Treating or preventing long covid

Abstract

In the various aspects and embodiments, the present disclosure provides compositions and methods for treating a human subject having long Covid or at risk of long Covid. In accordance with this disclosure, the subject receives an oral dosage form of larazotide or a derivative thereof.

Description

[0001] TREATING OR PREVENTING LONG COVID

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 665,926, filed June 28, 2024, the entire contents of which are hereby incorporated by reference in their entirety.

[0004] DESCRIPTION OF THE TEXT FILE SUBMITTED ELECTRONICALLY

[0005] This application contains a Sequence Listing in XML format submitted electronically herewith via Patent Center. The contents of the XML copy, created on June 30, 2025, is named “INT-063PC_137776-5063.xml” and is 5,925 bytes in size. The Sequence Listing is incorporated herein by reference in its entirety.

[0006] BACKGROUND

[0007] Long Covid is a chronic condition that occurs after SARS-CoV-2 infection in some individuals. Long Covid symptoms and conditions can emerge, persist, resolve, and reemerge over weeks and months. These symptoms and conditions can range from mild to severe, may require comprehensive care, and can even result in a disability. Long Covid symptoms can affect essentially any organ system, including muscles and joints, GI, kidneys, reproductive organs, cardiovascular system, respiratory, and nervous system.

[0008] Long Covid remains a serious public health concern as millions of U.S. adults and children have been affected by long Covid. Accordingly, compositions and methods for treating or preventing long Covid are needed.

[0009] DETAILED DESCRIPTION

[0010] In the various aspects and embodiments, the present disclosure provides compositions and methods for treating a human subject having long Covid or at risk of long Covid. In accordance with this disclosure, the subject having long Covid or at risk of long Covid is administered an oral dosage form of larazotide or a derivative thereof. In embodiments, the larazotide or derivative thereof is administered at an effective amount and schedule to treat long Covid. Coronavirus disease (Covid) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). There are three general phases of infection with SARS-CoV- 2: (i) Incubation Period, which is the time between getting infected and when symptoms appear (generally, symptoms may start two to 14 days after infection); (ii) Acute Phase, which starts once symptoms appear (though some having Covid are asymptomatic) and generally lasts one to two weeks; and (iii) Covid Recovery, which is the period after active Covid symptoms have abated but can include lingering symptoms. Long Covid (also known as post-acute sequalae of COVID-19, or PASC) is defined as a chronic condition that occurs after SARS-CoV-2 infection, and which can persist for weeks or months (e.g., at least 4 weeks from initial infection). The etiology of long Covid remains unclear, and long Covid may even encompass multiple distinct etiologies, such as persisting reservoirs of SARS- CoV-2 in tissues, immune dysregulation (including autoimmunity), herpesvirus reactivation (e.g., EBV), endothelial dysfunction, as well as impacts on the microbiome.

[0011] There is no established treatment for long Covid, except to treat the individual symptoms of the subject’s condition. In addition to conventional pharmaceuticals and supplements useful for treating symptoms, treatment may include physical therapy, lifestyle changes, and counseling. Symptoms of long Covid can include fatigue, dizziness, headache, dyspnea, cough, joint pain and stiffness, myalgia, concentration impairment, weakness, breathlessness, thoracic pain, irritable bowel syndrome, diarrhea, constipation, nausea, vomiting, chest pain, depression, anxiety, sleep disorders, palpitations, anosmia, ageusia, and skin problems such as rash, among others.

[0012] Larazotide has the amino acid sequence: Gly Gly Vai Leu Vai Gin Pro Gly (SEQ ID NO: 1). Derivatives of larazotide comprise from one to three amino acid modifications with respect to SEQ ID NO: 1, and the modifications may be independently selected from substitutions, deletions, insertions or additions with respect to SEQ ID NO: 1. In some embodiments, the larazotide derivative is a derivative having 1, 2, or 3 amino acid substitutions with respect to SEQ ID NO: 1. By way example, in some embodiments, the larazotide derivative is a derivative described in U.S. Pat. Nos. 8,785,374, 8,957,032, and 9,279,807, which are each hereby incorporated by reference in their entirety. In some embodiments, the derivative has one or more non -genetically encoded amino acids, or one or more (or all) (d)-amino acids. The term “larazotide” or “larazotide treatment” refers to treatment with larazotide or a derivative that promotes tight junction integrity, for example, in the small intestine. In some embodiments, the treatment is with (d)-larazotide, that is, where all non-glycine residues are in (d) form.

[0013] In embodiments, the subject has long Covid. In some embodiments, the present disclosure contemplates that the subject has long Covid for at least one month, at least two months, at least three months, at least four months, at least five months, or at least six months at the initiation of treatment described herein. In these embodiments, the disclosure helps to resolve long Covid symptoms that are insufficiently resolved with other treatment modalities.

