Regulators of nausea and vomiting

Abstract

Nausea and vomiting are unpleasant events 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 that can 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, an antibody against CGRP was approved for the prevention of migraine headaches. This paper describes the use of an anti-CGRP monoclonal antibody 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 is the clinical development of monoclonal antibodies (mAbs) that can inhibit peripheral CGRP function. The mAbs fremanezumab, galcanezumab, and eptinezumab bind to and eliminate neuropeptides, whereas erenumab binds to and inhibits neuropeptide receptors (collectively defined as "anti-CGRP mAbs"). These mAbs are administered subcutaneously or intravenously and are only effective in preventing migraines. Significant efforts have been made to identify the mechanisms underlying the anti-migraine effects of anti-CGRP mAbs. The current state of the art is that the blood-brain barrier is impermeable to immunoglobulins (proteins with a molecular weight of approximately 150 kDa, consisting of a four-component structure). Therefore, it is known from the current state of the art that anti-CGRP mAbs cannot penetrate the blood-brain barrier and into the brain parenchyma, thereby exerting their pharmacodynamic effects only in the periphery (J Neurosci. 2019;39:6001-6011; Cephalalgia 2020;40:229-240; Cephalalgia. 2020;40:924-934; BMC Neurology, 2022, 22: 205-213). Experts in the field actually attribute the anti-migraine effects of anti-CGRP mAbs to their peripheral actions. Specifically, it is generally accepted that the anti-migraine effects of anti-CGRP mAbs are due to their ability to attenuate CGRP-dependent pain signaling in trigeminovascular afferents in the meninges. (Nat. Rev. Neurol. 2018;14:338-350; CNS Neurol. Disord. Drug. Targets. 2020;19:344-359).

[0010] Therefore, experts in the field have found no clues in the current state of the art that anti-CGRP mAbs can penetrate the central nervous system and exert a functional effect. The putative brain activity of these antibodies is unclear because the blood-brain barrier is impermeable to immunoglobulins and, as previously reported, fremanezumab cannot reach the brain parenchyma (Cephalgia 2020;40:229-240).

[0011] Furthermore, experts in the art have found no clue from the current state of the art that anti-CGRP mAbs can suppress CINV or other types of drug-induced nausea and vomiting. According to the art, this effect is unclear because antibodies do not cross the blood-brain barrier, while brain-penetrating drugs are required to treat drug-induced nausea and vomiting, including CINV. Summary of the Invention [Means for solving the problem]

[0012] Unexpectedly, the inventors have now discovered that subcutaneous (i.e., peripheral) administration of anti-CGRP mAbs such as fremanezumab, galcanezumab, eptinezumab, and erenumab results in the accumulation of the antibodies in the brain, in contrast to the current state of the art (Cephalalgia 2020;40:229-240). Furthermore, the inventors have unexpectedly discovered that subcutaneous (i.e., peripheral) administration of anti-CGRP mAbs such as fremanezumab, galcanezumab, eptinezumab, and erenumab exerts a functional effect in the brain and can reduce nausea and vomiting caused by antitumor chemotherapy drugs, in contrast to the current state of the art (Cephalalgia.2020;40:924-934).

[0013] Specifically, we unexpectedly found that the anti-CGRP antibodies fremanezumab, galcanezumab, eptinezumab, and erenumab were present in the brain parenchyma of rats that had received subcutaneous injections of these antibodies (30 mg / kg in the interscapular region) 7 days before sacrifice. To remove blood residues, including antibodies present in the plasma, from the brain parenchyma, experimental animals were perfused transcardially with cold saline for 10 minutes. After this extensive perfusion, specimens of the cerebral cortex (across the blood-brain barrier) and the trigeminal ganglion (before the barrier) were collected and processed for Western blotting. The presence of anti-CGRP mAbs in the brain parenchyma was revealed by examining the presence of human antibodies in rat brain extracts. Indeed, the potential presence of human antibodies in rat brain extracts must result from the brain penetration of the subcutaneously injected anti-CGRP antibodies. Specifically, after electrophoresis and blotting of the protein extract, the membrane was incubated with polyclonal anti-human IgG, which can recognize both the heavy and light chains of the injected anti-CGRP mAbs. To confirm complete removal of blood by transcardial perfusion in rats, the membrane was also incubated with anti-human hemoglobin (as a blood contamination marker). The inventors unexpectedly discovered that anti-CGRP mAbs could be detected not only in the trigeminal ganglion but also in the cerebral cortex of animals, without the simultaneous detection of hemoglobin (Figure 1). This indicates that the presence of human antibodies in the brain parenchyma is not due to residual blood in the brain tissue extract. Therefore, in contrast to the current state of the art (Cephalgia 2020;40:229-240), the presence of the anti-CGRP mAbs fremanezumab, galcanezumab, eptinezumab, and erenumab detected in rat cerebral cortex extracts must be attributed to unexpected penetration of the blood-brain barrier and accumulation in the brain parenchyma.

