INTERVENTION:

Trade Name: Aimovig Pharmaceutical Form: Solution for injection INN or Proposed

INN:

ERENUMAB Other descriptive name: Aimovig Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 140‐ Pharmaceutical form of the placebo: Solution for injection Route of administration of the placebo: Subcutaneous use Pharmaceutical form of the placebo: Solution for injection Route of administration of the placebo: Subcutaneous use

CONDITION:

Therapeutic area: Diseases [C] ‐ Nervous System Diseases [C10] Trigeminal neuralgia ; MedDRA version: 20.0 Level: PT Classification code 10044652 Term: Trigeminal neuralgia System Organ Class: 10029205 ‐ Nervous system disorders

INCLUSION CRITERIA:

• A diagnosis of primary TN (idiopathic or classical) according to criteria of The Interna‐tional Classification of Headache Disorders 3rd edition. • Age between 18 and 85 years. • Subjects must have a minimum mean of 3 TN related pain paroxysms per day with a mean ADP of 4 to 10, inclusive, on the 11‐point NRS (0= no pain; 10= maximum pain imaginable) during the 7‐day screening phase to enter the baseline phase. • Subjects must have a minimum mean of 3 TN related pain paroxysms per day with a mean ADP of 4 to 10, inclusive, on the 11‐point NRS (0= no pain; 10= maximum pain imaginable) during the 4‐week baseline phase to enter the treatment phase (to be ran‐domized). Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18‐64 years) yes F.1.2.1 Number of subjects for this a

PRIMARY OUTCOME:

; Primary end point(s): 1. To evaluate the proportion of subjects classified as responders at the evaluation period (i.e. week 1‐4).; a. A subject who meets the following criterion will be classified as a responder:; i. Has a reduction of = 30% in mean average daily pain intensity score (mean ADP) assessed using the 11‐point numerical rating scale (NRS) during the evaluation period (week 1‐4) compared with baseline (weeks ‐4 to ‐1).; ii. Patients that are protocol violators, e.g., patients having to increase cur‐rent medications or who will undergo surgery in the evaluation period as well as patients who drop out due to worsening of symptoms or side ef‐fects will be recorded as non‐responders.; The change/reduction in mean ADP from baseline to evaluation period is calculated as follow‐ing: (mean ADP of evaluation period) – (mean ADP of baseline period). If this reduction is = 30% the given subjects is classified as a responder.; ; Secondary Objective: To evaluate the proportion of:; ‐ Subjects reaching a reduction of =50% and =75% respectively in mean ADP during the evaluation period compared with baseline.; ‐ Subjects with a response in mean daily number of paroxysms at evaluation period (i.e. reduction of = 30% in mean of daily number of paroxysms at evaluation period compared with baseline).; ‐ Subjects with a Patient Global Impression of Change (PGIC) scale response at evaluation period ( i.e. has a PGIC response of “much improvedâ€? or “very much improvedâ€? at week 4.); To evaluate the change from baseline to week 4 in the active and placebo group respectively:; ‐ Mean ADP.; ‐ Number of paroxysms.; ‐ The Penn Facial Pain Scale‐Revised (PENN‐FPS‐R) score.; To evaluate the percentage of drop‐outs in active and placebo group caused by:; ‐ Increased intake of TN‐medication.; ‐ Side‐effects.; To evaluate the percentage of subjects with side‐effects registered in weeks 1‐4 during treatment compared with placebo.; Main Objective: 1. To evaluate the proportion of subjects classified as responders at the evaluation period (i.e. week 1‐4). A subject who meets the following criterion will be classified as a responder: has a reduction of = 30% in mean average daily pain intensity score (mean ADP) assessed using the 11‐point numerical rating scale (NRS) during the evaluation period (week 1‐4) compared with baseline (weeks ‐4 to ‐1). Patients that are protocol violators, e.g., patients having to in‐crease current medications or who will undergo surgery in the evaluation period as well as patients who drop out due to worsening of symptoms or side effects will be recorded as non‐responders. Timepoint(s) of evaluation of this end point: See above.

