Nausea and vomiting regulator

Abstract

Nausea and vomiting are unpleasant events caused by a variety of triggering factors. Wherein medicines often cause nausea and vomiting. An anti-tumor chemotherapeutic agent is one of the most emetic drugs, and often causes chemotherapy-induced nausea and vomiting (CINV). The latter seriously impairs the therapeutic effect and the quality of life of the patient. It is of great interest in determining agents capable of preventing and combating drug-induced nausea and vomiting, including CINV. The invention relates to a calcitonin gene related peptide (CORP) which is a neuropeptide with various effects in a human body. However, neuropeptide effects in the brain are still to be clarified. Anti-CORP antibodies have been recently approved for the prevention of migraine. The use of anti-CGRP monoclonal antibodies for the direct treatment of nausea and vomiting, including CINV, is described.

Description

Technical Field

[0001] The present invention relates to the field of medicaments for the treatment of drug-induced nausea and vomiting. Background Art

[0002] It is well known that nausea and vomiting frequently occur in cancer patients. The latter is often associated with the use of chemicals by these patients to combat cancer growth. Among different drugs, anti-tumor chemotherapeutic agents are most frequently associated with nausea and vomiting, and this symptom is generally defined as "chemotherapy-induced nausea and vomiting (CINV)". CINV has significant clinical implications because on the one hand, it impairs the health status of patients, and on the other hand, it limits the dosage of administered drugs and leads to treatment interruption.

[0003] The molecular mechanism of CINV has been partially understood. The drug acts at the brainstem level, specifically in the area postrema, also known as the "chemoreceptor trigger zone", thereby triggering nausea and vomiting. Here, a neuronal population capable of detecting different toxic xenobiotics present in the blood sends projections and activates the vomiting center. These responses are closely related to survival because once a given toxic substance is ingested, it allows gastric emptying. Given the strong cytotoxic properties of anti-tumor chemotherapeutic agents, it makes sense that they rapidly activate the chemoreceptor trigger zone and cause CINV. Therefore, the prior art teaches that the mechanism triggering nausea and vomiting during CINV is different from the mechanism of nausea and / or vomiting caused by different symptoms such as pregnancy, dizziness, pain, or anxiety. In fact, CINV is induced by the toxic effect of anti-tumor chemotherapeutic agents in the intestine and their detection by the chemoreceptor trigger zone, while other forms of nausea and vomiting are not caused by the activation of the chemoreceptor trigger zone.

[0004] Given the high incidence of CINV and its significant clinical implications, the identification of effective compounds capable of preventing or counteracting this disorder has received substantial attention. In this regard, the prior art teaches that antiemetics capable of counteracting vomiting caused by motion sickness (travel sickness), pregnancy, food poisoning, pain, or migraine, such as scopolamine, metoclopramide, domperidone, meclizine, doxylamine, dimedrinate, or vitamin B6, are ineffective against CINV. As described above, this ineffectiveness is due to the intrinsic cytotoxic properties of the antineoplastic chemotherapeutic agents detected in the area postrema, which are the main cause of the CINV pathogenesis. Depending on the specific mechanisms involved in CINV development, CINV is counteracted by specific drugs, such as serotonin 5HT3 receptor antagonists (ondansetron, palonosetron, granisetron), neurokinin-1 receptor antagonists (aprepitant, netupitant), or corticosteroids (dexamethasone). In fact, these compounds are not used to treat nausea and vomiting caused by disorders other than CINV. On this basis, it is not clear to the experts in the field that antiemetics that non-specifically treat CINV can be used to prevent CINV. On the contrary, the experts in the field know that the CINV treatment guidelines defined by the prior art (New Eng. J. Med., 2016, 374, 1356 - 67) involve the use of antiemetics that specifically treat this disorder.

[0005] Unfortunately, it is well known that drugs used to treat CINV are ineffective in some patients and tend to lose efficacy during the treatment cycle. Therefore, the technical problem to be solved is to identify new drugs that can act, either alone or in a combination treatment modality, on the brain regions that trigger nausea and vomiting, in order to improve the treatment of CINV and the quality of life of cancer patients.

[0006] In the field of nausea and vomiting, the underlying neurochemistry remains partially obscure. In this regard, a great deal of attention has been focused on identifying neuropeptides that regulate signaling in different brainstem regions related to nausea and vomiting. Neuropeptides are small protein molecules (10 to 40 amino acids) capable of regulating numerous neuronal and endocrine functions. Neuropeptides are released through the classical presynaptic apparatus, but unlike neurotransmitters such as norepinephrine, acetylcholine, or serotonin, neuropeptides generate long-lasting signals (so-called "volume transmission") that can reach regions far from the presynaptic terminal.

