Fremanezumab for the Preventive Treatment of Chronic Migraine.

BACKGROUND: Fremanezumab, a humanized monoclonal antibody targeting calcitonin gene-related peptide (CGRP), is being investigated as a preventive treatment for migraine. We compared two fremanezumab dose regimens with placebo for the prevention of chronic migraine. METHODS: In this phase 3 trial, we randomly assigned patients with chronic migraine (defined as headache of any duration or severity on ≥15 days per month and migraine on ≥8 days per month) in a 1:1:1 ratio to receive fremanezumab quarterly (a single dose of 675 mg at baseline and placebo at weeks 4 and 8), fremanezumab monthly (675 mg at baseline and 225 mg at weeks 4 and 8), or matching placebo. Both fremanezumab and placebo were administered by means of subcutaneous injection. The primary end point was the mean change from baseline in the average number of headache days (defined as days in which headache pain lasted ≥4 consecutive hours and had a peak severity of at least a moderate level or days in which acute migraine-specific medication [triptans or ergots] was used to treat a headache of any severity or duration) per month during the 12 weeks after the first dose. RESULTS: Of 1130 patients enrolled, 376 were randomly assigned to fremanezumab quarterly, 379 to fremanezumab monthly, and 375 to placebo. The mean number of baseline headache days (as defined above) per month was 13.2, 12.8, and 13.3, respectively. The least-squares mean (±SE) reduction in the average number of headache days per month was 4.3±0.3 with fremanezumab quarterly, 4.6±0.3 with fremanezumab monthly, and 2.5±0.3 with placebo (P CONCLUSIONS: Fremanezumab as a preventive treatment for chronic migraine resulted in a lower frequency of headache than placebo in this 12-week trial. Injection-site reactions to the drug were common. The long-term durability and safety of fremanezumab require further study. (Funded by Teva Pharmaceuticals; ClinicalTrials.gov number, NCT02621931 .)

Subcutaneous interferon β-1a in pediatric patients with multiple sclerosis: Regional differences in clinical features, disease management, and treatment outcomes in an international retrospective study

AbstractBackgroundTo further understand management of pediatric patients with multiple sclerosis (MS), we examined disease features, clinical practice patterns, and response to treatment in the United States (US) and seven other countries ('rest of World'; ROW).MethodsAnonymized data, recorded as part of routine clinical practice, were obtained from medical records (1997–2009) of study participants (who received subcutaneous interferon β-1a before age 18years) from the US and ROW. Samples were stratified by age (preadolescents [<12years] and adolescents [12–17years]).ResultsUS adolescents had a higher mean body mass index versus ROW adolescents (BMI; 27.2 versus 22.5kg/m2), started disease-modifying therapy (DMT) earlier after the first relapse, were more likely to have received a DMT before initiating subcutaneous interferon β-1a, had a higher relapse rate, and were more likely to switch from subcutaneous interferon β-1a to another DMT before the end of the observation period.ConclusionsThis retrospective analysis of a multinational sample of pediatric MS patients who received subcutaneous interferon β-1a found that those from the US had higher BMI, relapsed more frequently, and were managed differently, compared with ROW patients. Future prospective studies are needed to confirm these observations and ascertain their clinical significance

TEV-48125 for the preventive treatment of chronic migraine:Efficacy at early time points

OBJECTIVE: To evaluate the onset of efficacy of TEV-48125, a monoclonal antibody against calcitonin gene-related peptide, recently shown to be effective for the preventive treatment of chronic migraine (CM) and high-frequency episodic migraine. METHODS: A randomized placebo-controlled study tested once-monthly injections of TEV-48125 675/225 mg or 900 mg vs placebo. Headache information was captured daily using an electronic headache diary. The primary endpoint was change from baseline in the number of headache hours in month 3. Herein, we assess the efficacy of each dose at earlier time points. RESULTS: The sample consisted of 261 patients. For headache hours, the 675/225-mg dose separated from placebo on day 7 and the 900-mg dose separated from placebo after 3 days of therapy (p = 0.048 and p = 0.033, respectively). For both the 675/225-mg and 900-mg doses, the improvement was sustained through the second (p = 0.004 and p < 0.001) and third (p = 0.025 and p < 0.001) weeks of therapy and throughout the study (month 3, p = 0.0386 and p = 0.0057). For change in weekly headache days of at least moderate intensity, both doses were superior to placebo at week 2 (p = 0.031 and p = 0.005). CONCLUSIONS: TEV-48125 demonstrated a significant improvement within 1 week of therapy initiation in patients with CM. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for patients with CM, TEV-48125 significantly decreases the number of headache hours within 3 to 7 days of injection

Treatment-emergent adverse events.

<p>Treatment-emergent adverse events affecting ≥15% of subjects treated with BG00010 (any dose) or ≥15% of subjects treated with placebo.</p><p>i.v., intravenous; N/A, not applicable; s.c., subcutaneous.</p><p>Treatment-emergent adverse events.</p

Baseline demographics and clinical characteristics.

<p>BMI, body mass index; i.v., intravenous; N/A, not applicable; s.c., subcutaneous; SD, standard deviation; SF-MPQ, Short-Form McGill Pain Questionnaire; VAS, visual analog scale.</p><p>Baseline demographics and clinical characteristics.</p

Subject disposition. i.v., intravenous; s.c., subcutaneous.

<p>Subject disposition. i.v., intravenous; s.c., subcutaneous.</p

Summary of pharmacokinetic parameters of i.v. BG00010.

<p>^aPharmacokinetic parameters for BG00010 i.v. 0.3 μg/kg were not calculable due to low serum concentrations of BG00010.</p><p>^bOne subject in the BG00010 1 μg/kg cohort was excluded due to low serum concentrations of BG00010.</p><p>^cOne subject in the BG00010 3 μg/kg cohort was excluded due to a high serum concentration of BG00010 at predose and low subsequent serum concentrations.</p><p>AUC_inf, area under the serum concentration-time curve from time zero to infinity; Cl, total body clearance; C_max, maximum observed serum concentration; i.v., intravenous; s.c., subcutaneous; SD, standard deviation; T_max, time to C_max; t_½,terminal half-life; V_ss, steady-state volume of distribution.</p><p>Summary of pharmacokinetic parameters of i.v. BG00010.</p

BG00010 serum concentrations over time.

<p>Mean (standard deviation) BG00010 serum concentrations over (a) 120 h and (b) 15 h (expanded time axis) following i.v. administration of BG00010. Note that data were only available for two subjects treated with BG00010 25 μg/kg at 9, 12, 18 and 48 h. Where data points are not shown, the mean BG00010 serum concentration was equal to 0.00 ng/ml. h, hours; i.v., intravenous.</p

Change in IEFND between baseline and day 28.

<p>Data points indicate data for individual subjects following intravenous administration of BG00010 or placebo; lines indicate mean and range. IEFND, intra-epidermal nerve fiber density.</p

Incidence and duration of temperature perception, pruritus and rash AEs.

<p>Subjects were treated as follows: intravenous BG00010 (a) 50 μg/kg, (b) 100 μg/kg, (c) 200 μg/kg, (d) 400 μg/kg, (e) 800 μg/kg, or (f) placebo. AE, adverse event.</p