Effect of CGRP Inhibitors on Patients With Cluster Headaches

Stephen Silberstein, MD: Anybody have off-label experience with cluster headache with any of the antibodies? What’s your opinion?

Stewart J. Tepper, MD: I’ve had very good success in patients who have migraine plus some trigeminal autonomic cephalgia—usually cluster, sometimes hemicrania continua—and patients have had both. That’s how I am able to actually say that they have migraine in order to get the monoclonal antibody for them. Most of the patients have reported some benefit from this.

Stephen Silberstein, MD: Steph?

Stephanie J. Nahas, MD, MSEd, FAHS, FAAN: It’s still a little bit early for me to say. Having patients who have both is much less common than having patients who have just cluster. My sense is the same, that both phenotypes of headache will respond.

Andrew Blumenfeld, MD: In cluster headache, CGRP [calcitonin gene-related peptide] levels are elevated, so we’d anticipate this.

Stephen Silberstein, MD: Have you had any practical experience?

Andrew Blumenfeld, MD: I’ve had 1 case, with similar experience to Stew, who had migraine features associated with cluster.

Deborah Friedman, MD, MPH: I’ve prescribed it to patients with cluster, but I really haven’t gotten much feedback yet. However, we did participate in the trial and we did the chronic cluster trial. Despite the fact that the primary outcome was negative, we were a pretty high enroller, and all of our patients got better with chronic cluster.

Stewart J. Tepper, MD: With galcanezumab or with fremanezumab?

Deborah Friedman, MD, MPH: With galcanezumab. Some of them got dramatically better, and there was no doubt that our patients had chronic cluster. Sometimes, in clinical trials, you wonder who gets put in the trials, and our patients were legit. They did very well.

Deborah Friedman, MD, MPH: I think that their endpoint was measured too soon.

Stephen Silberstein, MD: The fundamental problem is what you hit on. The way they enrolled a lot of those trials, particularly for episodic, is you had to spend a week with a diary, then you got your medication, and then they either use 3 or 4 weeks later. If your trial is 6 weeks, by the time you get to the doctor and you get everything done, you’re going to end naturally. I’ve treated a couple of patients now, 1 not much, but 1, for the first time in his entire life, was basically cluster-free. I’ve taken care of this guy for 10 years in a cycle. I think it works. I don’t know if it’s going to work in everybody, but it’s something to think about.

Deborah Friedman, MD, MPH: We think about it with the dosing, too.

Stewart J. Tepper, MD: I think we ought to summarize though where the 4 studies ended up. For galcanezumab, there were 2 studies, 1 to prevent chronic cluster headache that was negative, possibly because the endpoint was evaluated too early, and 1 that was for episodic cluster headache, which was positive. For fremanezumab, there were 2 studies, 1 to prevent chronic cluster headache and 1 to prevent episodic cluster, and both failed to reach their primary endpoint.

Stephen Silberstein, MD: I wouldn’t say that. The episodic cluster trial with fremanezumab was poorly designed, and if it used the same endpoints as the study that Eli Lilly did, it would have been positive. It’s extremely important that people who designed the studies didn’t have enough knowledge of how cluster behaves. They tried it like chronic migraine. That’s the problem. It wasn’t that the drug failed, it was the study design that failed.

Stewart J. Tepper, MD: I agree. I think that was a methodologically flawed study.

Stephen Silberstein, MD: Next question.

Stephanie J. Nahas, MD, MSEd, FAHS, FAAN: What about with any other types of headaches, such as post-traumatic or unusual headache syndromes?

Stephen Silberstein, MD: In progress.

Deborah Friedman, MD, MPH: I have anecdotal experience. I saw this patient last week; he’s in his 70s and he had a horrible work-related injury 30 years ago. He sustained a really terrible traumatic brain injury with memory loss and just terrible headaches that would never go away. He entered our practice. We tried a whole bunch of different medications on him, including onabotulinumtoxin and everything else. Nothing really worked. He started on a monoclonal antibody sometime in the fall, and I just saw him back in follow-up. It was amazing. It was a miracle. It was a totally different person.

Stephen Silberstein, MD: What you’re saying is, you treated the phenotype.

Deborah Friedman, MD, MPH: We treated the phenotype. Obviously, there is some CGRP involvement in some patients who have post-traumatic headache. I’ll be interested to see what the trials show, but certainly for him, it was very dramatic. He got his life back.

Stewart J. Tepper, MD: We know about the son of one of our colleagues, who was a medical student, who had post-traumatic headache and had tried absolutely everything. He went to the Mayo Clinic in Scottsdale; every conceivable treatment was given to this kid, and he was in medical school doing poorly, with 8 or 9 over 10 daily continuous headache. He went on 1 of the monoclonal antibodies. His headaches went down to 1 or 2 over 10 every day. They transformed his life. His grades improved. There are clearly people like you said.

Stephen Silberstein, MD: He’s going to become a headache doctor, isn’t he?

Stewart J. Tepper, MD: He’s going to be a neurologist. I think it’s what Deb said. It’s that there are forms of chronic post-traumatic headache that have a CGRP biology. I think that’s what this is telling us.