[0014] We also unexpectedly discovered that subcutaneous injection of anti-CGRP antibodies, fremanezumab, galcanezumab, eptinezumab, and erenumab, reduced nausea and vomiting in rats exposed to antitumor chemotherapy 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 the antibodies, fremanezumab, galcanezumab, eptinezumab, and erenumab, 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 15 days after subcutaneous injection of anti-CGRP mAbs to allow complete tissue distribution of the antibodies. The inventors unexpectedly discovered that experimental animals pretreated with fremanezumab, galcanezumab, eptinezumab or erenumab antibodies had a reduced incidence of gating episodes (4 hours of monitoring) 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 anti-CGRP mAbs suppressed emesis in shrews exposed to anticancer chemotherapy drugs. Specifically, we evaluated the effect of subcutaneous injections of fremanezumab, galcanezumab, eptinezumab, and erenumab (100 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 distribution of the antibodies, cisplatin and cyclophosphamide were administered 15 days after the anti-CGRP mAb injection. Unexpectedly, we found that the number of emesis episodes (4-hour monitoring) was reduced in animals exposed to fremanezumab, galcanezumab, eptinezumab, and erenumab compared to controls (Figure 3).

[0016] According to the present invention, anti-CGRP antibodies can be formulated and administered intravenously, intraarterially, intramuscularly, intranasally, or subcutaneously for the treatment of nausea and vomiting. The antibody is administered in amounts typically used for this type of drug, e.g., 10 to 3000 mg daily, weekly, or monthly. [Brief explanation of the drawings]

[0017] [Figure 1] This figure shows Western blotting analysis of the ability of the anti-CGRP antibodies fremanezumab, galcanezumab, eptinezumab, and erenumab to cross the blood-brain barrier and accumulate in the brain parenchyma. As shown, fremanezumab, galcanezumab, eptinezumab, or erenumab (30 mg / kg) are present (along with heavy and light chains) in the rat brain cortex 7 days after subcutaneous injection. The amount of fremanezumab in the rat trigeminal ganglion (TG) is shown as an indicator of the amount of anti-CGRP antibodies present in the periphery of these animals. Animals were perfused transcardially with cold saline to remove blood / plasma contamination. Complete removal of blood / plasma is evidenced by the absence of hemoglobin in tissue extracts. The data demonstrate that fremanezumab, galcanezumab, eptinezumab, and erenumab can penetrate and accumulate in the brain. The figure also shows the positive controls of fremanezumab and hemoglobin (both at 10 ng). [Figure 2] This figure shows the effect of anti-CGRP antibodies on cisplatin- or cyclophosphamide-induced nausea in rats. Rats (10 per group) were subcutaneously injected with fremanezumab, galcanezumab, eptinezumab, or erenumab (100 mg / kg). 15 days later, the animals were exposed to intraperitoneally injected cisplatin (6 mg / kg) or cyclophosphamide (40 mg / kg), and the number of gapping episodes over a 4-hour period was assessed as an indicator of nausea. Rats pretreated with fremanezumab, galcanezumab, eptinezumab, or erenumab showed reduced gating episodes compared to controls. By ANOVA and Tukey's post-hoc test, * indicates p<0.05, and ** indicates p<0.01 compared to controls. [Figure 3]This figure shows the effect of anti-CGRP antibodies on cisplatin- or cyclophosphamide-induced emesis in shrews. Shrews (10 per group) were subcutaneously injected with fremanezumab, galcanezumab, eptinezumab, or erenumab (100 mg / kg). Fifteen days later, animals were exposed to intraperitoneal injections of cisplatin (6 mg / kg) or cyclophosphamide (40 mg / kg), and the incidence of vomiting was assessed over a 4-hour period. Shrews pretreated with fremanezumab, galcanezumab, eptinezumab, or erenumab had reduced incidence of vomiting compared to controls. *p<0.05, **p<0.01 compared to controls by ANOVA and Tukey's post-hoc test. 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 fremanezumab, galcanezumab, eptinezumab or erenumab administered by different routes, for example subcutaneously or intravenously, before, during and / or after exposure to agents that induce nausea and / or vomiting.

Claims

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

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

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

4. An anti-CGRP antibody, an anti-CGRP receptor antibody, or an antigen-binding fragment thereof, in a pharmaceutically acceptable formulation for the prevention and treatment of drug-induced nausea and vomiting.

5. An anti-CGRP antibody, an anti-CGRP receptor antibody, or an antigen-binding fragment thereof, in a pharmaceutically acceptable formulation for the prevention and treatment of nausea and vomiting in an individual with cancer.

6. An anti-CGRP antibody, an anti-CGRP receptor antibody, or an antigen-binding fragment thereof, in a pharmaceutically acceptable formulation for the prevention and treatment of nausea and vomiting resulting from activation of the vomiting center.

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

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

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

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

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