SECONDARY OUTCOME:

; Secondary end point(s): Efficacy:; 1. To evaluate the proportion of subjects reaching =50% reduction in mean ADP during the evaluation period (week 1‐4) compared with baseline (week ‐4 to ‐1).; ; 2. To evaluate the proportion of subjects reaching =75% reduction in mean ADP during the evaluation period (week 1‐4) compared with baseline (week ‐4 to ‐1).; ; 3. The proportion of subjects with a response in number of paroxysms at evaluation period.; a. A subject who meets the following criterion will be classified as a responder:; i. Has a reduction of = 30% in mean of daily number of paroxysms during the evaluation period (week 1‐4) compared with baseline (week ‐4 to ‐1).; The change/reduction in mean number of paroxysms from baseline to evaluation period is cal‐culated as following: (mean number of paroxysms of evaluation period) – (mean number of paroxysm of baseline period). If this reduction is = 30% the given subjects is classified as a responder.; ; 4. Proportion of subjects with a Patient Global Impression of Change (PGIC) scale re‐sponse at evaluation period. A subject who meets the following criterion will be classi‐fied as a responder: has a PGIC response of “much improvedâ€? or “very much improvedâ€? at week 4.; ; 5. Change from baseline to week 4 in mean ADP in active and placebo group.; This is calculated as following: (mean ADP of evaluation period) – (mean ADP of baseline pe‐riod) and is a measure for the absolute change in mean ADP.; ; 6. Change from baseline to week 4 in number of paroxysms in active and placebo group.; This is calculated as following: (mean number of paroxysms of evaluation period) – (mean number of paroxysms of baseline period) and is a measure for the absolute change in mean number of paroxysms.; ; 7. Change from baseline to week 4 in the Penn Facial Pain Scale‐Revised (PENN‐FPS‐R) score.; ; 8. Drop‐outs caused by increased intake of TN‐medication in active group compared to placebo.; ; 9. Drop‐outs caused by side‐effect in active group compared to placebo.; Safety:; 1. Percentage of subjects with side‐effects registered in weeks 1‐4 during treatment with erenumab compared with placebo.; Timepoint(s) of evaluation of this end point: See above.

BACKGROUND:

Novel therapeutic options with improved efficacy and safety profiles are needed for the prophylaxis of migraine. In recent years, the inhibition of calcitonin gene-related peptide (CGRP) signaling has attracted growing interest in the pharmacological research on migraine. Erenumab is the first fully human monoclonal antibody directed against the CGRP receptor to be approved for use in migraineurs.

OBJECTIVE:

To evaluate the efficacy and safety of erenumab as preventive treatment in patients with migraine using meta-analytical techniques.

METHODS:

Randomized, placebo-controlled, single- or double-blinded trials were identified through a systematic literature search (October week 4, 2018). Main outcomes included the changes from baseline in monthly migraine days (MMD) and monthly acute migraine-specific medication days (MSMD) at week 12, and the incidence of adverse events (AEs), severe AEs (SAEs) and treatment withdrawal due to AEs. Mean difference (MD) and risk ratio (RR) with 95% confidence intervals (95% CIs) were estimated.

RESULTS:

Across the five included trials, erenumab given as a subcutaneous injection at a monthly dosage of 70 mg and 140 mg was associated with a significantly greater reduction in baseline MMD (70 mg: MD − 1.3, 95% CI − 1.7 to − 1.0, p < 0.001; 140 mg: MD − 1.9, 95% CI − 2.3 to − 1.4, p < 0.001) and MSMD (70 mg: MD − 1.0, 95% CI − 1.6 to − 0.4, p < 0.001; 140 mg: MD − 1.8, 95% CI − 2.5 to − 1.1, p < 0.001) than placebo. There were no differences in the occurrence of AEs, SAEs, and drug withdrawal due to AEs between the erenumab and placebo groups.