[0014] In other embodiments, the subject is at risk of long Covid. For example, in embodiments, the subject is in the acute phase of Covid, and the treatment described herein reduces the probability that the subject will experience long Covid, or will reduce the severity or duration thereof. In embodiments, the subject has moderate or severe Covid- 19.

[0015] While long Covid can affect subjects of any age, older age subjects and subjects with comorbidities are more susceptible to developing long Covid, including long Covid affecting multiple organs and systems. In embodiments, the subject is at least 50 years of age, or at least 60 years of age, or at least 70 years of age. However, in embodiments, the subject is a child (i.e., 16 years or younger, or 12 years of younger). In some embodiments, the subject is overweight or obese, and / or the subject is immune compromised. In embodiments, the subject has long Covid affecting multiple organ systems.

[0016] In some embodiments, the subject having long Covid or at risk of long Covid had one or more comorbidities, before Covid infection, that may make the subject more susceptible to long Covid. In embodiments, the subject had a comorbidity selected from Inflammatory Bowel Syndrome (IBS), Inflammatory Bowel Disease (IBD), arthritic disease (e.g., rheumatoid arthritis), Type 2 diabetes mellitus, celiac disease, psoriasis, systemic lupus erythematosus (SLE), and dysbiosis. In embodiments, the subject having long Covid or at risk of long Covid had one or more comorbidities that affect intestinal permeability or involve persistent gastrointestinal inflammation. In still other embodiments, the subject having long Covid or at risk of long Covid did not exhibit any obvious signs of gastrointestinal comorbidity (e.g., persistent gastrointestinal inflammation and / or dysbiosis). The present disclosure provides that a subject’s long Covid symptoms can include, but are not limited to, gastrointestinal symptoms. In embodiments, gastrointestinal symptoms include one or more of nausea, vomiting, abdominal pain, diarrhea, constipation, colitis, and dysbiosis. In embodiments, the larazotide regimen resolves gastrointestinal symptoms of long Covid, as well symptoms affecting other organ systems.

[0017] In a Phase 2a trial, children with Multisystem Inflammation Syndrome (MIS-C) were treated with larazotide acetate or placebo. It was observed that gastrointestinal symptoms resolved faster with larazotide treatment. Patients received 0.25 mg or 0.5 mg of larazotide acetate, depending on whether the patient weighed less or more than 25 kg, respectively. GI symptoms were self-reported using the PedsQL™ GI Symptoms Scale.

[0018] In other embodiments, the subject’s long Covid symptoms do not include any overt gastrointestinal symptoms. In such embodiments, non-GI symptoms can show quicker resolution with the treatment described herein.

[0019] In embodiments, the subject’s long Covid symptoms include, or further include, one or more of: irritability, fatigue, muscle weakness, and / or myalgia; arthralgia; dyspnea, cough, and / or pulmonary dysfunction; palpitations; headache and / or dizziness; taste and / or smell disorder and / or sore throat; rash; and herpes virus or Epstein-Barr virus (EBV) reactivation.

[0020] In the Phase 2a trial, it was observed that larazotide treatment was likely associated with a reduction in neurological symptoms. In particular, larazotide treatment was associated with improved irritability (as determined by survey of symptoms).

[0021] In some embodiments, the subject at risk of Covid or having long Covid, exhibits gastrointestinal symptoms during the acute phase of Covid, optionally including one or more of nausea, vomiting, abdominal pain, diarrhea, constipation, colitis, and dysbiosis. In other embodiments, the subject’s Covid symptoms do not include gastrointestinal symptoms (e.g., overt gastrointestinal symptoms) during the acute phase of Covid. In some embodiments, the subject had MIS-C or MIS-A during the acute phase of Covid. Multisystem inflammatory syndrome (MIS) is a rare but serious condition associated with SARS-CoV-2, in which various tissues and organs become inflamed. In embodiments, the subject exhibits acute respiratory distress syndrome (ARDS) during the acute SARS-CoV-2 infection, and optionally required ventilation. In some embodiments, the subject exhibits one or more neurological symptoms during the acute phase of Covid, optionally selected from headache and / or dizziness; irritability; fatigue; and taste and / or smell disorder.

[0022] In embodiments, the subject receives Paxlovid during the acute phase of Covid, and / or receives a second round of Paxlovid with treatment of larazotide or derivative described herein. Paxlovid is a 5-day oral prescription treatment for mild-to-moderate Covid. When the treatment of larazotide or derivative described herein is administered with Paxlovid or after Paxlovid, long Covid (or symptoms thereof) may be ameliorated or reduced substantially in duration. In embodiments, the subject does not receive Paxlovid during the acute phase or for long Covid.

