Improved methods of treating diseases resulting from maladaptive stress responses - Patents.com

Abstract

The present disclosure relates to compositions and methods for treating maladaptive stress responses involving the corticotropin releasing factor receptor subtype 2 (CRFR2), such as myalgic encephalomyelitis / chronic fatigue syndrome or musculoskeletal or nervous system dysfunction, resulting in measurable symptomatic improvement.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims benefit of and priority to U.S. Provisional Patent Application No. 63 / 200,609, filed March 17, 2021, which is hereby incorporated by reference in its entirety. The present disclosure relates to formulations and methods for treating diseases resulting from maladaptive stress responses. Certain aspects of the disclosure are directed to formulations and methods for treating myalgic encephalomyelitis / chronic fatigue syndrome. [Background technology]

[0002] Previous studies suggest that myalgic encephalomyelitis / chronic fatigue syndrome (ME / CFS) (also known as systemic exertion intolerance disease, post-viral fatigue syndrome, or chronic fatigue immune dysfunction syndrome), a disorder of unknown etiology with significant overlap in symptoms and abnormalities with a group of disorders often referred to as functional somatic syndromes (FSS), is associated with upregulation of corticotropin releasing factor receptors (CRFR and particularly CRFR2) in neurons of the raphe nuclei and limbic system. Internalization of receptors or G protein-coupled receptors (GPCRs), also called clathrin-mediated endocytosis, has been extensively studied in vitro using variants of the CRF receptor. Such in vitro studies have shown that receptor agonists (e.g., endogenous urocortins 1, 2, and 3 or UCN1, UCN2, UCN3 in the case of CRFR2) induce dose-dependent intracellular signaling (measured via cyclic adenosine monophosphate or cAMP in the case of CRFR2) that is attenuated and / or abolished by agonist pre-exposure, depending on agonist potency, agonist concentration, and duration of pre-exposure. Summary of the Invention

[0003] Applicant has recognized an urgent and unmet need to treat diseases resulting from maladaptive stress responses, including ME / CFS. Applicant has identified that the ability to stimulate CRF receptors is lost after prior exposure to receptors resulting from internalization or endocytosis. Thus, Applicant has developed therapeutic formulations and methods of treatment for ME / CFS that target this mechanism against specific CRF receptors. Embodiments include a method of treating corticotropin releasing factor receptor 2 (CRFR2) maladaptation in a subject in need thereof. One such method includes measuring the plasma concentration of a CRFR2 agonist in the subject at a stimulation threshold concentration (C TThe method includes administering a CRFR2 agonist to the subject in an amount that maintains the patient's CRFR2 maladaptation level below 100%. In certain embodiments, sustained improvement of at least one symptom associated with CRFR2 maladaptation occurs in the absence of concomitant administration of a CRFR2 agonist. Examples of symptoms associated with CRFR2 maladaptation include fatigue, pain, sleep problems, cognitive problems, orthostatic intolerance, temperature perception, flu-like symptoms, headache or hyperesthesia, shortness of breath, gastrointestinal problems, urinary problems, musculoskeletal problems, nervous system problems, anxiety, depression, or one or more of the other characteristics or symptoms described above. In some instances, the patient experiences extreme fatigue or is characterized as paralysis. In other instances, dysfunction of skeletal muscles or nervous system manifests as tremor, ataxia, or dyskinesia. Such sustained improvement of one or more symptoms may continue for at least one week or more after cessation of administration of the CRFR2 agonist. The CRFR2 agonist may be one or more of UCN1, UCN2, UCN3, stresscopin-related peptide (SRP), stresscopin (SCP), CT38, CT37, or pharma- ceutically acceptable salts or solvates thereof. In certain embodiments, the CRFR2 agonist comprises an acetate salt of CT38 (CT38s). In certain embodiments, CT38s is administered to maintain a CT38 plasma concentration below about 0.25 ng / ml (nanograms per milliliter) to induce sustained improvement of at least one symptom associated with CRFR2 maladaptation. In certain embodiments, CT38s can be administered to a subject to achieve an AUC of about 5 ng·h / ml, which reflects the actual body exposure to CT38 after administration of a CT38s dose. In certain embodiments, CT38s can be administered at a rate of at least about 0.0001 μg / kg / h.

[0004] In certain embodiments, the CRFR2 maladaptation is myalgic encephalomyelitis / chronic fatigue syndrome (ME / CFS) as determined by the Fukuda Research Case Definition for CFS, the Revised Canadian Consensus Criteria for ME / CFS, or the National Academy of Medicine Clinical Diagnostic Criteria for ME. The CRFR2 maladaptation can be a post-acute sequelae of SARS-CoV-2 infection. The CRFR2 maladaptation can be a musculoskeletal or nervous system dysfunction, e.g., Parkinson's disease.

[0005] Certain embodiments of treating CRFR2 maladaptation in a subject in need thereof include administering to the subject a controlled release dose of a CRFR2 agonist, the controlled release dose of which reduces the plasma concentration to below the stimulation threshold (C) of the CRFR2 agonist. T) and is effective to induce sustained improvement of at least one symptom associated with CRFR2 maladaptation. Examples of symptoms associated with CRFR2 maladaptation include fatigue, pain, sleep problems, cognitive problems, orthostatic intolerance, temperature perception, flu-like symptoms, headache or hyperesthesia, shortness of breath, gastrointestinal problems, urinary problems, musculoskeletal problems, neurological problems, anxiety, depression, or one or more of the other characteristics or symptoms described above. In certain embodiments, the CRFR2 maladaptation is a functional somatic syndrome. In certain embodiments, the functional somatic syndrome is myalgic encephalomyelitis / chronic fatigue syndrome. The CRFR2 maladaptation can be a post-acute sequelae of SARS-CoV-2 infection. In certain embodiments, the sustained improvement includes improvement of at least one symptom associated with ME / CFS for at least one week or more after cessation of administration of the CRFR2 agonist. In certain embodiments, the CRFR2 agonist is one or more of UCN1, UCN2, UCN3, SRP, SCP, CT38, CT37, or pharma- ceutically acceptable salts or solvates thereof. The CRFR2 agonist may include an acetate salt of CT38 (CT38s). In certain embodiments, a controlled release dose of CT38s is administered at a rate of about 0.03 μg / kg / h or less. In certain embodiments, CT38s is administered to maintain CT38 plasma concentrations below about 0.25 ng / ml to induce sustained improvement of at least one symptom associated with CRFR2 maladaptation. Numerous other aspects, features and advantages of the present disclosure will become apparent from the following detailed description taken in conjunction with the drawings. It is to be further understood that both the foregoing general description and the following detailed description are exemplary and explanatory and are intended to provide further explanation of the invention as claimed. Various examples are shown in the accompanying drawings for illustrative purposes, which should not be construed as limiting the scope of the embodiments. Moreover, various features of the various disclosed embodiments may be combined to form further embodiments, which are part of this disclosure. [Brief description of the drawings]

[0006] [Figure 1A-1B]Figure 1A is a stylized representation of typical behavior of a GPCR agonist on a GPCR. Increasing agonist concentration increases GPCR-evoked output, beginning at CT and continuing through CL. After this, GPCR-evoked output declines, presumably via receptor endocytosis. Figure 1A illustrates this response in the context of cAMP production from GPCRs in vitro, while Figure 1B illustrates the response in terms of rat heart rate (e.g., CRFR2 receptor output) in vivo from administration of CT38 (a CRFR2 selective agonist). [Figure 2A-2B] Graphical representation of the effect of mean CT38 maximum plasma concentration (Cmax) (Figure 2A) or mean area under the plasma concentration-time curve (AUC) (Figure 2B) on the change in mean maximum heart rate (HRmax) in ME / CFS patients (black line) and healthy subjects (grey line). Plots of mean heart rate change (bpm) versus CT38 Cmax (ng / ml) or AUC (ng h / ml) are shown. [Figure 3A-3B] Graphical representation of the effect of mean CT38Cmax (FIG. 3A) or mean AUC (FIG. 3B) on the change in mean minimum diastolic blood pressure (dBPmin) in ME / CFS patients (black line) and healthy subjects (grey line). Plots of mean diastolic blood pressure change (mmHg) versus CT38Cmax (ng / ml) or AUC (ng h / ml) are shown. [Figure 4] Figure 1 shows the effect of CT38s on pre / post-treatment change in mean daily total symptom score (TDSS) and daily individual symptom scores by dose group in ME / CFS patients (associated p-values ​​shown). Bar graphs showing the relative change in TDSS and each symptom in each dose cohort (D01, D03, D06 and D20) are shown. In these, improvement (light grey) and worsening (black) of TDSS or symptoms are highlighted. [Figure 5A-5B]Figure 5 shows the effect of CT38s (bars) on pre / post-treatment change in 28-day averages of TDSS and individual symptom scores with standard deviation (error bars). These are for CT38: Cmax<0.25ng / ml (Figure 5A) or Cmax>0.25ng / ml (Figure 5B) and show either improvement (green) or worsening (purple) with associated p-values ​​(italics). Note that the scales of TDSS and individual symptoms are different. [Figure 6A-6B] Graphical representation of the effect of mean CT38 exposure (total AUC) on patient-specific pre- / post-treatment change in mean daily total symptom score (TDSS), stratified by pre-treatment symptom severity and whether the achieved Cmax remained below (Fig. 6A) or exceeded (Fig. 6B) the CT of CT38 in humans (0.25 ng / ml). Plots of mean TDSS change versus total CT38 AUC (ng h / ml) are shown, stratified by CT38 Cmax of either below (Fig. 6A, green) or above (Fig. 6B, purple) 0.25 ng / ml, and further stratified by pre-treatment TDSS of either mild (Fig. 6A, open circles) or moderate (Fig. 5A, filled circles). [Figure 7A-7B] FIG. 7A is a graphical representation of the effect of CT38s administration on SF-36 physical component scores (FIG. 7A) and SF-36 mental component scores (FIG. 7B) by dose group in ME / CFS patients. Bar graphs showing SF-36 scores for each dose cohort are shown, with error bars indicating standard deviation. [Figure 8A-8B] The effect of CT38 on the mean pre-treatment (purple bars) and post-treatment (green bars) SF-36 Physical Component Score (PCS) (Figures 8A and 8B, top panels) and SF-36 Mental Component Score (MCS) (Figures 8A and 8B, bottom panels) is shown with standard deviations (error bars) for CT38s at Cmax<0.25ng / ml (Figure 8A) and Cmax>0.25ng / ml (Figure 8B). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0007] Reference will now be made to the exemplary embodiments shown in the drawings, and specific technical terms will be used herein to describe them. Nevertheless, it is understood that this is not intended to limit the scope of the present invention. Changes and further modifications of the features of the present invention shown herein, and further application of the principles of the present invention shown herein, which are found by those skilled in the relevant arts who have ownership of this disclosure, should be considered within the scope of this disclosure. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs. All patents and publications mentioned herein are incorporated herein by reference.

