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A monoclonal antibody to prevent migraine!

This last week a monoclonal antibody injection for migraine was released, with fanfare and great hopes of becoming a commercial success. Amgen developed Aimovig (erenumab) and published its findings in the New England Journal of Medicine last November. It is an injection that targets calcitonin gene-related protein (CGRP), a chemical released in the brain during migraine which dilates blood vessels. The monoclonal antibody inactivates this protein for a long time, on the order of one and a half months.

Migraine is often involves head pain, nausea, weird neurological symptoms including vision loss and even stroke symptoms. The combination of symptoms is frequently disabling and "migraineurs" suffer not only from their nausea and headache, but also from large financial burdens associated with the condition, on average around $6000/year for chronic migraine sufferers. The economy loses over $13 billion in lost workdays. Over 44 million people in the US have migraines, though this probably underestimates the numbers since many never come to medical attention. Migraine is a worldwide problem. In a rural area in Haiti where I have seen patients, the most common complaint was "tet fe mal, vant fe mal" meaning "my head and my stomach are bad." I was confused because of how nearly universal the complaint was. In retrospect they were describing migraine. I come from a family of migraineurs and can attest to how chronic and episodic migraine affects the rest of us: children with migraine vomiting their Saturday French toast, a mother with migraine spending what seemed like half my childhood in a darkened bedroom, a partner with alarming neurological symptoms. It's enough to give those of us without headaches headaches.

Theories of what causes migraines have evolved over the years and presently I understand that the phenomenon is felt to be a "spreading depression" of brain electrical activity, resulting in hypersensitivity to normal processes including the pulsating of blood vessels. Migraine is hereditary and common, and includes some annoying but tolerable symptoms such as caffeine withdrawal headache, carsickness and ice cream headaches. It can also be a disablingly horrible, usually pulsating, headache with nausea and vomiting, light and sound sensitivity, sometimes preceded by sparkles or blind spots that move across the visual field. It can be brought on by a change in routine, certain foods or drinks, menses and stresses. Home remedies bring mixed results: caffeine helps but can perpetuate headache, as can normal analgesics. Anti-inflammatories including aspirin can be very effective, but daily use can induce migraine and can cause ulcers and intestinal bleeding. Herbal remedies such as feverfew have gained attention from the medical community in the last few years but are not very effective for most people. "Triptans" (including sumatriptan, the first in the class) which can be taken by pill, shot or nasal inhalation, can be quite effective, but not universally so, and are still costly. Many patients, in the throes of a migraine they can't control at home, end up in emergency rooms for intravenous treatments which can leave them or their insurance companies with multi-thousand dollar bills.

Preventing migraines by the use of medication has been an effective approach for decades. When lifestyle approaches such as regular sleep and meal schedules, exercise and management of specific triggers is not effective, drugs in the beta blocker, antidepressant and anticonvulsant categories can be tried. Not all migraine prone people need to take medication to prevent headaches, but if the headaches are severe or frequent or associated with severe neurological symptoms, this is a good approach. One of the earliest drugs used for migraine prevention was methysergide, an ergotamine derivative, which was very effective but caused a frequently fatal side effect of scarring of the internal organs in one in 5000 patients. It is rarely used now, and is not available in the US. Several beta blockers, also used to treat high blood pressure, are effective, with the main side effects being change in the heartrate and feeling cold in the hands or feet. With prolonged use they can lead to weight gain and increase the risk of diabetes. Amitryptilene, an older tricyclic antidepressant, can be effective in migraine and other pain syndromes, but does lead to weight gain and can cause intolerable sleepiness. Valproic acid, a drug originally for epilepsy, can be quite effective, but also causes weight gain, can upset the stomach and cause lethargy. Topiramate, a more recently developed drug for epilepsy, has been remarkably effective, without causing weight gain. In fact it can help with weight loss. It can cause sleepiness and brain fog however. I used to say that these drugs made you fat, stupid and poor, but they are all now generic, so with the exception of topiramate, just fat and stupid. For those who get these side effects, the trade-offs are often unacceptable.

Enter, now, the monoclonal antibodies. There are four of them, with the unpronouncable names of eptinezumab, erenumab, fremanezumab and galcanezumab. Erenumab is the first to have been approved by the FDA. It is given as a subcutaneous injection once a month and, in the study reported in the New England Journal of Medicine last year, at the higher dose tested it reduced the number of headache days by about 50%. The study lasted 6 months and the primary side effect was upper respiratory and sinus infections. There was an excellent editorial in the JAMA (Journal of the AMA) by Elizabeth Loder MD and Matthew Robbins MD which mentions some other concerning information. In clinical trials of fremanezumab and erenumab there have been 3 deaths: one due to suicide, one to chronic obstructive lung disease and another to an arteriosclerotic event. These were probably people thought to be relatively healthy, or they wouldn't have been included in a clinical trial. Also, although these causes of death seem to be far removed from migraine prevention, the target of this monoclonal antibody, the protein CGRP, could definitely have something to do with any of the three. Trials of these drugs have been pretty short, and we don't really know whether there are any long term safety problems. This is a real concern, since migraine is often a lifelong disease that can start in childhood.

The cost of these drugs is a real concern as well. Erenumab has been priced below what was initially predicted, out of concern that a higher price point would invoke the wrath of everyone who is already angry about ridiculous drug costs. Erenumab is considered "affordable" at an estimated cost of $6900 per year. Almost $20 per day. Wow. I sure wouldn't want to deprive a fellow human of a chance to be relieved of pain, but if even 1% of migraine sufferers use this medication for a year, it will add tens of millions of dollars to the healthcare budget. In comparison, a drug like topiramate costs less than a dollar a day and is about as effective. Methysergide, when it was studied, was even more effective.

The bottom line on all of this as I see it: Migraines are terrible and common and the treatments are far from perfect. Prevention is important and the drugs for this are also far from perfect. There is a new option out there which is wickedly expensive and has unknown long term side effects but may work where other drugs do not. We will all pay for it (and its yet to be released cousins) via higher taxes and insurance costs.






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