[0023] The present disclosure contemplates, in embodiments, that the subject has detectable SARS-CoV-2 virus in stool or urine. In these embodiments, the subject may have persisting reservoirs of virus in the intestines. Without being bound by theory, treatment with larazotide can help eliminate these persisting reservoirs, and / or reduce impacts of this persisting reservoir on other organ symptoms.

[0024] The present disclosure contemplates, in embodiments, that the subject has detectable SARS-CoV-2 spike protein in the blood, optionally in the serum or plasma. In the Phase 2a trial for MIS-C, it was observed that larazotide treatment was associated with faster clearance of spike protein antigenemia (e.g., spike protein detected in blood). There was further a strong correlation between spike protein levels and markers of inflammation including IFNy. IL-6, IL-8, IL- 10, and IL- 10. Meanwhile, there was a negative correlation with IL-22 and IL-4. There was further a correlation between spike antigen levels and GI symptoms. There was further an association between spike protein levels and levels of CRP, ferritin, and d-dimer.

[0025] In some embodiments, the subject has an elevated zonulin level. In embodiments, despite whether the subject exhibits any (overt) gastrointestinal symptoms, the subject may have an elevated zonulin level. In embodiments, the subject has a high serum zonulin level or a high fecal zonulin level. In embodiments, the subject’s zonulin range is at least 1.5 times a mean reference value for a healthy subject (e.g., with no inflammatory disease), or at least about 2-fold, or at least about 3 -fold, or at least about 4-fold, or at least about 5-fold higher than the mean reference value for a healthy subject. For example, the reference value may be determined for a Laboratory Developed Test (LDT) and / or using any of the commercial zonulin detection kits. For example, in embodiments, zonulin levels are determined by ELISA. In embodiments, the subject has a serum zonulin level of greater than about 100 ng / mL, or greater than about 150 ng / mL, or greater than about 200 ng / mL, or greater than about 250 ng / mL, and the subject may or may not have signs of gastrointestinal comorbidity. Upon the treatment according to this disclosure, zonulin levels can decline and be maintained at lower levels, and in embodiments, can decline and be maintained below about 150 ng / mL or below about 100 ng / mL.

[0026] In embodiments, the subject is vaccinated for SARS-CoV-2. Exemplary vaccines include COMIRNATY, SPIKEVAX, NOVAXOVOID, and COVOVAX. In embodiments, the larazotide treatment with vaccination reduces long Covid duration and / or symptoms. In other embodiments, the subject having long Covid is unvaccinated for SARS-CoV-2.

[0027] In some embodiments, the subject is further administered a non-steroidal antiinflammatory drug (NSAID) for Covid or long Covid symptoms. NSAIDs are a family of drugs that can be used to treat pain, fever, redness, and swelling by inhibiting the enzyme cyclooxygenase (COX), which prevents the body from producing prostaglandins, hormone- like chemicals that cause inflammation. Examples of NSAIDs can include, but are not limited to, aspirin, ibuprofen, naproxen, diclofenac, celecoxib, mefenamic acid, etoricoxib, and indomethacin.

[0028] Larazotide and its derivatives, among other things, promote tight junction integrity of epithelial and endothelial tissues, including of the intestinal epithelium. In accordance with certain embodiments, the present invention provides larazotide derivatives that confer, among other things, increased resistance to exopeptidase degradation, including aminopeptidase degradation. In embodiments, the larazotide derivative comprises one or more amino acid substitutions, deletions, and / or insertions with respect to the peptide having the amino acid sequence of SEQ ID NO: 1. Exemplary modifications are described in US 8,785,374, US 8,957,032, US 9,279,807, PCT / US2019 / 19350, and PCT / US21 / 27410 (all of which are hereby incorporated by reference). In embodiments, the peptide derivative of larazotide contains one or more (d) amino acids. For example, the larazotide derivative may contain 1, 2, 3, 4, or 5 (d) amino acids (that is, the D configuration as opposed to the L configuration). In embodiments, the larazotide derivative has the amino acid sequence of Gly-Gly-Val-Leu-Val-Gln-(d)Pro-Gly (SEQ ID NO: 2). This peptide is referred to herein as “(d)-Pro” or (d)-Pro larazotide. In other embodiments, the larazotide derivative has the amino acid sequence of Gly-Gly-(d)Val-(d)Leu-(d)Val-(d)Gln-(d)Pro-Gly (SEQ ID NO: 3). This peptide is referred to herein as “(d)-larazotide”.

