Author: David Dodick

CGRP therapies work better in clinical practice than in trials

CGRP therapies have proved more effective in clinical practice than in trials, though adverse events (AEs) and discontinuations are more common. There is potential for both rapid and delayed responses, and there appear to be additive and synergistic effects between CGRP therapies and other preventive treatments such as botulinum toxin.

These were the main conclusions drawn by Professor David Dodick, from the Mayo Clinic, Phoenix, Arizona, USA, during the Migraine Trust Lecture 2020, CGRP therapies: what I have learned since launch.

“Efficacy seems to outperform what has been seen in clinical trials, even though we are seeing a more treatment resistant population, often on multiple medications and with multiple comorbidities that would have excluded them from clinical trials,” said Professor Dodick. “Of course, we can be more flexible than in trials and are combining treatment with lifestyle modifications and other medications and interventions but it does appear that we are seeing greater efficacy in practice.”

He reported that clinicians are seeing ‘pure responders’ who respond so well to CGRP therapies that they need infrequent or even no further injections over prolonged periods, and ‘pure non-responders’ who get no benefit at all. He discussed real world data showing that 30-35% of patients discontinue therapy due to lack of response. In small case series, up to 8-12% have discontinued treatment due to AEs, compared to approximately 2.5% in clinical trials, and it it is unclear if this is related to more severely affected populations and greater prevalence of comorbidities in clinical practice.

Professor Dodick drew attention to Food and Drug Administration (FDA) label changes for erenumab since launch as a result of emerging data showing new or exacerbated hypertension, generally within the first week of treatment and after the first dose. He explained that more research is needed to find out if this is an effect related to blocking the CGRP receptor or ligands.

“We also need to learn a lot more about who’s at risk of the hypertensive response and how best to monitor for it,” he added.

In addition, Professor Dodick referred to FDA label updates for erenumab related to warnings about hypersensitivity and serious complications of constipation.

“We knew that constipation was a bit of an issue with erenumab because it occurred in up to 3% of patients in clinical trials but we didn’t quite recognise that in some patients this might be severe,” he said.

Turning to types of response, Professor Dodick explained that clinicians are seeing both rapid and delayed responses to CGRP therapies, with some patients not responding until the second or third month of treatment, together with similar cumulative benefits over time as previously seen with other preventive agents.  Additive or synergistic effects are seen with CGRP therapies and other preventive agents, including botulinum toxin, and ‘wearing off’ effects of CGRP therapies are seen in patients before their next dose is due – something that Professor Dodick said he would not have expected from pharmacokinetic studies. However, he advised against stopping treatment because of ‘wearing off’ effects.

“We don’t know whether there is true tachyphylaxis or if a patient is having a bad month or two for reasons that are unclear. But I wouldn’t suggesting discontinuing any of these antibodies if patients previously had a good sustained response and they just happen to have had a bad month,” he said.

On the potential of switching, he reported that all the specialist clinicians in his own area reported successful switching of patients between CGRP therapies following an inadequate response to initial treatment.

“Overall, experience of CGRP therapies since launch shows that there appears to be a reduction in severity and frequency of migraine attacks and an improved response to acute medication, including gepants, triptans and non specific analgesics. Hopefully, there are controlled trials underway right now that will also demonstrate whether there is a reduction in intensity and duration of individual attacks,” concluded Professor Dodick.

Anti-CGRP therapy: where does it fit in our clinics?

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.

 

Initiating therapy

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.

 

Target reductions

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.

 

2017 American Academy of Neurology Annual Meeting: Reduction in migraine days with single dose eptinezumab

In chronic migraine patients, a single infusion of eptinezumab (previously known as ALD403), a calcitonin gene-related peptide (CGRP) antibody, led to significant reduction in migraine days as measured by 75% responder rates.  Efficacy was maximal after 1 to 4 weeks and sustained for 12-weeks.1,2  These findings were reported by CGRP Forum Co-Editor Professor David Dodick.

This was a parallel group, double-blind, randomized, placebo controlled, dose-ranging Phase 2b trial which evaluated the efficacy, safety and pharmacokinetics of eptinezumab in 616 patients with chronic migraine.3 Diagnosis of chronic migraine was confirmed during the 28 day screening period, by ≥15 headache days, of which ≥ 8 days were assessed as migraine days, with ≥5 migraine attacks recorded in the electronic migraine diary. Patients were allocated to either single intravenous infusion of 10 mg, 30 mg, 100 mg, or 300 mg eptinezumab, or placebo.

The primary endpoint was the reduction in migraine days as measured by 75% responder rates from baseline to week 12. At the 100 mg dose, the primary endpoint was attained by significantly more patients on eptinezumab than placebo (33% vs 21%); in addition, 50% responder rates were also significantly greater than placebo (57% vs 41%).

In addition to significant reduction in the primary endpoint, a single dose of eptinezumab led to:

  • Reduction in the number of patients with migraine during 24 to 48 hours post infusion (post hoc analysis)
  • Reduction in the percentage of migraine attacks reported by patients as severe.

A single dose of eptinezumab also reduced the impact of migraine on daily functioning, as assessed by the Headache Impact Test-6 at baseline and week 12. The tolerability profile of eptinezumab was similar to placebo, with no serious treatment-related adverse events or infusion reactions reported.

This rapid onset of action with dosing every 3 months could be a counter to the potential disadvantages of intravenous administration, compared with subcutaneous administration with erenumab, galcanezumab and fremanezumab.

Top-line data from the first Phase III trial (PROMISE-1)4 with intravenous eptinezumab are expected by the end of the second quarter of 2017.

References

  1. Dodick D, et al. Randomized, double-blind, placebo-controlled trial of ALD403, an anti-CGRP peptide antibody in the prevention of chronic migraine. Presented at: 2017 American Academy of Neurology Annual Meeting. April 28, 2017; Boston, USA.
  2. Lipton R, et al. 75% responder rates provide improvement in HIT-6 scores from week 4 through 12 following a single infusion of ALD403, or placebo. 2017 American Academy of Neurology Annual Meeting. Poster P2.165. April 24, 2017; Boston, USA.
  3. A Multicenter Assessment of ALD403 in Chronic Migraine. ClinicalTrials.gov Identifier: NCT02275117. https://clinicaltrials.gov/ct2/show/NCT02275117
  4. A Multicenter Assessment of ALD403 in Frequent Episodic Migraine (PROMISE 1). ClinicalTrials.gov Identifier: NCT02559895. https://clinicaltrials.gov/ct2/show/NCT02559895

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