Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • A61K38/22—Hormones
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • A61K38/22—Hormones
  • A61K38/2228—Corticotropin releasing factor [CRF] (Urotensin)
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

• This disclosure relates to formulations and methods of treating diseases resulting from a maladapted stress response. Certain aspects of the disclosure are directed to formulations and methods of treating myalgic encephalomyelitis/chronic fatigue syndrome.
• MERS myalgic encephalomyelitis/chronic fatigue syndrome
• FSS functional somatic syndromes
• CRFRs corticotropin-releasing factor receptors
• G protein-coupled receptor (GPCR) internalization also referred to as receptor- or clathrin-mediated endocytosis
• receptor agonists such as the endogenous urocortins 1, 2 and 3, or UCN1, UCN2, UCN3, in the case of CRFR2
• UCN1, UCN2, UCN3, in the case of CRFR2 receptor agonists
• cAMP cyclic adenosine monophosphate
• Applicant has recognized an unmet and urgent need for treating diseases resulting from a maladapted stress response, including ME/CFS. Applicant has identified the loss of ability to stimulate the CRF receptors following pre-exposure to result from the internalization, or endocytosis, of the receptor. Therefore, therapeutic formulations and methods of treatment of ME/CFS have been developed that are directed to this mechanism on specific CRF receptors.
• Embodiments include methods of treating a corticotropin-releasing factor receptor 2 (CRFR2) maladaptation in a subject in need thereof.
• CRFR2 corticotropin-releasing factor receptor 2
• One such method includes administering to the subject a CRFR2 agonist in an amount to maintain plasma concentration of the CRFR2 agonist in the subject below a threshold concentration of stimulation (C T ) of CRFR2 agonist.
• a persistent improvement in at least one symptom associated with the CRFR2 maladaptation occurs in the absence of a concurrent administration of the CRFR2 agonist.
• the symptoms associated with the CRFR2 maladaptation include one or more of fatigue, pain, sleep issues, cognitive issues, orthostatic intolerance, body temperature perceptions, flu-like symptoms, headaches or sensory sensitivity, shortness of breath, gastrointestinal issues, urinary issues, musculoskeletal issues, nervous system issues, anxiety, depression, or other characterizations or manifestations of the foregoing.
• the CRFR2 agonist can be one or more of UCN 1 , UCN2, UCN3, stresscopin-related peptide (SRP), Strescopin (SCP), CT38, CT37, or a pharmaceutically acceptable salt or solvate thereof.
• the CRFR2 agonist contains an acetate salt of CT38 (CT38s).
• CT38s is administered to maintain the plasma concentration below about 0.25 ng/ml (nanograms per milliliter) of CT38 to induce persistent improvement in at least one symptom associated with the CRFR2 maladaptation.
• CT38s can be administered to the subject to achieve an AUC of ⁇ 5 ng h/ml, which reflects the actual body exposure to CT38 after administration of a dose of the CT38s.
• CT38s can be administered at a rate of at least about 0.0001 pg/kg/h.
• 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 an impairment of the musculoskeletal or the nervous system, such as Parkinson’s disease.
• Certain embodiments of treating a CRFR2 maladaptation in a subject in need thereof include administering to the subject a controlled-release dose of a CRFR2 agonist.
• This controlled- release dose of the CRFR2 agonist is effective to maintain plasma concentrations below a threshold of stimulation of the CRFR2 agonist (C T ) and to induce persistent improvement of at least one symptom associated with the CRFR2 maladaptation.
• the symptoms associated with the CRFR2 maladaptation include one or more of fatigue, pain, sleep issues, cognitive issues, orthostatic intolerance, body temperature perceptions, flu-like symptoms, headaches or sensory sensitivity, shortness of breath, gastrointestinal issues, urinary issues, musculoskeletal issues, nervous system issues, anxiety, depression, or other characterizations or manifestations of the foregoing.
• the CRFR2 maladaptation is a functional somatic syndrome.
• the functional somatic syndrome is myalgic encephalomyelitis/chronic fatigue syndrome.
• the CRFR2 maladaptation can be a post-acute sequelae of SARS-CoV-2 infection.
• the persistent improvement comprises improvement in the at least one symptom associated with ME/CFS for at least 1 week or longer following cessation of the administration of the CRFR2 agonist.
• the CRFR2 agonist is one or more of UCN1, UCN2, UCN3, SRP, SCP, CT38, CT37, or a pharmaceutically acceptable salt or solvate thereof.
• the CRFR2 agonist can contain an acetate salt of CT38 (CT38s).
• CT38s acetate salt of CT38
• the controlled-release dose of the CT38s is administered at a rate not exceeding about 0.03 pg/kg/h.
• CT38s is administered to maintain the plasma concentration below about 0.25 ng/ml of CT38 to induce persistent improvement of the at least one symptom associated with the CRFR2 maladaptation.
• FIGS. 1A and IB are stylized illustrations of the typical behavior of a GPCR agonist on a GPCR. Increasing agonist concentrations increase the output triggered by the GPCR, commencing at C T and continuing until C L , after which output triggered by the GPCR declines, putatively occurring via receptor endocytosis.
• FIG. 1A illustrates this response in the context of cAMP production from the GPCR in vitro
• FIG. IB illustrates the response in terms of rat heart rate in vivo (such as CRFR2 receptor output) from dosing CT38 (a CRFR2-selective agonist).
• FIGS. 2A and 2B are graphical representations of the effect of mean CT38 maximum plasma concentration (Cmax) (FIG. 2A) or mean area under the plasma concentration-time curve (AUC) (FIG. 2B) on change in mean maximum heart rate (HRmax) in ME/CFS patients (black line) and healthy subjects (grey line). Shown are plots of mean heart rate change (bpm) versus CT38 Cmax (ng/ml) or AUC (ng h/ml).
