With anti-CGRP therapy rapidly becoming available to clinicians, it’s a good time to consider where it fits within our therapeutic options for migraine, says Professor David Dodick, from the Mayo Clinic, Scottsdale, Phoenix, Arizona, USA.
In the USA, erenumab, fremanezumab and galcanezumab are approved for the preventive treatment of migraine in adults, while the EU licence for erenumab – the only agent approved to date – is a little more restrictive. The indication is for migraine prophylaxis in adults who have at least four migraine days per month.
Of course, many of the patients for whom we may be considering anti-CGRP therapy have far more than four migraine days per month. Most will have failed to respond to multiple conventional prophylactic options – oral and injectable – and many will have failed neuromodulation devices and other non pharmacological therapies. These patients are generally considered treatment refractory and have been waiting a long time for something new. They are unlike the patients in clinical trials of anti-CGRP agents who tend to be not nearly so severely affected by migraine.
Who is likely to respond?
Unfortunately, we can’t identify which patients are likely to respond to erenumab, fremanezumab or galcanezumab as there are no clinical or imaging features or blood biomarkers that identify responders. So we don’t know who will respond positively or who will experience side effects. That’s precision medicine and we’re not there yet with anti-CGRP therapy.
While we are currently evaluating our data, our clinical experience thus far, in a treatment refractory population of patients mostly with chronic migraine, has been encouraging and largely mirrors the efficacy rates and tolerability profile that has been seen in the Phase 2 and Phase 3 clinical trial programmes.
How we initiate therapy depends on how familiar and comfortable we are with a new drug. If we look at the clinical trials of anti-CGRP treatment, there is really no statistically significant difference in the effectiveness of different doses of these agents – but nor is there a significant penalty in terms of higher rates of side effects with the higher dose.
For erenumab, I start patients with a normal body mass index on erenumab 70 mg and see how they are doing at one month. If there has been a substantial response, I’ll leave them at that dose. Otherwise, I will increase the dose to 140 mg. In obese patients, I will start at 140 mg.
At this point, fremanezumab and galcanezumab have just recently been FDA approved and become commercially available so our experience is very limited with these monoclonal antibodies (mAbs). Fremanezumab is available in monthly (225 mg) and quarterly (675 mg) dosing options. The manufacturer’s recommendation for galcanezumab is to start treatment with a 240 mg loading dose (two subcutaneous injections of 120 mg each), followed by monthly doses of 120 mg injected subcutaneously.
There is evidence that a meaningful subgroup of patients who are non-responders (less than 50% reduction in monthly migraine days) to anti-CGRP mAbs in the first month will become responders in the second or third months. For that reason, it’s reasonable to continue treatment for three months (three injections).
When starting anti-CGRP therapy, I don’t stop any other prophylactic agents that my patients are taking, such as topiramate, amitriptyline, propranolol or botulinum toxin, because no drug-drug interactions have been reported between anti-CGRP agents and other drugs.
My patients define the level of response they are aiming for. I recommend using patient diaries to capture reduction in migraine days and acute medication use, and to calculate the percentage reduction in migraine days. I also recommend capturing patient-reported outcomes using a disability scale or a migraine-specific quality of life measurement. When we’re using relatively expensive therapies, I believe it’s incumbent on the physician and the patient to provide objective documentation for improvement. A disability instrument that takes less than a minute to complete before and after therapy shouldn’t be an obstacle to documentation. That said, it’s up to the patient to define success or the lack of it. If a patient who has failed other therapies gets only a 20% reduction in frequency but they get a 70% reduction in intensity, they’re going to feel substantially better even though they may not meet an arbitrary threshold of success that I may have set.
How long will patients need anti-CGRP therapy?
Very few patients have been on therapy for more than three years so we don’t have long term data. From the small number who have been on therapy for a few years, there does not seem to be any wearing off effect. As the side effect profile is very favourable, patients are able to continue to adhere to therapy.
I have spoken to a woman who became migraine free with erenumab and stopped treatment after four years. Within two months, she started getting migraine symptoms, such as mental fogginess, sensitivity to light and intermittent nausea but not headache. Then, after four months, she started getting migraine again, with increasing frequency.
Migraine does tend to remit in a proportion of patients, with age and over time. So, if a patient has been migraine free for six months or a year, we may consider stopping therapy but it depends on patient comfort. If a patient has suffered for 20 or 25 years with migraine and they get on a treatment that changes their life, without side effects, they won’t want to stop. But another patient may want to try and come off treatment – it’s very much an individual decision that will be made through dialogue between patient and physician.