[0029] In embodiments, the pharmaceutical compositions for administration comprise larazotide or a derivative (i.e., or pharmaceutically acceptable salt thereof) at about 1.0 mg or less, or at about 0.75 mg or less, or at about 0.5 mg or less. In some embodiments, the pharmaceutical composition contains about 0.4 mg of the larazotide derivative or less, or about 0.3 mg of the larazotide derivative or less, or about 0.25 mg of the larazotide derivative of less, or about 0.2 mg of the larazotide derivative or less, or about 0.15 mg of the larazotide derivative or less, or about 0.1 mg of the larazotide derivative or less. In some embodiments, the pharmaceutical composition contains from about 100 pg to about 500 pg of a larazotide derivative (e.g., d-larazotide), or from about 100 pg to about 400 pg of the larazotide derivative (e.g., d-larazotide). In embodiments, the present invention contemplates a pharmaceutical composition that contains more than about 0.5 mg of a larazotide derivative (e.g., d-larazotide), and substantially avoids the inverse dose or “bell shape” response observed with larazotide. For example, in some embodiments, the pharmaceutical composition contains about 0.6 mg of the larazotide derivative or more, or about 0.75 mg of the larazotide derivative or more, or about 1.0 mg of the larazotide derivative or more, or about 1.25 mg of the larazotide derivative or more, or about 1.5 mg of the larazotide derivative or more, or about 2.0 mg of the larazotide derivative or more. In some embodiments, the larazotide derivative (e.g., (d)-larazotide or (d)-Pro), is administered at about 0.5 mg or at about 0.25 mg. In embodiments, larazotide is administered in oral doses of about 0.5 mg or about 0.25 mg, which may be larazotide acetate.

[0030] The terms “subject” and “patient” are used interchangeably herein, and generally refer to mammalian subjects / patients. In various embodiments the subject is a human subject, but in embodiments may be a veterinary subject, such as a dog or horse. In some embodiments, the peptide or pharmaceutical composition is administered to the gastrointestinal tract (GI) of a subject. Pharmaceutical compositions can be formulated for release in affected portions of the GI (e.g., stomach, small intestine, and / or large intestine). Larazotide derivatives of the present invention may be administered in any suitable form, including as a salt. For example, peptides may be administered as an acetate salt. Alternative salts may be employed, including any pharmaceutically acceptable salt such as those listed in Journal of Pharmaceutical Science, 66, 2-19 (1977) and The Handbook of Pharmaceutical Salts; Properties, Selection, and Use. P. H. Stahl and C. G. Wermuth (eds.), Verlag, Zurich (Switzerland) 2002, which are hereby incorporated by reference in their entirety.

[0031] In embodiments, the compositions are administered to a subject by contacting the epithelial tissues or mucosal surfaces of the gastrointestinal tract. For example, the compositions may be formulated for delivery to one or more of the stomach, small intestine, and / and large intestine. Release of the peptide from the composition can be designed for affected region(s) (e.g. duodenumjejunum and ileum, colon transversum, colon descendens, colon ascendens, colon sigmoidenum and cecum). Targeted delivery of the peptide in the small or large intestine can be achieved by coating beads or particles with the peptide, along with a delayed-release coating that prevents release in the stomach and degrades at or near the targeted location(s). In some embodiments, the larazotide or larazotide derivative is administered in a sustained release or controlled release formulation that releases from about 0.25 to about 5 mg of larazotide or derivative in the intestine (or a dose as already described). In certain embodiments, the controlled release formulation contains at least 0.25, 0.5, or 1 mg of larazotide or derivative. In some embodiments, the peptide (e.g., larazotide or larazotide derivative) is formulated for sustained or modified or controlled delivery in one or more locations of the GI. For example, this disclosure contemplates a sustained or controlled release formulation that may functionally release the peptide in the small and / or large intestine over the course of at least about 2 hours, or over the course of at least about 2.5 hours, or over the course of at least about 3 hours, or over the course of at least about 4 hours, or over the course of at least about 5 hours. In some embodiments, the sustained or controlled release composition begins to release peptide starting within about 10 to about 30 minutes of exposure to simulated intestinal fluid, with release of peptide continuing for at least about 180 minutes, or at least about 210 minutes, or at least about 240 minutes, or at least about 280 minutes of exposure to simulated intestinal fluid. Release profiles can be prepared, for example, using compositions with different enteric polymer coats and / or different thicknesses of the polymer coats.