• Cmax mean CT38 maximum plasma concentration
• AUC mean area under the plasma concentration-time curve
• FIGS. 3A and 3B are graphical representations of the effect of mean CT38 Cmax (FIG. 3A) or mean AUC (FIG. 3B) on change in mean minimum diastolic blood pressure (dBPmin) in ME/CFS patients (black line) and healthy subjects (grey line). Shown are plots of mean diastolic blood pressure change (mmHg) versus CT38 Cmax (ng/ml) or AUC (ng h/ml).
• FIG. 4 shows the effect of CT38s on the pre-/post-treatment change in means of total daily symptom score (TDSS) and individual daily symptom score, by dose group (showing relevant p-values), in ME/CFS patients. Shown are bar graphs depicting relative change for TDSS and each symptom in each dose cohort (D01, D03, D06, and D20), emphasizing TDSS or symptom improvement (light grey) and worsening (black).
• FIGs. 5A and 5B show the effect of CT38s on the pre-/post-treatment change in the 28- day means (bars), with standard deviations (error bars), of TDSS and individual symptoms scores, for CT38: Cmax ⁇ 0.25 ng/ml (FIG. 5A); or Cmax > 0.25 ng/ml (FIG. 5B), either improving (green) or worsening (purple) with relevant p-values (in italics). Note that scales for TDSS and individual symptoms are different.
• FIGS. 6A and 6B are graphical representations of the effect of mean CT38 exposure (total AUC) on the patient-specific pre-/post-treatment change in mean total daily symptom scores (TDSS), stratified by pre-treatment symptom severity and whether achieved Cmax remained below (FIG. 6A) or exceeded (FIG. 6B) C T of CT38 in humans (0.25 ng/ml). Shown are plots of mean TDSS change versus Total CT38 AUC (ng h/ml), stratified by CT38 Cmax, either less than 0.25 ng/ml (FIG. 6A, green) or greater than 0.25 ng/ml (FIG.
• FIGS. 7A and 7B are graphical representations of the effect of CT38s dosing on the SF- 36 physical component score (FIG. 7A) and on the SF-36 mental component score (FIG. 7B), by dose group, in ME/CFS patients. Shown are bar graphs depicting SF-36 score for each dose cohort; error bars indicate standard deviation.
• FIGS. 8A and 8B are graphical representations of the effect of CT38s on the means of pre-treatment (purple bars) and post-treatment (green bars), with standard deviations (error bars), of SF-36 physical component score (PCS) (FIGS. 8A and 8B, top panels) and SF-36 mental component score (MCS) (FIGS. 8A and 8B, bottom panels) for CT38s at Cmax ⁇ 0.25 ng/ml (FIG. 8A) and at Cmax > 0.25 ng/ml (FIG. 8B).
• PCS physical component score
• MCS mental component score
• treatment or “treating” or “alleviating” are used interchangeably. These terms refer to an approach for obtaining beneficial or desired results including but not limited to therapeutic benefit.
• therapeutic benefit is meant eradication or alleviation of the symptoms or the characterizations or manifestations of the underlying disorder being treated.
• a therapeutic benefit is achieved with the eradication or alleviation of at least one of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient may still be afflicted with the underlying disorder.
• a “therapeutic effect”, as that term is used herein, encompasses a therapeutic benefit of a treatment as described above.
• antagonist includes any molecule that partially or fully blocks, inhibits, or neutralizes a biological activity of a native polypeptide disclosed herein (e.g., CRFR2).
• Methods for identifying antagonists of a polypeptide can include contacting a native polypeptide with a candidate antagonist molecule and reducing one or more biological activities normally associated with agonist activity at the native polypeptide.
• agonist is used in the broadest ordinary sense and includes both natural small molecules and peptides as well as synthetic small molecules that partially or fully induce a biological activity of a native polypeptide disclosed herein (e.g., CRFR2).
• Suitable agonist molecules specifically include native polypeptides, variants of native polypeptides, peptides, small organic molecules, etc.
• Methods for identifying agonists of a native polypeptide may include contacting a native polypeptide with a candidate agonist molecule and measuring a detectable change in one or more biological activities normally associated with the native polypeptide.
• the term “ligand” is used in the broadest sense and includes any molecule that binds to another molecule.
• both agonists and antagonists of a native polypeptide e.g., CRFR2
• CRFR2 native polypeptide
• Activity refers to an action or effect of a polypeptide or a synthetic molecule mimicking a polypeptide consistent with that of the corresponding native biologically active protein, wherein “biological activity” refers to an in vitro , in vivo or in human biological function or effect, including but not limited to receptor binding, antagonist activity, agonist activity, or a cellular, biochemical, or physiologic response.
• C T and C L represent the plasma concentrations that invoke an effect at a receptor, and thus C L in particular may vary with the rate at which the agonist is administered (so different for bolus and infused dosing).
• Cmax maximum plasma concentration achieved by the drug and AUC (area under the plasma drug concentration time curve) refer to their standard usage in pharmacology.
• a “safe and effective amount” means an amount of the compound (e.g., CRFR2 agonist) according to the disclosure sufficient to induce a significant positive modification in the condition to be treated, but low enough to avoid serious side effects (such as 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 in the manner of this disclosure.
• the specific “safe and effective amount” will, obviously, vary with such factors as the particular condition being treated, the physical condition of the subject, the duration of treatment, the nature of concurrent therapy (if any), the specific dosage form to be used, the specific delivery route used, the carrier employed, the solubility of the compound therein, and the dosage regimen for the composition.
• One skilled in the art may use the following teachings to determine a “safe and effective amount” in accordance with the present disclosure.
