Treatment of interoceptive disorders with CGRP receptor antagonists

Abstract

Interoception is the mechanism by which an individual obtains information about his or her own bodily state. When interoception is dysfunctional, it turns into a detrimental event for the individual's well-being. The use of calcitonin gene-related peptide (CGRP) receptor antagonists (gepants) for the treatment and prevention of interoceptive disorders has been described.

Description

[Technical field]

[0001] The present invention refers to the field of drugs for the treatment of disorders of interoception. [Background technology]

[0002] Interoception is the mechanism by which an individual obtains information about the state of his or her body. It allows each individual to gather certain information of the functioning of the internal organs so that, in case of malfunction, a specific response can be activated to restore homeostasis. In doing so, interoception allows an individual to identify the correct or disrupted functioning of organs and functions (health states) such as the digestive tract, respiratory tract, appetite and satiety, emotional state, sentiment, motivation, and the presence of pain. From this perspective, the perception of fatigue is due to interoceptive information signaling a negative health state. Interoception is therefore the polar opposite of exteroception, which regulates the awareness of the body in the environment.

[0003] From a neurophysiological perspective, health states defined by interoceptive signaling are mediated by neuronal afferents belonging to both the sensory (mechanical, thermal, nociceptive) and autonomic nervous systems. These peripheral afferents first project to brainstem nuclei (mainly the parabrachial nucleus) and are then redirected to the hypothalamus, amygdala and thalamus, from where interoceptive information reaches the parietal, frontal and insular cortices, where conscious and affective components of health states are decoded.

[0004] It is well accepted that one of the most common homeostatic responses activated in individuals receiving negative interoceptive sensory information (signals of fatigue) is loss of appetite, also known as anorexia. Although such a response may seem paradoxical, it is actually an important vicariously response in animals aimed at protecting the subject by preventing the assumption of food that could potentially have caused a disease state. Naturally, if the anorexic response is prolonged, it turns into a detrimental event for the health state, leading to an excessive reduction in caloric intake, weight loss, weakness and a general disruption of the organism's defenses. It is known that numerous hepatic, renal, gastrointestinal, immune, infectious and pain disorders are invariably associated with reduced appetite and anorexia. Similarly, similar anorexic responses are induced by poisoning or pharmacological treatments. Among the latter, anticancer chemotherapy is very frequently associated with anorexia.

[0005] Unfortunately, this type of anorexia frequently reaches such a severe level that it critically reduces the calorie intake of patients. This then prompts the interruption of treatment, which inevitably leads to chemotherapy failure and uncontrolled tumor growth. It is also worth noting that tumor patients are exposed to another risk of weight loss / anorexia, namely tumor cachexia, a serious clinical condition in which loss of appetite is accompanied by the loss of fat and muscle tissue induced by tumor-derived signals.

[0006] Given the high frequency of food disorders associated with negative interoceptive signaling and the severe clinical consequences that follow, considerable effort has been focused on identifying drugs capable of restoring nutritional homeostasis in these individuals.

[0007] Therefore, a problem to be solved is to identify drugs capable of counteracting interoceptive sensory signaling during various types of disorders.

[0008] Although the neurochemistry of interoception is still largely undeciphered, specific neuropeptides that modulate the central processing and signal efflux of sensory afferents have been identified at the preclinical level. Neuropeptides are small (10-40 amino acids) proteinaceous molecules that perform a myriad of neuronal and neuroendocrine functions within the central and peripheral nervous systems. Remarkably, neuropeptides are released in a vesicle-dependent manner, but unlike classical small molecule neurotransmitters such as glutamate, serotonin or noradrenaline, neuropeptides facilitate long-lasting postsynaptic signaling that usually reaches neurons very far from the site of release, thereby sustaining the so-called "volume transmission".

