The Clinical and Economic Impact of New Treatment Options for Migraine   Part 1 of 3 in an expert interview e-newsletter series on migraine. Alan M. Rapoport, MD, is Clinical Professor of Neurology at the David Geffen School of Medicine at UCLA in Los Angeles, California. He is Past President of the International Headache Society and Founder and Director-Emeritus of The New England Center for Headache in Stamford, Connecticut. Dr. Rapoport is Editor-in-Chief of Neurology Reviews.    In this first part Dr. Alan Rapoport discusses the clinical and economic impact of the new treatment options for migraine. In future installments, Dr. Richard Lipton will discuss the clinical landscape of migraine prevalence and Dr. Merle Diamond will discuss the disability of migraine and associated costs.   What are the newer preventive medications that are expected to reach the migraine market?   Dr. Rapoport: There are two basic types of medications that involve calcitonin gene-related peptide (CGRP).   The first type consists of the small molecule CGRP receptor antagonists (also referred to as “gepants”). Olcegepant—the first small molecule CGRP receptor antagonist—was an IV preparation that was studied against placebo and found to be effective. Approximately 66% of patients demonstrated improvement 2 hours after treatment compared with 27% of the patients taking placebo. Mild paresthesia was the only notable adverse event. It was determined in animal studies that this drug did not constrict blood vessels like triptans. However, because the drug could not be put into oral form for quite some time, it was never fully developed.   The second major drug of this type was telcagepant. Telcagepant was studied as an acute treatment option in two phase 3 trials against placebo and against both rizatriptan and zolmitriptan. In both trials the drug worked approximately as well as the triptan in terms of relieving headache in patients and much better than placebo. Telcagepant had fewer adverse events than the triptans. However, when telcagepant was studied as a preventive option given twice daily, it caused signs of liver toxicity. After another trial, it was again shown that telcagepant caused liver toxicity, so the drug was no longer developed.   The other drugs that were being made at the time all had positive studies and none showed signs of liver toxicity; but none of them were further developed and they were all put on hold. They’re just being brought back now for further study.   There are two oral, small molecule, CGRP receptor antagonists in development for the acute care of migraine: ubrogepant and rimegepant.  Both of them show promise in clinical trials, and so far, they don’t seem to be causing liver toxicity. Two others are being investigated as preventive drugs that will be given once or twice a day.   Because the original gepants showed promise, but sometimes caused liver toxicity, there was the thought that an antibody could be made to either CGRP or to its receptor that wouldn’t cause liver toxicity because antibodies aren’t broken down in the liver. This led to the development of the second type of CGRP treatment, the CGRP monoclonal antibodies.   Antibodies are exquisitely specific. They are engineered to do exactly what you want them to do. So, if you want an antibody to the CGRP ligand, or you want an antibody to the receptor where the ligand docks, that’s exactly what you get. As antibodies are not broken down in the liver but rather in the lymphatic system or the reticuloendothelial system, antibodies have a long half life of about 28 to 30 days so they can be used as preventive therapies. Instead of being given daily, they are given once a month, or even less frequently. They don’t cross the blood brain barrier because of their large size and will not cause central nervous system side effects. They have to be given by injection and can’t be given by the oral route because if you swallow an antibody it gets broken down into amino acids in the GI tract.   CGRP is a potent vasodilator and it increases pain signaling in the peripheral and probably the central nervous system. When CGRP or its receptor is blocked, it causes lack of vasodilation, but no vasoconstriction. It also causes increase in pain signaling.   There are four antibodies in development and all have somewhat similar phase 2 and 3 clinical trial results.  The recently approved erenumab-aooe (Aimovig) is the only one that’s an antibody against the CGRP receptor itself. The other three are antibodies against the CGRP ligand.     Aimovig (erenumab-aooe) was approved by the US Food and Drug Administration on May 17, 2018 for the preventive treatment of migraine with or without aura in adults. Erenumab is administered subcutaneously once a month by a self injected autoinjector.   The next CGRP therapy that we might see is fremanezumab. It will also be given subcutaneously once a month just like erenumab, but it was also studied once every three months, and appears effective. Fremanezumab was studied in episodic and chronic migraine (like erenumab), but it is also being studied in cluster headache.   The third CGRP therapy that might be released is galcanezumab. This drug will be an injection given once a month and it was studied episodic and chronic migraine, as well as cluster headache.   The last one will probably be eptinezumab. This will be administered intravenously in the doctor’s office, or at home if it can be arranged, every three months.   