• salts refers herein to salts derived from a variety of organic and inorganic counter ions and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like.
• agent refers herein to a biological, pharmaceutical, or chemical compound or another moiety.
• Non-limiting examples include a simple or complex organic or inorganic molecule, a peptide, a protein, an oligonucleotide, an antibody, an antibody derivative, antibody fragment, a vitamin derivative, a carbohydrate, a toxin, or a chemotherapeutic compound.
• Various compounds can be synthesized, for example, small molecules and oligomers (e.g., oligopeptides and oligonucleotides), and synthetic organic compounds based on various core structures.
• various natural sources can provide compounds for screening, such as plant or animal extracts, and the like. A skilled artisan can readily recognize that there is no limit as to the structural nature of the agents of the present disclosure.
• the term “about” generally refers to a plus or minus of 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.
• about 50 can be interpreted as between 40-60, 43.5-57.5, or 45-55.
• controlled-release refers to any delivery methodology for administering a substance, or a therapeutic drug (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 some period or periods of time and at a therapeutic level sufficient to achieve a given therapeutic effect.
• Controlled-release can be continuous-release, time-release, extended-release, sustained-release, delayed-release, prolonged-release, periodic intermittent release, or any combination thereof.
• a controlled-release could utilize a priming bolus dose in combination with a continuous infusion.
• a controlled-release could utilize a series of immediate release or bolus doses, provided the concentration of the agent is maintained within a limited range. Controlled- release is effective for maintaining or extending the dissolution, absorption, or administration of the drug to the subject to meet certain parameters for safe and effective treatment (e.g., maintaining a concentration and a duration of dosing with an agent).
• the substance or therapeutic drug can be a peptide, a drug, or a prodrug described herein.
• the peptide, drug, or prodrug can be administered via controlled-release using intravenous infusion, subcutaneous infusion, an implantable osmotic pump, subcutaneous depot, a transdermal patch, liposomes, subcutaneous depot injection containing a biodegradable material, or other modes of administration.
• a pump is used.
• polymeric materials are used.
• the flow rate of the peptide, drug, or prodrug is controlled by pressure via a controlled-release system or device.
• a polymer-based drug-delivery system wherein drugs are delivered from polymer or lipid systems.
• Suitable systems may include: AtrigelTM drug delivery system from Atrix Labs; DepoFoaMTM from SkyPharma; polyethylene glycol-based hydrogels from Infimed Therapeutics, Inc.; ReGelTM, SQZGelTM oral, HySolvTM and ReSolvTM solubilizing drug-delivery systems from MacroMed; ProGelzTM from ProGelz' Products; and ProLeaseTM injectable from Alkermes.
• continuous release refers to a delivery methodology for administering a substance, or a therapeutic drug, or one or more therapeutic agent(s) that is introduced into the body of a human or other mammal and continuously or continually release or infuse an amount of one or more therapeutic agents over a determined time period and at a therapeutic level sufficient to achieve a given therapeutic effect throughout a determined time period.
• Reference to a continuous or continual release is intended to encompass release that occurs as the result of biodegradation in vivo of the drug depot, or a matrix or component thereof, or as the result of metabolic transformation or dissolution of the therapeutic agent(s) or conjugates of therapeutic agent(s).
• a bolus dose is a delivery methodology for introducing a relatively large quantity of one or more therapeutic agent(s) into the body of a subject via a single rapid administration.
• the therapeutically effective dose can be delivered in the form of a single bolus dose or a series of bolus doses.
• a bolus dose of a therapeutic agent can rapidly dissolve or become absorbed at the location to which it is administered.
• a single bolus of a therapeutic agent delivers a controlled-release formulation that releases the therapeutic agent over time to maintain the concentration of the therapeutic agent in a determined range.
• the bolus dose 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 body of a subject.
• Functional somatic syndrome or “FSS” as used herein is meant to indicate a stress- related (or stress-induced) disease resulting from a maladapted stress response associated with a CRFR2 maladaptation (e.g., upregulation of CRFR2) in a certain brain region or regions.
• FSS examples 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), pediatric acute-onset neuropsychiatric syndrome (PANS), pediatric autoimmune neuropsychiatric disorder associated with Streptococcal infections (PANDAS), Gulf War Illness (GWI, sometimes Gulf War Syndrome), non-ulcer dyspepsia, premenstrual syndrome, chronic pelvic pain, interstitial cystitis, low back pain, repetitive strain injury, atypical chest pain, non-cardiac chest pain, hyperventilation syndrome, migraine, tension headache, temporomandibular joint disorder, atypical facial pain, Globus syndrome, food hypersensitivity, and sick building syndrome.
• MCS multiple chemical sensitivity
• “Dysautonomia” as used herein is meant to indicate a disorder of the autonomic nervous system and is generally characterized by an abnormal heart rate variability, high resting heart rate, inability to alter heart rate with exercise, and exercise intolerance, orthostatic intolerance/hypotension, thermoregulatory intolerance, digestive or urinary abnormalities.
• Primary dysautonomia is generally considered to be caused by either genetic factors or degenerative neurologic diseases while secondary dysautonomia may occur due to injury or de regulation of the autonomic nervous system from an acquired disorder.
• the CRFR2 agonist CT38 may contain free base (CT38) or acetate salt (CT38s) forms. Where pharmacokinetics are reported herein, pharmacokinetics are measured and reported in terms of CT38 (free base).
• the “first pg” term may include the first pg value and the “second pg” term may include the second pg value.
• Regulation or treatment of a condition in which CRFR2 is upregulated can benefit a variety of subjects.
• the subject can be a mammal. In a preferred embodiment, the subject can be a human. In some embodiments, the subject is an adult. In other embodiments, the subject is a child.
