by Lawrence Robbins, M.D.
(Note: this article will be published in full in Practicalpainmanagment.com)
INTRODUCTION: The monoclonal antibodies (mAbs) targeting calcitonin gene-related peptide (CGRP) are a valuable addition to our preventives. However, there are significant conceivable long-term adverse effects associated with them. We will have a better feel for the true risks in 10 years. For each patient, we have to decide whether the benefits outweigh the possible risks. With luck, it may come to pass that the biologics targeting CGRP carry very few long-term risks. Certainly, these have been safe compounds for the short-term. Three- year safety data has recently been presented. This paper discusses some of the possible long-term issues, concerns, and questions.
CARDIOVASCULAR AND PULMONARY SYSTEM:
- CGRP plays an important role in resisting the onset of hypertension (HTN); how relevant is this when prescribing to young patients, particularly those at higher risk for HTN? How much does vascular dilation redundancy matter (with other vasodilator mediators, such as PGs and NO, compensating for the loss of CGRP)?
- With the onset of HTN, there is a compensatory release of CGRP: how relevant is this, and what effects do the antagonists have? In the face of HTN, CGRP release may become attenuated over time.
- CGRP may delay or protect against the development of C-V disease. For which patients is this relevant?
- CGRP depletion may produce oxidative stress in the aorta; how clinically relevant is this?
- If CGRP is knocked out, and the vasodilator effects are diminished, do other compounds (nitrous oxide, substance P, prostaglandins) help to compensate (primarily at the resistance vessel level)?
- We need angiographic (and other) studies in patients with CAD, ideally prior to and after treatment with the antagonist. Are further studies planned?
- Could smaller cardiac or cerebral infarcts become more dangerous resulting from the protective effects of CGRP being blocked? CGRP protects against ischemia, cell death, and vascular inflammation in various organs (heart, brain, GI, kidney).
- CGRP plays a role in heart failure. Infusion of CGRP improves circulation in the face of heart disease. Regarding microvascular growth, CGRP is an angiogenic facilitator. Should patients at high risk for failure, or with actual heart failure, not be prescribed these medications?
- There is evidence that CGRP helps to protect the heart, and this effect is lessened in the presence of diabetes. For patients with both diabetes and CAD, should CGRP inhibitors be withheld?
- CGRP levels decline with age (although there may be a bimodal effect) and CGRP helps to protect the myocardium; should CGRP inhibitors be withheld in older patients, particularly for those with heart disease?
- Do the Amylin 1 receptors (or other calcitonin-group receptors) help to “cover” for the loss of beneficial effects, particularly vasodilatory, after the blocking of CGRP?
- With regards to the C-V system, is there a difference between antagonizing the ligand of CGRP, and blocking the receptor?
- Regarding advanced CAD, how important is CGRP as a vasodilator? CGRP levels are increased during myocardial infarction. Could antagonizing CGRP lead to a more severe infarct? There was an erenumab study of 90 patients with stable angina, who were given 140mg IV as a one-time dose. There were no problems found in the 3 months post-infusion. Are there further studies planned?
- How clinically relevant is CGRP in the cerebral vasculature?
- Is CGRP a vasodilator in both smaller and larger cerebral arteries?
- CGRP and pulmonary HTN: CGRP is abundant in the lung; for high- risk individuals, would blocking CGRP increase the chance of developing pulmonary HTN?
CENTRAL NERVOUS SYSTEM (Within the Blood Brain Barrier):
- There is slight penetration of these large molecule mAbs into the CNS, from 0.1% to 1%; is this clinically relevant as to MOA of the mAbs? Probably not, but certainly it is possible.
- Botox does undergo transcytosis (tracking along the axon from the trigeminal ganglion, into the brainstem): does this occur with mAbs? Most likely it does not, but it may happen to a small degree. Radioisotope studies to identify elements of the mAb in the brainstem would be helpful.