[0032] In some embodiments, the disclosure provides a composition comprising an effective amount of larazotide or derivative (or salt thereof), contained within a biodegradable or erodible polymer matrix, which further comprises an enteric coating. Formulations employing a biodegradable or erodible matrix are described in WO 2021 / 034629, which is hereby incorporated by reference in its entirety. Further, the erodible polymer matrix can comprise a polysaccharide matrix. In some embodiments, the matrix comprises one or more of cellulose, chitin, chitosan, alginate, amylose, pectin, callose, laminarin, chrysolaminarin, xylan, arabinoxylan, mannan, fucoidan, galactomannan, xanthan gum, dextran, welan gum, gellan gum, diutan gum, pullulan, hyaluronic acid, and derivatives thereof. In further embodiments, the matrix comprises microcrystalline cellulose. In these embodiments, the composition leverages the low effective dose of larazotide or a larazotide derivative (e.g., (d)-larazotide or (d)-Pro), while also minimizing any local accumulation of inactive fragments. Further, the formulation in these embodiments has the benefit of treating large surfaces of the GI with small doses of the peptide deposited continually during transit. In various embodiments, the pharmaceutical composition may be formulated to have a delayed- release profile, i.e. not immediately release the active ingredient(s) upon ingestion; rather, postponement of the release of the active ingredient(s) until the peptide passes the stomach and is lower in the gastrointestinal tract; for example, for release in the small intestine (e.g., one or more of duodenumjejunum, ileum) or the large intestine (e.g., one or more of cecum, ascending, transverse, descending or sigmoid portions of the colon).

[0033] In embodiments, the pharmaceutical composition is formulated to have a delayed- release profile as described in, for example, U.S. Patent No. 8,168,594, the entire contents of which are hereby incorporated by reference. For example, the peptide may be administered to at least the duodenum of the patient, as an oral dosage, delayed-release composition that contains the peptide. In such embodiments, the composition comprises a first population of beads having a coating that is stable in gastric fluid (i.e., gastro-resistant coating) and unstable in intestinal fluid so as to degrade and substantially release the peptide in the duodenum. In embodiments, the gastro-resistant coating begins to release the larazotide or derivative within about 5 to about 60 minutes, or within about 5 minutes to about 30 minutes, of exposure to simulated intestinal fluid. The composition may further comprise a second population of beads with a pH-dependent coating to affect release of the peptide in the jejunum and / or ileum of the patient. For example, the second population of beads may release the peptide about 30 minutes or about 45 minutes after the beads releasing peptide in the duodenum. The oral dosage composition can be in the form of a capsule or tablet. The pH-dependent coating in some embodiments is a 1 : 1 co-polymer of methacrylic acid and ethyl acrylate, wherein the thickness of the layer determines the release profile of each bead. The beads may have one or more additional coatings such as a base coat, a separating layer, and an overcoat layer.

[0034] In an exemplary oral dosage composition, an effective amount of the peptide (e.g., as the acetate salt) is provided in first delayed-release particles that are capable of releasing the peptide in the duodenum of a patient, and second delayed release particles that are capable of releasing the peptide in the jejunum of a patient. Each particle has a core particle, a coat comprising the peptide over the core particle, and a delayed-release coating (e.g., a 1: 1 co-polymer of acrylate and methacrylate) outside the coat comprising the peptide. Whereas the first delayed-release particles release at least 70% of the peptide in the first delayed-release particles by about 60 minutes of exposure to simulated intestinal fluid having a pH of greater than 5; the second delayed-release particles release at least 70% of the peptide by about 30 and about 90 minutes of exposure to simulated intestinal fluid having a pH of greater than 5.

[0035] In some embodiments, the pharmaceutical composition involves a coated tablet, or coated beads or granules, having a delayed-release profile as described in, for example, U.S. Patent No. 8,168,594, the entire contents of which are hereby incorporated by reference. An exemplary enteric coating comprises a co-polymer of acrylate and methacrylate, which is a 1 : 1 co-polymer in some embodiments. Other fillers, binder, and plasticizers, including for seal coats or topcoats, are described in US 8,168,594, which is hereby incorporated by reference. In embodiments, the delayed-release coating may degrade as a function of time without regard to the pH and / or presence of enzymes. Such a coating may comprise, for example, a water insoluble polymer. Its solubility is therefore independent of the pH. The term “pH independent” as used herein means that the permeability of the polymer and its ability to release pharmaceutical ingredients is not a function of pH and / or is only very slightly dependent on pH. Such coatings may be used to prepare, for example, sustained release formulations. Suitable water insoluble polymers include, but are not limited to, cellulose ethers, cellulose esters, or cellulose ether-esters, i.e., a cellulose derivative in which some of the hydroxy groups on the cellulose skeleton are substituted with alkyl groups and some are modified with alkanoyl groups. Examples include ethyl cellulose, acetyl cellulose, nitrocellulose, and the like.

[0036] Polymers for constructing delayed release coatings include, but are not limited to, lacquer, and acrylic and / or methacrylic ester polymers, polymers or copolymers of acrylate or methacrylate having a low quaternary ammonium content, or mixture thereof and the like. Examples of insoluble polymers include EUDRAGIT RS®, EUDRAGIT RL®, and EUDRAGIT NE®. Insoluble polymers include, for example, polyvinyl esters, polyvinyl acetals, polyacrylic acid esters, butadiene styrene copolymers, and the like. Various types of enteric coatings for delayed yet substantial delivery of active agents to the GI tract are known.