• CRFR2-5HT maladaptations also explain other characteristics of ME/CFS, including sudden onset (high stress) or gradual onset (cumulative low stress exposure), the variety of triggers (since all provoke the release of CRF and would thus affect CRFR2 within the raphe nuclei, limbic system and/or cortex), post-puberty sex bias (as, relative to males, females may have a heightened stress response mostly through CRFR1- and CRFR2-related mechanisms that emerge at puberty), varied symptom presentation/severity (individual symptoms and their severity respectively result from the precise neurons in which the CRFR2 upregulation exists and the extent of such CRFR2 upregulation), risk factors including early life stress or cumulative psychological distress (which would increase CRFR2 upregulation), familial association (which can be genetic or due to similar stress exposure), etc.
• CRFR2 is susceptible to intracellular mechanisms that rapidly attenuate signaling output to prevent cell overstimulation.
• G protein activation and subsequent GPCR kinases GRKs
• GPCR kinases GRKs
• b-arrestin and clathrin GPCR kinases
• FIGS. 1A and IB are stylized illustrations of the typical behavior of a GPCR agonist on a GPCR.
• FIG. 1A is an illustration of the phenomenon, where escalating agonist concentrations, fail to increase cAMP below a threshold of stimulation (“C T ”), then increasing cAMP in a dose- dependent manner eventually achieving maximum effect at a limit of stimulation (“C L ”), with diminished cAMP response beyond.
• C T threshold of stimulation
• C L limit of stimulation
• Dosing regimen/ligand combinations can achieve ligand- induced endocytosis of CRFRs such as CRFR2 to provide therapeutic benefit.
• Increasing agonist concentrations increase the output triggered by the GPCR, commencing at C T and continuing until C L , after which output triggered by the GPCR declines, putatively occurring via receptor endocytosis.
• CRFR2 agonists are able to reduce CRFR2 output through an endocytotic mechanism.
• WO2018075973A2 demonstrated that increasing concentrations of a proprietary CRFR2 agonist, CT38 (administered as its acetate salt, CT38s), exhibits a dose curve for physiological parameters of rats (e.g., heart rate, mean arterial pressure, and core body temperature) where beyond C L (-1.5 ng/ml), the capacity of CT38 to induce changes in these physiological parameters diminished (stylized as FIG. IB, and concordant with the scheme shown in FIG. 1A).
• CRFR1 and CRFR2 activation in the limbic system specifically in the bed nucleus of the stria terminalis or BNST
• CRFR2 endocytosis can occur in the parts of the brain where ME/CFS (and FSS) dysfunction may originate.
• embodiments include administering a CRFR2 agonist in conditions where CRFR2 is deemed to be upregulated (or maladapted).
• CRFR2 agonist can reach the site of CRFR2 upregulation (i.e., the raphe nuclei and limbic system), displace CRF (i.e., have a binding affinity for CRFR2 greater than that of CRF), and be administered at a dose that maintains the plasma concentration of the CRFR2 agonist below C T (of the CRFR2 agonist), to induce CRFR2 endocytosis.
• a treatment scheme may involve b-arrestin recruitment without G protein (and/or GRK) activation.
• Embodiments include treatment of any condition involving CRFR2 maladaptations within the raphe nuclei and/or limbic system by administering a CRFR2 agonist, provided the CRFR2 agonist: (i) is capable of reaching the raphe nuclei/limbic system; (ii) is maintained at a concentration below the minimum threshold at which the CRFR2 agonist stimulates CRFR2 (“C T ”); and (iii) is administered to provide a certain total exposure (i.e., area under the plasma concentration-time curve or AUC).
• the presence and extent of CRFR2 upregulations (or maladaptations) in a given patient are determined by methods that assess the responsiveness of physiological parameters of a subject to concentrations of a CRFR2 agonist.
• One such method involves determining the threshold bolus dose of a given CRFR2 agonist in a given patient that is capable of inducing a change in a physiological parameter (such as heart rate, diastolic blood pressure, core body temperature, respiratory rate), and comparing this physiological parameter to a corresponding value for that physiological parameter in healthy subjects (see below), with the difference indicating the presence and extent of CRFR2 maladaptations.
• a physiological parameter such as heart rate, diastolic blood pressure, core body temperature, respiratory rate
• compositions and methods disclosed herein are used to treat CRFR2 maladaptations of the stress response that appear in a variety of conditions, including ME/CFS, fibromyalgia syndrome, post-traumatic stress disorder, multiple chemical sensitivities, chronic Lyme disease, post-acute sequelae of viral infections (such as pursuant to a SARS-CoV-2 infection), irritable bowel syndrome, atypical depression, pediatric acute-onset neuropsychiatric syndrome, pediatric autoimmune neuropsychiatric disorder associated with Streptococcal infections, Gulf War Illness, and others (e.g., non-ulcer dyspepsia, premenstrual syndrome, chronic pelvic pain, interstitial cystitis, low back pain, repetitive strain injury, atypical or non cardiac chest pain, hyperventilation syndrome, migraine, tension headache, temporomandibular joint disorder, atypical facial pain, Globus syndrome, food hypersensitivity, sick building syndrome, etc.), which are understood to represent a single underlying common basic
• compositions and methods disclosed herein are used to treat dysautonomia (including postural orthostatic tachycardia syndrome, neurocardiogenic syncope, multiple system atrophy, hereditary sensory and autonomic neuropathies, Holmes-Adie syndrome), immune dysfunction (including allergies and autoimmune diseases such as 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, hypogonadism.
