CGRP receptor antagonists for treatment of chemotherapy-induced nausea and vomiting (CINV)

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. A calcitonin gene-related peptide (CGRP) is a neuropeptide having various effects in a human body. However, neuropeptide effects in the brain are still to be clarified. CGRP receptor antagonists (named as gezepam) have been recently approved for use in the treatment of migraine. The use of gezepams 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 cancer patients often experience nausea and vomiting. 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 often associated with nausea and vomiting, which is generally defined as "chemotherapy-induced nausea and vomiting (CINV)". CINV has significant clinical implications because on the one hand it impairs the patient's health status, and on the other hand it limits the dosage administered and causes 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 they allow gastric emptying once a given toxic substance has been ingested. Given the strong cytotoxic properties of anti-tumor chemotherapeutic agents, it makes sense that they rapidly activate the chemoreceptor trigger zone and cause CINV. Thus, 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 caused 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 due to 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 a great deal of attention. In this regard, the prior art teaches that antiemetic drugs 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 not effective 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 antiemetic drugs 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 in the prior art (New Eng. J. Med., 2016, 374, 1356-67) involve the use of antiemetic drugs 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 their 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 combined 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 partly obscure. In this regard, a great deal of attention has been focused on identifying neuropeptides that regulate the signalling in different brainstem regions related to nausea and vomiting. Neuropeptides are small proteinaceous 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 noradrenaline, 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 this pharmacokinetic problem 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 that can modulate CGRP neurotransmission is the use of viruses, which are also directly injected into the brains of experimental animals and carry genetic information that allows 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 aforementioned inability of current CGRP-modulating drugs to penetrate the blood-brain barrier, 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 development of significant therapeutic importance is the clinical development of CGRP receptor antagonists that can counteract the peripheral functions of the neuropeptide. These drugs, named "gepants", have been approved for the symptomatic and prophylactic treatment of migraine. First-generation gepants (e.g., olcegepant and telcagepant) are effective in migraine treatment but cause hepatotoxicity. Second-generation gepants (e.g., ubrogepant, atogepant, rimegepant, and zavegepant) exhibit antimigraine properties without any hepatotoxic effects.

[0010] Prior art indicates that gepants do not enter the brain because their structure and polarity prevent them from crossing the blood-brain barrier (J. Pharmacol. Exp. Ther. 2013; 347:478 - 86). Thus, prior art teaches that gepants exert their antimigraine effect by acting on the trigeminovascular afferent nerves within the meninges. Here, gepants counteract the pain-sensitizing effect of CGRP and associated headache. Due to this analgesic effect, gepants can also indirectly alleviate migraine-associated symptoms such as photophobia, phonophobia, and nausea (Nat. Rev. Neurol. 2018; 14:338 - 350; Cephalalgia. 2020; 40:924 - 934; CNS Neurol. Disord. Drug Targets. 2020; 19:344 - 359).

[0011] Therefore, experts in the field did not find any teaching in the prior art regarding the action of gepants in the central nervous system and their influence on neurotransmission. Similarly, experts in the field did not find any teaching in the prior art regarding the ability of gepants to counteract drug-dependent nausea and vomiting (including CINV). This putative effect is not obvious because prior art indicates that for counteracting this type of nausea and vomiting, antiemetics need to reach the vomiting center in the brainstem, and gepants cannot cross the blood-brain barrier. Summary of the Invention

[0012] Unexpectedly, we now find that oral (i.e., peripheral) administration of rimegepant, ubrogepant, atogepant, and zavegepant results in the accumulation of the gepants within the central nervous system. Additionally, we also unexpectedly find that oral administration of rimegepant, ubrogepant, atogepant, and zavegepant exerts a functional effect in the brain and can reduce nausea and vomiting caused by antineoplastic chemotherapeutic agents.

[0013] Specifically, we unexpectedly found that 6 hours after oral administration (3 mg / kg), rimegepant, ubrogepant, atogepant, and zavegepant were present in the cerebral cortex extracts of rats. The animals were perfused with cold saline for 10 minutes through the heart to remove blood contamination and any possible gepants present in the plasma. After perfusion, tissue specimens of the cerebral cortex (the area behind the blood-brain barrier) and trigeminal ganglia (the area before the blood-brain barrier) were collected and extracted with a 10-volume (weight / volume) solution of water / acetonitrile (50% / 50%). The tissue extracts were injected into an LC / MS instrument to reveal the possible presence of orally administered gepants. We found that the gepants were not only present in the trigeminal nerves but also unexpectedly present in the cerebral cortex extracts ( Figure 1)。Therefore, contrary to current prior art (J.Pharmacol.Exp.Ther.2013; 347:478-86), we unexpectedly found that when administered peripherally, the gepants remimagine, uliprant, atogepant, and zavegepant are able to cross the blood-brain barrier and accumulate within the brain parenchyma.