[0037] In some embodiments, the sustained-release composition includes an enteric agent that is substantially stable in acidic environments and substantially unstable in near neutral to alkaline environments. In embodiments, the sustained-release coating contains an enteric agent that is substantially stable in gastric fluid. The enteric agent can be selected from, for example, solutions or dispersions of methacrylic acid copolymers, cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate, polyvinyl acetate phthalate, carboxymethylethylcellulose, and EUDRAGIT®-type polymer (poly(methacrylic acid, methylmethacrylate), hydroxypropyl methylcellulose acetate succinate, cellulose acetate trimellitate, shellac or other suitable enteric coating polymers. The EUDRAGIT®- type polymer include, for example, EUDRAGIT® FS 30D, L 30 D-55, L 100-55, L 100, L 12,5, L 12,5 P, RL 30 D, RL PO, RL 100, RL 12,5, RS 30 D, RS PO, RS 100, RS 12,5, NE 30 D, NE 40 D, NM 30 D, S 100, S 12,5, and S 12,5 P In some embodiments, one or more of EUDRAGIT® FS 30D, L 30 D-55, L 100-55, L 100, L 12,5, L 12,5 P RL 30 D, RL PO, RL 100, RL 12,5, RS 30 D, RS PO, RS 100, RS 12,5, NE 30 D, NE 40 D, NM 30 D, S 100, S 12,5 and S 12,5 P is used. The enteric agent may be a combination of the foregoing solutions or dispersions. In some embodiments, the enteric agent is EUDRAGIT F30D, which comprises a co-polymer of methyl acrylate, methyl methacrylate, and methacrylic acid. The co-polymer has a ratio of free carbonyl groups to ester groups of about 1 : 10.

[0038] In some embodiments, the beads comprise an enteric coating that is substantially resistant to dissolution in simulated gastric fluid. The composition remains essentially intact, or may be essentially insoluble, in gastric fluid. The stability of a gastric-resistant coating can be pH dependent. For example, the enteric coating may prevent substantial release of the peptide in simulated gastric fluid as well as simulated intestinal fluid having a pH of about 5.5. In some embodiments, the matrix provides for the sustained release of the peptide in simulated intestinal fluid having a pH of about 6 or more, such as from about 6.5 to about 7.0. Thus, the enteric coating is stable in simulated gastric fluid but unstable in simulated intestinal fluid having a pH above about 6.0. The enteric coating in such embodiments does not substantially release peptide in the duodenum, but delays release until the composition enters the jejunum, and thereafter providing a sustained release in the jejunum and ileum.

[0039] In some embodiments, the composition is a capsule for oral delivery comprising a population of beads, the population of beads comprising an effective amount of the larazotide or derivative (e.g., (d)-larazotide or (d)-Pro or salt thereof) contained within an erodible polymer matrix, the beads further comprising an enteric coating, which may comprise a co-polymer of methyl acrylate, methyl methacrylate, and methacrylic acid. The ratio of free carbonyl groups to ester groups in the co-polymer may be about 1 : 10 (e g., EUDRAGIT F30D). In such embodiments, the enteric coating may be from about 20% to about 30% of the total weight of the composition. In some embodiments, the erodible matrix comprises microcrystalline cellulose. In some embodiments, the composition provides for less than about 15% release of peptide after about 2 hours in simulated gastric fluid. Further, the composition provides for less than about 25% release of peptide after about 2 hours in simulated intestinal fluid having a pH of about 5.5. In various embodiments, the composition releases at least about 40% but no more than about 80% of peptide after about 2 hours in simulated intestinal fluid having a pH of about 7.0. In various embodiments, 100% release in simulated intestinal fluid having a pH of about 7 is not reached until at least three hours, or in some embodiments, at least about 3.5 or at least about four hours.

[0040] In embodiments, the present disclosure provides for the composition described herein to be administered one or more times daily. In embodiments, the oral dosage form is administered more than once daily, and may be administered at least two times daily or at least three times daily, or at least four times daily, or at least five times daily. In embodiments, the oral dosage form is administered three times daily. In embodiments, the oral dosage form is administered four times daily.

[0041] In embodiments, the present disclosure provides for the composition described herein to be administered one or more times daily for a period of at least about 2 weeks, or at least about 3 weeks, or at least about 4 weeks.

[0042] In embodiments, about 0.25 mg or about 0.5 mg of the composition described herein is administered to a subject at least four times per day for a period of at least about 2 weeks, or at least about 3 weeks, or at least about 4 weeks. As used herein, and unless the context required otherwise, the term “about” or

[0043] “approximately” mean a range of ±10% of an associated value.