• dysautonomia including postural orthostatic tachycardia syndrome, neurocardiogenic syncope, multiple system atrophy, hereditary sensory and autonomic neuropathies, Holmes-Adie syndrome
• immune dysfunction including allergies and autoimmune diseases such as lupus, multiple sclerosis, inflammatory bowel disease, rheumatoid arthritis, type 1 diabetes, celiac disease, and Sjogren's syndrome
• compositions and methods disclosed herein are used to treat conditions such as chronic pain, anxiety and addiction, which also arise at least in part from CRFR adaptations in the limbic system.
• compositions and methods disclosed herein are used to treat an impairment of the musculoskeletal or the nervous system that manifests as tremors, ataxia, or dyskinesia.
• the CRFR2 agonist is capable of reaching the limbic system, which can be tested, for example, by imaging techniques utilizing radio-labeled agonist in vivo.
• the stress response can be mediated by CRFR2
• administration of the CRFR2 agonist to healthy animals alongside observation of significant changes in physiological functions known to be modulated via limbic system CRFR2 (e.g., core body temperature or respiratory rate), can be used to identify suitable CRFR2 agonists.
• subcutaneous bolus doses of CT38s induce dose-dependent changes in core body temperature and respiratory rate in laboratory animals, consistent with reaching the limbic system.
• CRFR2 agonists meeting the above criteria are partial agonists or agonists selective for both CRFR2 and CRFRl (such as UCN1) and are capable of displacing CRF from its receptors in vivo.
• CT38s CT38s
• UCN1, UCN2, UCN3, stresscopin a putative precursor peptide of UCN3
• SRP stresscopin-related peptide
• the CRFR2 agonist is one or more of the agents presented in Table 1.
• the CRFR2 agonist includes one or more of the amino acid sequence of SEQ ID NO:l, 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 combinations thereof.
• the CRFR2 agonist contains an amino acid sequence having 90%, 91%, 92%, 93% 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to sequences of SEQ ID NOs. 1-8.
• the CRFR2 agonist contains an amino acid sequence according to the formula: ZGPPISIDLPXl 1X12LLRKX 17IEIEKQEKEKQQ AX31X32NAX35X36LX38X39X40 (SEQ ID NO:8) wherein: XI 1 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; X40 is selected from I and V, and wherein Z (i.e., Glx or Pyrrolidone carboxylic acid) is used to indicate N-terminal glutamic acid or glutamine that optionally has formed an internal cyclic lactam.
• Z i.e., Glx or Pyrrolidon
• a CRFR2 antagonist is administered to displace CRF, then maintained for a period of time.
• Such antagonists include, but are not limited to CRFR2-selective Astressin2-B and non-selective Astressin-B.
• C T can be determined in healthy animals, including healthy humans. Phase 1 clinical trials routinely identify the profile of an agonist at a receptor.
• determining its C T at CRFR2 involves administering an escalating bolus dose of the CRFR2 agonist to healthy animals or subjects, measuring the induced change in a physiological parameter associated with CRFR2 stimulation (e.g., heart rate, blood pressure, core body temperature, respiratory rate), and identifying the lowest dose of the CRFR2 agonist that stimulates a significant change in a physiological parameter.
• a physiological parameter associated with CRFR2 stimulation e.g., heart rate, blood pressure, core body temperature, respiratory rate
• CT38s in healthy human subjects with measurement of physiological parameters such as heart rate or diastolic blood pressure
• the C T of CT38s at CRFR2 is estimated to be at or close to 0.25 ng/ml.
• CT38s dosed by subcutaneous infusion at a rate of 0.03 pg/kg/hour achieving a mean maximum plasma concentration of CT38 of 0.18 ⁇ 0.03 ng/ml; range: 0.14 to 0.24 ng/ml, Table 5
• achieving a mean maximum plasma concentration of CT38 of 0.18 ⁇ 0.03 ng/ml; range: 0.14 to 0.24 ng/ml, Table 5 maintained for 3.5 hours over 3 separate treatments (achieving an average total AUC of 2.46 ⁇ 0.51 ng-h/ml; range: 1.94 to 3.44 ng-h/ml), resulted in a mean TDSS improvement of -7.52 (range: -0.3 to -16.0).
• Cmax cannot exceed 0.25 ng/ml (C T ), and total AUC must be ⁇ 5 ng-h/ml for mild symptoms, less for moderate symptoms and even less for severe symptoms.
• C T total AUC
• all patients should receive an AUC of ⁇ 5 ng-h/ml, especially as there is no safety issue with providing a higher AUC.
• the Cmax limit is determined by C T (which can be derived for any agonist as above), and the required AUC will be directly related to agonist potency (i.e., a more potent agonist will require less AUC).
• the precise dosing regimen is then determined by standard pharmacokinetic-pharmacodynamic methods.
• methods include administering CT38s to a subject having a CRFR2 maladaptation such as ME/CFS, by subcutaneous infusion at a dose level of 0.03 pg/kg/hour, sufficient to ensure a CT38 plasma concentration of no more than 0.25 ng/ml, then maintained for a period of 12 hours to deliver an AUC of ⁇ 2.5 ng-h/ml, and repeated at a second treatment for a total AUC of ⁇ 5.0 ng-h/ml.
• the same dose level could be maintained for a period of 6 hours to deliver an AUC of -1.2 ng-h/ml in each of 5 treatments, for a total AUC of ⁇ 6.0 ng-h/ml.
• CT38s is delivered initially via a subcutaneous priming bolus followed by a subcutaneous infusion, where the priming bolus is intended to shorten the duration of the infusion that would otherwise be required to achieve the target AUC, while maintaining CT38 plasma concentration below 0.25 ng/ml.
• a priming bolus of CT38s of 0.03 pg/kg an infusion at a dose-level of 0.03 pg/kg/hour could deliver an AUC of 1.28 ng-h/ml in each of 4 treatments for a total AUC of ⁇ 5.1 ng-h/ml.
