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

Abstract

Nausea and vomiting are unpleasant experiences triggered by multiple triggers. Among these, drug-induced nausea and vomiting are common. Antitumor chemotherapy drugs are among the most emetogenic and frequently cause chemotherapy-induced nausea and vomiting (CINV). This emesis significantly impairs the efficacy of treatment as well as the patient's quality of life. There is considerable interest in identifying drugs to prevent and suppress drug-induced nausea and vomiting, including CINV. Calcitonin gene-related peptide (CGRP) is a neuropeptide with pleiotropic actions in the human body. However, the neuropeptide's role in the brain remains unclear. Recently, CGRP receptor antagonists (called gepants) have been approved for the treatment of migraine. This paper describes the use of gepants for the direct treatment of nausea and vomiting, including CINV.

Description

[Technical Field]

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

[0002] It is well known that oncology patients often suffer from nausea and vomiting. In particular, vomiting is often associated with the use of chemicals employed to inhibit cancer growth in these patients. Among various medications, it is antineoplastic chemotherapy drugs that are most frequently associated with nausea and vomiting, and this condition is generally defined as "chemotherapy-induced nausea and vomiting (CINV)." CINV has remarkable clinical relevance because, on the one hand, it impairs the patient's health and, on the other hand, it limits the dosage and causes treatment interruptions.

[0003] Some of the molecular mechanisms underlying CINV have already been elucidated. Drugs induce nausea and vomiting at the brainstem level, particularly in the posterior lobe, also known as the "chemoreceptor trigger zone." Here, a population of neurons capable of detecting various toxic foreign substances present in the blood sends out projections and activates the vomiting center. This response is fundamentally related to survival, as it enables stomach emptying after ingesting toxic substances. Given the potent cytotoxicity of antitumor chemotherapeutic drugs, it makes sense that they would rapidly activate the chemoreceptor trigger zone and cause CINV. Therefore, current state-of-the-art evidence indicates that the mechanisms responsible for nausea and vomiting in CINV are distinct from those involved in nausea and / or vomiting induced by other conditions, such as pregnancy, dizziness, pain, and anxiety. Indeed, CINV is precipitated by the toxic effects of antitumor chemotherapeutic drugs in the intestine, as well as by their detection by the chemoreceptor trigger zone, whereas other forms of nausea and vomiting are not due to activation of the chemoreceptor trigger zone.

[0004] Given the high incidence of CINV and its alarming clinical significance, the identification of effective compounds capable of preventing or combating this disorder is of great interest. In this regard, the current state of the art has shown that antiemetic drugs capable of suppressing vomiting induced by motion sickness, pregnancy, food poisoning, pain, or migraine, such as scopolamine, metoclopramide, domperidone, meclizine, doxylamine, dimedrinate, or vitamin B6, are unable to suppress CINV. As mentioned above, this ineffectiveness is due to the fact that the intrinsic cytotoxicity profile of anticancer chemotherapy drugs detected in the posterior lobe region is the primary cause of the pathogenesis of CINV. According to the specific mechanisms involved in the development of CINV, vomiting is suppressed by specific drugs such as serotonin 5HT3 receptor antagonists (ondansetron, parosetron, granisoetron), neurokinin-1 receptor antagonists (aprepitant, netupitant), or corticosteroids (dexamethasone). These compounds are not used at all to treat nausea and vomiting caused by diseases other than CINV. Therefore, it is not clear to those skilled in the art that antiemetics that are not specific for the treatment of CINV can be used to prevent CINV. On the contrary, those skilled in the art know that the current state of the art defines treatment guidelines for CINV (New Eng. J. Med., 2016, 374, 1356-67) that involve the use of antiemetics specific for the treatment of the disease.

[0005] Unfortunately, it is well known that drugs used to treat CINV are inactive in some patients and often tend to lose efficacy during treatment cycles. Therefore, a technical problem to be solved is to identify new drugs that can act alone or in a co-treatment paradigm in the brain regions that cause nausea and vomiting to treat CINV and improve the quality of life of tumor patients.

[0006] The underlying neurochemistry of nausea and vomiting remains unclear. In this regard, much attention has focused on identifying neuropeptides that regulate signaling between various brainstem regions involved in nausea and vomiting. Neuropeptides are small proteinaceous molecules (10–40 amino acids) that can regulate numerous neuronal and endocrine functions. Neuropeptides are released from classical presynaptic organs, but unlike neurotransmitters such as norepinephrine, acetylcholine, and serotonin, they generate long-lasting signaling that can reach regions distant from the presynaptic terminal (so-called "volume transmission").