[0008] As used in this specification and claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. As used herein, "treatment" or "alleviation" are used interchangeably. Such terms refer to an approach for obtaining beneficial or desired results, including, but not limited to, a therapeutic benefit. A therapeutic benefit refers to the eradication or alleviation of a symptom or characteristic or sign of the underlying disorder being treated. A therapeutic benefit is also achieved by the eradication or alleviation of at least one physiological symptom associated with the underlying disorder, such that an improvement in the patient is observed, although the patient may still be afflicted by the underlying disorder. The term "therapeutic effect" as used herein encompasses the therapeutic benefits of such treatments.

[0009] The term "antagonist" as used herein includes any molecule that partially or completely blocks, inhibits or neutralizes a biological activity of a native polypeptide (e.g., CRFR2) disclosed herein. Methods for identifying antagonists of a polypeptide may include contacting the native polypeptide with a candidate antagonist molecule and reducing one or more biological activities normally associated with agonist activity in the native polypeptide. The term "agonist" is used in the broadest general sense and includes both naturally occurring small molecules and peptides, as well as synthetic small molecules that partially or fully induce the biological activity of a naturally occurring polypeptide (e.g., CRFR2) disclosed herein. Suitable agonist molecules specifically include naturally occurring polypeptides, variants of naturally occurring polypeptides, peptides, small organic molecules, and the like. Methods for identifying agonists of a naturally occurring polypeptide may include contacting the naturally occurring polypeptide with a candidate agonist molecule and measuring a detectable change in one or more biological activities normally associated with the naturally occurring polypeptide.

[0010] The term "ligand" is used in the broadest sense and includes any molecule that binds to another molecule. For example, both agonists and antagonists of a native polypeptide (e.g., CRFR2) disclosed herein are ligands of the native polypeptide. "Activity", for purposes of this specification, refers to the action or behavior of a polypeptide, or a synthetic molecule that mimics a polypeptide, consistent with that of a corresponding naturally occurring biologically active protein, where "biological activity" refers to biological functions or effects in vitro, in vivo or in humans, including, but not limited to, receptor binding, antagonist activity, agonist activity, or cellular, biochemical or physiological responses. For all agonists, C T (stimulation threshold) and C L The term (stimulation threshold) is defined by Figures 1A and 1B. In vivo, as shown in Figure 1B, C T and C L represents the plasma concentration that produces an effect at the receptor, and therefore C L can vary especially with the rate at which the agonist is administered (and thus is different for bolus and infusion administration). Cmax (the maximum plasma concentration achieved by the drug and AUC (area under the drug plasma concentration time curve)) refer to these standard usages in pharmacology.

[0011] "Safe and effective amount" refers to an amount of a compound (e.g., a CRFR2 agonist) according to the present disclosure that is sufficient to induce a significant positive correction in the symptoms being treated, but low enough to avoid significant side effects (e.g., toxicity or irritation) in an animal, preferably a mammal, more preferably a human subject in need thereof, commensurate with a reasonable benefit / risk ratio when used according to the methods of the present disclosure. A particular "safe and effective amount" will obviously vary depending on factors such as the particular symptoms being treated, the health status of the subject, the duration of treatment, the nature of the concomitant therapy (if necessary), the particular dosage form being used, the particular delivery route being used, the carrier being utilized, the solubility of the compound in the liquid, and the administration schedule of the composition. Those skilled in the art can use the following teachings to determine the "safe and effective amount" according to the present disclosure. The term "pharmaceutically acceptable salts" as used herein refers to salts derived from a variety of organic and inorganic counterions, including, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like, and, where the molecule contains a basic functional group, salts of organic or inorganic acids, such as, for example, hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate, and the like.

[0012] As used herein, "agent" or "biologically active agent" refers to a biological, pharmaceutical or chemical compound or other moiety. Non-limiting examples include single or complex organic or inorganic molecules, peptides, proteins, oligonucleotides, antibodies, antibody derivatives, antibody fragments, vitamin derivatives, carbohydrates, toxins or chemotherapeutic compounds. A variety of compounds can be synthesized, such as small molecules and oligomers (e.g., oligopeptides and oligonucleotides) as well as synthetic organic compounds based on various core structures. In addition, various natural sources, such as plant or animal extracts, can provide compounds for screening. Those skilled in the art can readily recognize that there is no limit as to the structural nature of the agents of the present disclosure.

[0013] The term "about" generally refers to plus or minus 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20% of the indicated value. For example, about 50 can be interpreted as 40 to 60, 43.5 to 57.5, or 45 to 55. As used herein, a "subject" refers to an animal, e.g., a mammal, preferably a human.

[0014] As described herein, "controlled release" refers to any delivery method for administering an agent or therapeutic agent (e.g., a CRFR2 agonist) to a mammal, including a human, that is intended to maintain the concentration of the agent in the mammal within a limited range over a period or time at a therapeutic level sufficient to achieve a given therapeutic effect. Controlled release can be continuous release, timed release, extended release, sustained release, delayed release, extended release, intermittent release, or any combination thereof. Controlled release can utilize a priming bolus administration in combination with continuous infusion. Controlled release can utilize a series of immediate release or bolus administrations, provided that the concentration of the agent is maintained within a limited range. Controlled release is effective to maintain or extend the dissolution, absorption, or administration of a drug to a subject to meet certain parameters for safe and effective treatment (e.g., maintaining the concentration and duration of administration by the agent). The substance or therapeutic agent can be a peptide, drug, or prodrug as described herein. For example, peptides, drugs or prodrugs can be administered via controlled release using intravenous infusion, subcutaneous infusion, implantable osmotic pumps, subcutaneous depots, transdermal patches, liposomes, subcutaneous depot injections including biodegradable materials or other administration methods. In some cases, pumps are used. In some cases, polymeric materials are used. In some cases, the flow rate of peptides, drugs or prodrugs is controlled by pressure through a controlled release system or device. In some cases, in polymer-based drug delivery systems, drugs are delivered from polymer or lipid systems. Such systems deliver drugs by three general mechanisms: (1) diffusion of drug species by or through the system, (2) chemical or enzymatic reactions that cause degradation of the system or cleavage of the drug from the system, and (3) solvent activation, both through permeation or swelling of the system.Suitable systems are described in the review articles: Langer, Robert, "Drug delivery and targeting," Nature: 392 (Supp):5-10 (1996); Kumar, Majeti NV, "Nano and Microparticles as Controlled Drug Delivery Devices," J Pharm Pharmaceut Sci, 3(2):234-258 (2000); Brannon-Peppas, "Polymers in Controlled Drug Delivery," Medical Plastics and Biomaterials, (November 1997). See also Langer, 1990 supra; Treat et al., in Liposomes in the Therapy of Infectious Disease and Cancer, Lopez-Berestein and Fidler (eds.), Liss, New York, pp. 353-365 (1989); Langer, Science, 249:1527-1533 (1990). Suitable systems may include Atrigel™ drug delivery system from Atrix Labs, DepoFoaM™ from SkyPharma, polyethylene glycol-based hydrogels from Infimed Therapeutics, Inc., ReGel™ from MacroMed, oral SQZGel™, HySolv™ and ReSolv™ solubilized drug delivery systems, ProGelz™ from ProGelz' Products, and injectable ProLease™ from Alkermes.

[0015] The phrases "continuous release," "sustained release," and "extended release" are used herein to refer to a delivery method for administering a substance or therapeutic agent or one or more therapeutic agents for introduction into the human or other mammalian body, and for continuously or constantly releasing or infusing an amount of one or more therapeutic agents over a given period of time at therapeutic levels sufficient to achieve a given therapeutic effect throughout the given period of time. Reference to continuous or uninterrupted release is intended to encompass release that occurs as a result of in vivo biodegradation of the drug depot or matrix or components thereof, or as a result of metabolic transformation or dissolution of the therapeutic agent or a conjugate of the therapeutic agent. Bolus administration is a delivery method for introducing a relatively large amount of one or more therapeutic agents into the subject's body via a single rapid administration. In certain embodiments, a therapeutically effective dose can be delivered in the form of a single bolus administration or a series of bolus administrations. In some embodiments, the bolus administration of the therapeutic agent can be dissolved or absorbed quickly at the site of administration. In certain embodiments, the single bolus administration of the therapeutic agent delivers a controlled release formulation that releases the therapeutic agent over time to maintain the concentration of the therapeutic agent within a predetermined range. In such embodiments, the bolus administration is still administered at a single time point and is formulated to delay, prolong or sustain the introduction, dissolution or absorption of the therapeutic agent into the subject's body.