• the CT38s dosing regimens are designed by taking into account one or more of the use of a priming bolus, the rate of infusion, the duration of infusion, and the number of such treatments.
• the CT38s dosing regimens are designed to deliver the target AUC (at least ⁇ 5 ng-h/ml) while maintaining CT38 plasma concentration below C T (-0.25 ng/ml).
• a series of subcutaneous boluses of a CRFR2 agonist is used to achieve the target exposure, and in such a way that the combined effects of the level and rate of dosing maintain the achieved Cmax below C T .
• the rate of infusion determines Cmax and is further affected by the use of a priming bolus.
• a composition of the disclosure can be administered in a single controlled-release dose, with the total duration of dosing governed by the severity of patient dysfunction at the onset, which bear an inverse relationship (milder severity requires longer duration).
• a composition of the disclosure can be administered in multiple controlled-release doses.
• the total duration of dosing is still governed by the severity of patient dysfunction at the onset, and the number of doses and the dosing interval are set by convenience and/or a desire to reassess the level of patient dysfunction before commencing the next dose.
• an effective amount of the compositions of this invention ranges from nanograms/kg to micrograms/kg amounts for young children and adults. Equivalent dosages for lighter or heavier body weights can readily be determined. The dose should be adjusted to suit the individual to whom the composition is administered and may vary with age, weight, and metabolic status of the individual.
• compositions 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, its mode of administration and the like. An appropriate amount can be determined by one of ordinary skill in the art using only routine experimentation given the teachings herein. Optimal dosages to be administered may be readily determined by those skilled in the art, and will vary with the particular compound used, the mode of administration, the strength of the preparation, the mode of administration, the number of consecutive administrations within a limited period of time, and the advancement of the disease condition.
• Another aspect of the disclosure is a method to determine when to cease treatment in a given patient.
• the initially-determined threshold bolus dose of a CRFR2 agonist to induce a heart rate increase in a given patient with a CRFR2 maladaptation increases following treatment as described above.
• the threshold bolus dose is then redetermined, and when the threshold bolus dose for the patient approximates that of healthy subjects (e.g., about 0.083 pg/kg of body weight of CT38s in healthy young males determined in the prior Phase 1), this indicates that CRFR2 is no longer upregulated in the BNST.
• the threshold bolus dose of a CRFR2 agonist to induce a heart rate increase is measured in the patient following a treatment, and treatment is stopped when the threshold bolus dose for the patient approximates that of healthy subjects.
• CRFR2 it may still be appropriate to continue treatment, even after the heart rate suggests a return of CRFR2 expression to levels similar to that of healthy subjects.
• therapeutic effect can be measured via global scales (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, Kamofsky 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, visits to the hospital/emergency room, etc.), or individual symptom scales (examples of which include, but are not limited to, Modified Fatigue Impact Scale, pain visual analog scales, Pittsburgh Sleep Quality Index, American Academy of Sleep Medicine-approved scales for sleep satisfaction quality and improved daytime functioning, Perceived Deficits Questionnaire for cognitive dysfunction, tilt- table tests for orthostatic intolerance, use of concomitant medication,
• CRFR2 endocytosis occurs when a CRFR2 agonist is administered in such a way to reach the upregulated receptors in the raphe nuclei/limbic system and to be present at a level below the C T of the agonist.
• dosage is adjusted for the severity of dysfunction of an individual patient.
• An example of a case, where treatment adjustment was useful, is partially demonstrated in Example 1 (Table 3 and Table 5), where Patient ID 35 found the relatively low concentration of 0.12 ng/ml difficult to tolerate.
• the dose may be reduced to ensure target plasma concentrations well below C T and the length of administration extended accordingly to provide the appropriate AUC.
• CT38 or any of the CRFR2 agonists described herein can be delivered by any route of administration, e.g., subcutaneous, intravenous, transdermal, transmucosal, intranasal, inhaled, gastrointestinal etc., to achieve the target plasma concentrations that modulate or reduce a condition associated with a CRFR2 maladaptation.
• routes of administration e.g., subcutaneous, intravenous, transdermal, transmucosal, intranasal, inhaled, gastrointestinal etc.
• Modes of administration of CT38 or any of the CRFR2 agonists described herein can include rectal, oral, buccal, intra-arterial injection, intra-peritoneal, parenteral, intra-muscular, intrathecal, or other appropriate routes.
• the dosage form is formulated for use in treating and/or assessing the severity of an FSS in a subject in need thereof.
• the dosage is formulated for subcutaneous administration.
• the CRFR2 agonist includes one or more of the amino acid sequences in Table 1.
• the CRFR2 agonist includes the amino acid sequence of SEQ ID NO:l, 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.
• the polypeptide has a sequence having at least 90%, 91%, 92%, 93% 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to sequences of SEQ ID NOs. 1-8 as shown in Table 1.
• the controlled-release or bolus dose or dosage form is a pharmaceutical composition containing the protein having the sequence as set forth in Table 1 (e.g., SEQ ID NO: 1) and a pharmaceutically acceptable carrier.
• An effective amount of a CRFR2 agonist, or any analogs or derivatives thereof may be administered to a subject according to various dosing regimens.
• a composition containing the effective amount of a CRFR2 agonist, or any analog or derivatives thereof may be administered in single dose or in more than one dose.
• the effective amount of a CRFR2 agonist, or any analog or derivatives thereof may be administered in about one dose to about 28 doses, one dose to about 5 doses, or one dose to about 10 doses.
• Administration can be initiated at the onset of a disorder or at a time after onset of the disorder.
• the compositions containing a CRFR2 agonist, or any analogs or derivatives thereof can be administered to a subject who is diagnosed with a CRFR2 maladaptation, or a FSS.