[0007] Calcitonin gene-related peptide (CGRP) is a 37-amino acid neuropeptide present in both the central and peripheral nervous systems. The peripheral functions of CGRP are well known, primarily mediating vasodilation and pain sensitization. In contrast, the central functions of CGRP remain largely unknown. One of the main reasons for this lack of knowledge is the lack of brain-penetrant CGRP receptor agonists or antagonists. In fact, current peripherally administered CGRP receptor-interacting drugs cannot cross the blood-brain barrier and are unable to modulate CGRP-dependent neurotransmission (Nat. Rev. Neurol., 2018; 14:338). Concomitantly, experts in the field know that the only strategy to circumvent the above-mentioned pharmacokinetic issues and modulate CGRP neurotransmission is to inject receptor agonists or antagonists directly into the brain via microiontophoresis or intracerebroventricular routes. Furthermore, a recently adopted strategy to modulate CGRP neurotransmission involves the use of viruses carrying genetic code that can modulate the expression of CGRP or its cognate receptors, which are also injected directly into the brains of experimental animals.

[0008] Thanks to these modern gene therapy approaches, which require direct injection into the brain, the important role of CGRP in regulating neurotransmission between central nervous system regions, such as the amygdala, parabrachial nucleus, nucleus of the solitary tract, trigeminal nucleus, and several hypothalamic nuclei, has recently become clear. However, experts in the art are aware that, due to the above-mentioned impermeability of the blood-brain barrier to current CGRP-modulating drugs, there is currently no information available in the state of the art regarding the possibility of modulating CGRP neurotransmission in the brain by peripherally administered (i.e., orally, subcutaneously, or intravenously) compounds.

[0009] A recent therapeutically significant advance has been the clinical development of CGRP receptor antagonists, which can inhibit the peripheral function of neuropeptides. These drugs, termed "gepants," have been approved for the symptomatic and preventive treatment of migraine. First-generation gepants, such as olcegepant or telcagepant, were effective in treating migraine but caused hepatotoxicity. Second-generation gepants, such as ubrogepant, atogepant, rimegepant, and zabegepant, exhibit antimigraine properties but lack the hepatotoxic effects.

[0010] The current state of the art indicates that gepants, due to their structure and polarity, cannot cross the blood-brain barrier and therefore do not enter the brain. (J. Pharmacol. Exp. Ther. 2013;347:478-86) Therefore, the current state of the art indicates that gepants exert their antimigraine effects by acting on intrameningeal trigeminovascular afferents. Here, gepants alleviate the pain-sensitizing effects of CGRP and the associated headache. Thanks to this analgesic effect, gepants also indirectly alleviate migraine-associated symptoms, such as phonophobia, photophobia, 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 art cannot find in the current state of the art that gepants act within the central nervous system and affect neurotransmission. Similarly, experts in the art cannot find in the current state of the art that gepants alleviate drug-dependent nausea and vomiting, including CINV. This supposed effect is not self-evident, because the current state of the art knows that antiemetic drugs must reach the vomiting center in the brainstem to combat this type of nausea and vomiting, whereas gepants do not cross the blood-brain barrier. Summary of the Invention [Means for solving the problem]

[0012] The inventors have unexpectedly found that oral (i.e., peripheral) administration of rimegepant, ubrogepant, atogepant, and zavegepant results in the accumulation of the gepants in the central nervous system. Furthermore, the inventors have unexpectedly found that oral administration of rimegepant, ubrogepant, atogepant, and zavegepant exerts functional effects in the brain and can reduce nausea and vomiting caused by antitumor chemotherapeutic drugs.

[0013] Specifically, we unexpectedly discovered the presence of rimegepant, ubrogepant, atogepant, and zavegepant in rat brain cortex extracts 6 hours after oral administration (3 mg / kg). To remove potential gepants and blood contamination from plasma, experimental animals were perfused transcardially with cold saline for 10 minutes. After perfusion, tissue specimens from the cerebral cortex (across the blood-brain barrier) and trigeminal ganglion (before the blood-brain barrier) were collected and extracted with 10 volumes (mass / volume) of water / acetonitrile (50% / 50%). The tissue extracts were injected into an LC / MS system, revealing the possible presence of orally administered gepants. We unexpectedly discovered that gepants were present not only in the trigeminal nerve but also in the cerebral cortex extract (Figure 1). Thus, the inventors have unexpectedly discovered that, in contrast to the current state of the art (J. Pharmacol. Exp. Ther. 2013;347:478-86), the gepants rimegepant, ubrogepant, atogepant and zavegepant cross the blood-brain barrier upon peripheral administration and accumulate in the brain parenchyma.

