Several people have recently commented on the publicity surrounding the new class of drug being touted as a “breakthrough” treatment for migraines. This drug known now as erenumab, is what’s called a CGRP (calcitonin gene-related peptide) receptor inhibitor and works by blocking the effects of CGRP which is thought to play a role in migraines. Let me first say, that anyone who has read my blog posts over the past few years knows that I am a firm believer in the multidisciplinary approach to chronic headaches and chronic pain in general. Therefore, I applaud the hard work and resource commitment that has gone into the development of this drug class. Any advance is good for our patients and ultimately, like in breast cancer, I believe that if we put several of these treatment modalities (i.e. medication, surgery, injections, PT) together in precise ways for each individual patient, we will we see a monumental improvement in headache care. All this being said, I think some clarity into what the actually data show with regard to erenumab is warranted so people are properly informed.
There are several trials of erenumab that have been completed and several ongoing so the data presented here are not the only numbers available, but rather what I consider to be a reasonable sample of what is available and what is likely to be seen in the next few months. As of this post, erenumab is not even FDA approved and is therefore not commercially available although approval is expected as early as this later this month. Furthermore, we don’t know for which indications erenumab will be approved and therefore for what conditions doctors will be “allowed” to prescribe it. This point is important because many of the studies published focus on ‘episodic migraines’ which are defined as fewer than 15 headache days/month with or without aura. Already, there is a difference in the uses for this medication and headache surgery as the majority of patients I see have many more headache days per month, in fact many have pain 24/7. Secondly, the numbers must be explained with respect to the results. What I mean by this statement is that as physicians and patients, we must distinguish between statistical significance and clinical significance. Allow me to elaborate.
In one of the pivotal publications on this topic in the New England Journal of Medicine in late 2017, erenumab was noted to “significantly reduce migraine frequency, the effects of migraines on daily activities, and the use of acute migraine-specific medication over a period of six months”. Sounds awesome, right? But a look at the actual data tell a slightly less impressive story. The average number of headache days per month in both the placebo and experimental (i.e. erenumab) groups was 8. The patients who are candidates for headache surgery often have many more headache days per month and hence can be considered much more debilitated on that parameter alone. Moreover, the average days of use per month of acute-migraine-specific medication in these patients was 3. In other words, these patients were only using abortive medications 3 days per month on average, so aging, the group of patients in this study weren’t as sick as those I often see in my office. The trial lasted six months with monthly injections of the drug and these same parameters were evaluated over the last three months of the trial. At the highest dose of erenumab (presumably the one with the most efficacy), over the last three months of the trial, the patients receiving the active drug had about 4 fewer headache days/month – almost a 50% reduction in frequency. Sounds good so far. But in the same trial, patients who were given the placebo had 2 fewer headache days per month. Let me say that again, if you were given the drug at the highest dose possible in this trial, you would have two fewer headache days/month than if you received saline injections. Furthermore, only 50% of the patients at the highest dose, got this type of result! Now if you have 8 headache days a month, maybe 4 fewer headache days/month is great, but what if you have 28 headache days a month – perhaps not as dramatic? If you suffer from 28 headache days/month and if I as your doctor told you that you needed monthly injections for the rest of your life, at an estimated cost of $10,000/year and that if you were lucky you would have 4 fewer headache days/month would that be worth it? The data show statistically significant improvements in those receiving the drug versus placebo, this statement is true, but clinically – meaning to the patient sitting in front of you in the office – are these actual numbers compelling enough? Would the same percentage improvement (50%) hold true for patients with chronic migraines, meaning those who have more than 15 headache days/month? We don’t know. Perhaps in those patients, the drug would be completely ineffective or more effective. However, based upon these initial studies, I would wager that the FDA will approve erenumab only for episodic migraines, so if you have over 15 headache days/month, you won’t even be eligible to get this drug. While these indications may change over time, there is no telling how long that timeline will be.
And these are some of the best data. Another trial completed and published in early 2018 (ARISE) used the lower dose of erenumab (70 mg monthly) and showed that only 40% of patients achieved the 50% reduction in headache days/month yet in the placebo group, 30% had the same reduction – only a 10% difference. In addition, the actual numbers showed that these results translated to one fewer headache day/month compared with a placebo! In the more recently reported LIBERTY trial, which included patients with a more debilitating migraine burden, only 30% of patients receiving erenumab had the 50% reduction in monthly headache days which translated to 1.6 fewer headache days/month compared with placebo. Hardly the breakthrough that some in the press would have you believe. The results with headache surgery in patients who seem to suffer many more monthly headaches demonstrate that 88% of patients experience at least a 50% reduction in frequency, severity or duration of symptoms.
There are other unknowns as well. For example, patients in the New England Journal study were only followed for six months (in the ARISE and LIBERTY trials for only 3 months). What happens afterward? Does the drug continue to be effective, does it become more effective or does it lose its efficacy with time like so many migraine drugs before it? There are 5-year follow-up data for headache surgery that demonstrate continued good results even that far out from an operation. I have seen this in quite a few patients whom I’m lucky enough to be in touch with that far out. Most are too busy getting on with their lives. What about side effects? So far, I believe there is data on erenumab one year out which shows no significant adverse effects. That’s wonderful, but CGRP acts on the vascular system so there are concerns about the long-term risks of stroke and heart attack. What if you have hypertension, can you use this drug safely? What if you are a woman of child-bearing age (the major demographic in those suffering from migraines) – can you get pregnant while being on a drug that affects the vascular system and hence possibly the placenta? This question is valid since you will presumably have to take this drug forever. In the ARISE trial, women of child-bearing age were only included if they were using contraceptives and hence presumably couldn’t get pregnant.
I certainly don’t mean to be a glass is half-empty type of guy as many of you know I am not. I think this class of drug has a lot of potential and should certainly be studied further. Maybe with time, we’ll see better results with higher doses or in patients more precisely selected. Maybe we’ll see this drug used in combination with patients who also have surgery and see more amazing results than in patients having only one or the other. Time will tell, but I post this so that people who are anxiously awaiting these developments are realistic about what they can practically offer. Hopefully, that helps.