• the FSS is myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).
• 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), pediatric acute-onset neuropsychiatric syndrome (PANS), pediatric autoimmune neuropsychiatric disorder associated with Streptococcal infections (PANDAS), or Gulf War Illness (GWI, sometimes Gulf War Syndrome).
• FMS fibromyalgia syndrome
• PTSD post-traumatic stress disorder
• IBS irritable bowel syndrome
• MCS multiple chemical sensitivity
• CLD chronic Lyme disease
• PANS pediatric acute-onset neuropsychiatric syndrome
• PANDAS pediatric autoimmune neuropsychiatric disorder associated with Streptococcal infections
• GWI Gulf War Illness
• the FSS is a result of an infectious disease and includes a spectrum of symptoms after acute infection.
• post-viral symptoms can include post-acute sequelae of SARS-CoV-2 infection (PASC), also referred to as post-coronavirus disease 2019 syndrome or long COVID, whose symptoms overlap considerably with those of ME/CFS.
• PASC post-acute sequelae of SARS-CoV-2 infection
• 2019 syndrome post-coronavirus disease 2019 syndrome
• COVID long COVID
• poliomyelitis also abortive poliomyelitis, acute anterior poliomyelitis, resembling poliomyelitis, encephalomyelitis associated with poliomyelitis virus
• encephalitis epidemic encephalitis, persistent myalgia, epidemic neuromyasthenia, epidemic myositis, benign myalgic encephalomyelitis, lymphocytic meningo-encephalitis, epidemic malaise, epidemic diencephalomyelitis, infectious venulitis, multi-system 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.
• the composition can be administered to the subject for a period of time from between about 1.0 hour to about 12 hours, 24 hours, or 48 hours.
• the composition is administered as a bolus dose of CT38s, or equivalent, of about 0.025 pg/kg, in combination with a continuous infusion dose of about 0.025 pg/kg/hour suitable for a total administration time of about 24 hours.
• the continuous infusion dose is subdivided, and contains, for instance, multiple continuous infusion doses that together provide the AUC equivalent of about ⁇ 5 ng h/ml (of CT38).
• such a dose combination is additionally adjusted for the severity of the patient’s condition.
• the composition can be administered to the patient by controlled-release over separate treatment periods.
• the dosing regimen determines the duration of treatment.
• each of the separate treatment periods are separated by specific time intervals to achieve the desired AUC.
• agonist concentrations, durations of dosing, and intervals of dosing specified in the present disclosure are patient-specific and are also affected by the route of administration and the pharmacokinetic and pharmacodynamic parameters (e.g., potency, half-life) of the specific CRFR2 agonist utilized.
• pharmacokinetic and pharmacodynamic parameters e.g., potency, half-life
• achieved plasma concentrations and AUCs are related, and therefore any reduction in the achieved maximum plasma concentration necessitates an increase in exposure to achieve the target AUC, e.g., via additional boluses or longer duration infusions.
• the present disclosure provides a pharmaceutical composition containing a dosage form of a CRFR2 agonist described herein.
• the pharmaceutical composition can further contain a pharmaceutical carrier or excipient.
• the compositions can be formulated as pharmaceutical compositions to provide an effective amount of a composition containing a CRFR2 agonist.
• the CRFR2 agonist can be the active ingredient in the formulated pharmaceutical composition.
• compositions containing (a) an amount of a CRFR2 agonist present that is a safe and effective in treating, reducing and/or alleviating a CRFR2 maladaptation, and (b) a pharmaceutically acceptable carrier.
• composition formulated for injection can include sterile aqueous or non-aqueous solutions, suspensions, and emulsions.
• 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 conventionally used for injection.
• Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and the like (and suitable mixtures thereof), tromethamine, cyclodextrin derivatives, and vegetable oils may also be employed.
• the proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, for the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
• a composition formulated for injection can include 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, antimicrobials, anti-oxidants, chelating agents, and inert gases and the like.
• Sterile injectable solutions are prepared by incorporating the compound 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.
• dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle, which contains the basic dispersion medium and the required other ingredients from those described herein.
• kits include a compound or composition of the present disclosure as described herein, in suitable packaging, and written material that can include instructions for use, discussion of clinical studies, listing of side effects, and the like.
• kits may also include information, such as scientific literature references, package insert materials, clinical trial results, and/or summaries of these and the like, which indicate or establish the activities and/or advantages of the composition, and/or which describe dosing, administration, side effects, drug interactions, or other information useful to the patient and healthcare provider (such information may include direction for administering an effective amount of a CRFR2 agonist to treat or alleviate a CRFR2 maladaptation such as an FSS.
• kits also include a first dosage form of a CRFR2 agonist suitable for administration to a patient in order to detect a CRFR2 maladaptation by a heart rate, blood pressure or other physiological response as described herein.
• Kits may additionally contain a therapeutic formulation of a CRFR2 agonist appropriate to treat the CRFR2 maladaptation according to the methods described herein.
• Kits may additionally contain a dosage form of a CRFR2 agonist suitable for administration to a patient to detect a decrease in a CRFR2 maladaptation by a heart rate, blood pressure response or other physiological response following some level of treatment.
• kits and articles of manufacture containing materials useful for the treatment and/or diagnosis of disease (e.g., FSS) according to methods described herein.
• the disclosure provides kits that include packaging material and at least a first container containing a dosage form or pharmaceutical composition of e.g., a CRFR2 agonist and a label identifying the dosage form or pharmaceutical composition and storage and handling conditions, and a sheet of instructions for the reconstitution and/or administration of the dosage form or pharmaceutical compositions to a subject.
• the kit includes a container and a label, which can be located on the container or associated with the container.