[0016] "Functional somatic syndrome" or "FSS", as used herein, is intended to refer to stress-related (or stress-induced) disorders resulting from a maladaptive stress response (e.g., upregulation of CRFR2) associated with CRFR2 maladaptation in one or more specific brain regions. Examples of FSS include, but are not limited to, diseases such as myalgic encephalomyelitis / chronic fatigue syndrome (ME / CFS), fibromyalgia syndrome (FMS), post-traumatic stress disorder (PTSD), irritable bowel syndrome (IBS), atypical depression, multiple chemical sensitivity (MCS), post-acute sequelae of SARS-CoV-2 infection, chronic Lyme disease (CLD), childhood acute-onset neuropsychiatric syndrome (PANS), pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS), Gulf War illness (GWI, sometimes also called Gulf War syndrome), non-ulcer dyspepsia, premenstrual syndrome, chronic pelvic pain, interstitial cystitis, lower back pain, repetitive tension trauma, atypical chest pain, non-cardiac chest pain, hyperventilation syndrome, migraine, tension headache, temporomandibular joint disorder, atypical facial pain, laryngopharyngeal syndrome, food hypersensitivity, and sick building syndrome. An overview of the terminology and current approaches to treatment for functional somatic syndromes can be found, for example, in Henningsen et al. (Lancet 369(2007): 946-55).

[0017] "Autonomic neuropathy," as used herein, is intended to refer to a disorder of the autonomic nervous system and is generally characterized by abnormal heart rate variability, high resting heart rate, inability to change heart rate with exercise and exercise intolerance, orthostatic intolerance / hypotension, thermoregulatory intolerance, digestive or urinary abnormalities. Primary autonomic neuropathy is generally believed to result from either genetic factors or neurodegenerative diseases, whereas secondary autonomic neuropathy may result from trauma or dysregulation of the autonomic nervous system due to acquired disorders. As used herein, the CRFR2 agonist CT38 can include the free base (CT38) or acetate salt (CT38s) forms. When pharmacokinetics are reported herein, they are measured and reported with respect to CT38 (free base). When referring to a composition, pharmaceutical composition or dosage comprising an amount of a CRFR2 agonist from about a first μg to about a second μg, the term "first μg" can include the first μg value and the term "second μg" can include the second μg value. A variety of subjects can benefit from modulation or treatment of conditions that upregulate CRFR2. The subject can be a mammal. In preferred embodiments, the subject can be a human. In some embodiments, the subject is an adult. In other embodiments, the subject is a child.

[0018] Previous studies have described stress-induced interactions between the corticotropin-releasing factor (CRF) and serotonin (5HT) systems, which lead to downstream regulation of 5HT and its interaction with other neurotransmitters in the brain (e.g., gamma-aminobutyric acid or GABA, glutamate, dopamine, norepinephrine, acetylcholine, histamine) to regulate most body systems. This leads us to hypothesize that ME / CFS and other FSS arise from upregulation of CRFR2 in neurons of the brain's raphe and limbic systems. Under such upregulation or maladaptation of CRFR2, low levels of stress that would normally stimulate CRFR1 to release GABA and inhibit 5HT instead stimulate CRFR2 and elevate the release of 5HT, responding efficiently to minor stress as if it were major stress.

[0019] Such CRFR2 maladaptation and their effects on stress responses via 5HT, norepinephrine / epinephrine, and cortisol (among other mediators) may result in fatigue (elevated 5HT in the raphe-spinal pathway inhibits neuronal signaling via 5HT1A), pain (elevated 5HT sensitizes the dorsal horn via 5HT3A in the descending pathway, increasing pain sensation in cortical and limbic regions), sleep problems (elevated 5HT and norepinephrine promote wakefulness), and other conditions that may contribute to stress and anxiety. cognitive impairment (elevated norepinephrine promotes reflexive amygdala function over reflexive prefrontal cortex function); autonomic neuropathy (elevated norepinephrine causes autonomic neuropathy, which may manifest as heart rate variability, high resting heart rate, inability to change heart rate with exercise and exercise intolerance, orthostatic intolerance / hypotension, thermoregulatory intolerance, digestive or urinary abnormalities); temperature instability (elevated 5HT increases temperature via 5HT2 or 5HT1A in the preoptic area of ​​the anterior hypothalamus) This explains virtually all ME / CFS symptoms, including: headaches (5HT is implicated in migraines), hyperesthesia (5HT regulates vision, hearing, smell, taste and touch), shortness of breath (elevated 5HT in medullary respiratory neurons inhibits breathing), depersonalization (elevated 5HT induces transient depersonalization via 5HT2A or 5HT2C), immune dysfunction (5HT originating from either platelets or sympathetic neurons innervating lymphoid tissues may regulate immune responses at sites of inflammation and increase systemic susceptibility to infections, allergies and autoimmune disorders), metabolic dysfunction (5HT regulates hypothalamic energy balance affecting circulating levels of insulin, ghrelin and leptin, cortisol dysfunction promoting elevated plasma insulin and the development of insulin resistance and metabolic syndrome), post-exertional fatigue or PEM (5HT is elevated during motor and cognitive exertion, which exacerbates symptoms). Importantly, such CRFR2 dysadaptation is neurospecific and may be present in certain neurons but not others, resulting in symptomatic diversity among ME / CFS patients.

[0020] CRFR2-5HT maladaptation also explains other characteristics of ME / CFS, including sudden onset (high stress) or gradual onset (cumulative low stress exposure), diverse triggers (as all induce the release of CRF and therefore affect CRFR2 in the raphe nuclei, limbic system and / or cortex), post-pubertal sex differences (as females versus males may have an increased stress response primarily due to CRFR1 and CRFR2 related mechanisms that emerge during puberty), variable symptom presentation / severity (each of the individual symptoms and their severity results from the precise neuronal location where CRFR2 upregulation resides and the degree of such CRFR2 upregulation), risk factors including early life stress or cumulative psychological distress (which increases CRFR2 upregulation), familial association (which may be genetic or similar stress exposures), etc. Methods to restore such CRFR2 maladaptation, for example by chronically blocking or masking the stress response (e.g., via CRF / UCN1 / 5HT antibodies or 5HT1A / GABA agonists) or abrogating the aberrant expression of CRFR2 (e.g., via chronic administration of CRFR2 antagonists), are not feasible given the highly dynamic nature of such systems. Like most G protein-coupled receptors (GPCRs), CRFR2 is susceptible to intracellular mechanisms that rapidly reduce signaling output to prevent hyperstimulation of the cell. This process has been shown to involve G protein activation and subsequent GPCR kinase (GRK) regulation, which phosphorylates the receptor and recruits β-arrestin and clathrin to the plasma membrane, triggering receptor endocytosis at a rate that depends on agonist potency, agonist concentration, and duration of exposure.

[0021] Ligand-induced G protein-coupled receptor (GPCR) endocytosis provides a mechanism for alleviating CRFR-associated and, in particular, CRFR2-associated signaling dysfunction in the brain. Figures 1A and 1B are stylized illustrations of the typical behavior of GPCR agonists on GPCRs. Figure 1A shows that increasing concentrations of agonist increase cAMP above the stimulation threshold ("C T "), and then finally reaches the stimulation threshold ("CL This is an illustration of the phenomenon whereby a CRFR achieves maximal activity at 1000 C (the cAMP response) followed by a decline in the cAMP response. Dosage regimens / ligand combinations can achieve ligand-induced endocytosis of CRFR, e.g., CRFR2, to provide therapeutic benefit. Increasing agonist concentration increases GPCR-induced output, resulting in increased C T Starting in C L After this, GPCR-induced output declines, presumably via receptor endocytosis.

[0022] Previous studies have demonstrated that certain dosing regimens of CRFR2 agonists can reduce CRFR2 output by an endocytic mechanism. For example, WO2018075973 showed that increasing concentrations of the proprietary CRFR2 agonist CT38 (administered as its acetate salt, CT38s) reduced C-terminal cellular physiologic parameters (e.g., heart rate, mean arterial pressure, and core body temperature) in rats. L Dose curves above 1.5 ng / ml were shown, demonstrating a decreased ability of CT38 to induce changes in such physiological parameters (stylized as FIG. 1B and consistent with the scheme shown in FIG. 1A). Moreover, because heart rate changes under stress are due to CRFR1 and CRFR2 activation in the limbic system (specifically, the bed nucleus of the stria terminalis or BNST), such data showing CRFR2 endocytosis may occur in parts of the brain where ME / CFS (and FSS) dysfunction occurs. Previous studies, whether in vitro or in vivo, have measured endocytosis in the absence of any effect, and L For example, UCN2 achieved maximal CRFR2 endocytosis of 100 nmol in vitro, which is substantially higher than the EC50 of 4.3 nmol, and CT38 achieved maximal CRFR2 endocytosis of 100 nmol in vivo, which is substantially higher than the EC50 of 4.3 nmol. LIt has been demonstrated that C achieves higher plasma concentrations of CRFR2 endocytosis than C [see WO2018075973, Example 7]. That is, such studies demonstrate endocytosis at the high end of the dose curve. However, T No such information has been reported for receptor internalization at ligand concentrations below 100 mM.