[0009] Among numerous neuropeptides, calcitonin gene-related peptide (CGRP) is a 37 amino acid molecule with central and peripheral actions. Although the peripheral vasodilatory effect of CGRP has been deeply studied and characterized, the central effects of neuropeptides remain largely unidentified. It is well known that this lack of knowledge must be mainly due to the inability of peripherally acting CGRP receptor agonists and antagonists to cross the blood-brain barrier. Such impermeability inevitably hampers the possibility of using these tools to modulate CGRP neurotransmission and understand its role in neurophysiopathology (Nat Rev Neurol. 2018;14:338-35). To circumvent such technical problems, scientists have been modulating CGRP neurotransmission using intracerebral injection of drugs that modulate neuropeptide receptors or viruses expressing proteins that modulate CGRP neurotransmission. Notably, this technique is not clinically suitable or available.

[0010] As a result of these invasive experimental procedures, a key role for CGRP in regulating emotional functions such as responses to stress and aversive stimuli has recently been discovered. As far as aversive stimuli are concerned, CGRP is now known to be a central player in the interoceptive information that reaches the parabrachial nucleus and is subsequently redirected to the amygdala. This signaling pathway appears to play a key role in integrating sensory and autonomic afferents carrying interoceptive information in a way that generally promotes specific homeostatic responses to various types of stress, pain, and fatigue (Trends Neurosci. 2018;41:280~293). On this basis, it is theoretically possible to modulate interoceptive sensation by modulating CGRP neurotransmission in the central nervous system. Unfortunately, no drugs have been identified so far that, when administered peripherally using clinically relevant and available methods, can reach the brain and modulate CGRP-dependent interoceptive signaling in the central nervous system.

[0011] Antagonists of the CGRP receptor, commonly referred to as "gepants", have been developed for the symptomatic treatment of migraine. The first gepants, such as olcegepant and telcagepant, proved effective as antimigraine drugs, but their development was halted due to the occurrence of hepatotoxicity. In recent years, new non-hepatotoxic gepants, such as ubrogepant, rimegepant, atogepant and zabegepant, have been developed for the symptomatic treatment of migraine. Gepants are known not to penetrate into the brain because they are unable to cross the blood-brain barrier (J. Pharmacol. Exp. Ther. 2013,347:478-86). Indeed, gepants are known to exert their antimigraine effects at the level of intrameningeal trigeminovascular afferents (Nat. Rev. Neurol. 2018;14:338-350, Cephalosalgia. 2020;40:924-934).

[0012] Thus, experts in the field have no cutting edge clues that gepants act within the central nervous system, nor have experts in the field no cutting edge clues that gepants modulate interoception and homeostatic responses driven by brain processing of interoceptive information. [Prior art documents] [Non-patent literature]

[0013] [Non-Patent Document 1] Nat Rev Neurol. 2018;14:338~35 [Non-Patent Document 2] Trends Neurosci. 2018;41:280~293 [Non-Patent Document 3] J. Pharmacol. Exp. Ther. 2013,347:478~86 [Non-Patent Document 4] Nat. Rev. Neurol. 2018;14:338~350 [Non-Patent Document 5] Cephalalgia. 2020;40:924~934 Summary of the Invention [Problem to be solved by the invention]

[0014] Therefore, a technical problem to be solved is to identify drugs that can inhibit the action of CGRP in the brain and modulate the CGRP-dependent interoceptive sensory information and responses prompted by interoceptive sensory signaling that causes fatigue and negatively impacts the well-being of an individual. [Means for solving the problem]

[0015] Unexpectedly, the inventors have now found that oral (i.e., peripheral) administration of gepants, such as rimegepant, ubrogepant, atogepant and zavegepant, is capable of modulating brain processing of interoceptive sensory information (i.e., fatigue) in multiple experimental models of human disorders.

[0016] Specifically, the inventors unexpectedly found that oral administration of rimegepant, ubrogepant, atogepant and zavegepant reduced food aversion / anorexia, weight loss and promoted weight regain in rats exposed to the chemotherapeutic drug cisplatin (6 mg / kg, i.p.) as an experimental model of antitumor chemotherapy-induced fatigue (Figure 1).

[0017] Furthermore, the inventors unexpectedly found that oral administration of rimegepant, ubrogepant, atogepant and zavegepant reduced food aversion / anorexia, weight loss and increased locomotor activity in mice with chronic arthritis induced by Freund's adjuvant injection as an experimental model of fatigue due to chronic pain (Figure 2).

