Advances in the Treatment of Migraine

Transcription

1 Advances in the Treatment of Migraine C. Philip O Carroll, M.D. Director Neurobehavioral Medicine Hoag Neurosciences Institute Guyuron B Headache, 2015;55: I m sorry your head hurts, sweetie.is there anything I can do to make you shut up about it?

2 Migraine: is a Prototypical Neurological Disorder Migraine is a chronic neurovascular disorder, characterized by severe headache, and in some patients, an aura involving other symptoms Approximately 30 million people in the US suffer from migraines Peak prevalence occurs between 30 and 49 years of age, with women suffering from migraine at more than twice the rate of men 1 1. Lipton RB, et al. Headache 2001;41: Migraine:Frequently Reported Symptoms Migraine symptom Percent (Individuals reporting) Pulsatile Pain 85% Light sensitivity 80% Sound sensitivity 76% Nausea 73% Unilateral pain 59% Blurred vision 44% Aura 36% Vomiting 29% Adapted from Lipton RB, et al. Headache 2001;41: Migraine is One of the Top Ten Causes of Years Lived with Disability Worldwide Impact of Migraine Percent (Individuals reporting) 1 to 4 attacks per month 62.7% Severe impairment requiring bedrest 53.7% Missed at least a day of work or school 25% Missed family or social activity 30% WHO rates severe migraine along with quadriplegia, psychosis, and dementia as one of the most disabling chronic disorders. Lipton RB, et al. Headache. 2001;41:

3 Barriers to Successful Treatment Less than 50% ever consult a health care professional Often misdiagnosed as Sinus Disease, Tension Headache, Allergy, Cervical Disc Disease, etc Fewer than 25% of patients receive appropriate treatment 50% of patients still rely on over-the-counter medication and 20% use prescription medication Lipton RB, et al. Headache. 2001;41:

4 Migraine is a Spectrum Disorder Episodic / Phasic Chronic / Non-phasic Levels of distress, functional disability, health resource utilization, associated psychopathology increase in linear fashion 1 CM (2-4%) accounts for 85% of all migraine costs 1. Kroenke, Arch Int Med 1993

5 A Timeline of FDA Approved Migraine Preventives 1962 Methysergide 1979 Propranolol 1990 Timolol 1996 Divalproex sodium 2000 Divalproex sodium ER 2004 Topiramate approval 2010 Botox 83% of patients started on a preventive medicine are not taking it one year later THE CGRP REVOLUTION 37- amino acid peptide discovered at UCSD while studying the thyroid hormone calcitonin 1 CGRP containing nerve fibers innervate nearly every organ system of the body 2 It is the most potent vasodilatory peptide known, and is especially potent in intracranial arteries 3 1. Amara et al, Nature, 298: Raddant et al, 2011 Expert Rev. Mol. Med. 13:e36 3. Rosenfeld et al, Nature 1983, 304: Clinical Evidence Implicating CGRP in Migraine 1. Elevated CGRP levels in the jugular outflow during migraine attacks (CGRP was the only peptide that was significantly released) 1 2. IV injection caused moderate to severe migraines in migraineurs only, suggesting that migraineurs are unusually sensitive to CGRP actions 2 3. Sumatriptan returned CGRP levels to normal 4. CGRP receptor antagonists are effective in the treatment of migraine. These drugs relieve both pain and associated symptoms 3 1. Goadsby et al 1990, Ann. Neurol. 28: Olesen et al 2002, Cephalagia. 22: Villalon et al 2009, Pharmacol Ther. 124:309-23

6 CGRP Receptor Antagonists Small Molecules To date 6 CGRP receptor antagonists have been clinically tested 1 Telcagepant (MK-0974) showed significant benefits over placebo, but was discontinued because of liver toxicity 2 Other small molecule antagonists have been tested but future uncertain 3 1. Bigal et al 2013, Headache. 53: Ho et al 2008, Neurology. 70: Diener 2011, Cephalalgia, 31: Monoclonal Antibodies and CGRP 1 Less risky alternative than small molecule CGRP antagonists Delivered via IV, SC or IM because of their size and hydrophilicity 3 companies, Alder, Teva, Lilly have antibodies that bind to CGRP ligand Amgen antibody binds to CGRP receptors Average half-life approximately 3 weeks allowing them to be administered monthly 1. Silberstein et al, Sept Headache Humira (Adalimumab) vs. TNF Rituxan (Rituximab) vs. CD20 Remicade (Infliximab) vs. TNF Natalizumab (Tysabri) vs. α 4 Integrin Erenumab (Amgen) vs. CGRP-R Eptinezumab (Alder) vs. CGRP Fremanezumab (Teva) vs. CGRP Galcanezumab (Lilly) vs. CGRP

7 Phase 2 and 3 Placebo Controlled Trials in Patients with Episodic or Chronic Migraine have shown a Significant Decrease in Monthy Migraine Days Erenumab (Amovig) Episodic 70 mg q4kwk for 12 weeks 3.2 days vs mg q4wk for 12 weeks 3.7 days vs. 1.8 Chronic 70 mg q4wk for 12 weeks 6.6 days vs. 4.2 Fremanezumab (Teva) Episodic 675 mg SC q4wk 12 weeks 6.0 days vs. 3.5 Chronic 900 mg SC q4wk 12 weeks 59.8 hrs vs Galcanezumab (Lilly) Episodic 150 mg SC q2wk 12 weeks 4.2 days vs. 3.0 Eptinezumab (Alder) Episodic 1000 mg IV single dose 5.6 days vs. 4.6 Botox: therapeutic gain of 1.7 days per month Other End Points from Phase III Trials The 50% Rule 43-50% of MABs Reduction in MMD in treatment failures 3 to 5 days Migraine Specific Medication Days 3 to 5 days Greater than 75% reduction 21% and 17% Approx. 45% of FDA approved preventive medicines including Divalproex, Topiramate, Propranolol and Timelol achieve the 50% reduction..but side effects In the Clinical Trials, with over 8,000 Patients Screened, there have been virtually no Side Effects other than Site of Injection Irritation and constipation

8 MABs are not metabolized and do not cross the blood brain barrier, so no neuro-cognitive or hepatotoxic side effects, but. CGRP plays a protective role in the vascular system. It is a potent vasodilator and can buffer the effects of cerebral or cardiac ischemia CGRP receptors are present in peripheral and central nervous system CGRP is active in wound healing and other physiologic functions In animal studies CGRP MABs causes mucosal damage leading to inflammatory bowel disease