There are 2 types of migraine treatment. Crisis treatment, aimed at reducing or stopping the headache when it occurs. And the basic treatment which, administered regularly, will help reduce the frequency and intensity of attacks. In both camps, nothing new has appeared for years. Due to the complexity of migraine and a pathophysiology that is still poorly understood. Several pharmaceutical laboratories are studying anti-CGRP monoclonal antibodies. The first sales authorizations are arriving. In this article, we provide an update on the evolution of these promising new treatments.
AN ACTION ON THE CGRP, BUT WHAT IS IT EXACTLY?
CGRP (Calcitonin Gene Related Peptide) is a neuropeptide widely expressed in the central and peripheral nervous system. Powerful vasodilator, it is involved in sensory transmission. Identified in 1982, its role in the pathophysiology of migraine has been discussed for more than 30 years. Today it is unanimously recognized. It is expressed by more than 50% of neurons in the trigeminal system. The trigeminal nerve is at the origin of the sensory innervation of the face, scalp and meninges. It plays a role in the vasodilation of intracranial arteries. Hence its name trigeminovascular system (TVS). STV is one of the key elements in the pathophysiology of migraine. For reasons still unknown, during a crisis this system is “hyperactive”. One of the consequences is the massive secretion of inflammatory substances, mainly the CGRP peptide. Blocking this peptide therefore amounts to reducing inflammation due to STV runaway.
NEW TREATMENTS TARGETED AGAINST CGRP
CGRP is therefore recognized as a real biomarker of migraine. Consequently, it currently constitutes a preferred therapeutic target leading to numerous clinical development projects. CGRP antagonists have shown positive results in reducing seizure frequency. These are the gepants (olcegepant and tolcagepant), unfortunately the pharmacological trials were interrupted due to strong liver toxicity. Recently several pharmaceutical laboratories have developed monoclonal antibodies targeting CGRP. Four monoclonal antibodies are in clinical development for the prophylactic treatment of migraine with phase 2 and 3 study data available. These antibodies are: LY2951742 (galcanezumab) resulting from Pfizer research, but developed by Arteaus Pharmaceutics and for which the operating rights were acquired by Eli Lilly. ALD403 developed by Alder Biopharmaceuticals, AMG 334 (erenumab) developed by Amgnen in association with Novartis and TEV-48125 developed by Teva pharmaceuticals. LYS2951742, ALD403 and TEV-48125 are antibodies against CGRP as a ligand, while AMG334 is an antibody against the CGRP receptor.
EFFECTIVENESS OF ANTIBODIES TARGETING CGRP
The question arises of the effectiveness of these monoclonal antibodies, because even if the first studies date back a few years, the hindsight on the potential side effects still remains very weak. Recently, a meta-analysis published in “Brain & Behavior” made it possible to analyze a set of results from several independent studies. The results are very encouraging, 37% of patients treated with antibodies had an improvement of at least 50% compared to 20% in the placebo group. The LIBERTY study published in LANCET conducted by the Novartis laboratory (erenumab) is international, multicentre, randomised, double-blind. Its aim is to evaluate the effectiveness of erenumab against a placebo treatment. A total of 382 patients participated in this study. At 12 weeks, the number of patients who achieved a reduction of at least 50% in the number of migraine days per month (primary endpoint) was 30% in the erenumab group versus 14% on placebo (p=0.002 ). The proportion of those achieving a reduction of at least 75% or 100% was 12% versus 4% (p=0.025) and 6% versus 0%, respectively. Several other studies conducted by other laboratories are currently underway to confirm the efficacy and non-toxicity of these new treatments. It will take a few more years to have the necessary perspective, but marketing authorizations have already been validated. This is the case for Aimovig (erenumab), Emgality (galcanezumab) and even Ajovy from Teva. A fourth antibody, eptinezumab, should be authorized in 2019. These drugs are mainly administered by self-injection by subcutaneous route, at the rate of one injection per month (erenumab, galcanezumab) or per quarter (fremanezumab).
A TREATMENT FOR ALL PATIENTS?
In March 2019, the American Headache Society (AHS) unveiled the recommendations for the use of these new treatments. Patients who will be able to have access to these treatments, following the approval of their specialist doctor, are: -Patients suffering from at least 15 days of headache per month; -Including 8 meeting the criteria for migraine (photophobia, digestive signs, increased pain with exercise, etc.); -And must have at least 2 failures of conventional treatments.
SIDE EFFECTS?
The physiological functions of CGRP are numerous. Particularly in terms of cardiovascular homeostasis (maintenance of constants), due to its participation in the control of blood pressure in normal and pathological conditions. CRGP antagonism thus raises 2 safety questions: 1: Can it cause vasoconstriction in small arteries and potentially induce hypertension? 2: Is it likely to counterbalance the effects of antihypertensive treatments acting via vasodilation? Also, the long-term safety of the use of monoclonal antibodies directed against CGRP could also be limited by possible passage of the blood-brain barrier. This then allows inhibition of the CGRP system at the central level. A possible toxicity should be considered due to the blocking of CGRP at the level of other brain structures which are not linked to the migraine mechanism, such as the cerebellum for example.
Finally, the safety of use relating to the occurrence of pregnancy in a migraine sufferer who uses an antibody targeting CGRP remains to be confirmed. This last question is far from theoretical, because antibodies targeting CGRP are immunoglobulins that can cross the placenta. The cost of treatment is estimated between 5,000 and 6,000 euros per year per patient and at the moment no agreement for reimbursement has been validated.