[0007] Calcitonin gene-related peptide (CGRP) is a 37-amino acid neuropeptide present in the central and peripheral nervous systems. The peripheral functions of CGRP are well known and mainly consist of mediating vasodilation and sensitization to pain. In contrast, the central functions of CGRP remain largely unknown. One of the main reasons for this lack of knowledge is the absence of brain-penetrant CGRP receptor agonists and antagonists. Indeed, currently available CGRP receptor-interacting drugs administered peripherally are unable to cross the blood-brain barrier and modulate CGRP-dependent neurotransmission (Nat. Rev. Neurol., 2018; 14:338). Accordingly, experts in the field know that in order to circumvent such pharmacokinetic problems and modulate CGRP neurotransmission, the only strategy is to directly inject receptor agonists or antagonists into the brain via microiontophoresis or the intracerebroventricular route. Another recently adopted strategy capable of modulating CGRP neurotransmission is the use of viruses, which are also directly injected into the brains of experimental animals and carry genetic information allowing the modulation of CGRP or its cognate receptor expression.

[0008] Due to the fact that these modern gene therapy methods require direct brain injection, the key role of CGRP in modulating neurotransmission between central nervous system regions such as the amygdala, parabrachial nucleus, nucleus of the solitary tract, trigeminal nucleus, and multiple hypothalamic nuclei has recently emerged. However, experts in the field know that due to the inability of currently available CGRP-modulating drugs to penetrate the blood-brain barrier as mentioned above, there is no information in the prior art regarding the possibility of modulating CGRP neurotransmission in the brain with compounds administered peripherally (i.e., orally, subcutaneously, or intravenously).

[0009] A recent significant therapeutic advance has been the clinical development of monoclonal antibodies (mAbs) that can inhibit peripheral CGRP function. The mAbs fremanezumab, galcanezumab, eptinezumab bind to and clear the neuropeptide, while erenumab binds to and inhibits the neuropeptide receptor (these antibodies are collectively referred to as "anti-CGRP mAbs"). These mAbs are administered subcutaneously or intravenously and are only effective in migraine prophylaxis. Considerable effort has been invested in determining the potential mechanisms of the antimigraine action of anti-CGRP mAbs. The prior art teaches that the blood-brain barrier is impermeable to immunoglobulins (proteins with a quaternary structure and a molecular weight in the order of 150 kDa). Thus, the prior art teaches that anti-CGRP mAbs cannot cross the blood-brain barrier and penetrate into the brain parenchyma, and thus exert their pharmacodynamic effects only peripherally (J Neurosci. 2019; 39: 6001-6011; Cephalalgia 2020; 40: 229-240; Cephalalgia. 2020; 40: 924-934; BMC Neurology, 2022, 22: 205-213). In fact, experts in the field attribute the antimigraine action of anti-CGRP mAbs to their peripheral effects. Specifically, it is generally believed that the antimigraine action of anti-CGRP mAbs is due to their ability to counteract CGRP-dependent pain signals in the trigeminovascular afferent neurons within the meninges (Nat. Rev. Neurol. 2018; 14: 338-350; CNS Neurol. Disord. Drug. Targets. 2020; 19: 344-359).

[0010] Thus, experts in the field have found no clues in the prior art regarding anti-CGRP mAbs entering the central nervous system and exerting a functional role therein. The putative brain activity of these antibodies is not obvious because the blood-brain barrier is impermeable to immunoglobulins and it has been reported that fremanezumab cannot reach the brain parenchyma (Cephalalgia 2020; 40: 229-240).

[0011] In addition, experts in the field have found no clues in the prior art regarding anti-CGRP mAbs being able to counteract CINV or other types of drug-induced nausea and vomiting. According to the prior art, such an effect is not obvious because the antibodies do not cross the blood-brain barrier, and brain-penetrating drugs are necessary for the treatment of drug-induced nausea and vomiting, including CINV. SUMMARY OF THE INVENTION

[0012] Surprisingly, we have now found that, contrary to the prior art (Cephalalgia 2020; 40: 229-240), subcutaneous (i.e., peripheral) administration of anti-CGRP mAbs (e.g., rimegepant, galcanezumab, eptinezumab, and erenumab) results in accumulation of the antibody in the brain. Furthermore, we unexpectedly found that, contrary to the prior art (Cephalalgia. 2020; 40: 924-934), subcutaneous (i.e., peripheral) administration of anti-CGRP mAbs (e.g., rimegepant, galcanezumab, eptinezumab, and erenumab) exerts a functional effect in the brain and is capable of reducing nausea and vomiting caused by anti-tumor chemotherapeutic agents.