[0023] Previous studies have focused on C L We proposed the induction of CRFR2 endocytosis by utilizing high concentrations of CRFR2 agonists exceeding C (FIG. 1B). In contrast, the present disclosure uses various concentration regimes for the agonist, particularly unexpectedly low concentrations, e.g., C T We demonstrate endocytosis in < 10 μg / mL (see, e.g., Example 1). In a healthy stress response, a given level of stress response is generated by the release of some level of CRF in appropriate centers in the brain. Upon cessation of the stressor, termination of this ongoing stress response is likely dependent on CRFR2 endocytosis, possibly mediated by UCN1, which competitively displaces CRF (the inhibitory constants of UCN1 and CRF at CRFR2 are 0.4 and 44.5 nmol, respectively). However, to avoid stimulation of CRFR2 and thus halt the rise of the extreme stress response, the level of UCN1 is reduced below the threshold for stimulating CRFR2 (i.e., the C of UCN1). T ) below CRFR2. Thus, embodiments include administering a CRFR2 agonist in conditions where CRFR2 is believed to be upregulated (or maladaptive). In certain embodiments, the CRFR2 agonist reaches the sites of CRFR2 upregulation (i.e., the raphe nuclei and limbic system) and displaces CRF (i.e., has a higher binding affinity for CRFR2 than that of CRF), and inhibits CFR2 activation. TThe CRFR2 agonist may be administered at a dose that maintains a plasma concentration of CRFR2 agonist below 100 mg / kg / day (of the CRFR2 agonist) to induce CRFR2 endocytosis. Without wishing to be bound by theory, such a treatment scheme may involve the recruitment of β-arrestin without involving G protein (and / or GRK) activation. Previous reports of CRFR2 endocytosis have been limited to contexts involving β-arrestin following G protein (and / or GRK) activation. Such reports have shown a C vs. dose curve. T Above all, C L Concentrations greater than 10 ...

[0024] Embodiments include the treatment of any condition involving CRFR2 maladaptation in the raphe nuclei and / or limbic system by administering a CRFR2 agonist, provided that the CRFR2 agonist (i) is capable of reaching the raphe nuclei / limbic system and (ii) does not exceed the minimum threshold at which the CRFR2 agonist stimulates CRFR2 ("C T "), and (iii) is dosed to provide a specific overall exposure (i.e., area under the plasma concentration-time curve, AUC). In one embodiment, the presence and extent of CRFR2 upregulation (or maladaptation) in a given patient is determined by a method of evaluating the responsiveness of a subject's physiological parameter to a concentration of a CRFR2 agonist. One such method involves determining a threshold bolus dose of a given CRFR2 agonist in a given patient that is capable of inducing a change in a physiological parameter (e.g., heart rate, diastolic blood pressure, core body temperature, respiratory rate) and comparing this physiological parameter to the corresponding value of this physiological parameter in a healthy subject (see below), the difference indicating the presence and extent of CRFR2 maladaptation.

[0025] In certain aspects, the compositions and methods disclosed herein are used to treat CRFR2 dysadaptation of the stress response manifested in a variety of conditions including ME / CFS, fibromyalgia syndrome, post traumatic stress disorder, multiple chemical sensitivity, chronic Lyme disease, post acute sequelae of viral infection (e.g., following SARS-CoV-2 infection), irritable bowel syndrome, atypical depression, pediatric acute onset neuropsychiatric syndrome, pediatric autoimmune neuropsychiatric disorder associated with streptococcal infection, Gulf War illness, and others (e.g., non-ulcer dyspepsia, premenstrual syndrome, chronic pelvic pain, interstitial cystitis, lower back pain, repetitive strain trauma, atypical or non-cardiac chest pain, hyperventilation syndrome, migraine, tension headache, temporomandibular joint disorder, atypical facial pain, pharyngeal syndrome, food sensitivities, sick building syndrome, etc.), which are understood to represent an underlying, generally basic, single syndrome (FSS, also called somatic distress syndrome).

[0026] In other aspects, the compositions and methods disclosed herein are used to treat autonomic neuropathy (including postural orthostatic tachycardia syndrome, neurocardiogenic syncope, multiple system atrophy, hereditary sensory autonomic neuropathies, Holmes-Adie syndrome), immune dysfunction (including allergies and autoimmune diseases, e.g., lupus, multiple sclerosis, inflammatory bowel disease, rheumatoid arthritis, type 1 diabetes, celiac disease, and Sjogren's syndrome), Parkinson's disease and other movement disorders, metabolic dysfunction (including insulin resistance, type 2 diabetes, metabolic syndrome), hypothyroidism, and hypogonadism. In other aspects, the compositions and methods disclosed herein are used to treat conditions such as chronic pain, anxiety, and addiction, which also result, at least in part, from CRFR adaptation in the limbic system. In other aspects, the compositions and methods disclosed herein are used to treat musculoskeletal or nervous system dysfunction manifested as tremor, ataxia, or dyskinesia. For any CRFR2 agonist, its binding affinity at the receptor can be determined and compared to the binding affinity of CRF at CRFR2 (inhibitory constant=44.5 nmol) to determine whether the CRFR2 agonist can displace CRF at CRFR2. For example, the binding affinity of CT38 at CRFR2 (estimated to be similar to that of UCN2, in this case with an inhibitory constant=1.1 nmol) is such that it displaces CRF.

[0027] In certain embodiments, CRFR2 agonists can reach the limbic system, which can be examined, for example, by imaging techniques using radiolabeled agonists in vivo. Alternatively, since stress responses can be mediated by CRFR2, suitable CRFR2 agonists can be identified by observing significant changes in physiological functions (e.g., core body temperature or respiratory rate) that are known to be regulated via limbic system CRFR2 in parallel with administration of CRFR2 agonists to healthy animals. For example, subcutaneous bolus administration of CT38s induces dose-dependent changes in core body temperature and respiratory rate in experimental animals, consistent with reaching the limbic system. In some embodiments, a CRFR2 agonist that meets the above criteria is a partial or selective agonist for both CRFR2 and CRFR1 (e.g., UCN1) and is capable of displacing CRF from this receptor in vivo.

[0028] In another embodiment of the disclosure, various CRFR2 agonists are utilized, where the agonist is more potent than CT38. Tand may require adjustment to the target AUC. Particular agonists include CT38 (CT38s), CT37, UCN1, UCN2, UCN3, stresscopin (putative precursor peptide of UCN3), stresscopin-related peptide (SRP) or any of the sequences listed in Table 1. The embodiments described herein relate to the natural process of endocytosis and therefore preferentially relate to all CRFR2 agonists that have a binding affinity for CRFR2 that is at least higher than that of CRF (of CRFR2). Thus, in particular embodiments, the CRFR2 agonist is one or more of the agents listed in Table 1. In some embodiments, the CRFR2 agonist comprises one or more of the amino acid sequences of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7 and SEQ ID NO:8, or a combination thereof. In some embodiments, the CRFR2 agonist comprises an amino acid sequence having 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the sequences of SEQ ID NOs:1-8. In some embodiments, the CRFR2 agonist comprises an amino acid sequence according to the formula: ZGPPISIDLPX11X12LLRKX17IEIEKQEKEKQQAX31X32NAX35X36LX38X39X40 (SEQ ID NO: 8), where X11 is selected from F, Y, L, I, and T, X12 is selected from Q, W, and Y, X17 is selected from V and M, X31 is selected from T and A, X32 is selected from N and T, X35 is selected from R and L, X36 is selected from L and I, X38 is selected from D and A, X39 is selected from T and R, and X40 is selected from I and V, where Z (i.e., Glx or pyrrolidone carboxylic acid) is used to represent an N-terminal glutamic acid or glutamine, optionally forming an internal lactam ring. In another embodiment, an acetate salt of the CRFR2 agonist is used.

[0029] [Table 1]

[0030] In some embodiments, a CRFR2 antagonist is administered to replace CRF and then maintained for a period of time. Such antagonists include, but are not limited to, CRFR2 selective astressin 2-B and non-selective astressin-B. In any CRFR2 agonist, C T can be determined in healthy animals, including healthy humans. Phase I clinical trials routinely identify the profile of the agonist at the receptor. In the case of CRFR2 agonists, this C at CRFR2 T Determining the CRFR2 agonist activity involves administering increasing bolus doses of a CRFR2 agonist to a healthy animal or subject, measuring the induced changes in physiological parameters associated with CRFR2 stimulation (e.g., heart rate, blood pressure, core body temperature, respiratory rate), and identifying the lowest dose of CRFR2 agonist that stimulates a significant change in the physiological parameter.

[0031] For example, by measuring physiological parameters such as heart rate or diastolic blood pressure, CT38s administered in healthy human subjects identified a threshold bolus dose of CT38s at CRFR2 in healthy subjects of between 0.033 (no change in heart rate) and 0.083 μg / kg (mean heart rate increase of 8 bpm), which is equivalent to a plasma concentration of CT38 (free base) of about 0.095 and about 0.250 ng / ml, respectively. Given that the increase in heart rate at 0.083 μg / kg was small, the C of CT38s at CRFR2 was approximately 0.025 and 0.045 ng / ml. T The C is estimated to be at or close to 0.25 ng / ml. T Although the range of influences on the estimate of the mean, for all practical purposes, a representative range can be determined for the population.

[0032] In Example 1, CT38s was administered by subcutaneous infusion at a rate of 0.03 μg / kg / hour (achieving a mean peak plasma concentration of CT38 of 0.18±0.03 ng / ml; range: 0.14-0.24 ng / ml, Table 5) and maintained for 3.5 hours across three separate treatments (achieving a mean total AUC of 2.46±0.51 ng·h / ml; range: 1.94-3.44 ng·h / ml), resulting in a mean TDSS improvement of -7.52 (range: -0.3 to -16.0). Notably, dose was limited by tolerability with respect to Cmax, but not by AUC. In a particular embodiment, for CT38, Cmax was 0.25 ng / ml (C T ) or less, and the total AUC should be about 5 ng·h / ml for mild symptoms, lower for moderate symptoms, and even lower for severe symptoms. However, since this is normal for patients with somewhat severe symptoms and somewhat mild symptoms, all patients should receive an AUC of about 5 ng·h / ml, especially so that there are no safety issues that would result from a higher AUC. Generalizing to any agonist, the Cmax limit is C T The AUC required is determined by standard pharmacokinetic and pharmacodynamic methods (obtained for any of the agonists listed above) and the AUC required is directly related to the potency of the agonist (i.e., a stronger agonist requires a lower AUC). The exact dosing regimen is then determined by standard pharmacokinetic and pharmacodynamic methods.