CONCLUSIONS:

Erenumab is an efficacious and well tolerated preventive treatment in adult patients with episodic and chronic migraine.

Background and aims: Erenumab is a fully human monoclonal antibody that inhibits the calcitonin gene-related peptide (CGRP) receptor. In a Phase III study (NCT02456740), erenumab demonstrated a significant reduction in the mean monthly migraine days (MMD) compared with placebo. Here, we report a subgroup analysis assessing the efficacy of erenumab in episodic migraine patients with/without history of aura (self-reported). Methods: Patients were randomised 1:1:1 to erenumab 70mg, 140mg or placebo monthly for 6 months. This subgroup analysis assessed changes in MMD, acute migraine-specific medication days (MSMD), and proportion of patients achieving ≥50% reduction in MMD averaged over months 4-6. Nominal p-values were presented without multiplicity adjustment and were not used for pre-planned hypothesis testing. Results: of 955 patients randomised, 52% had a history of aura. Baseline characteristics were similar among the groups. Compared with placebo, erenumab induced greater reductions in MMD in both the subgroups. In patients without history of aura, least-squares mean (SE) changes from baseline were -1.5 (0.3) for placebo vs -2.7 (0.3) for 70mg (p=0.002) and -3.8 (0.3) for 140mg (p<0.001). In patients with history of aura, changes were -2.1 (0.3) for placebo vs -3.8 (0.2) for 70mg (p<0.001) and -3.5 (0.3) for 140mg (p<0.001). In both the subgroups, treatment with erenumab 70 and 140mg resulted in more patients achieving ≥50% reduction in MMD and fewer acute migraine-specific medication days than with placebo (Table). Conclusion: Erenumab was efficacious in migraine patients with and without history of aura.

OBJECTIVE:

To identify and analyze postmarketing case reports of elevated blood pressure (BP) associated with erenumab use.

METHODS:

A retrospective analysis of postmarketing (spontaneous) case reports of erenumab-associated elevated BP submitted to the FDA Adverse Event Reporting System from May 17, 2018 through April 30, 2020. A case of elevated BP was defined as (a) an initiation of a pharmacological intervention or emergency department visit or hospitalization for emergent de novo or worsening of preexisting hypertension, or (b) BP measurement of ≥140 mm Hg systolic or ≥90 mm Hg diastolic with or without baseline BP measurement reported. Reports of elevated BP associated with erenumab use were analyzed for baseline and demographic information, latency, drug-event causal association, and clinical outcome.

RESULTS:

Sixty-one cases of elevated BP were identified, 86% (49/57) were women and the median age was 56 [range 24-88] years. Forty-one cases were associated with a serious outcome per regulatory criteria, including seven that specified hospitalization. No case reported an outcome of death. The median systolic BP increase was 39 (interquartile range (IQR) 32, 59) mm Hg and median diastolic BP increase was 28 (IQR 18, 41) mm Hg. A total of 27/61 (44%) cases reported treatment for elevated BP (i.e., pharmacologic intervention or emergency department visit/hospitalization). Elevated BP occurred most frequently (28/61, 46%) within a week of the first dose of erenumab. Nineteen cases (19/61, 31%) reported a history of preexisting hypertension.

CONCLUSIONS:

This case series suggest an association between elevated BP and use of erenumab. In light of our findings, the erenumab (Aimovig) prescribing information was amended to include hypertension in the Warnings and Precautions section.