[0013] Specifically, we unexpectedly found the presence of antibodies in the brain parenchyma of rats that received subcutaneous injections of the anti-CGRP antibodies rimegepant, galcanezumab, eptinezumab, and erenumab (30 mg / kg in the interscapular region) 7 days before sacrifice. The animals were perfused through the heart with cold saline for 10 minutes to remove trace amounts of blood containing the antibodies present in the plasma from the brain parenchyma. After such adequate perfusion, samples of the cerebral cortex (a structure behind the blood-brain barrier) and trigeminal ganglia (a structure before the barrier) were collected and subjected to Western blot analysis. The presence of anti-CGRP mAbs in the brain parenchyma was demonstrated by studying the human antibodies present in the rat brain extracts. In fact, the possible presence of human antibodies in the rat brain extracts necessarily originated from the brain penetration of the subcutaneously injected anti-CGRP antibodies. Specifically, after electrophoresis and blotting of the protein extracts, the membrane was incubated with a polyclonal anti-human IgG capable of recognizing the heavy and light chains of the injected anti-CGRP mAb. The membrane was also incubated with anti-human hemoglobin (as a marker of blood contamination) to confirm complete removal of blood after rat heart perfusion. By doing so, we unexpectedly found that the anti-CGRP mAbs were detected not only in the trigeminal ganglia but also in the cerebral cortex of the animals without hemoglobin being detected simultaneously ( Figure 1 ). This indicates that the presence of human antibodies in the brain parenchyma cannot be attributed to residual blood within the brain tissue extracts. Thus, contrary to the prior art (Cephalalgia 2020; 40: 229-240), the anti-CGRP mAbs rimegepant, galcanezumab, eptinezumab, and erenumab found in the rat cortical extracts must be attributed to their unexpected passage through the blood-brain barrier and accumulation in the brain parenchyma.

[0014] We also unexpectedly found that subcutaneous injection of the anti-CGRP antibodies rimegepant, galcanezumab, eptinezumab, and erenumab reduced nausea and vomiting in rats exposed to anti-tumor chemotherapeutic agents. Chemically induced nausea can be evaluated by measuring the repeated gaping (so-called "gape") of rats (Autonomic Neuroscience, 2006, 129, 36-41). Accordingly, we evaluated the effects of the antibodies rimegepant, galcanezumab, eptinezumab, and erenumab on gape in rats caused by the anti-cancer drugs cisplatin (6 mg / kg, intraperitoneally) or cyclophosphamide (40 mg / kg, intraperitoneally). These drugs were injected 15 days after subcutaneous injection of the anti-CGRP mAb to allow complete tissue antibody distribution. We unexpectedly found that the number of gape events (4 h monitoring) was reduced in animals pretreated with the antibodies rimegepant, galcanezumab, eptinezumab, or erenumab compared to control animals ( Figure 2 ).

[0015] Vomiting can be preclinically induced and evaluated in the shrew (Suncus Murinus). We unexpectedly found that anti-CGRP mAb reduced vomiting in shrews exposed to anti-cancer chemotherapeutic agents. Specifically, we have evaluated the effects of subcutaneous injection of rimegepant, galcanezumab, eptinezumab, and erenumab (100 mg / kg) on vomiting events in shrews induced by cisplatin (6 mg / kg intraperitoneally) or cyclophosphamide (40 mg / kg intraperitoneally). Cisplatin and cyclophosphamide were administered 15 days after injection of the anti-CGRP mAb to allow complete tissue antibody distribution. We unexpectedly found that the number of vomiting events (4 h monitoring) was reduced in animals exposed to rimegepant, galcanezumab, eptinezumab, or erenumab compared to the control group ( Figure 3 ).