[0033] In certain embodiments, the method includes administering CT38s to a subject with CRFR2 maladaptation, e.g., ME / CFS, by subcutaneous infusion at a dose level of 0.03 μg / kg / hour sufficient to ensure a CT38 plasma concentration of 0.25 ng / ml or less, then maintaining for a 12 hour period to deliver an AUC of about 2.5 ng·h / ml, and repeating a second treatment with a total AUC of about 5.0 ng·h / ml. Alternatively, the same dose level may be maintained for a 6 hour period to deliver an AUC of about 1.2 ng·h / ml in each of five treatments with a total AUC of about 6.0 ng·h / ml. In some embodiments, CT38s is delivered first via a subcutaneous priming bolus followed by a subcutaneous infusion, where the priming bolus is intended to maintain CT38 plasma concentrations below 0.25 ng / ml while shortening the infusion period otherwise required to achieve the target AUC. For example, a priming bolus of 0.03 μg / kg of CT38s followed by an infusion at a dose level of 0.03 μg / kg / hour can deliver an AUC of 1.28 ng·h / ml in each of four treatments with a total AUC of about 5.1 ng·h / ml. The CT38s dosing schedule is designed by considering one or more of the use of a priming bolus, the infusion rate, the infusion period, and the number of such treatments. The CT38s dosing schedule is designed to deliver the target AUC (at least about 5 ng·h / ml) while simultaneously maintaining the C T Maintain CT38 plasma concentrations below 0.25 ng / ml.

[0034] In certain embodiments, a series of subcutaneous boluses of the CRFR2 agonist are used to achieve the target exposure, thus improving C T Achieving a Cmax of less than 100 mg / kg is maintained. For any agonist with a specific clearance rate, the infusion rate determines the Cmax, which is further influenced by the use of a priming bolus. The composition of the present disclosure can be administered in a single controlled release dose, but the total administration period is governed by the severity of the patient's dysfunction at the time of onset, which has an inverse relationship (the less severe the severity, the longer the period required). The compositions of the present disclosure may be administered in multiple controlled release doses, in which case the overall duration of administration will still be governed by the severity of the patient's impairment at the time of onset, with the number of doses and the interval between doses being set by the convenience and / or desire to reassess the patient's level of impairment before initiating the next dose. Illustratively, effective amounts of the compositions of the present invention range from nanograms / kg to micrograms / kg for infants and adults. Equivalent amounts for light or heavy body weights can be readily determined. Dosage should be adjusted to suit the individual to whom the composition is administered and may vary according to the age, weight and metabolic state of the individual. The exact amount of composition required will vary from subject to subject depending on the species, age, weight and general condition of the subject, the particular peptide or polypeptide used, the method of administration, etc. Appropriate amounts can be determined by one of skill in the art using only routine experimentation in light of the teachings herein. Optimal dosages to be administered can be readily determined by one of skill in the art and will vary according to the particular compound used, the method of administration, the strength of the preparation, the method of administration, the number of consecutive doses within a limited period of time, and the progression of the disease condition.

[0035] Another aspect of the present disclosure is a method for determining when to stop treatment in a given patient. In this embodiment, the initially determined threshold bolus dose of CRFR2 agonist that induces heart rate increase in a given patient with CRFR2 maladaptation is increased after the above treatment. The threshold bolus dose is then re-determined, and if the patient's threshold bolus dose approaches that of a healthy subject (e.g., CT38s of about 0.083 μg / kg of body weight in healthy young males, as determined in the first phase), this indicates that CRFR2 is no longer upregulated in the BNST. Thus, in some embodiments, the threshold bolus dose of CRFR2 agonist that induces heart rate increase is measured in the patient after treatment, and if the patient's threshold bolus dose approaches that of a healthy subject, treatment is stopped. Because CRFR2 can remain upregulated in other brain regions and does not affect heart rate, it may still be appropriate to continue treatment even after heart rate suggests that CRFR2 expression has returned to a level similar to that of a healthy subject.

[0036] In addition, neuron-specific expression of CRFR2 or release of 5HT cannot currently be measured in the stressed living brain, and therefore assessments of symptoms must be based on global measures (examples of which include, but are not limited to, the Fatigue Severity Scale, Multidimensional Fatigue Inventory, Patient Global Impression of Change scale, Clinical Global Impression of Change scale, Karnofsky Performance Scale, Fibromyalgia Impact Questionnaire, Short Form-36 or SF-36, Mental Health Inventory, Clinical-Administered PTSD, Inventory of Depression Symptomology, Hamilton Depression Scale, Activities of Daily Living Index, hospital / emergency room visits, etc.) or individual symptom measures (examples of which include, but are not limited to, the Modified Fatigue Impact Scale, visual analog scale for pain, Pittsburgh Sleep Quality Index, scales approved by the American Academy of Sleep Medicine for improving sleep satisfaction and daytime functioning, Perceived Deficits Scale for cognitive impairment, etc.). The effect of treatment may be measured through measures of physical activity (including, but not limited to, the Postural Intolerance Questionnaire, tilt table test for orthostatic intolerance, use of concomitant medications, etc.) and treatment may be discontinued if such measures approach scores in healthy subjects.

[0037] In certain embodiments, a CRFR2 agonist is administered in this manner to reach upregulated receptors in the raphe / limbic system and inhibit C TWhen present at agonist levels below 100 mg / mL, CRFR2 endocytosis occurs. However, the degree of CRFR2 maladaptation in the raphe and limbic system can be variable, and therefore, in some embodiments, the dosage is adjusted to the severity of the functional impairment in an individual patient. An example of when treatment adjustment is useful is partially demonstrated in Example 1 (Tables 3 and 5), where patient ID 35 was found to be difficult to tolerate at a relatively low concentration of 0.12 ng / ml. To improve treatment tolerability in individual patients, the dosage can be reduced to sufficiently T To ensure a target plasma concentration below 100 mg / kg / day, the length of administration can be extended accordingly to provide an appropriate AUC. In some embodiments, such reduction in CT38 target plasma concentration is used when the patient exhibits at least one severe symptom (eg, pain, hyperesthesia, brain fog).

[0038] In other embodiments, CT38 or any of the CRFR2 agonists described herein (e.g., those described in Table 1) can be delivered by any route of administration, such as subcutaneous, intravenous, transdermal, transmucosal, intranasal, inhalation, gastrointestinal, etc., to achieve a target plasma concentration that regulates or reduces symptoms associated with CRFR2 maladaptation. Methods of administration of CT38 or any of the CRFR2 agonists described herein can include rectal, oral, buccal, intra-arterial injection, intraperitoneal, parenteral, intramuscular, intrathecal, or other suitable routes. In other embodiments, the dosage form is formulated for use in treating and / or assessing the severity of FSS in a subject in need thereof. In some embodiments, the dosage form is formulated for subcutaneous administration. In other embodiments, the CRFR2 agonist comprises one or more of the amino acid sequences in Table 1. In some embodiments, the CRFR2 agonist comprises the amino acid sequence of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, or combinations thereof. In some cases, the polypeptide has a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the sequences of SEQ ID NOs:1-8 shown in Table 1. In certain embodiments, the controlled release or bolus dose or dosage form is a pharmaceutical composition comprising a protein having a sequence set forth in Table 1 (e.g., SEQ ID NO:1) and a pharma- ceutically acceptable carrier.

[0039] An effective amount of a CRFR2 agonist or any analog or derivative thereof may be administered to a subject according to various dosing schedules. A composition comprising an effective amount of a CRFR2 agonist or any analog or derivative thereof may be administered in a single dose or in two or more doses. An effective amount of a CRFR2 agonist or any analog or derivative thereof may be administered in about 1 dose to about 28 doses, 1 dose to about 5 doses, or 1 dose to about 10 doses. Administration can begin at the onset of the disorder or at a time after the onset of the disorder. A composition comprising a CRFR2 agonist or any analog or derivative thereof can be administered to a subject diagnosed with CRFR2 maladaptation or FSS. In some embodiments, the FSS is myalgic encephalomyelitis / chronic fatigue syndrome (ME / CFS). In other embodiments, the FSS is fibromyalgia syndrome (FMS), post-traumatic stress disorder (PTSD), irritable bowel syndrome (IBS), atypical depression, multiple chemical sensitivity (MCS), chronic Lyme disease (CLD), childhood acute-onset neuropsychiatric syndrome (PANS), pediatric autoimmune neuropsychiatric disorder associated with streptococcal infection (PANDAS), or Gulf War illness (GWI, also known as Gulf War syndrome).

[0040] In other embodiments, FSS is the result of an infectious disease and includes a range of post-acute infectious symptoms. Such post-viral symptoms may include post-acute sequelae of SARS-CoV-2 infection (PASC), also known as post-coronavirus disease 2019 syndrome or long COVID, which has significant overlap with symptoms of ME / CFS. Since 1934, there have been 76 "outbreaks" worldwide in which patients developed ME / CFS-like symptoms following pathogen infection (including viral, bacterial, and fungal) variously described as atypical poliomyelitis (and abortive poliomyelitis, acute anterior poliomyelitis, similar poliomyelitis, and encephalomyelitis associated with poliovirus), encephalitis, epidemic encephalitis, persistent myalgia, epidemic neuromyasthenia, epidemic myositis, benign myalgic encephalomyelitis, lymphocytic meningoencephalitis, epidemic malaise, epidemic diencephalomyelitis, psoriatic venulitis, multisystem stealth virus infection with encephalopathy, chronic fatigue syndrome caused by SARS, chronic fatigue syndrome caused by Giardia, etc. The composition can be administered to the subject over a period of time. By way of example, the composition can be administered to the subject for a period of about 1.0 hour to about 12 hours, 24 hours, or 48 hours. In some embodiments, the composition is administered as a CT38 bolus dose or equivalent of about 0.025 μg / kg in combination with a continuous infusion dose of about 0.025 μg / kg / hour suitable for a total administration time of about 24 hours. In some embodiments, the continuous infusion dose is subdivided, for example, to include multiple continuous infusion doses that together provide an AUC equivalent (CT38) of about 5 ng·h / ml. In some embodiments, such dose combinations are further adjusted to the severity of the patient's symptoms.