[0044] All publications, patents, patent applications, and / or other documents cited in this application are incorporated by reference in their entirety.

Claims

CLAIMSWhat is claimed is:

1. A method for treating a human subject having long Covid or at risk of long Covid, comprising: administering an oral dosage form of larazotide or a derivative thereof to said subject at an effective amount and schedule to treat long Covid.

2. The method of claim 1, wherein the subject has long Covid.

3. The method of claim 2, wherein the subject has long Covid for at least one month, at least two months, or at least six months at the initiation of treatment.

4. The method of claim 2 or 3, wherein the subject is at least 50 years of age, or at least 60 years of age, or at least 70 years of age.

5. The method of any one of claims 2 to 4, wherein the subject is overweight or obese.

6. The method of any one of claims 2 to 5, wherein the subject is immune compromised.

7. The method of any one of claims 2 to 6, wherein the subject’s long Covid symptoms include gastrointestinal symptoms, which optionally include one or more of nausea, vomiting, abdominal pain, diarrhea, constipation, colitis, and dysbiosis.

8. The method of any one of claims 2 to 6, wherein the subject’s long Covid symptoms do not include gastrointestinal symptoms.

9. The method of any one of claims 2 to 8, wherein the subject’s long Covid symptoms include one or more of: fatigue, muscle weakness, and / or myalgia; arthralgia; dyspnea, cough, and / or pulmonary dysfunction; palpitations; headache and / or dizziness; taste and / or smell disorder and / or sore throat; rash; and herpes virus or Epstein-Barr virus (EBV) reactivation.

10. The method of any one of claim 2 to 9, wherein the subject had gastrointestinal symptoms during the acute phase of Covid, optionally including one or more of nausea, vomiting, abdominal pain, diarrhea, constipation, colitis, and dysbiosis.

11. The method of any one of claims 2 to 9, wherein the subject’s Covid symptoms did not include gastrointestinal symptoms during the acute phase.

12. The method of any one of claims 2 to 11, wherein the subject had MTS-C or MIS-A during the acute phase.

13. The method of any one of claims 2 to 12, wherein the subject had acute respiratory distress syndrome (ARDS) during the acute SARS-CoV-2 infection, and optionally required ventilation.

14. The method of any one of claims 2 to 13, wherein the subject had one or more neurological symptoms during the acute phase, optionally selected from headache and / or dizziness; fatigue, and taste and / or smell disorder.

15. The method of any one of claims 2 to 14, wherein the subject had a co-morbidity before Covid infection selected from Inflammatory Bowel Syndrome (IBS), Inflammatory Bowel Disease (IBD), arthritic disease, Type 2 diabetes mellitus, celiac disease, psoriasis, systemic lupus erythematosus (SLE), and dysbiosis.

16. The method of any one of claims 2 to 15, wherein the subject has detectable SARS- CoV-2 virus in stool or urine.

17. The method of any one of claims 2 to 16, wherein the subject has detectable SARS- CoV-2 spike protein in the blood, optionally serum or plasma.

18. The method of any one of claims 2 to 17, wherein the subject has an elevated zonulin level.

19. The method of any one of claims 2 to 18, wherein the subject received Paxlovid during the acute phase, and / or receives a second round of Paxlovid with treatment of larazotide or derivative.

20. The method of any one of claims 2 to 19, wherein the subject is unvaccinated for SARS-CoV-2.

21. The method of any one of claims 2 to 19, wherein the subj ect is vaccinated for SARS- CoV-2.

22. The method of any one of claims 2 to 21, wherein the subject is further administered a non-steroidal anti-inflammatory drug (NS AID) for long Covid symptoms.

23. The method of claim 1, wherein the subject is at risk of long Covid.

24. The method of claim 23, wherein the subject is in acute phase of Covid.

25. The method of claim 23 or 24, wherein the subject is at least 50 years of age, or at least 60 years of age, or at least 70 years of age.

26. The method of any one of claims 23 to 25, wherein the subject is overweight or obese.

27. The method of any one of claims 23 to 26, wherein the subject is immune compromised.

28. The method of any one of claim 24 to 27, wherein the subject has gastrointestinal symptoms, optionally including one or more of nausea, vomiting, abdominal pain, diarrhea, constipation, colitis, and dysbiosis.

29. The method of any one of claims 24 to 27, wherein the subject is not experiencing gastrointestinal symptoms during the acute phase.

30. The method of any one of claims 24 to 29, wherein the subject has MIS-C or MIS- A.

31. The method of any one of claims 24 to 30, wherein the subject has acute respiratory distress syndrome (ARDS), and optionally requires ventilation.

32. The method of any one of claims 24 to 31, wherein the subject has one or more neurological symptoms, optionally selected from headache and / or dizziness; fatigue, and taste and / or smell disorder.

