group arms.
An adverse event (AE) is any unfavorable and unintended sign (including a clinically significant abnormal laboratory finding, for example), symptom, or disease temporally associated with the study or use of investigational drug product, whether or not the AE is considered related to the investigational drug product. A TEAE is defined as an adverse event with an onset that occurs after receiving study drug. An SAE is any untoward medical occurrence that at any dose that results in death, is life threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, leads to a congenital anomaly/birth defect, or is an important medical event. TEAEs considered related to the study drug as assessed by the Investigator are reported.
Vital signs included blood pressure, heart rate, respiratory rate, and temperature. Only categories with at least one participant with event are reported.
As prespecified in the protocol, percentage of participants with change from baseline in weight is reported in 2 categories, decrease of ≥7% from Baseline and increase of ≥7% from Baseline.
Clinical laboratory tests included the analysis of chemistry, haematology, and urinalysis. Any value outside the normal range will be flagged for the attention of the investigator who will assess whether or not a flagged value is of clinical significance. Only those categories with at least one participant with event are reported. Normal range of creatinine clearance is 110 to 150 mL/min in males and 100 to 130 mL/min in females. Normal urine protein to creatinine (P/C) ratio= \<0.2. Normal range for Alanine Aminotransferase (ALT) is 4 to 36 units per liter (U/L). Platelets normal range=140×10\^9/L to 400×10\^9/L.
Normal QTcF at Baseline is defined as ≤450 milliseconds (ms) for males or ≤470 ms for females. Percentage of participants with QT interval outside of normal range are reported.
A concomitant therapy was any non-protocol-specified drug or substance (including over-the counter medications, herbal medications, and vitamin supplements) administered between signing of informed consent and the final post-treatment visit for treating nervous and cardiovascular system disorders.
The mNIS+7 composite score is a measure of neurologic impairment that evaluates muscle weakness, sensation, reflexes, nerve conduction, and autonomic function. The mNIS+7 Composite Score has a range of -22.32 to 346.32 and a higher mNIS+7 composite score indicates lower function.
| Arm | Type | Description |
|---|---|---|
| Inotersen | ACTIVE_COMPARATOR | Participants received inotersen, 300 milligrams (mg), subcutaneously (SC), once weekly up to Week 34. After Week 35 assessment, participants received eplontersen, 45 mg, SC, once every 4 weeks starting from Week 37 up to Week 81. |
| Eplontersen | EXPERIMENTAL | Participants received eplontersen, 45 mg, SC, once every 4 weeks up to Week 81. |
| Previous Placebo-Inotersen 300 mg | EXPERIMENTAL | Participants received subcutaneous (SC) doses of 300 milligrams (mg) inotersen once weekly for up to 260 weeks. Participants who received inotersen-matching placebo in the previous study- ISIS 420915-CS2 (NCT01737398) were included in this group. |
| Previous Inotersen-Inotersen 300 mg | EXPERIMENTAL | Participants received SC doses of 300 mg inotersen once weekly for up to 260 weeks. Participants who received inotersen in the previous study- ISIS 420915-CS2 were included in this group. |
| Placebo | ACTIVE_COMPARATOR | Placebo administered SC 3 times on alternate days in the first week and then once-weekly for 64 weeks |
| Name | Type | Description |
|---|---|---|
| Inotersen | DRUG | Inotersen by subcutaneous injection |
| Eplontersen | DRUG | Eplontersen by subcutaneous injection |
| Placebo | DRUG | - |
Key Inclusion Criteria: 1. Aged 18 to 82 years at the time of informed consent 2. Females must be non-pregnant and non-lactating, and either surgically sterile or post-menopausal or abstinent 3. Males must be surgically sterile or, abstinent or, if engaged in sexual relations with a woman of child-...
Inotersen is an investigational RNA therapy developed for hereditary transthyretin-mediated amyloid polyneuropathy, also called familial amyloid polyneuropathy (FAP). It is designed to reduce transthyretin (TTR) protein production in patients with this rare, progressive nerve disorder. It is not approved and remains in clinical development.
Inotersen targets transthyretin (TTR) mRNA. It is an antisense inhibitor, meaning it is designed to bind TTR messenger RNA and reduce production of the TTR protein that forms amyloid deposits in familial amyloid polyneuropathy. This mechanism addresses the underlying protein source rather than only managing symptoms.
Inotersen is developed by Ionis Pharmaceuticals, Inc., which trades on the Nasdaq under the ticker IONS. Ionis is the sponsor of the clinical program evaluating the drug in hereditary transthyretin-mediated amyloid polyneuropathy and familial amyloid polyneuropathy.
Inotersen has been studied in Phase 3 clinical development. Two Phase 3 trials are completed, and a Phase 2 trial is also completed. The program includes randomized, double-blind, active-controlled studies, and no trials are currently listed as active.
Inotersen has been evaluated in completed trials including NCT01737398, a Phase 2 study in familial amyloid polyneuropathy, and NCT02175004, a Phase 3 long-term extension study in FAP. The Phase 3 NEURO-TTRansform study, NCT04136184, evaluated eplontersen in hereditary transthyretin-mediated amyloid polyneuropathy.
No. Inotersen and eplontersen are distinct compounds. Eplontersen was formerly known as ION-682884, IONIS-TTR-LRx and AKCEA-TTR-LRx, and was studied in the Phase 3 NEURO-TTRansform trial (NCT04136184). Inotersen is a separate antisense drug evaluated in its own Phase 2 and Phase 3 trials.