[0041] The compositions can be administered to a patient by controlled release over separate therapeutic periods. For example, T Having determined the limit (0.25 ng / ml for CT38) and the required AUC (5 ng·h / ml for CT38), the dosing regimen determines the duration of treatment, hi one embodiment, each separate treatment period is separated by a specific time interval that achieves the desired AUC.

[0042] Those skilled in the art will appreciate that the agonist concentrations, dosing periods and dosing intervals specified in this disclosure are patient-specific and influenced by the route of administration and the pharmacokinetic and pharmacodynamic parameters (e.g., potency, half-life) of the particular CRFR2 agonist employed. For example, it is readily apparent that the plasma concentration and AUC achieved are correlated, and thus, to reduce the peak plasma concentration achieved, it is necessary to increase the exposure to achieve the target AUC, for example, by an additional bolus or a longer infusion. It is also apparent that the plasma concentration and AUC achieved are dependent on both the dose level and the route of administration of the CRFR2 agonist, which changes the level of the CRFR2 agonist at the receptor. Routine experimentation may be used to characterize the pharmacokinetics and pharmacodynamics of CRFR2 agonists administered via a particular route of administration, and such data allows for the conversion of dosing parameters (e.g., dose concentration, length of treatment, interval) between various routes of administration. Given knowledge of the potency and pharmacokinetics of a particular CRFR2 agonist for the route of administration, a dosing model can be constructed to achieve the target plasma concentration. Exemplary information regarding routes of administration, dosing models and calculation methods can be found in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, HA and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999).

[0043] In some embodiments, individualization of dosing regimens is performed due to patient-to-patient variability in both symptom severity and compound pharmacokinetics. Dosing of the disclosed compounds can be found by routine experimentation in light of the present disclosure. In another aspect, the disclosure provides a pharmaceutical composition comprising a dosage form of a CRFR2 agonist as described herein. The pharmaceutical composition may further comprise a pharmaceutical carrier or excipient. The composition can be formulated as a pharmaceutical composition that provides an effective amount of the composition comprising a CRFR2 agonist. The CRFR2 agonist can be the active ingredient in the formulated pharmaceutical composition. The present disclosure provides pharmaceutical compositions comprising (a) an amount of a CRFR2 agonist as presented that is safe and effective in treating, reducing and / or ameliorating CRFR2 maladaptation, and (b) a pharma- ceutically acceptable carrier.

[0044] Forms in which the compositions of the present disclosure for administration by injection may be incorporated include sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, aqueous or oily suspensions or emulsions in mannitol, dextrose, or sterile aqueous solutions and similar pharmaceutical vehicles. Compositions formulated for injection may include sterile aqueous or non-aqueous solutions, suspensions and emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil and injectable organic esters such as ethyl oleate. Aqueous solutions in saline are also used for injection in a conventional manner. Aqueous carriers include water, alcoholic / aqueous solutions, emulsions or suspensions, including saline and buffered media. Also, ethanol, glycerin, propylene glycol, liquid polyethylene glycol, and the like (and suitable mixtures thereof), tromethamine, cyclodextrin derivatives, and vegetable oils may be used. Proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, to maintain the required particle size in dispersion, and by the use of surfactants. Prevention of microbial activity can be achieved by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.

[0045] Compositions formulated for injection may contain parenteral vehicles, preservatives and other additives. Parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's or fixed oils. Preservatives and other additives may also be present, such as, for example, antibacterial agents, antioxidants, chelating agents, and inert gases and the like. Sterile injectable solutions are prepared by incorporating the compounds of the present disclosure in the required amount in the appropriate solvent with various other ingredients as enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and other ingredients as required from those described herein. The present disclosure also provides kits. The kits include the compounds or compositions of the present disclosure described herein in suitable packaging, and documentation that may include instructions for use, clinical trial discussions, lists of side effects, and the like. Such kits may also include information such as scientific references, package inserts, clinical trial results and / or summaries thereof, etc., that show or establish the activity and / or benefits of the composition, and / or describe dosage, administration, side effects, drug interactions, or other information useful to patients and health care providers (such information may include instructions for administering an effective amount of a CRFR2 agonist to treat or alleviate CRFR2 maladaptation, e.g., FSS). Such information may be based on the results of various studies, for example, studies using laboratory animals, including in vivo models, and studies based on human clinical trials.

[0046] Such kit embodiments also include a first dosage form of a CRFR2 agonist suitable for administration to a patient to detect CRFR2 maladaptation via heart rate, blood pressure, or other physiological response as described herein. The kit may additionally include a therapeutic formulation of a CRFR2 agonist suitable for treating CRFR2 maladaptation according to the methods described herein. The kit may additionally include a dosage form of a CRFR2 agonist suitable for administration to a patient to detect a reduction in CRFR2 maladaptation via heart rate, blood pressure response, or other physiological response after a certain level of treatment.

[0047] In another aspect, the disclosure also provides kits and articles of manufacture that contain materials useful for treating and / or diagnosing disorders (e.g., FSS) according to the methods described herein. In another embodiment, the disclosure provides kits that contain packaging materials, e.g., at least a first container that contains a dosage form or pharmaceutical composition of a CRFR2 agonist and a label that identifies the dosage form or pharmaceutical composition and storage and handling conditions, and a sheet of instructions for reconstituting the dosage form or pharmaceutical composition and / or administering it to a subject. In another embodiment, the kit includes a container and a label that may be disposed on or associated with the container. The container may be a bottle, vial, syringe, cartridge (including an autoinjector cartridge) or any other suitable container and may be formed from a variety of materials, e.g., glass or plastic. The container may hold a composition having a CRFR2 agonist, analog or derivative thereof, and may have a sterile connection port. An example of a container includes a vial that has a stopper that can be pierced by a hypodermic needle. The kit may have additional containers that hold various reagents, e.g., diluents, preservatives, and buffers. The label can provide a description of the composition as well as directions for its intended use.

[0048] In one aspect, the disclosure provides a kit comprising a container holding a pharmaceutical composition for administration to a human patient, the pharmaceutical composition comprising a CRFR2 agonist. In one embodiment, the CRFR2 agonist comprises an amino acid sequence having at least about 80%, at least about 85%, at least about 90%, or at least about 95% sequence identity to one of the sequences set forth in Table 1. In another embodiment, the kit further comprises a package insert associated with such container. In another embodiment, the package insert indicates that such composition is for treating ME / CFS or FSS by administration of at least one dose of the composition. The examples included below demonstrate the therapeutic potential of delivery of CRFR2 agonists. EXAMPLES

[0049] Example 1 A clinical trial to evaluate the safety, tolerability, and efficacy of the specific CRFR2 agonist CT38 in patients with ME / CFS. A single-center, proof-of-concept, open-label, Phase 1 / 2 clinical trial was conducted to evaluate the safety, tolerability, and efficacy of CT38 administered as acetate (CT38s) by subcutaneous infusion at one of four dose levels in 17 patients with ME / CFS. The study was conducted under an investigator-sponsored Investigational New Drug (IND) application submitted to the US Food and Drug Administration (FDA) and approved by the relevant Institutional Review Board (IRB). CT38 is a selective CRFR2 agonist with no known off-target activity, except at very high concentrations of CRFR1. It is highly potent against CRFR2 (EC50nmol / % of Emax: 17.1 / 100) and has a similar binding affinity to CRFR2 as UCN2 (inhibitory constant 1.1nmol). Data from previous Phase 1 studies (see, for example, International Publication No. WO2018075973, which is incorporated herein in detail for purposes of CT38 pharmacokinetics) show that CT38 has a half-life of about 1.5 hours. The Phase 1 / 2 study was completed after a recruitment and screening period, which included enrollment, a pretreatment evaluation period of at least 4 weeks, a 2-week intervention period (including three drug infusions), and a posttreatment evaluation period of at least 4 weeks.

[0050] The primary objective of this study was to test whether a limiting dose of CT38s could induce sustained CRFR2 endocytosis, which would manifest as a reduction (or elimination) of symptoms that would be maintained long after CT38s had been cleared from the body. Thus, the study sought to evaluate: (i) safety, tolerability and pharmacokinetic data following administration of CT38s; (ii) primary efficacy measured as the change in mean daily total symptom score (TDSS) summed for each of 13 daily patient-reported symptoms (specifically fatigue, pain, sleep problems, cognitive problems, orthostatic intolerance, temperature paresthesia, flu-like symptoms, headache or hyperesthesia, shortness of breath, gastrointestinal problems, urinary problems, anxiety and depression), each assessed on a scale of 0 to 5 (0=none, 1=very mild, 2=mild, 3=moderate, 4=severe, 5=very severe), averaged over the 28 days prior to treatment (pre-treatment TDSS) and the 28 days prior to the end of the study (post-treatment TDSS); and (iii) secondary efficacy measured by general health status, as assessed by the SF-36 Physical and Mental Component Scores (PCS and MCS, respectively), each measured on a scale of 0 (maximum disability) to 100 (no disability).

