Date: 2015-09-30
Type of information: Publication of results in a medical journal
phase: 2b
Announcement: publication of results in The Lancet Neurology
Company: Teva Pharmaceutical Industries (Israel)
Product: TEV-48125 (formerly LBR-101/ RN-307)
Action
mechanism: monoclonal antibody. TEV -48125 (formerly LBR-101/ RN-307) is a monoclonal antibody that binds to calcitonin gene-related peptide (CGRP), a well-validated target in migraine. CGRP signaling may be disrupted by targeting the ligand itself or its receptor.
Teva\'s approach targets the ligand, allowing for some CGRP signaling during therapy, which may avoid the potential, unknown, effects of a long-term total disruption to the normal physiological functions of the CGRP system. TEV-48125 is being developed for two distinct migraine indications; chronic migraine and high frequency episodic migraine. Positive results from the Phase IIb chronic migraine study were announced in February 2015 , demonstrating a significant reduction in both the number of monthly cumulative headache hours, and the number of headache days of at least moderate severity, relative to baseline, and for the first time validating the target in chronic migraine.
TEV-48125 successfully completed five Phase I trials with 94 healthy volunteers. Results were published in Cephalalgia, the official journal of the International Headache Society , in December 2013 , and presented at the 2014 annual meeting of the American Academy of Neurology .
Disease: migraine
Therapeutic area: CNS diseases
Country: USA
Trial
details: The HFEM Study was a multicenter, randomized, double-blind, placebo-controlled, parallel-group, study comparing the efficacy and safety of two doses of subcutaneous TEV-48125 with placebo for the preventive treatment of high frequency episodic migraine in 297 patients. Multiple doses were selected for testing to define dose-response and allow selection of doses for a Phase 3 study. Treatment was administered once every 28 days (i.e.; once monthly) over a 3-month period. 300 patients were enrolled and randomized to one of three treatment arms receiving high dose TEV-48125, low dose TEV-48125 or placebo, administered subcutaneously once a month. The study was conducted in approximately 60 centers in the USA . (NCT02025556) The purpose of the Chronic Migraine Study (CM Study is to determine whether monthly subcutaneous administration of LBR-101 is safe and provides migraine prevention in patients with chronic migraine. Two distinct doses of subcutaneous LBR-101/TEV-48125 administered monthly will be compared to placebo for safety and efficacy. The mean change from baseline in the number of cumulative headache hours measured at the 28-day period ending with week 12. (NCT02021773)
Latest
news: * On September 30, 2015, Teva Pharmaceutical Industries announced today that Lancet Neurology published online, as back-to-back articles, the results from two Phase 2b studies of TEV-48125, a monoclonal anti-calcitonin gene-related peptide (CGRP) antibody investigational treatment for the prevention of chronic migraine and high frequency episodic migraine (HFEM). The Lancet Neurology ranks first among 194 journals in the clinical neurology category (2013 Journal Citation Reports®, Thomson Reuters 2014). The Phase 2b clinical development program consistently met all primary and secondary efficacy and safety endpoints for TEV-48125 in 564 patients and across multiple doses. Clinical improvements were exhibited after a single administration of all tested doses of TEV-48125 in both episodic and chronic migraine studies. These results were achieved in the presence of patients being allowed to remain on existing migraine prevention therapy and the results demonstrated significant separation in favor of TEV-48125 even in patients considered to be failing current optimal therapy. The studies are available online at: HFEM and CM. The Chronic Migraine Study: Both assessed doses of TEV-48125 (loading of 675mg followed by monthly injections of 225mg or 900mg), were significantly superior to placebo in reducing, relative to baseline, the number of headache-hours (primary endpoint: p = 0.038 and p = 0.0057) and the number of headache days of moderate or severe intensity in month 3 (secondary endpoint: p < 0.0345 and p =0.0237). Consistent clinical improvements were evident as early as one month after treatment initiation, demonstrating a rapid onset of relief. Post-hoc analysis indicated that over half of the patients in both dose groups experienced a 50% or more decrease in headache frequency (p<0.01 for both doses vs. placebo), nearly one third of patients in both dose groups had a 75% decrease in headache frequency (p < 0.05 for both doses) and around 15% were totally free of headaches at month three. Treatment with TEV-48125 was also associated with statistically significant decreases in acute drug consumption in parallel. These results were achieved amongst highly severe chronic migraine patients (suffered from migraines for a mean period of 18 years, with approximately 17 migraine days per month), who were allowed to remain on other migraine prevention therapies. * On May 14, 2015, Teva Pharmaceutical Industries announced the presentation of further data from its chronic migraine phase 2b study evaluating the efficacy and safety, versus placebo, of two doses of TEV-48125, an anti-calcitonin gene-related peptide (CGRP) ligand monoclonal antibody. These data will be presented on Friday, May 15th, 2015, as a late breaking oral presentation at the 17th Congress of the International Headache Society (IHC 2015). Both assessed doses of TEV-48125 (loading of 675 followed by monthly injections of 225 mg or 900 mg), were significantly superior to placebo in reducing, relative to baseline, the number of hours with headache (primary endpoint - p < 0.05 and p < 0.01). TEV-48125 also significantly decreased the number of headache days of moderate or severe intensity in month 3 (secondary endpoint - p < 0.05 and p < 0.05). A priori analyses indicated that separation from placebo was seen after a single dose of therapy, and exploratory analyses also showed both doses of TEV-48125 