33. The method of any one of claims 24 to 32, wherein the subject has a co-morbidity before Covid infection selected from Inflammatory Bowel Syndrome (IBS), Inflammatory Bowel Disease (IBD), arthritic disease, type 2 diabetes mellitus, celiac disease, psoriasis, SLE, and dysbiosis.

34. The method of any one of claims 24 to 33, wherein the subject has detectable SARS- CoV-2 virus in stool or urine.

35. The method of any one of claims 24 to 34, wherein the subject has detectable SARS- CoV-2 spike protein in the blood, optionally serum or plasma.

36. The method of any one of claims 24 to 34, wherein the subject has an elevated zonulin level.

37. The method of any one of claims 24 to 36, wherein the subject further receives Paxlovid therapy.

38. The method of any one of claims 24 to 37, wherein the subject is unvaccinated for SARS-CoV-2.

39. The method of any one of claims 24 to 37, wherein the subject is vaccinated for SARS-CoV-2.

40. The method of any one of claims 24 to 39, wherein the subject is administered a nonsteroidal anti-inflammatory drug (NSAID) for Covid symptoms.

41. The method of any one of claims 23 to 40, wherein the treatment with larazotide or derivative is initiated within two days of Covid diagnosis, or within 5 days of Covid diagnosis, or within one week of Covid diagnosis.

42. The method of any one of claims 23 to 40, wherein the treatment with larazotide or derivative is initiated within two days of a first negative Covid test after SARS-CoV-2 infection, or within the first two symptom-free days.

43. The method of any one of claims 1 to 42, wherein the oral dosage form comprises larazotide or a pharmaceutically acceptable salt thereof, which is optionally larazotide acetate.

44. The method of claim 43, wherein the oral dosage form comprises less than about 1 mg of larazotide or salt thereof.

45. The method of claim 44, wherein the oral dosage form comprises less than about 0.75 mg of larazotide or salt thereof, or less than about 0.5 mg of larazotide or salt thereof, or less than about 0.25 mg of larazotide or salt thereof.

46. The method of claim 44, wherein the oral dosage form comprises about 0.5 mg of larazotide of salt thereof, and which is optionally larazotide acetate.

47. The method of claim 44, wherein the oral dosage form comprises about 0.25 mg of larazotide of salt thereof, and which is optionally larazotide acetate.

148. The method of any one of claims 1 to 42, wherein the oral dosage form comprises a larazotide derivative having one or more d-amino acids, and optionally where all amino acids other than glycine are in d-form.

49. The method of claim 48, wherein the oral dosage form comprises at least about 1 mg of the larazotide derivative, or at least about 1.5 mg of the larazotide derivative.

50. The method of claim 48, wherein the oral dosage form comprises about 1 mg of the larazotide derivative or less, or about 0.5 mg of the larazotide derivative or less, or about 0.25 mg of the larazotide derivative or less.

51. The method of claim 48, wherein the oral dosage form comprises about 0.5 mg of the larazotide derivative.

52. The method of any one of claims 1 to 51, wherein the oral dosage form delivers the larazotide or derivative to the small intestine.

53. The method of claim 52, wherein the oral dosage form delivers the larazotide or derivative to one or more of the duodenum, jejunum and ileum.

54. The method of claim 53, wherein the oral dosage form delivers the larazotide or derivative to at least the jejunum and ileum.

55. The method of any one of claims 1 to 54, wherein the oral dosage form comprises beads having a gastro-resistant coating.

56. The method of claim 55, wherein the oral dosage form comprises beads having at least two different types or amounts of gastro-resistant coating to release the larazotide or derivative at different times.

57. The method of claim 56, wherein the gastro-resistant coatings begins to release the larazotide or derivative within about 5 to about 60 minutes, or within about 5 minutes to about 30 minutes, of exposure to simulated intestinal fluid.

58. The method of any one of claims 52 to 57, wherein the oral dosage form comprises a biodegradable matrix providing a sustained release of the larazotide or derivative in the small intestine.

59. The method of any one of claims 52 to 58, wherein the oral dosage form releases larazotide or derivative over at least 90 minutes in simulated intestinal fluid, or over at least 120 minutes in simulated intestinal fluid, or over at least 210 minutes in simulated intestinal fluid.

60. The method of any one of claims 1 to 59, wherein the oral dosage form is administered more than once daily, and is optionally administered at least 2 times daily or at least 3 times daily, or at least four times daily, or at least five times daily.

61. The method of claim 60, wherein the oral dosage form is administered three times daily.

62. The method of claim 60, wherein the oral dosage form is administered four times daily.

63. The method of any one of claims 60 to 62, wherein the oral dosage form is administered for a period of at least about 2 weeks, or at least about 3 weeks, or at least about 4 weeks.