CGRP: What You Need to Know

By Dr. James Banks, National Headache Foundation Board Member

What is CGRP?

First, some background: CGRP is the abbreviation for Calcitonin Gene-Related Peptide, a protein in the brain and nervous system involved in the transmission of pain and the resultant reaction of tissues and blood vessels. The new medications you are hearing about are actually monoclonal antibodies to either the CGRP itself or the receptors where CGRP lands. 

There are various forms of CGRP in different parts of the body. They all have very different actions. These new drugs are very specific for the nerves and blood vessels involved in migraine.

What are monoclonal antibodies?

Monoclonal means all the antibodies are made from the same genetic material. They are grown in living humanized cell cultures. The antibodies are also made repeatedly, over and over, so that they are all identical. This process is very difficult and expensive. 

Antibodies are proteins that counter or interfere with very specific parts of another protein or the locations where a protein is supposed to bind to the receptor. These are most known in regards to preventing or fighting off infections. For example, the vaccines used to help prevent measles, mumps, rubella, and influenza (among others). In these antibodies, there is a small portion of the infectious material of the virus or bacteria—the antigen—which is recognized by the body. The body produces antibodies that, in simple terms, float around the body waiting for a signal to activate and attach to the antigen. This blocks the virus from attaching to cells and furthering the infection.  It is the body’s defense system.

Monoclonal antibodies have been developed to more precisely target specific processes in the body.  Monoclonal antibodies are already being used in treating some cancers and autoimmune diseases. 

How does the CGRP Medication Work?

In the case of the new monoclonal antibodies to CGRP, or CGRP antagonists, antibodies have been created that when administered to an individual with migraine will block the receptor sites on blood vessels or attach to CGRP itself so that it cannot fit into the receptor sites and thus interferes with the series of events that leads to migraine.

One way to visualize this is to think of a parking lot.

You have a special car, say a large blue CGRP van, and there are only certain spots in which your car can fit to park (receptors). One brand of the new anti-CGRP drugs (the white van) fills up those parking spaces (by binding to the receptors), thus preventing your van from being able to park (Figure 1).

Figure 1

The other CGRP antagonist drugs work by circulating around the parking lot on the lookout for CGRP vans. When they detect a van, they attach to the van so that it no longer fits into the parking spot (Figure 2).

Figure 2

If the CGRP van cannot park, it gives up and leaves. The process of migraine does not start or it is only a mild attack.

Because these antibodies remain active in the body for weeks or months, the migraine process is inhibited for that period of time. This is unlike the triptan medicines which stay in the body for only hours. Triptans, however, work much differently.

There are a lot of things about these CGRP antagonist drugs that make it appear to be ideal for the prevention of migraine. Up until now, all the other drugs used for migraine prevention were originally developed and marketed for other conditions. Some of these conditions are quite unlike migraine. These new anti-CGRP antibodies are the first to be developed against the specific processes of migraine.

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8 comment on “CGRP: What You Need to Know

  1. joann m bullerin

    Can I be a test patient I need help fast

  2. jnk

    Are these medications available? If so, what are the medical names? If not, when might they be available? They sound great for treating migraine.

  3. Cynthia Tarver

    I am so looking forward to trying this new drug. I have tried every other new migraine drug or cefly, TMS, Botox which I could not swallow, & was terribly ill in bed for 6 weeks…. 38 years of preventative medications, which are somewhat helpful for severity ( amiltriplyne, small does topamax)I’m ready for relief from the progression of 8 or so per month to daily. Thankfully I do get relief, I am not 24/7!!!

  4. R. Jerome Rauch, M.D.

    How soon will such treatments become available or are they in fact available now?
    I have suffered from common migraines for a long time and get some relief from Botox and Topamax but this has been inadequate. I live an Eastern suburb of San Francisco.
    Thank you.

  5. Nicci Eisenhauer

    I have two clarifications here. Firstly, the four medicines we know as “CGRP-mAbs” are not all created from the same origin. Each medicine does start with “monoclonal” DNA, meaning that the DNA used all comes from “one” (mono) original cell that has been cloned (clonal) over and over again. Kinda like reproducing exact genetic copies of a human female egg cell. However, our CGRP-mAbs are not all of the same ORIGIN and this bears noting. (And no, the “Zoo-mAbs” do not come from bear DNA.)

    As we know, there are four companies making four different CGRP-mAbs molecules:

    One of the drugs, ‘erenumab’ is derived from completely human DNA and the other three are of zooligical origin (sorry, not grizzly bear DNA, though). How do we know this without super-sleuthery?

    Because the World Health Organization ensures that via its International Nonproprietary Naming (INN) System, whether you are a French, Spanish, English or almost-any language-speaking pharmacologist or physician, The International Nonproprietary Naming system (established by the World Health Organization) will tell you very, very precisely “What’s in a name!”:

    Via the syllables in what we commonly call “the generic name” (INN) of a drug, you will find info like: the class of drug, the action of the drug, and even the derivation of the drug. Read backwards from the end of the name and you will learn all about the drug right up until you get to the “stem” of the word. This is why naproxen sodium can be called “Aleve” and “Naprosyn” and goodness knows what else across the globe! So…

    In the case of CGRP-mAbs, the suffix, “ab” means the drug’s ACTION is an antibody. (Like the suffix “vir” means “anti-viral”.) All four CGRP-mAbs names end in the suffix “ab”: Erenumab, FremanZenumab, Galacanzenumab, Eptinezumab

    Now step back a syllable… all are “m-ab” drugs. The “m” means “monoclonal”. Voila! Now… Go back another syllable: “u-mab”. All are “u” for humanized. But…

    Go back another letter and only ONE medication does NOT have a “Z” in its name. Hmmm…here is where we get to the part of the name where we talk about the “origin” of the drug.