separating from placebo as early as one week post-treatment: decrease of headache hours from baseline (primary endpoint) at week 1 was -9.1 for TEV-48125 675/225mg (p = 0.03), -11.4 for 900 mg (p = 0.003), and -2.8 for placebo. This benefit increased progressively at 1 month, with decreases of -44.1 hours for 675/225 mg (p = 0.003), -56.82 hours for 900 mg (p < 0.001) and -18.1 hours for placebo. At three months decreases were -59.8 for 675/225 mg (p = 0.04) -67.5 for 900 mg (p = 0.006) and -37.1 for placebo. Similar decreases were seen for number of moderate/severe headache days (secondary endpoint), where both doses separated from placebo at 2 weeks, and maintained at 1 month and 3 months. Additionally, TEV-48125 was associated with a significant decrease in the consumption of acute migraine medications. No treatment-related serious adverse events were reported with use of TEV-48125. Most common AEs were mild injection-site pain or pruritus. No other relevant differences in the rate of treatment-emergent adverse events occurred for those receiving TEV-48125 doses relative to placebo. Antibodies anti-drug were the lowest in class up to this point (1.1% for TEV-48125 in this trial, and present before drug exposure). Furthermore, over half of the patients in both dose groups experienced a 50% or more decrease in headache frequency (p The study was conducted amongst 264 highly severe chronic migraine patients who suffered from a mean of approximately 162 headache hours per month (approx. 17 migraine days per month, and around 21 days of headache per month). They had suffered from migraines for mean period of 18 years. Amongst the most affected of these patients (upper third), 42% reverted to episodic migraine in the 675/225 mg arm and 43% in the 900 mg arm, vs 22% in placebo. Overall, by the end of the study nearly 60% of patients reverted from chronic to episodic migraine. * On March 23, 2015, Teva Pharmaceutical Industries announced the successful completion of its Phase IIb migraine prevention program with positive top-line results from a Phase IIb study evaluating the efficacy, safety and tolerability of two doses of subcutaneous TEV-48125 for the prevention of high frequency episodic migraine (characterized by 8-14 days of headache per month). The study compared two active arms of high and low dose TEV-48125, administered as a subcutaneous injection, once a month for three months, against placebo. In this study no important safety or tolerability concerns were identified. The adverse event profile for TEV-48125 appeared similar to placebo for most parameters and supportive of previous Phase I and II safety data. Of the adverse events reported, mild, transient injection site discomfort and redness was infrequent but higher than that observed in the placebo group. No serious treatment-related serious adverse events were seen.These data, together with the recent results achieved in the difficult to treat chronic migraine setting, make this the first therapy to successfully meet efficacy endpoints in the prevention of both chronic and episodic migraine, and at multiple doses, in advanced clinical trials. Initial analysis of results demonstrated that both doses of TEV-48125 met primary and secondary endpoints achieving significant reductions in mean monthly migraine days and monthly headache days relative to baseline. These are considered as validated endpoints to assess benefits of new migraine treatments. Additionally, a single administration of both tested doses of TEV-48125 resulted in a statistically significant separation from placebo. Data confirm that treatment with TEV-48125 resulted in separation for both primary and secondary endpoints, at all months of therapy, in both the chronic and episodic migraine clinical trials. Furthermore, these results were achieved in the presence of patients being allowed to remain on existing migraine prevention therapy, and without limitation on the amount of acute migraine treatment used. This was an attribute of the TEV-48125 phase IIb studies not seen in other reported anti-CGRP studies, and the results demonstrated separation in favor of TEV-48125 even in patients considered to be on optimal current therapy. Overall, four different doses across two indications studied in a total of 561 patients met all study endpoints establishing clinical proof of concept for anti-CGRP ligand therapy. Full results from the study will be presented at a forthcoming scientific meeting and will be submitted to a peer-reviewed journal for publication.
The High Frequency Episodic Migraine (HFEM) Study: This is the first study to report on more than one dose of a monoclonal anti-CGRP antibody for the preventive treatment of HFEM, and the study was highly positive, especially considering the severity of the disorder. Participants had migraine for nearly two decades, with a mean of 11.4 migraine-days per month, and 12.5 headache-days per month.
Following 12 weeks, both doses of TEV-48125 (225 mg and 675 mg) exceeded primary and secondary endpoints, achieving statistically significant and clinically meaningful reductions in mean monthly migraine days and monthly headache days as well as significantly diminished number of days and hours of headaches of at least moderate severity.
A decrease of at least 50% of migraine days for the duration of the study were seen in 53% (p = 0.0005) and 59% (p<0.0001) of the individuals given 225mg and 675mg correspondingly versus 28% of those receiving placebo. A decrease of at least 75% in episodic migraine days was observed in 11%, 34% (p = 0.0001) and in 31% (p = 0.0008) of the individuals given placebo, 225mg and 675mg respectively. Design and analyses also had the same rigor of a phase 3 trial.
In both studies no treatment-related serious adverse events were reported with use of TEV-48125. No relevant differences in the rate of treatment-emergent adverse events occurred for those receiving TEV-48125 doses relative to placebo. Anti-drug antibodies (1% for TEV-48125, and present before drug exposure) detected an optimized assay of regulatory quality and much lower than detected with other monoclonal anti-CGRP antibodies.