[0016] According to the present invention, anti-CGRP antibodies can be formulated and administered by intravenous, intraarterial, intramuscular, intranasal, and subcutaneous routes to treat nausea and vomiting. The amount of antibody to be administered is the amount typically employed for such drugs, for example, 10 to 3000 mg are administered daily, weekly, or monthly. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1. The ability of anti-CGRP antibodies rimegepant, galcanezumab, eptinezumab, and erenumab to cross the blood-brain barrier and accumulate within the brain parenchyma was evaluated by Western blot. Rimegepant, galcanezumab, eptinezumab, or erenumab (30 mg / kg) was present in the cerebral cortex 7 days after subcutaneous injection (as its light and heavy chains). The amount of rimegepant in the trigeminal ganglia (TG) of rats was shown as an indicator of the amount of anti-CGRP antibody present in the periphery of these animals. Animals were perfused through the heart with cold saline to eliminate blood / plasma contamination. The absence of hemoglobin in tissue extracts demonstrated complete removal of blood / plasma. Data indicate that rimegepant, galcanezumab, eptinezumab, and erenumab are able to penetrate and accumulate in the brain. In the figure, a positive control of rimegepant and hemoglobin (both 10 ng) was also shown.

[0018] Figure 2 . The effect of anti-CGRP antibodies on cisplatin- or cyclophosphamide-induced nausea in rats. Rimegepant, galcanezumab, eptinezumab, or erenumab (100 mg / kg) was injected subcutaneously into rats (10 animals / group). After 15 days, the animals were exposed to cisplatin (6 mg / kg) or cyclophosphamide (40 mg / kg) injected intraperitoneally, and the number of gaping episodes within 4 h was evaluated as an indicator of nausea. Rats pretreated with rimegepant, galcanezumab, eptinezumab, or erenumab showed a reduced number of gaping episodes compared to the control group. *p < 0.05, **p < 0.01 vs control group, ANOVA and Tukey post hoc test.

[0019] Figure 3 . The effect of anti-CGRP antibodies on cisplatin- or cyclophosphamide-induced vomiting in shrews. Rimegepant, galcanezumab, eptinezumab, or erenumab (100 mg / kg) was injected subcutaneously into shrews (10 animals / group). After 15 days, the animals were exposed to cisplatin (6 mg / kg) or cyclophosphamide (40 mg / kg) injected intraperitoneally, and the number of vomiting episodes within 4 h was evaluated. Shrews pretreated with rimegepant, galcanezumab, eptinezumab, or erenumab showed a reduced number of vomiting episodes compared to the control group. *p < 0.05, **p < 0.01 vs control group, ANOVA and Tukey post hoc test. Detailed Description of the Invention

[0020] The best mode for carrying out the present invention is to treat a patient by administering rimegepant, galcanezumab, eptinezumab, or erenumab daily, weekly, or monthly by different routes (such as but not limited to subcutaneous or intravenous injection) before, during, and / or after the patient is exposed to a nausea and / or vomiting inducer.

Claims

1. An anti-CGRP antibody, an anti-CGRP receptor antibody, or an antigen-binding fragment thereof, which is applied in a pharmaceutically acceptable formulation for preventing chemotherapy-induced nausea and vomiting (CINV).

2. An anti-CGRP antibody, an anti-CGRP receptor antibody, or an antigen-binding fragment thereof, which is applied in a pharmaceutically acceptable formulation for treating chemotherapy-induced nausea and vomiting (CINV).

3. An anti-CGRP antibody, an anti-CGRP receptor antibody, or an antigen-binding fragment thereof, which is applied in a pharmaceutically acceptable formulation for enhancing the effect of a drug for preventing or treating chemotherapy-induced nausea and vomiting.

4. An anti-CGRP antibody, an anti-CGRP receptor antibody, or an antigen-binding fragment thereof, which is applied in a pharmaceutically acceptable formulation for preventing and treating drug-induced nausea and vomiting.

5. An anti-CGRP antibody, an anti-CGRP receptor antibody, or an antigen-binding fragment thereof, which is applied in a pharmaceutically acceptable formulation for preventing and treating nausea and vomiting in an individual with cancer.

6. An anti-CGRP antibody, an anti-CGRP receptor antibody, or an antigen-binding fragment thereof, which is applied in a pharmaceutically acceptable formulation for preventing and treating nausea and vomiting induced by activation of the vomiting center.

7. The anti-CGRP antibody according to any one of claims 1 to 6, wherein, The antibody is rimegepant.

8. The anti-CGRP antibody according to any one of claims 1 to 6, wherein, The antibody is galcanezumab.

9. The anti-CGRP antibody according to any one of claims 1 to 6, wherein, The antibody is eptinezumab.

10. The anti-CGRP receptor antibody according to any one of claims 1 to 6, wherein, The antibody is erenumab.

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