[0051] Study-selected male and female ME / CFS patients aged 18-60 years who met three case definitions of ME / CFS (i.e., Fukuda Research Case Definition for CFS, 1994, Revised Canadian Consensus Criteria for ME / CFS, 2010, and the National Academy of Medicine Clinical Diagnostic Criteria for ME / CFS, 2015) and had been relatively stable for the previous three months, voluntarily complied with study procedures, and provided informed consent. Specific exclusions included active or uncontrolled comorbidities, pregnancy / lactation, body mass index >35, smoking, substance abuse, specific medications (including antivirals, antiretrovirals, antibiotics and those that interact with the 5HT, norepinephrine, dopamine or cortisol pathways, or a history of severe tachycardia (heart rate >100 bpm), bradycardia (heart rate ≤45 bpm), hypotension (resting sitting systolic / diastolic blood pressure <100 mmHg or 60 mmHg), respectively) or renal impairment. There were other minor exclusions including those related to exercise.

[0052] Dose Evaluation and Selection In WO 2018075973, C L (by infusion) was defined as approximately 1.5 ng / ml and a total AUC of approximately 40 ng·h / ml, which is equivalent to approximately 1.4 ng / ml and approximately 7.0 ng·h / ml in healthy humans, based on the pharmacokinetic-pharmacodynamic model of bolus administration in previous Phase 1 trials. The initial treatment plan proposed two separate subcutaneous treatments, each involving an initial priming bolus of 0.15 μg / kg followed by an infusion of 0.20 μg / kg / h (titrating to 0.24 μg / kg / h) over 3 hours. This resulted in a total dose of 0.825 μg / kg, less than the maximum tolerated bolus dose in healthy humans of 0.833 μg / kg determined in a previous Phase 1 study, and was designed to achieve a Cmax of 1.4 ng / ml and an AUC of 5.6 ng·h / ml (per treatment), thereby meeting the theoretical targets determined in rats. This was deemed optimal based on in vivo studies, which showed minimal CRFR2-related changes in heart rate and blood pressure at the high end of the dose curve when administered by infusion.

[0053] Planned first dose D20 pb (see Table 2) increased heart rate and reduced diastolic blood pressure (more than systolic) in the first patient. This was tolerable (i.e. did not meet protocol dose discontinuation criteria), but the level of change made a priming bolus unsafe, which was ruled out in favor of extending the infusion by an additional 30 minutes. Therefore, the second treatment in the first patient and both treatments in the second patient utilized the D20 dose. Subsequent pharmacokinetic data showed that the D20 pb and D20 (all doses essentially identical) were found to induce levels of hemodynamic changes that had only been observed in healthy subjects in Phase 1 up to that point, at significantly higher concentrations and AUC. This was the first indication of increased sensitivity to CRFR2 effects in ME / CFS patients compared to healthy subjects (see below). These findings led to a dose reduction to an infusion rate of 0.03 μg / kg / h (D03), an extension of the dosing period to 3.5 hours, and the addition of a third infusion (as well as the elimination of the priming bolus and dose rate escalation). Two additional infusion rates of 0.06 and 0.01 μg / kg / h were also investigated to further characterize the dose-response curve (D06 and D01, respectively). All dosing changes were approved by the IRB and the FDA. The approved dosing schedule is shown in Table 2.

[0054] [Table 2]

[0055] Patient breakdown and demographics A total of 17 patients were screened in the study, and 14 were enrolled. Of these, 2 patients (IDs 23 and 24) received D20 (or modifications of this), 2 patients (IDs 34 and 36) received D06, 7 patients (IDs 27, 29, 30, 31, 32, 33, and 46) received D03, and 3 patients (IDs 35, 38, and 45) received D01. During the study, minor unanticipated changes occurred to the approved dosing schedule shown in Table 2. These are listed in Table 3 with explanations. Patient demographics, including those disrupted by the dosing schedule, are shown in Table 4.

[0056] [Table 3]

[0057] [Table 4]

[0058] Compared to healthy human subjects in previous Phase 1 trials, ME / CFS patients exhibited increased sensitivity to the acute effects of CRFR2 agonist administration (i.e., increased heart rate and decreased diastolic blood pressure). Examples of this phenomenon can be seen in Figures 2A-2B and 3A-3B, which show that objectively measured acute heart rate (Figures 2A-2B) and diastolic blood pressure (Figures 3A-3B) changes began at lower concentrations in ME / CFS patients (0.10 ng / ml) than in healthy subjects (0.25 ng / ml), consistent with CRFR2 upregulation in ME / CFS. In Figure 4, pre- / post-treatment changes in TDSS (total daily symptom score) and individual symptoms are compared by dose group for the 28-day period before treatment initiation and the 28-day period before the end of the study. It is shown that symptom changes were biphasic depending on dose. TDSS was persistently elevated on D03 (Pre: 29.2 ± 3.7; After: 21.7 ± 4.1; p = 0.009; change: -25.7%), showed a trend towards better on D01 (Pre: 28.7 ± 3.4; After: 25.5 ± 4.1; p = 0.136; change: -11.1%) and D06 (Pre: 31.3 ± 2.4; After: 29.5 ± 2.1; p = 0.451; change: -5.6%), but worsened on D20 (Pre: 30.1 ± 5.1; After: 33.0 ± 2.5; p = 0.240; change: +9.6%). Most individual symptoms were persistently altered to reflect this biphasic dose response. For example, on D03, the treatment response was strong for most of the core symptoms of ME / CFS, whereas on D20, symptoms mainly worsened. The pharmacokinetics and TDSS for individual patients are shown in Table 5.

[0059] [Table 5]

[0060] C LPrevious studies describing CRFR2 endocytosis as a therapeutic approach speculated that it occurs primarily within that range, based on the attenuation of CT38's ability to stimulate increased heart rate in rats subjected to concentrations higher than 0.1 ng / ml (1.5 ng / ml in rats; human equivalent of approximately 1.4 ng / ml) (stylized as Figure 1B). This study attempted to replicate the rat study in humans, but found that concentrations above approximately 0.7 ng / ml were not tolerated. However, surprisingly, the C of CT38s was not significantly different from that of CT38s in healthy human subjects in previous Phase 1 trials. T Sustained symptomatic improvement occurred in ME / CFS patients in D01 and D03, where Cmax remained below 0.25 ng / ml, identified as the CRFR2-specific peptide (Figure 4). Moreover, because only CT38 binds to CRFR2, and because the symptoms observed were evident at least 28 days after the last treatment with a peptide with a half-life of about 1.5 hours and long clearance, this suggests that CRFR2 endocytosis may have occurred. This is consistent with UCN1 terminating the stress response by effecting CRFR2 endocytosis at low concentrations, as discussed above. This suggests that its Cmax may be related to the CRFR2-specific peptide (Figure 4). T This is also consistent with a mechanism in which optimal CT38-induced endocytosis occurs in the raphe / limbic system, which contains both concentrations of CT38 below (approximately 0.25 ng / ml).

[0061] Thus, when stratifying for the Cmax threshold of 0.25 ng / ml (above which symptomatic improvement declines), the mean 28-day TDSS was significantly elevated for those with Cmax < 0.25 ng / ml (n = 10, TDSS 前 : 29.1 ± 3.6, TDSS 後 TDSS: 22.9 ± 4.1, p = 0.003, change: -6.2 ± 1.6 or -21.4%), all individual symptoms improved, some reaching significance (Figure 5A). The increase in mean 28-day TDSS correlated directly with AUC and indirectly with pretreatment symptom severity (Figure 6A, for patients with moderate symptoms, Pearson correlation coefficients: -0.67 and -0.80, respectively, TDSS 前= 32-45, or mild symptoms, TDSS 前 At Cmax > 0.25 ng / ml, the mean TDSS on day 28 worsened, although not significantly (Fig. 5B, n = 4, TDSS 前 : 30.7 ± 4.0, TDSS 後 : 31.3 ± 2.3, p = 0.740, change: +0.6 ± 2.0 or +1.8%), this lack of significance was due to the different AUCs, as there was a strong direct correlation between the mean 28-day TDSS change and the AUC (Figure 6B, Pearson correlation coefficient: +0.88).

[0062] Figures 6A and 6B show sustained changes in patient-specific TDSS (total AUC) that are dose-dependent with CT38 exposure. However, at ng / ml Cmax below 0.25 (D01 and D03), symptoms improved and correlated inversely with pretreatment symptom severity (Figure 6A, for mild symptoms, Pearson correlation coefficient is -0.80, pre-TDSS = 14-25 and for moderate symptoms, -0.67, pre-TDSS = 32-45). This is consistent with endocytosis occurring below 0.25 ng / ml, and the inverse correlation with pretreatment symptom severity is consistent with the view of endocytosis as protection against high stimulation. That is, mild patients with only pretreatment with mildly stimulating receptors require relatively more drug to achieve high stimulation than moderate patients with pretreatment with moderately stimulating receptors. At Cmax above 0.25 ng / ml (D06 and D20), CRFR2 stimulation occurred and symptoms worsened (Figure 6B, Pearson correlation coefficient = +0.88). Note that at D06, the mean Cmax ranged from 0.27 to 0.31 ng / ml, although above 0.25 ng / ml, was below this for most infusions and thus TDSS was elevated, but not as elevated as at D03. Extrapolation of Figure 6A suggests that subjects who remained below 0.25 ng / ml, with mild symptoms (max TDSS25) and moderate symptoms (max TDSS45), would be excluded by a total AUC of approximately 4.9 and 3.7 ng·h / ml, respectively. CT38 showed that C TThe finding that heart rate is not elevated below 0.25 ng / ml, and thus G proteins and second messengers are not activated, and appears to be similar at 0.10 ng / ml in ME / CFS patients (Figure 2A), is consistent with elevated constitutive (i.e., agonist-dependent) activity and is presumed to be due to elevated CRFR2 expression levels. It should also be noted that the observed CRFR2 sensitivity (Figures 2A-2B and 3A-3B) has potential use as a diagnostic method for ME / CFS, where a given dose of CT38 induces changes in heart rate or blood pressure (or other physiological parameters) that can determine the degree of CRFR2 upregulation in a given ME / CFS patient compared to a reference standard in healthy subjects).

