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  1. #1
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    Post Promising New Drug for Migraine Prevention

    Promising New Drug for Migraine Prevention
    Medscape Medical News
    October 08, 2014

    Excitement is mounting about a new class of drugs for migraine prevention.

    In one of the most recent developments, a new phase 2 trial of ALD403, a humanized monoclonal antibody directed against calcitonin gene-related peptide (CGRO) showed that the drug was safe and effective.

    Results also showed that adverse events associated with the drug were transient and mild to moderate in severity. The study also suggests the agent significantly reduced the mean number of migraine headache days, with some patients experiencing no migraines at all.

    Although preliminary, the results are promising, said lead author, David W. Dodick, professor, neurology, Mayo Clinic, Phoenix, Arizona.

    "In 30 years of preclinical work in animals, and clinical work in humans, this is the most validated target in migraine," Dr Dodick told Medscape Medical News.

    The study was published online October 6 in The Lancet.

    Desperate Need
    Fast and effective preventive treatments for migraine, which is the third most prevalent and seventh most disabling disease in the world, are lacking, said Dr Dodick.

    "If you spent a day in my clinic, this would become obvious. There is an absolutely desperate need for preventative medications which dramatically reduce, if not eliminate, migraine attacks. The drugs we have now are fraught with side effects and they work in 50% or less of patients."

    ALD403 is a monoclonal antibody that selectively binds to CGRP, which is crucial in the pathophysiology of migraine headaches. It was designed specifically to prevent migraine.

    In contrast, triptans which are used in the acute treatment of migraine may reduce circulating CGRP concentrations, but this is not their primary effect.

    Triptans also have a number of drawbacks, said Dr Dodick. As agonists, they may cause overuse headaches in patients taking them frequently. Four of 5 patients taking triptans "don't get the pain-free response that we'd like to see" in an acute medication. He added that triptans are also linked to numerous adverse effects.

    The new analysis included 163 adults (mean age about 39 years) at 26 centers in the united States. Patients had experienced migraines for more than 12 months and had 5 to 14 migraine days in each of the 3 months before screening. The mean Headache Impact Test 6 (HIT-6) score was about 64.

    Patients were randomly assigned to receive ALD403, 1000 mg, or placebo by intravenous injection. The 1000-mg drug dose was chosen because it had fully suppressed peripheral CGRP responses in healthy persons for at least 12 weeks in a previous trial.

    The study sponsor (Alder Biopharmaceuticals) designed the trial and was responsible for data collection, processing, and management; statistical analysis; and reporting of results. The sponsor wrote the first draft of the results, which the authors reviewed and approved.

    New Drug Class
    During the study, site investigators, patients, and the sponsor were masked to treatment allocation.

    No patient withdrew from the study because of adverse events of lack of efficacy, although two patients in the placebo group and five in the ALD403 group were lost to follow-up in the 12 weeks after receipt of the dose.

    During these 12 weeks, adverse events occurred in 52% of the placebo group and 57% of the treatment group. The most frequent adverse events in both groups were upper respiratory tract and urinary tract infections, fatigue, back pain, nausea and vomiting, and arthralgia. Most adverse events were transient and mild to moderate in severity.

    The groups were similar in terms of vital signs and laboratory safety data.

    During the study, patients completed an electronic headache diary. According to these diaries, the mean change in migraine days between baseline and weeks 5 to 8 was –5.6 for the ALD403 group and –4.6 for the placebo group (difference, –1.0; 95% confidence interval, –2.0 to 0.1; P = .0306).

    Dr Dodick attributed the high placebo response to heightened expectations.

    "It's one thing to take a tablet at home as part of study, but it's another to come to the hospital, get hooked up to IV [intravenous line] and get an infusion. There's a whole sort of medical theater created around the administration of the drug. This increases the expectations that whatever is being infused is going to be powerful and it's going to work."

    He added that in this age of social media, prospective participants were likely well aware that the scientific community was developing targeted antibodies to treat migraine. "There was a lot of excitement and enthusiasm around this; we were finally getting a new drug class that was designed specifically to treat migraine."

    A secondary analysis showed that at all times points (weeks 4, 8, and 12), more patients in the ALD403 than in the placebo group had a 50%, 75%, and 100% reduction in migraine days; the treatment group rate was generally about 20% higher. Of the 143 patients who consistently completed their diary, 11 had no migraine attacks — all of these were treated with ALD403.

    Researchers noted a reduction at week 8 in both study groups for scores on the HIT-6 (change, –9.9 for ALD403 and –8.1 for placebo) and on the Migraine Specific Quality of Life Instrument. Although the study wasn't powered to detect differences for these patient-reported outcomes, "these findings are promising and provide justification to undertake future studies that are appropriately powered," the authors write.

    ALD403 doesn't work in everyone because in some patients, other neuropeptides, such as glutamate, may be triggering migraines, said Dr Dodick. "While CGRP is important, and for some patients it appears to be crucially important, for other patients it may not be important at all."