- How effectively does the peripheral (trigeminal ganglion) effects of the mAb dampen down central sensitization, and/or cortical spreading depression?
CENTRAL NERVOUS SYSTEM (Outside of the Blood Brain Barrier):
- The anterior pituitary contains CGRP. Evidence exists indicating that CGRP may play some role in stimulating ACTH. What is the possible effects on CGRP antagonism for the various hormones (GH, TSH, FSH, LH, ACTH, MSTH, and prolactin)? Should we be hesitant to prescribe for adolescents(off-label), due to possible effects on growth hormone? Should we measure hormone levels in those adolescents prescribed the mAbs?
- We do not know about the effect on those with thyroid disease: Should the mAbs be used with caution in those with thyroid disease?
- Should studies be done evaluating FSH, LH, and ACTH levels before and after these antagonists?
- What is the effect on prolactin? Should those with pituitary microadenomas be restricted from use?
- Might there be an effect on melatonin levels?
- The choroid plexus: could CGRP knockout affect CSF production? Would the CSF inflammatory homeostasis, partially controlled by the choroid plexus, be affected? Can this be evaluated?
- The median eminence: could CGRP knockout affect hypothalamic hormone release (of CRF, TRH, DA, GHRH, and GnRH)? Should these be tested?
- Area postrema (part of the circumventricular organs): would regulation of nausea/vomiting be affected?
- (beta) CGRP is primarily present in the GI system (versus alpha CGRP), and CGRP is important for mucosal protection. What is the effect of antagonizing CGRP on the GI mucosa?
- CGRP is involved in the healing of GI ulcers. Should antagonists be restricted for those with ulcers?
- For those with, or at high risk for, Inflammatory Bowel Disease (IBD), should these antagonists be restricted?
- CGRP acts in a biphasic manner on GI motility. Should the antagonists be used with caution for those with moderate or severe IBS?
SKIN, WOUND HEALING, BURNS, AND BONE HEALTH:
- CGRP contributes to flushing and thermoregulation; what are the effects of blocking CGRP on these functions?
- What clinical effect results from dampening the CGRP effects on local skin edema and itch? CGRP can inhibit allergic conditions, such as certain types of dermatitis (irritant dermatitis). What effects on dermatitis might be seen by inhibiting CGRP?
- CGRP facilitates tissue repair and wound healing. These effects are mediated via vasodilation, upregulating VEGF expression, and by limiting inflammatory processes. CGRP also promotes revascularization. What effect does blocking CGRP have on wound healing?
- CGRP plays some role in regeneration of the skin, via promoting proliferation of keratinocytes. Will skin be able to regenerate as well after CGRP is diminished?
- For those with burns, CGRP and SP facilitate acute edema formation. What is the clinical relevance of knocking out CGRP for those with more severe burns?
- CGRP may regulate bone metabolism through stimulation of osteoblastic differentiation, as well as an effect on osteoclastic formation. Amylin and calcitonin are also vital for bone health. Might the CGRP antagonists inhibit normal bone growth and metabolism? Does diminishing CGRP play a role in healing of bone?
RENAL, SEPSIS, DIABETES/OBESITY:
- Renal effects: during dialysis, CGRP levels are raised, possibly as a defense mechanism. How does antagonizing CGRP affect the person undergoing dialysis? CGRP may protect against renal damage in certain pathological conditions. In light of kidney disease, should the CGRP antagonists be used sparingly?
- CGRP levels are raised during sepsis. If a patient on an antagonist becomes septic, would the therapy change?
- CGRP is active within the pancreas and is involved with the regulation of insulin release; the effect may be to reduce insulin levels, which (in theory) may result in hyperglycemia. Would antagonizing CGRP theoretically help with diabetes?
- CGRP knockout may affect metabolism, energy use, and body weight. Could the CGRP mAbs affect body weight? Could this be included in long-term post-approval studies?
