Getting to Grips With the Science of CGRP and Migraine

Disclosure

CGRP Is Involved in the Pathophysiology of Migraine ^[1]

• Calcitonin gene-related peptide (CGRP) was first discovered in pain fibers that innervate the cerebral blood vessels
• Fast forward 30 years, we know that CGRP and its receptor are located on pain fibers in the trigeminal ganglion and on the peripheral trigeminal vascular nerve fibers
• CGRP is also located centrally throughout the brain in areas that process pain and modulate pain
• CGRP levels in the blood rise during a migraine attack
  • When you treat with a triptan, elevated levels of CGRP go back to normal
• Treatments that target CGRP are effective in migraine

Treatments Targeting the CGRP Pathway ^[2-10]

Trial Results: Small Molecules ^[11-13]

• Small molecules are being developed for both the acute and the preventive treatment of migraine
• Trial results are very similar across the 2 molecules and across all 4 studies
• Atogepant works as a migraine preventive

Trial Results: mAbs^[14]

• One of the most astonishing things about the studies of CGRP-targeted therapies is they seem to always work

mAbs vs Current Preventive Therapy for Migraine^[15,16]

• The overall response rates in clinical trials, the percentage of patients who get a 50% reduction in the frequency of migraine or in monthly migraine days, are roughly comparable to some of the preventive oral treatments that we currently use
• Dr Dodick: When we are starting patients on an oral prophylactic medication, we tell them to start low, go slow, and we titrate the dose
• That is not to say that there is not a cumulative benefit over time, but they work quickly
• There have been no serious treatment-related adverse events with monoclonal antibodies (mAbs)
• While response rates at 3 months with oral prophylactic medications look comparable, if you cannot adhere to treatment, then you do not continue with treatment

Gepants vs Current Acute Therapy of Migraine with Triptans^[2,17-19]

• Dr Lipton: Triptans are the most widely used acute prescription drugs for migraine. Triptans have several issues or problems that I think the gepants may be able to address
• Triptans do not work for everyone; having other molecular targets will be advantageous to treat people who do not respond to triptans
• For people with tolerability problems with triptans, the gepants will be very helpful
• Triptans are contraindicated in people who are at high risk for cardiovascular disease
  • It is estimated that 3.5 million of the 40 million Americans who have migraine fall into that category
• Most classes of acute migraine medications cause overuse
• Dr Lipton: The gepants work as preventives; we are very hopeful that we will not have that problem with medication overuse

FDA Status of mAbs ^[7-10]

Secondary Endpoints in Phase 3 CGRP Trials for Migraine Prevention: 50% Responder Rate ^[20-27]

• Studies have been positive and met their primary endpoint
• The response rate varies somewhere between 45% and 60%, depending on the antibody, while the placebo response varies
• If you look at placebo-subtracted responses and the overall magnitude of the responses, these antibodies look comparable in terms of the response rate

Secondary Endpoints in Phase 3 CGRP Trials for Migraine Prevention: 75% Responder Rate^{[20,21,24,25,28]}

• There is a subgroup of patients who get a very robust response
• Across all of these antibodies, about a third of the patients treated have a greater than 75% reduction in the frequency of migraine headache days

Latest Data on Migraine Prevention^[29-32]

• Looking at open-label extension data out to 1 year or longer, we are seeing 50% responder rates that approximate 70%
• We are seeing 75% responder rates that are between 45% and 50%
• The longer one is able to stay on these antibodies, the more robust the efficacy over time; we've seen very encouraging responses with antibodies
• Dr Lipton: I have never seen anything like the super responders who have a greater than 75% response rate
• Dr Dodick: There are patients in practice who respond dramatically to a particular therapy, and yet they may have daily headache. I actually think the results of the clinical trials will likely be generalizable to clinical practice
• Dr Lipton: Another factor is a reduction in pain duration

Clinical Application of mAbs^[16]

• Dr Lipton: I think it makes sense for a patient who needs a migraine preventive drug to begin with relatively low cost oral generic medications
• With many oral generics, there is a balance between efficacy and tolerability
• Weighing the benefits of treatment against the side effects patients are experiencing is important

Thank You