    The next step is likely to carry out studies to determine the optimal and best-tolerated dose, said Dr Dodick. He said he hopes that a phase 3 study will be launched within a year.

    ALD403 is among 4 CGRP antibodies being tested in migraine.

    Exciting Development
    Commenting for Medscape Medical News, Noah Rosen, MD, a headache specialist and associate professor, Hofstra North Shore, Long Island Jewish Medical Center, New York, said he's excited about the advent of a novel class of drugs to prevent migraine.

    "Everything we use now preventively for migraine has been adapted for that purpose, or found separately to be effective for migraine prevention. This new class of medications is the first to be tailored to the treatment or designed for the treatment of migraines. That's what really makes it exciting."

    Current migraine preventive treatments include β-blockers (propranolol, timolol), anticonvulsants (sodium valproate, topiramate), and botulinum toxin type A (Botox). There is also good evidence for some antidepressants, including amitriptyline, said Dr Rosen.

    Dr Rosen's patients are also anxiously awaiting the new drugs.

    "They're tired of trial after trial of nonspecific treatments," he said. "My patient population is highly educated and is greatly anticipating this, but they know that they need to be patient because you're still talking years from being on the market."


    Lancet. Published online October 6, 2014. Abstract
    Steve

    Dum spiro spero....While I breathe, I hope

  2. #2
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    Re: Promising New Drug for Migraine Prevention

    New Data on CGRP Monoclonal Antibodies for Migraine Prevention
    Medscape Medical News
    June 23, 2015

    Washington, DC — New phase 2 data on the investigational calcitonin gene-related peptide (CGRP) monoclonal antibodies show significant efficacy in preventing migraine attacks with no major safety signals.

    Phase 2 data for three different anti-CGRP drugs from Amgen (AMG 334), Teva Pharmaceuticals (TEV-48125), and Eli Lilly & Co (LY2951742) were presented here at the American Headache Society (AHS) 57th Annual Scientific Meeting by representatives from the three companies.

    A fourth company, Alder Pharmaceuticals, is also developing an anti-CGRP agent but didn't present data at this meeting. All four companies are planning to move their agents into phase 3 trials.

    The drugs — administered as once-monthly injections — act by blocking CGRP, a vasodilator, without causing vasoconstriction. The Amgen product blocks the receptor for CGRP, while the other three are directed against the ligand itself. Lilly is developing its product for cluster headache as well as for migraine prophylaxis.

    "They're a new class to treat migraine preventatively," AHS president Lawrence C. Newman, MD, professor of neurology at Icahn School of Medicine at Mount Sinai and director of The Headache Institute at Mount Sinai-Roosevelt Hospital, New York, told Medscape Medical News.. "We're excited because there hasn't been a new medicine designed specifically to prevent migraine in over 50 years."

    Session moderator Robert Shapiro, MD, PhD, professor in the Department of Neurological Sciences at the University of Vermont, Burlington, told Medscape Medical News, "to have a new category developed specifically for migraine and to have them all show in these early-phase studies significant efficacy and at the same time not have significant signals that there's a serious adverse events is very encouraging…. This is not something we've experienced since 15 to 20 years ago when the triptans were rolling out."

    However, Dr Shapiro, who serves on the independent data monitoring committee for the Lilly drug, cautioned that these early studies are still too small and of short duration — none have data beyond 1 year — to fully establish efficacy and safety. "Any time there's a new molecular entity, one has to be highly vigilant for safety concerns to emerge."

    Indeed, Thomas N. Ward, MD, professor of neurology at the Geisel School of Medicine, Dartmouth College, Lebanon, New Hampshire, and editor-in-chief of the AHS journal Headache: The Journal of Head and Face Pain, pointed out that CGRP is widely distributed throughout the body — in the kidney, lungs, eyes, liver, and gastrointestinal tract — as well as the brain.

    "Could [the drugs] have a long-term effect on intraocular pressure, or renal function, or pulmonary function? CGRP is in your body for a reason and if you perturb it long enough, perhaps some people could accommodate well, but perhaps some people with underlying mild disease might not," Dr Ward said. "It's not really till you get to phase 3, with big, randomized, double-blind, placebo-controlled studies that you can really answer those questions."

    He pointed to previous experience with a related investigational drug that had generated similar excitement, Merck's CGRP antagonist telcagepant. The company halted development in 2011 after liver toxicity was seen in a phase 3 study. "So far the [current agents] look safer…but things can appear that you weren't expecting," Dr Ward cautioned.

    AMG 334
    Results of a 1-year open-label extension of a 12-week randomized, double-blind, placebo-controlled, phase 2 study of AMG 334 for the prevention of episodic migraine were presented by Robert Lenz, MD, from the Department of Global Development at Amgen.