[0018] Given these findings, we unexpectedly found that oral administration of rimegepant, ubrogepant, atogepant and zavegepant completely prevented weight loss and even some food aversion / anorexia in rats undergoing laparotomy and intestinal manipulation as an experimental model of abdominal surgery-induced malaise (Figure 3).

[0019] Furthermore, we tested gepants in a model of liver injury, a condition that normally promotes asthenia, weight loss, and anhedonia. We unexpectedly found that oral administration of rimegepant, ubrogepant, atogepant, and zavegepant reduced weight loss and induced increased fresh water consumption (the latter as an indicator of reduced motivational behavior and anhedonia) in rats treated with carbon tetrachloride as a model of fatigue due to liver injury (Figure 4).

[0020] Furthermore, the inventors surprisingly found that oral administration of rimegepant, ubrogepant, atogepant and zavegepant prevented weight loss and decreased locomotor activity in rats injected with caerulein as an experimental model of pancreatitis (Figure 5).

[0021] Furthermore, we tested gepants in rats treated with a diet containing 0.75% adenine as an experimental model of renal failure, and unexpectedly found that oral administration of rimegepant, ubrogepant, atogepant and zavegepant reduced weight loss and reduced food consumption / anorexia in the animals ( FIG. 6 ).

[0022] Furthermore, the inventors unexpectedly found that oral administration of rimegepant, ubrogepant, atogepant and zavegepant in mice sensitized and rechallenged with ovalbumin as a model of asthma or chronic obstructive pulmonary disease reduced parameters of fatigue such as reduced locomotor activity, weight loss and fresh water consumption (Figure 7).

[0023] As a further model of fatigue caused by interoceptive sensory information, the inventors adopted the model of tumor cachexia and sepsis. Figure 8 shows the unexpected ability of oral administration of rimegepant, ubrogepant, atogepant and zavegepant in reducing weight loss and countering both muscle mass loss and reduced food consumption / anorexia in rats injected with Yoshida hepatocellular carcinoma as a classical model of fatigue caused by tumor cachexia.

[0024] Similarly, we unexpectedly found that oral administration of rimegepant, ubrogepant, atogepant and zavegepant reduced weight loss and reduced food consumption / anorexia in rats injected intraperitoneally with lipopolysaccharide from Salmonella Typhimurium as a classical model of sepsis / systemic immune activation-induced fatigue (Figure 9).

[0025] According to the present invention, gepants can be formulated for the treatment of interoceptive disorders and administered via oral, intravenous, intraarterial, intramuscular, nasal, transdermal and subcutaneous routes. The amount of gepants to be administered is that commonly employed for this type of drug, e.g., 10-3000 mg for daily, weekly or monthly administration. [Brief description of the drawings]