• the container may be a bottle, vial, syringe, cartridge (including autoinjector cartridges), or any other suitable container, and may be formed from various materials, such as glass or plastic.
• the container holds a composition having a CRFR2 agonist, an analog or derivative thereof, and can have a sterile access port.
• Examples of containers include a vial with a stopper that can be pierced by a hypodermic injection needle.
• the kits may have additional containers that hold various reagents, e.g., diluents, preservatives, and buffers.
• the label may provide a description of the composition as well as instructions for the intended use.
• the present disclosure provides a kit including a container which holds a pharmaceutical composition for administration to a human patient containing a CRFR2 agonist.
• the CRFR2 agonist contains 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.
• the kit further includes a package insert associated with such container.
• the package insert indicates that such composition is for the treatment of ME/CFS or a FSS, by administration of at least one dose of the composition.
• Example 1 Investigation of the safety, tolerability and efficacy of a specific CRFR2 agonist, CT38, in ME/CFS patients.
• CT38 is a selective CRFR2 agonist with no known off-target activity, except CRFRl at very high concentrations.
• the Phase 1/2 trial included a recruitment and screening period, followed by enrollment, at least a 4-week pre-treatment assessment period, a 2-week interventional treatment period (involving 3 drug infusions), and at least a 4-week post-treatment assessment period, leading up to exit.
• exclusions included active or uncontrolled co-morbidities, pregnancy /breast-feeding, body-mass index > 35, cigarette- smoking, substance-abuse, certain medications (including antivirals, antiretrovirals, antibiotics and those interacting with 5HT, norepinephrine, dopamine or cortisol pathways, or a history of severe tachycardia (heart rate > 100 bpm), bradycardia (heart rate ⁇ 45 bpm), hypotension (rested sitting systolic/diastolic blood pressure ⁇ 100 mmHg or 60 mmHg, respectively) or renal impairment. There were other minor exclusions, including those related to exercise.
• WO2018075973A2 identified a C L (by infusion) in rats as -1.5 ng/ml, and a total AUC of -40 ng-h/ml — equivalent to -1.4 ng/ml and -7.0 ng-h/ml in healthy humans, based on the pharmacokinetic-pharmacodynamic modeling of the bolus dosing in a prior Phase 1 trial.
• the initial treatment regimen proposed 2 separate subcutaneous treatments, each involving an initial priming bolus of 0.15 pg/kg, followed by an infusion of 0.20 pg/kg/hour (escalating to 0.24 pg/kg/hour), over 3 hours.
• the planned initial dose, D20 pb (see Table 2) increased heart rate and decreased diastolic blood pressure (more so than systolic) in the first patient, and though this was tolerated (i.e., did not meet the protocol dose-stopping criteria), the level of change made the priming bolus unsafe, which was eliminated in favor of extending the infusion for an extra 30 minutes.
• the second treatment in the first patient, and both treatments in the second patient utilized the D20 dose.
• the subsequent pharmacokinetic data confirmed that D20 pb and D20 (essentially the same total dose) were inducing a level of hemodynamic change that was observed in the prior Phase 1 healthy subjects only at considerably higher concentrations and AUCs.
• FIGS. 2A-2B and 3A-3B show that changes in objectively measured acute heart rate (FIGS. 2A- 2B) and diastolic blood pressure (FIGS. 3A-3B) commenced 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.
• FIG. 2A-2B shows that changes in objectively measured acute heart rate (FIGS. 2A- 2B) and diastolic blood pressure (FIGS. 3A-3B) commenced 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.
• TDSS total daily symptom score
• individual symptoms in the 28-day period prior to the start of treatment with those in the 28- day period prior to exit from the trial, by dose group. It shows that symptom change was biphasic with dose.
• Table 5 Patient-reported symptom change, by patient ID
• 3A-3B has potential use as a diagnostic for ME/CFS, where a given dose of CT38 will induce a change in heart rate or blood pressure (or other physiological parameter) that can be compared to a reference standard in healthy subjects to determine the extent of CRFR2 upregulation in a given ME/CFS patient).
• FIGS. 7A-7B show the SF-36 physical (FIG. 7A) and mental (FIG. 7B) component scores for the 4-week periods prior to treatment (pre) and prior to exit from the trial (post).
• FIGS. 8A and 8B are graphical representations of the effect of CT38s on the means of pre-treatment (purple bars) and post-treatment (green bars), with standard deviations (error bars), of SF-36 physical component score (PCS) (FIGS. 8A and 8B, top panels) and SF-36 mental component score (MCS) (FIGS. 8A and 8B, bottom panels) for CT38s at Cmax ⁇ 0.25 ng/ml (FIG. 8A) and at Cmax > 0.25 ng/ml (FIG. 8B).
• PCS physical component score
• MCS mental component score
• TEAEs treatment-emergent adverse events
• TEAEs were similar to those before treatment and largely indistinguishable from the symptoms of ME/CFS in general, consistent with the proposed mechanism of action.
• Table 7 captures this long-term data. It tracks ‘hours of upright activity’ (HUA), which is a measure used at the principal investigator’s clinic to gauge function. Several patients show improvements in this metric. In addition, the principal investigator provided an assessment of the patients, showing that 6 patients improved, likely due to CT38 treatment. Moreover, it should be noted that the AUCs delivered (Table 7) were relatively low compared to target of ⁇ 5 ng-h/ml, determined in FIG. 6A, but as noted above, nothing prevents increasing the AUC (provided the concentration of the agonist is maintained below the threshold at which it stimulates CRFR2). These data support a long-term effect from an essentially ‘one-time’ dose, i.e., potentially a cure. [00116] Table 7: Long-term follow-up in a subset of patients

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