    A total 483 patients with migraines on 4 to 14 days per month at baseline were randomly assigned to a once-monthly injection of placebo (n = 160 patients) or AMG 334 in doses of 7 mg (n = 108), 21 mg (n = 108), or 70 mg (n = 107). Most (80.5%) were female, with a mean age of 41 years.

    The primary endpoint, a statistically significant change from baseline in monthly migraine days at week 12, was achieved with the 70-mg dose, with an average reduction of 3.4 days compared with 2.28 with placebo. Responses to lower doses were not statistically significant.

    After the 12-week double-blind part of the trial, the 70-mg dose was given to all the study patients open-label. At 1 year, they had an average 4.9-day reduction in migraine days per month, down from 8.7 days at baseline, with no difference between those who had previously received the drug or placebo.

    Also at 1 year, 62% of the patients achieved greater than a 50% reduction in monthly migraine days, 38% achieved greater than a 75% reduction, and 19% achieved a 100% reduction.

    Adverse events occurred in about half of the drug and placebo groups and serious adverse events in less than 1% overall.

    Events leading to discontinuation occurred in 2.8% with 70 mg vs 1.3% with placebo. Injection site pain or other problems occurred in less than 2% in all groups.

    TEV-48125
    Marcelo E. Bigal, MD, PhD, vice president of clinical development at Teva and formerly the chief medical officer at Labrys Biologics, where TEV-48125 was developed, presented the data for a randomized, double-blind, double-dummy, placebo-controlled, multidose, parallel-group study of once-monthly injections of the drug in patients with 8 to 14 days of migraine per month.

    Patients could also take triptans and other acute migraine drugs for up to 14 days, but no more than 4 days per month of opioids or barbiturates were permitted.

    A total 297 patients were randomly assigned to 225 mg or 675 mg of TEV-48125 or to placebo once monthly for 3 months.

    For both doses, there was more than a 6-day decrease in the number of monthly migraine days, a highly significant difference from baseline (P < .0001) and also superior to placebo at months 1 and 2 (P < .001). Results were similar for the secondary endpoint of decrease in headache days (P < .001).

    The proportions experiencing at least 50% improvement during the study were 59% with the 675-mg dose and 53% for the 225-mg dose, compared with 28% for placebo (P < .001). More than 75% improvement was seen in 31%, 34%, and 11%, respectively (P < .001).

    Tolerability was similar to that seen with placebo, and no treatment-related serious adverse events occurred.

    LY2951742
    Phase 2b data on efficacy and safety for LY2951742 in a randomized, double-blind, placebo-controlled, dose-ranging study were presented by Aaron Schacht, global brand development leader for Lilly's pain portfolio. Study participants had 4 to 14 migraine headache days and at least two attacks per month.

    Subcutaneous injections of LY2951742 doses of 5 mg (n = 68), 50 mg (n = 68), 120 mg (n = 70), 300 mg (n = 67), or placebo (n = 137) were given once every 28 days for 12 weeks.

    All four doses were numerically superior to placebo for the change from baseline in migraine headache days, although only the 120-mg dose achieved statistical significance in the last 28-day period of the 12-week treatment phase (P = .004).

    Also statistically significant were the proportions achieving responses of at least 50% (P = .038), 75% (P = .003), and 100% (P = .038).

    Treatment-emergent adverse events occurring in 5% or more of patients in any LY2951742 group and seen more often than in the placebo group included injection site pain, upper respiratory tract infection, nasopharyngitis, dysmenorrhea in women, and nausea. None of these occurred in more than 15% in any group.

    Lilly is enrolling patients for phase 3 trials of LY2951742 for both chronic and episodic cluster headache and has received fast-track designation from the US Food and Drug Administration for cluster headache, Schacht said.

    Awaiting Phase 3
    Dr Shapiro noted that it's also too early to be able to determine whether there are significant differences among the four anti-CGRP drugs, including whether the different target for the Amgen drug makes any difference in efficacy or safety.

    "It's way too soon on the basis of phase 2 trials to make significant comparisons between these agents," he said. "It really requires larger numbers in phase 3 trials and sorting out inclusion/exclusion criteria…. All of them have positive data, and some have extraordinary signals for subsets of patients, but we can't yet draw conclusions."

    However, Dr Ward noted, "If this class of medications pans out, it's almost essentially the holy grail of prevention for migraine because we wouldn't have a lot of side effects that we have with our current medications, such as weight gain, hair loss, or cognitive abnormalities. It might allow people to live a relatively normal life."

    Dr Newman is an advisor for Teva and Lilly. Dr Shapiro serves on the independent data safety monitoring board for the Lilly anti-CGRP drug trials. Dr Ward has disclosed no relevant financial relationships. Dr Lenz, Dr Bigal, and Mr Schacht are employees of Amgen, Teva, and Lilly, respectively.

    American Headache Society (AHS) 57th Annual Scientific Meeting. Abstracts OR12 (AMG 334) and LB02 (TEV-48125). Presented June 20, 2015.

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