    The letter “z” indicates that the original cell came from another species originally. That zoologically-derived cell was cloned, and cloned, and cloned again until it became as close to human as is required for human use.

    Interestingly, it also happens to be that the three drugs that are peptide binders (attaching to the blue van) are the “z-mAbs”: galcanZenumab, fremanZenumab, and eptineZumab are all “humanized” and not “fully-humanized” which only the drug erenumab — the receptor-binding — medication is. (Which should, by all rights make the name ‘erenUumab’, but I’m being picky!)

    Why does this matter, other than that ‘Z’ stands for some other zoo-animal than ‘grizzly bear’ or ‘Zebra’? Well, it may be that one type or the other may have longer Half-Life (or not). It may be that we don’t want to Rx them too close together and find out we have some Zoo-umabs still stuck on our blue vans (peptides) while we’ve got some white vans still in our parking slots. This is very important because CGRP does have functionality in the body and completely blocking it isn’t desirable. (Hence various doses and frequencies of Umabs and Zumabs in trials.) This indicates we need rigorous (as always) post-marketing data on wash-out times for CGRP-Mabs. We know our awesome specialists will stick to that research like “Zumab on a blue van!”

    Now, before anyone gets all “icky” about Zoo-mabs, I owe my life to one of these CGRP-mAbs of Z-derivation! I feel like I owe a little white rodent a happy home in return.

    So Zumab vs umab’s mechanism of interrupting the CGRP-pathway rather suggests that maybe (I dunno) somewhat less cloning is likely needed to go from “human DNA to human DNA” versus “zoo-DNA to humanized-DNA”. This might be our distinction as two why only the human-derivation (white vans) can successfully fit into parking spots successfully. “Almost human” mAbs aren’t a precise human fit, and therefore they work differently versus floating around on the peptide (blue van). As far as my personal opinion at this point — and as far as we scientifically know at this point: Blue vans are close enough for rock’n’rollin’ — and I like it, yes I do! (For now.)

    Now, also as a patient who knows it’s close enough for some seriously good rock’n’roll, I can tell you that it does NOT stop the migraine attack from happening. We do have Sx even without pain. The CGRP-neuronal pathway is a pain pathway. As Russell, King, et al, note, [PMCID: PMC4187032] CGRP is involved in predominantly sensory exchanges and is perceived as a pain pathway. Blocking this one pathway does seem to halt the overall storm of cortical-spreading depression. Personally, finding myself with prodrome and much-reduced attack Sx on the DC Beltway in traffic will remind a person right-quick that “Migraine still happens on CGRP-mabs therapy”.

    This will be different for every patient just like the disease has its various multi-tiered diagnoses.

    I’m here to personally attest that CGRP-mab therapy is ground-breaking. Truly so. We will see other applications for these medications in neurology and psychology at the very least. But we must stick close to the multidisciplinary research and understand them, too. Why?

    Pain exists for a reason, my friends. When someone is having cognitive issues on the I-495 in traffic, there was a reason pain confined her to bed in the past. She doesn’t realize she should be careful sometimes when uh-oh… The STOVE IS ON! I wouldn’t be cooking otherwise. CGRP-mabs are, in a way, a “license to carry” your migraine attack around with you.

    Love this therapy… LOVE, LOVE, LOVE this SCIENCE, but take care. We have a lot to learn! I’m guessing overall downregulation of CGRP might be a band-aid for pain in cortical spreading depression and thereby minimizing pain during what would otherwise be a higher spike in CGRP… perhaps just a lower overall baseline in the treated individual… But that is WAY, WAY above my (no)-pay grade. I’m thinking: “Watch for rebounding and maybe even some people producing more CGRP in their bodies in the future as their endogenous CGRP production might “normalize” over time? (Just a thought… who’s studying? Anybody game?)

    DISCLAIMER: I’m an armchair research junkie and Migraine disease sufferer who is fascinated by science. I don’t play a doctor on TV or in my own head! 🙂

  6. Mitzi Sereno

    I cannot wait until FDA approves this treatment for chronic migraine headaches! I have suffered from headaches since I was a child, from episodic migraines during my menstrual periods since I was 20, and from chronic daily migraines since I entered menopause at age 50. I am now 72, and my neurologist has tried every kind of prevention possible (even Botox, which worked OK for several years). Chronic migraine runs in my mom’s family, so I’m sure it’s genetic! Please hurry, FDA!

  7. ken

    Why is all (nearly all) the research and news regarding Migraine headaches. Like many others, I have cervicogenic/ muscle contraction headaches.
    Other folks have cluster headaches. I am quite sure that suffering from migraine headaches is a huge challenge and I am very grateful that I, nor any of my loved ones, are not effected by that horrible ailment. I hope and pray that the medical scientists find a cure/treatment asap. However, there are also lots of people who need new effective treatments for other types of headaches. I used to subscribe to the headaches.org newsletter, I cancelled my subscription because the content was 95% Migraine related.

  8. Gail Kirkwood

    While I am excited about the prospect of CGRP my Federal BCBS Insurance has just informed subscribers they will not pay for any newly approved FDA medications for at least 6 months. I understand the cost estimate is $8,000 per year. As if BCBS has better testing protocol than FDA.
    Does anyone have any suggestions about attempts to get this regulation reconsidered by BCBS. Are others hearing similar constraints from their insurers.
    Using the maximum amount of triptan meds per month and suffering the remaining days with almost daily migraines. Thanks

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