This study is a phase 3, randomized, double‐blind, placebo‐controlled, parallel‐group study to evaluate the efficacy and safety of erenumab in migraine prevention in children (6 to <12 years) and adolescents (12 to <18 years) with chronic migraine. The trial consists of four phases: screening (up to 3 weeks of initial screening and a 4‐week prospective baseline phase); the DBTP (24 weeks for Group 1 subjects; 12‐weeks for Group 2 subjects) in which participants receive placebo or erenumab dose 1, dose 2 or dose 3 (based on participant's body‐weight) via subcutaneous injection once a month; the optional dose level blinded extension phase (40 weeks), in which all participants are assigned to receive dose 1, dose 2 or dose 3 of erenumab; and a 12 weeks safety follow‐up phase (16 weeks after the last dose of investigational drug). The study intends to enrol 286 participants (256 adolescents and 30 children).

This study is a Phase 3, randomized, double‐blind, placebo‐controlled, parallel‐group study to evaluate the efficacy and safety of erenumab in migraine prevention in children (6 to <12 years) and adolescents (12 to <18 years) with episodic migraine. The trial consists of four phases: screening (up to 3 weeks of initial screening and a 4‐week prospective baseline phase); the DBTP (24 weeks for Group 1 participants; 12‐weeks for Group 2 participants) in which participants receive placebo or Erenumab dose 1, dose 2 or dose 3 (based on participant's body weight) via subcutaneous injection once a month; the optional dose level blinded extension phase (40 weeks), in which all participants are assigned to receive dose 1, dose 2 or dose 3 of Erenumab; and a 12 weeks safety follow‐up phase (16 weeks after the last dose of investigational drug). The study intends to enroll 456 participants (376 adolescents and up to 80 children).

Treatment of chronic migraineurs who have failed more than 3 preventive drugs with Erenumab alone, to reduce frequency of monthly migraine days or as an add on therapy

Objective: To determine the efficacy of erenumab, a human anti-CGRP receptor antibody, in episodic migraine patents with aura in a subgroup analysis of a phase 3 trial. Background: It is unknown whether monoclonal antibody treatments for migraine, which have little CNS penetration, are equally effective in patients with and without aura. Design/Methods: Patients were randomized 1:1:1 to erenumab (70-mg or 140-mg) or placebo monthly for 6 months. This subgroup analysis of patients with/without history of aura (self-reported) assessed changes in monthly migraine days (MMD), acute migraine-specific medication days (MSMD), and proportion of patients achieving ≥50% reduction in MMD averaged over months 4-6. Nominal pvalues presented without multiplicity adjustment and not used for pre-planned hypothesis testing. Results: Of 955 patients randomized, 52% (n=492) had history of aura. Baseline characteristics were similar among groups. Compared with placebo, erenumab induced greater reductions in MMD in both subgroups. In patients without aura history, least-squares mean (SE) changes from baseline were -1.5 (0.3) for placebo vs -2.7 (0.3) for 70-mg (p=0.002) and -3.8 (0.3) for 140-mg (p<0.001). In patients with aura history, changes were -2.1 (0.3) for placebo vs -3.8 (0.2) for 70-mg (p<0.001) and -3.5 (0.3) for 140-mg (p<0.001). Responder rates (≥50% reductions in MMDs) for patients without aura history were 23% (placebo) vs 39% (70-mg odds ratio (95% CI): 2.1 (1.3, 3.5); p=0.003) and 49% (140-mg OR.: 3.3 (2.0, 5.4); p<0.001) and with aura history were 30% (placebo) vs 47% (70-mg OR.: 2.1 (1.3, 3.3); p=0.001) and 51% (140-mg OR.: 2.4 (1.5, 3.8); p<0.001). Respective MSMD changes were -0.1 (0.2) vs -1.3 (0.2) and -2.0 (0.2) for patients without aura history (p<0.001 for both) and -0.3 (0.1) vs -1.0 (0.1) and -1.3 (0.1) for patients with aura history (p<0.001 for both). Conclusions: These data indicate that erenumab is efficacious in migraine patients with and without history of aura.

A phase 2a, multicenter, randomized, double-blind, placebo-controlled study in adults with stable angina to evaluate the effect of erenumab (AMG 334) compared to placebo on exercise time during an exercise treadmill test.

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