The typical primary endpoint in the trials for all four of these drugs was the number of migraine or headache days decreased per month registered at various time points. There were several secondary endpoints. The most common was the percentage of patients who had at least a 50% decrease in their monthly migraine days. Some also looked at the 75% responder rate or even the 100% responder rate. They also looked at the number of days of decrease in use of migraine specific medications.   When you look at the primary endpoint, the number of days decreased of migraine or headache in a month, it was somewhere between 2 and 3 days fewer than placebo. But when you look at the 50% responder rate and see that approximately half of the patients in the trials will have at least 50% fewer migraine days per month, you see that it is a clinically meaningful endpoint. Even the possibility, although smaller, for a 75% or 100% responder rate is pretty impressive.   These drugs were all well tolerated in the trials. Looking across all of the studies there were very few serious adverse events. Most of them were not related to the drugs themselves and they seem to have a very good safety profile. There are no contraindications listed for erenumab and the most common side effects were injection site reactions and constipation. There were no drug-drug interactions.   How does the clinical efficacy of current preventive options compare to the clinical trial results of newer medications?   Dr. Rapoport: The clinical efficacy of these drugs is reasonably good, but it doesn’t usually stop migraine, except in a few patients whom we call “super responders.” We can expect the average patient to be about 50% better, which will be very helpful for most patients.   Before the approval of erenumab, we had only four FDA-approved drugs for prevention of episodic migraine and only one approved for chronic migraine.   Of the four that are approved, two of them are beta blockers and two of them are anticonvulsants, and they usually have to be given at least once a day and sometimes twice a day. There are also a lot of possible side effects.   The drug most often used is topiramate, which is now generic, and that has the most troubling and sometimes serious possible side effects. It has been used in a large percentage of migraineurs and will continue to be used, maybe to a lesser extent.   The data show, and my clinical experience confirms, that it’s hard to keep people on this drug, or some of the other drugs, because of side effects and lack of efficacy.  We had no choice until now; doctors will consider future treatment carefully.   Currently, we counsel our patients and try to get them to stay on treatment. But the data show that at the end of six months fewer than 25% of patients will still be on a preventive drug they were placed on, and at the end of the year it will be probably 15% or less.   It varies with how willing the doctor is to struggle along with the patient; but in general patients don’t stay on these drugs very long. They get switched from drug to drug and most headache specialists like myself will have an office full of patients that have been on four or five drugs, sometimes from 4 different categories of medicine.   It’s impossible to compare the effectiveness of new therapies to the older ones unless they are compared head to head in the same trial. In general, the 50% responder rates of these older drugs is between 35% and 50% and of the newer drugs is between 40% and 55%. So there is not a dramatic difference; but the older drugs don’t usually have any patients who are 75% or 100% better in a double blind controlled clinical trial.   The other major differences are the frequency of administration and the lack of troublesome side effects from the newer antibodies.   What are the potential economic challenges for patients with migraine when the new drugs become available?   Dr. Rapoport:  All new therapies are much more expensive than older drugs. The older drugs are all generic and you can get them for $10 or $20 a month, or sometimes even less. So, you need some pretty good reasons to want to go to a newer therapy and I think I’ve given some of those reasons.   Erenumab will be $575 an injection, once a month, which comes out to exactly $6,900 a year, which is a lot more than $100 or $150 a year on generics.   But if it turns out that erenumab and the other newer therapies are more effective and easier to use with fewer side effects, I think they’ll become more popular, even though they’re expensive.   The manufacturer of erenumab has presented a plan to give everybody who is prescribed their drug two free injections, meaning two full months of care for free whether or not their insurance companies agree to pay for the therapy. Actually, although $6,900 per year sounds like a lot to pay for a therapy, headache specialists expected the cost would be higher. Antibodies for multiple sclerosis therapy usually cost multiples of that per year.   These newer therapies may be out of the price range of people who don’t have insurance coverage. But, hopefully, if they are as good as we hope they will be, insurance companies will eventually cover their cost. It is way too early to know how the PBMs and medical insurance companies will react to this new class of migraine preventive therapy; but I predict we will have a little less trouble getting our patient’s coverage than we expected.     This interview was produced by the Custom Programs division of Frontline Medical Communications. The editorial staff of Neurology Reviews was not involved in the content development.