[0014] We also unexpectedly discovered that oral administration of rimegepant, ubrogepant, atogepant, and zavegepant reduced nausea and vomiting in rats exposed to antitumor chemotherapeutic drugs. Chemical-induced nausea can be assessed by measuring repeated mouth opening (so-called "gaping") in rats (Autonomic Neuroscience, 2006, 129, 36-41). Therefore, we evaluated the effects of rimegepant, ubrogepant, atogepant, and zavegepant (3 mg / kg) on ​​gating induced in rats by the anticancer drugs cisplatin (6 mg / kg, intraperitoneal administration) or cyclophosphamide (40 mg / kg, intraperitoneal administration). These drugs were injected 6 hours after oral administration of gepant to allow the drugs to be completely absorbed and distributed in the tissues. Gaping was monitored for 4 hours. The inventors unexpectedly found that the number of gating episodes (an indicator of nausea) was reduced in experimental animals pretreated with the gepants rimegepant, ubrogepant, atogepant, and zabegepant compared to control experimental animals (Figure 2).

[0015] It is known that emesis can be induced and assessed preclinically in shrews (Suncus Murinus). We unexpectedly found that gepants suppressed emesis in shrews exposed to anticancer chemotherapy drugs. Specifically, we evaluated the effects of oral administration of rimegepant, ubrogepant, atogepant, and zavegepant (3 mg / kg) on ​​emesis induced in shrews by cisplatin (6 mg / kg, intraperitoneal administration) or cyclophosphamide (40 mg / kg, intraperitoneal administration). To ensure complete tissue absorption and distribution of gepants, cisplatin and cyclophosphamide were administered 6 hours after gepant administration, and the experimental animals were monitored for 4 hours. We unexpectedly found that emesis was reduced in experimental animals exposed to rimegepant, ubrogepant, atogepant, and zavegepant compared to the control group (Figure 3).

[0016] According to the present invention, gepants can be formulated and administered orally, intravenously, intraarterially, intramuscularly, transdermally, intranasally, and subcutaneously for the treatment of nausea and vomiting. The amount of gepant administered is that commonly employed for this type of drug, e.g., 10 to 3000 mg, administered daily, weekly, or monthly. [Brief explanation of the drawings]

[0017] [Figure 1] This figure shows the ability of gepants to accumulate in the trigeminal ganglion and cerebral cortex following oral administration to rats. As shown, 6 hours after oral administration of rimegepant, ubrogepant, atogepant, and zabegepant (3 mg / kg), the compounds were detectable not only in the trigeminal ganglion but also in cerebral cortex extracts (n=5 per group). To remove contamination by gepants present in plasma, experimental animals were perfused transcardially for 10 minutes. [Figure 2] This figure shows the effect of gepant on cisplatin- or cyclophosphamide-induced nausea in rats. Rats (10 per group) were orally administered rimegepant, ubrogepant, atogepant, or zavegepant (3 mg / kg) 6 hours before intraperitoneal injection of cisplatin (6 mg / kg) or cyclophosphamide (40 mg / kg). The number of gapping episodes over a 4-hour period was assessed as an index of nausea. Rats pretreated with rimegepant, ubrogepant, atogepant, or zavegepant had a reduced number of gating episodes (i.e., nausea) compared with controls. *p<0.05, **p<0.01 compared with control by ANOVA and Tukey's post-hoc test. [Figure 3]This figure shows the effect of gepant on cisplatin- or cyclophosphamide-induced emesis in shrews. Shrews (10 per group) were orally administered rimegepant, ubrogepant, atogepant, or zavegepant (3 mg / kg) 6 hours before intraperitoneal injection of cisplatin (6 mg / kg) or cyclophosphamide (40 mg / kg), and the incidence of vomiting was assessed over 4 hours. Shrews pretreated with rimegepant, ubrogepant, atogepant, or zavegepant had a reduced incidence of vomiting compared to controls. ANOVA and Tukey's post-hoc test indicated *p<0.05 and **p<0.01 compared to controls. DETAILED DESCRIPTION OF THE INVENTION

[0018] BEST MODE FOR CARRYING OUT THE INVENTION The best mode for practicing the present invention is to treat patients with daily, weekly or monthly administration of rimegepant, ubrogepant, atogepant and zavegepant administered by different routes, such as, but not limited to, oral or intravenous administration, before, during and / or after exposure to agents that induce nausea and / or vomiting.

Claims

1. CGRP receptor antagonists and pharmaceutically acceptable formulations thereof for the prevention of chemotherapy-induced nausea and vomiting (CINV).

2. CGRP receptor antagonists and pharmaceutically acceptable formulations thereof for the treatment of chemotherapy-induced nausea and vomiting (CINV).

3. CGRP receptor antagonists and pharmaceutically acceptable formulations thereof for enhancing the effect of drugs for the prevention or treatment of chemotherapy-induced nausea and vomiting.

4. CGRP receptor antagonists and pharmaceutically acceptable formulations thereof for the prevention and treatment of drug-induced nausea and vomiting.

5. CGRP receptor antagonists and pharmaceutically acceptable formulations thereof for the prevention and treatment of nausea and vomiting in cancer patients.

6. CGRP receptor antagonists and pharmaceutically acceptable formulations thereof for the prevention and treatment of nausea and vomiting caused by activation of the vomiting center.

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

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

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

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

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