[0063] Outcomes – Patient-rated survey instruments Figures 7A-7B show the SF-36 physical (Figure 7A) and mental (Figure 7B) component scores in the 4-week period before treatment (Pre) and before the end of the study (Post). Patients' pre-treatment general health was worse than the national average for (PCS: 25.9-30.6; MCS: 25.7-38.1), cancer (PCS=45.1; MCS=48.8), congestive heart failure (PCS=31.0; MCS=45.7) or diabetes (PCS=39.3; MCS=47.9). The trends in SF-36 scores showed the same biphasic characteristics, increasing on D03 (significant for PCS, p=0.016) and D01, worsening on D20 and intermediate values ​​on D06. Note that the co-occurrence of the unvalidated TDSS with the highly validated SF-36 endpoints (although not specific to ME / CFS) supports the former. As another way to look at this data, Figures 8A and 8B display graphs of the effect of CT38s on pre-treatment (purple bars) and post-treatment (green bars) means of SF-36 Physical Component Score (PCS) (Figures 8A and 8B, top panels) and SF-36 Mental Component Score (MCS) (Figures 8A and 8B, bottom panels) with standard deviations (error bars) for CT38s at Cmax<0.25ng / ml (Figure 8A) and Cmax>0.25ng / ml (Figure 8B).

[0064] Worsening tolerability and symptoms at concentrations above 0.25 ng / ml necessitated a slower infusion rate, limiting the AUC that could be delivered within the allotted time frame. However, if Cmax was maintained below 0.25 ng / ml, there were no safety concerns, and therefore efficacy should be improved by longer / further infusions that bring exposure closer to the target (3.7 and 4.9 ng·h / ml by extrapolation for moderate and mild symptoms, respectively, FIG. 6A). This aspect was validated in five patients (D03) who received 3-4 treatments that were separated enough to assess the effect of each treatment, resulting in a reduction in mean TDSS after combined treatments 1 and 2 (too close to separate), 3, and 4 (ID29). Overall, this data supports the idea that AUC can be delivered as a single or multiple treatments, and that increasing AUC improves effect.

[0065] Results – Safety Assessment Most treatment-emergent adverse events (TEAEs) were mild (mild 79.0%; moderate 18.5%; severe 2.5%), primarily acute in onset (within 10 hours of initiation of infusion), and resolved without the need for intervention (Table 6). The only severe TEAE, including tachycardia and hypotension in one patient (treated with intravenous saline), occurred at the highest dose (D20) and was partially associated with an inadvertent protocol deviation that failed to discontinue treatment despite meeting discontinuation criteria. With the exception of acute cardiovascular changes and flushing occurring during infusion (known to involve CRFR2-induced peripheral vasodilation), TEAEs were similar to those pretreatment, consistent with the proposed mechanism of action, and were generally largely indistinguishable from ME / CFS symptoms.

[0066] [Table 6]

[0067] Long-term follow-up of 9 (of 14) patients who are regular investigator patients indicates that effects appear to be retained for up to a year after treatment (and nearly 2 years in early-treatment patients). Patients reported modest improvements in sleep, cognition, appetite, and activity. They observed changes in the profile of their post-exertional fatigue in that they crashed less frequently and recovered from crashes more quickly, but did not recognize such improvements until several weeks / months after the last dose. This is consistent with a perturbed system and a disproportionate number of effector proteins (e.g., cytokines, hormones, etc.) and downstream effects, where CRFR2 downregulation removes the underlying sensitivity to the perturbation rather than the effector proteins that take longer to metabolize.

[0068] Table 7 captures this long-term data, tracking "hours of standing activity" (HUA), a measure of function used in the investigator's clinic. Several patients show improvement in this metric. In addition, the investigator provided patient evaluations, indicating that six patients improved, likely due to CT38 treatment. Moreover, it should be noted that the AUC delivered (Table 7) was relatively low compared to the target of approximately 5 ng·h / ml determined in Figure 6A, but as noted above, there was nothing to prevent the AUC from increasing (although the concentration of agonist is maintained below the threshold for stimulating CRFR2). Such data support long-term action, and potentially a cure, from what is essentially a "one-off" dose.

[0069] [Table 7] TIFF2024511066000009.tif71166

[0070] In order to provide a more concise description, some of the quantitative expressions herein are listed as a range of about the amount of X to about the amount of Y. When a range is listed, it is understood that the range is not limited to the upper and lower limits listed, but rather includes the entire range of about the amount of X to about the amount of Y, or any amount or range therein. In order to provide a more concise description, some of the quantitative expressions defined herein are not limited by the term "about". Regardless of whether the term "about" is explicitly used, all amounts defined herein are intended to refer to actual given values, and are also intended to refer to approximations to such given values, which are understood to be reasonably estimated based on ordinary skills in the art, including approximations based on experimental and / or measurement conditions to such given values.

[0071] The words used are words of description, rather than of limitation, and it is understood that changes may be made within the scope of the appended claims without departing from the true scope and spirit of the embodiments in their broader aspects. Although the embodiments have been described with some length and with some particularity with respect to certain aspects, it is not intended that the disclosure should be limited to any such features or embodiments or to any particular embodiment, but rather that the broadest possible interpretation of such claims should be provided in view of the prior art and therefore interpreted with reference to the appended claims as effectively encompassing the intended scope of the invention. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, section headings, materials, methods, and examples are illustrative only and not intended to be limiting.

Claims

1. The plasma concentration of the corticotropin releasing factor receptor 2 (CRFR2) agonist in the subject was measured using the stimulation threshold concentration (C T )と. CRFR2 agonist in an amount sufficient to maintain the body's immune system below 50%.

2. 2. The composition of claim 1, wherein sustained improvement of at least one symptom associated with CRFR2 maladaptation occurs in the absence of concomitant administration of a CRFR2 agonist.

3. The composition of claim 2 , wherein the sustained improvement continues for at least one week after administration of the CRFR2 agonist is discontinued.

4. The composition of any one of claims 1 to 3, wherein the CRFR2 agonist is one of a urocortin peptide (UCN1, UCN2 or UCN3), a stresscopin-related peptide, stresscopin, CT38, CT37 or a pharma- ceutically acceptable salt or solvate thereof.

5. The composition of any one of claims 1 to 3, wherein the CRFR2 agonist comprises an acetate salt of CT38 (CT38s).

6. The composition of claim 5, wherein treating CRFR2 maladaptation comprises administering CT38s to a subject to achieve an area under the plasma concentration-time curve (AUC) of approximately 5 ng·h / ml.

7. The composition of claim 5, wherein treating CRFR2 maladaptation comprises administering CT38s and maintaining a CT38s plasma concentration of less than about 0.25 ng / ml to induce sustained improvement of at least one symptom associated with CRFR2 maladaptation.

8. The composition of claim 5, wherein the treatment of CRFR2 maladaptation comprises administering CT38s at a rate of at least about 0.0001 μg / kg / h.

9. The composition according to any one of claims 1 to 8, wherein the CRFR2 maladaptation is myalgic encephalomyelitis / chronic fatigue syndrome (ME / CFS) as determined by the Fukuda Research Case Definition for CFS, the Revised Canadian Consensus Criteria for ME / CFS, or the National Academy of Medicine Clinical Diagnostic Criteria for ME.

10. The composition according to any one of claims 1 to 8, wherein the CRFR2 maladaptation is a post-acute sequela of SARS-CoV-2 infection.

11. A composition for treating CRFR2 maladaptation comprising a controlled release dose of a CRFR2 agonist, the controlled release dose of the CRFR2 agonist increasing the plasma concentration below the stimulation threshold (C T ) and in an amount effective to induce sustained improvement of at least one symptom associated with CRFR2 maladaptation.

12. The composition of claim 11, wherein the at least one symptom associated with CRFR2 maladaptation is fatigue, pain, sleep problems, cognitive problems, orthostatic intolerance, temperature perception, flu-like symptoms, headache or hyperesthesia, shortness of breath, gastrointestinal problems, urinary problems, musculoskeletal problems, neurological problems, anxiety, depression, or other characteristics or symptoms of the foregoing.

13. The composition of any one of claims 11 to 12, wherein the sustained improvement comprises improvement in at least one symptom associated with CRFR2 maladaptation for at least one week or more after cessation of administration of the CRFR2 agonist.

14. The composition of claim 11, wherein the CRFR2 maladaptation is a functional somatic syndrome.

15. The composition of claim 14, wherein the functional somatic syndrome is myalgic encephalomyelitis / chronic fatigue syndrome.

16. The composition of claim 11, wherein the CRFR2 maladaptation is a post-acute sequela of SARS-CoV-2 infection.

17. 17. The composition of any one of claims 11 to 16, wherein the CRFR2 agonist is one or more of UCN1, UCN2, UCN3, SRP, SCP, CT38, CT37, or a pharma- ceutically acceptable salt or solvate thereof.

18. The composition of any one of claims 11 to 16, wherein the CRFR2 agonist comprises an acetate salt of CT38 (CT38s).

19. The composition of claim 18, wherein treating CRFR2 maladaptation comprises administering a controlled release dose of CT38s at a rate of about 0.03 μg / kg / h or less.

20. The composition of claim 18, wherein treating CRFR2 maladaptation comprises administering CT38s and maintaining a CT38s plasma concentration of less than about 0.25 ng / ml to induce sustained improvement of at least one symptom associated with CRFR2 maladaptation.

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