[0026] [Figure 1] Effect of rimegepant, ubrogepant, atogepant and zavegepant (10 mg / kg orally daily, starting 2 days before cisplatin) on food consumption / anorexia, weight loss, weight loss and weight regain in rats exposed to cisplatin (6 mg / kg, i.p.) as an experimental model of fatigue due to antitumor chemotherapy. *p<0.05, **p<0.01, ***p<0.001 vs. control, ANOVA and Tukey's post-hoc test. [Diagram 2] Effect of rimegepant, ubrogepant, atogepant and zavegepant (10 mg / kg orally, daily, starting 2 days before arthritis induction) on food consumption / anorexia, weight loss and locomotor activity in mice with chronic arthritis due to Freund's adjuvant injection as an experimental model of chronic pain-induced fatigue. *p<0.05, **p<0.01, ***p<0.001 vs. arthritis, ANOVA and Tukey's post-hoc test. [Diagram 3] Effect of rimegepant, ubrogepant, atogepant and zavegepant (10 mg / kg orally, daily, starting 2 days before surgery) on weight loss and food consumption / anorexia in rats undergoing laparotomy and intestinal manipulation as an experimental model of abdominal surgery-induced malaise. *p<0.05, **p<0.01, ***p<0.001 vs. laparotomy, ANOVA and Tukey's post-hoc test. [Figure 4]Effect of rimegepant, ubrogepant, atogepant and zavegepant (10 mg / kg orally daily, starting 2 days before carbon tetrachloride) on weight loss and fresh water consumption in rats treated with carbon tetrachloride as a model of fatigue due to hepatitis / liver damage. *p<0.05, **p<0.01, ***p<0.001 vs. hepatitis, ANOVA and Tukey's post-hoc test. [Diagram 5] Effect of rimegepant, ubrogepant, atogepant and zavegepant (10 mg / kg orally daily, starting 2 days before caerulein treatment) on weight loss and locomotor activity in rats injected with caerulein as an experimental model of pancreatitis. *p<0.05, **p<0.01, ***p<0.001 vs. pancreatitis, ANOVA and Tukey's post-hoc test. [Figure 6] Effect of rimegepant, ubrogepant, atogepant and zavegepant (10 mg / kg orally daily, starting 2 days before exposure to the nephrotoxic diet) on weight loss and food consumption / anorexia in rats exposed to a diet containing 0.75% adenine as an experimental model of renal failure. *p<0.05, **p<0.01, ***p<0.001 vs. renal failure, ANOVA and Tukey's post-hoc test. [Figure 7] Effect of rimegepant, ubrogepant, atogepant and zavegepant (10 mg / kg orally daily, starting 2 days before antigen rechallenge) on locomotor activity, weight loss and fresh water intake in mice sensitized and rechallenged with ovalbumin as a model of asthma or chronic obstructive pulmonary disease. *p<0.05, **p<0.01, ***p<0.001 for renal failure, ANOVA and Tukey's post-hoc test. [Figure 8] Effect of rimegepant, ubrogepant, atogepant and zavegepant (10 mg / kg orally, daily, starting 2 days before tumor injection) on weight loss, muscle mass and food consumption / anorexia in rats injected with Yoshida hepatoma as a classical model of fatigue due to tumor cachexia. *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001 vs. hepatocellular carcinoma, ANOVA and Tukey's post-hoc test. [Figure 9] Effect of rimegepant, ubrogepant, atogepant and zavegepant (10 mg / kg orally, daily, starting 2 days before lipopolysaccharide injection) on weight loss and food consumption / anorexia in rats injected intraperitoneally with lipopolysaccharide from Salmonella typhimurium as a classical model of sepsis / systemic immune activation-induced malaise. *p<0.05, **p<0.01 vs. sepsis, ANOVA and Tukey's post-hoc test. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0027] The best mode for carrying out the present invention is to treat patients with interoceptive disorders or at risk of interoceptive disorders with daily, weekly, or monthly doses of rimegepant, ubrogepant, atogepant, and zavegepant administered by various routes, including but not limited to orally or intravenously.

Claims

1. Antagonists of the CGRP receptor and pharma- ceutically acceptable formulations thereof for use in the prevention and treatment of fatigue (a negative perception of well-being in an individual).

2. Antagonists of the CGRP receptor and pharma- ceutically acceptable formulations thereof for use in the prevention and treatment of eating disorders or weight loss.

3. Antagonists of the CGRP receptor and pharma- ceutically acceptable formulations thereof for use in stimulating appetite and weight regain.

4. 4. The antagonist of the CGRP receptor for use according to any one of claims 1 to 3, wherein the antagonist is rimegepant.

5. 4. The antagonist of the CGRP receptor for use according to any one of claims 1 to 3, wherein said antagonist is ubrogepant.

6. 4. The antagonist of the CGRP receptor for use according to any one of claims 1 to 3, wherein the antagonist is atogepant.

7. 4. The antagonist of the CGRP receptor for use according to any one of claims 1 to 3, wherein the antagonist is zavegepant.

8. Antagonists of the CGRP receptor (gepants) for use according to any one of claims 1 to 7 in individuals suffering from neoplastic (cachexia), inflammatory, autoimmune, rheumatic, respiratory chronic obstructive and fibrotic, gastrointestinal, hepatic, pancreatic, abdominal, renal, cardiological, neurological and psychiatric disorders.

9. 8. Antagonists of the CGRP receptor (gepants) for use according to any one of claims 1 to 7 in individuals suffering from chronic or post-operative pain.

10. Antagonists of the CGRP receptor (gepants) for use according to any one of claims 1 to 7 in individuals exposed or to be exposed to antitumor therapy (chemotherapy).

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