[0014] We also unexpectedly found that oral administration of remimagine, uliprant, atogepant, and zavegepant reduced nausea and vomiting in rats exposed to anti-tumor chemotherapeutic agents. It is known that chemically induced nausea can be evaluated by measuring the repeated gaping of rats (so-called "gaping"). Thus, we evaluated the effect of remimagine, uliprant, atogepant, and zavegepant (3 mg / kg) on gaping in rats induced by the anti-cancer drugs cisplatin (6 mg / kg, intraperitoneal injection) or cyclophosphamide (40 mg / kg, intraperitoneal injection). These drugs were injected 6 hours after oral administration of the gepants, thus allowing the drugs to be fully absorbed and distributed in the tissues. Gaping was detected for 4 hours. We unexpectedly found that the number of gaping events (as an indicator of nausea) was reduced in animals pretreated with the gepants remimagine, uliprant, atogepant, and zavegepant compared to control animals ( Figure 2 ).

[0015] It is known that vomiting can be preclinically induced and evaluated in the shrew (Suncus Murinus). We unexpectedly found that gepants reduced vomiting in shrews exposed to anti-cancer chemotherapeutic agents. Specifically, we have evaluated the effect of oral administration of remimagine, uliprant, atogepant, and zavegepant (3 mg / kg) on vomiting events in shrews induced by cisplatin (6 mg / kg intraperitoneal injection) or cyclophosphamide (40 mg / kg intraperitoneal injection). To allow for full absorption and tissue distribution of the gepants, cisplatin and cyclophosphamide were administered 6 hours after administration of the gepants, and the animals were monitored for 4 hours. We unexpectedly found that vomiting was reduced in animals exposed to remimagine, uliprant, atogepant, and zavegepant compared to the control group ( Figure 3 ).

[0016] According to the present invention, gepants can be formulated and administered by oral, intravenous, intra-arterial, intramuscular, transdermal, intranasal, and subcutaneous routes to treat nausea and vomiting. The amount of gepant to be administered is the amount typically employed for such drugs, for example, 10 mg to 3000 mg per day, week, or month. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1. To evaluate the ability of gepants to accumulate in the trigeminal ganglion and cerebral cortex after oral administration in rats. As shown in the figure, 6 hours after oral administration of remimagine, ubrogepant, atogepant, and zavegepant (3 mg / kg), these compounds could be detected not only in the trigeminal ganglion of rats (n = 5 per group), but also in the cerebral cortex extracts. The animals were subjected to cardiac perfusion for 10 minutes to remove gepant contamination present in the plasma.

[0018] Figure 2 . The effect of gepants on cisplatin- or cyclophosphamide-induced nausea in rats. Rats (10 animals / group) were orally administered remimagine, ubrogepant, atogepant, and zavegepant (3 mg / kg) 6 hours before intraperitoneal injection of cisplatin (6 mg / kg) or cyclophosphamide (40 mg / kg). The number of gaping events within 4 hours was evaluated as an index of nausea. Compared with the control group, rats pretreated with remimagine, ubrogepant, atogepant, and zavegepant showed a decrease in the number of gaping events (and thus nausea). *p < 0.05, **p < 0.01 vs control group, ANOVA and Tukey post hoc test.

[0019] Figure 3 . The effect of gepants on cisplatin- or cyclophosphamide-induced vomiting in shrews. Shrews (10 animals / group) were orally administered remimagine, ubrogepant, atogepant, and zavegepant (3 mg / kg) 6 hours before intraperitoneal injection of cisplatin (6 mg / kg) or cyclophosphamide (40 mg / kg), and the number of vomiting events within 4 hours was evaluated. Compared with the control group, shrews pretreated with remimagine, ubrogepant, atogepant, and zavegepant showed a decrease in the number of vomiting events. *p < 0.05, **p < 0.01 vs control group, ANOVA and Tukey post hoc test. Detailed implementation mode

[0020] The best way to implement the present invention is to treat patients by administering remimagine, ubrogepant, atogepant, and zavegepant daily, weekly, or monthly through different routes (such as but not limited to oral or intravenous injection) before, during, and / or after the patient is exposed to nausea and / or vomiting inducers.

Claims

1. A CGRP receptor antagonist and a pharmaceutically acceptable preparation thereof, which are used for preventing chemotherapy-induced nausea and vomiting (CINV).

2. A CGRP receptor antagonist and a pharmaceutically acceptable preparation thereof, which are used for treating chemotherapy-induced nausea and vomiting (CINV).

3. A CGRP receptor antagonist and a pharmaceutically acceptable preparation thereof, which are used for enhancing the effect of a drug for preventing or treating chemotherapy-induced nausea and vomiting.

4. A CGRP receptor antagonist and a pharmaceutically acceptable preparation thereof, which are used for preventing and treating drug-induced nausea and vomiting.

5. A CGRP receptor antagonist and a pharmaceutically acceptable preparation thereof, which are used for preventing and treating nausea and vomiting in an individual with cancer.

6. A CGRP receptor antagonist and a pharmaceutically acceptable preparation thereof, which are used for preventing and treating nausea and vomiting induced by the activation of the vomiting center.

7. The CGRP receptor antagonist according to any one of claims 1 to 6, wherein, The antagonist is remegolix.

8. The CGRP receptor antagonist according to any one of claims 1 to 6, wherein, The antagonist is ubrogepant.

9. The CGRP receptor antagonist according to any one of claims 1 to 6, wherein, The antagonist is atogepant.

10. The CGRP receptor antagonist according to any one of claims 1 to 6, wherein, The antagonist is zavegepant.

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