PREGNANCY, ARTHRITIS AND OTHER PAINS, AND AGING:
- Early in pregnancy, CGRP levels are minimal in the fetus: what are the risks if CGRP antagonists are given prior to pregnancy? Later in pregnancy, CGRP may play a role in mediating the adrenal glucocorticoid response to acute stress in the more mature fetus. Circulating CGRP levels (in the mother) are increased during pregnancy, peaking in the last trimester. CGRP levels are lower with pre-eclampsia. There was a prenatal and postnatal study in monkeys with erenumab. The animals received 50mg/kg of erenumab every 2 weeks. No effects were apparent on the fetus or infant, with regards to growth and development. The follow-up was through 6 months after delivery. Towards the end of pregnancy, CGRP plays a role in cervical ripening, and is present in the placenta and fetus: how would lessening CGRP affect the latter stages of pregnancy? Could a CGRP mAb render it more difficult to become pregnant? Do the mAbs affect sperm in any fashion? There is a CGRP pregnancy registry that is being organized: is it coordinated among the various companies, and how does one access it?
- Arthritis: could CGRP antagonism possibly help with rheumatoid or osteoarthritis? How about other pain syndromes, such as fibromyalgia, or peripheral neuropathy? What is the state of studies for these conditions?
- CGRP levels may decline as one ages, although circulating levels may be increased in certain individuals. There may be a bimodal effect. Would the mAbs have more (or less) risk at age 70? At age 85 or 90?
- The receptor occupancy of erenumab is approximately 89%. The blocking of the CGRP ligand (by the other 3 mAbs) is approximately 85%. Do these occupancy levels steadily decline over the weeks/months, or is there a precipitous fall off at some point? Is this clinically relevant
- Nerve growth factor (NGF) influences CGRP. What clinical relevance, if any, does NGF have regarding the mAbs? Also, TRPV1 agonists may help to regulate CGRP; what is the importance of this?
- Differences between the ligand antagonists (3 compounds in development) and the receptor antagonist (one is on the market): receptors (that CGRP may attach to) other than the CGRP receptor may compensate for loss of the CGRP receptor; on the other hand, antibodies directed at the ligand of CGRP would also block the effects at the other (particularly AMY 1) receptors. What is the clinical relevance of these differences between the ligand and the receptor antagonist?
- With other meds (example: methysergide), we had patients take a “drug holiday” every 6 months. Does that make sense with these CGRP antagonists, at least until we are sure of long-term safety? Would doing this produce more antibodies, after re-introduction? There would also be the risk that, after re-introduction, the mAb would not be as effective.
- Informed consent: should we obtain this from patients? (I think we should.) What should we put in the informed consent?
- Monitoring of adverse events: we should encourage reporting to the company or to the FDA. As with a pooled pregnancy registry, are there any plans for a pooled “mAb” adverse event registry?
- Should we develop a “CGRP Antagonist Risk Assessment Scale”?
- Russell, F., King, S., Smillie, J., Kodji,X., Brain,S. Calcitonin gene-related peptide: physiology and pathophysiology. Physiol Review. 2014 94: 1099-1142.
- Iyengar,S., Ossipov,M., Johnson,K. The role of calcitonin gene-related peptide in peripheral and central pain mechanisms including migraine Pain. 2017 Apr; 158(4): 543-559.
- Edvinsson,L. The trigeminovascular pathway: role of CGRP and CGRP receptors in migraine headache. 2017 57:47-55.
- Deen,M, Correnit,E., et al. Blocking CGRP in migraine patients- a review of pros and cons. The Journal of Headache and Pain. 2017 18:96.
- Walker,C., Hay, D. CGRP in the trigeminovascular system: a role for CGRP, adrenomedullin and amylin receptors? British Journal of Pharmacology. 2013 170: 1293-1307.
- Benemei,S., Nicoletti,P., Capone,J., Geppetti,P. CGRP receptors in the control of pain and inflammation. Current Opinion in Pharmacology. 2009 9:9-14.