Novel compositions for treatment of long covid and similar infection-associated chronic conditions

Abstract

The present invention provides for use of fenretinide, fenretinide analog or pharmaceutically acceptable salts for the preparation of medicaments useful for the treatment of Long COVID and similar infection-associated chronic diseases as well as for the treating or amelioration of symptoms associated with Long COVID and infection-associated chronic diseases.

Description

[0001] NOVEL COMPOSITIONS FOR TREATMENT OF LONG COVID AND SIMILAR INFECTION-ASSOCIATED CHRONIC CONDITIONS

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to compositions and methods of use of fenretinide (4- hydroxyphenyl retinamide) and its associated analogs and formulations for the treatment of Long COVID and other similar infection-associated chronic conditions.

[0004] BACKGROUND OF THE INVENTION

[0005] Coronavirus disease 2019 (COVID- 19) is a contagious infectious disease caused by the coronavirus SARS-CoV-2. Individuals with COVID-19 can experience ongoing symptoms after the initial acute infection, which may endure for over four weeks, relapse, or progress, leading to clinical manifestations that are observed beyond twelve weeks, and can persist for months or years, leading to functional impairments in conducting daily activities, and overall impact on quality of life. This lingering disease state is known as Long COVID (also referred to in the art as “post-COVID syndrome”, “post-acute COVID syndrome”, “post-acute sequelae of COVID-19”) and emerges as a distinct, multisystemic, infection-associated chronic condition that follows a severe, mild or even asymptomatic severe COVID-19 infection, with a negative impact on one or more organ systems (Davis et al, Nature Reviews Microbiology volume 21, pages133-146 (2023), https: / / doi.org / 10.1038 / s41579-022-00846-2; NASEM 2024-A Long COVID Definition- A Chronic, Systemic Disease State with Profound Consequences; NASEM 2024-Long-Term Health Effects of COVID-19- Disability and Function Following SARS-CoV-2 Infection, (2024)). Long COVID is a significant public health issue affecting millions of people worldwide and having profound medical, social, and economic consequences. Long COVID prevalence estimates vary widely, with some estimates of the percentage of those infected with COVID-19 who develop Long COVID ranging from 10 to 35 percent or higher (Davis et al, Nature Reviews Microbiology volume 21, pages133-146 (2023), https: / / doi.org / 10.1038 / s41579-022-00846-2).

[0006] While Long COVID is a well recognized clinical entity, it is still an emerging disease and knowledge of its pathophysiology is evolving. Emerging evidence suggests that Long COVID is not solely an extension of the acute COVID-19 infection, but a unique medical condition with distinct mechanisms. There are likely multiple, potentially overlapping, causes of Long COVID, potentially including lingering residual reservoirs of virus in the body, or a dysregulated immune-inflammatory response damaging small blood vessels or nerves which can impact one or more organ systems in the body. Genetic susceptibility, the host immune response, and viral factors likely dictate the severity and duration of Long COVID. (Tziolos, et al., Microorganisms. Oct; 11(10): 2458 (2023), https: / / doi.org / 10.3390 / microorganismsl 1102458) Two of the organ systems affected most frequently are the brain (brain fog, cognitive problems, depression, anxiety) and lungs (shortness of breath, fibrotic sequels) (Cai, et al, Nature Medicine volume 30, pagesl 564-1573 (2024)).

[0007] No common definition for Long COVID has yet been agreed upon worldwide. However, in June 2024, a broadly inclusive working definition of Long COVID was issued by the US National Academies of Sciences, Engineering, and Medicine (NASEM), according to which Long COVID is an infection-associated chronic condition (I ACC) that occurs after SARS- CoV-2 infection and is present for at least three (3) months as a continuous, relapsing and remitting, or progressive disease state that affects one or more organ systems. Long COVID manifests in multiple ways, any organ system can be involved, and Long COVID patients can present with single or multiple symptoms, such as shortness of breath, cough, persistent fatigue, post-exertional malaise, difficulty concentrating, memory changes, recurring headache, light-headedness, fast heart rate, sleep disturbance, problems with taste or smell, bloating, constipation, and diarrhea. Long COVID patients can present with single or multiple diagnosable conditions, such as interstitial lung disease and hypoxemia, cardiovascular disease and arrhythmias, cognitive impairment, mood disorders, anxiety, migraine, stroke, blood clots, chronic kidney disease, postural orthostatic tachycardia syndrome (POTS) and other forms of dysautonomia, myalgic encephalomyelitis / chronic fatigue syndrome (ME / CFS), mast cell activation syndrome (MCAS), fibromyalgia, connective tissue diseases, hyperlipidemia, diabetes, and autoimmune disorders such as lupus, rheumatoid arthritis, and Sjogren’s syndrome. Long COVID can follow asymptomatic, mild, or severe COVID-19 infection (NASEM 2024-A Long COVID Definition- A Chronic, Systemic Disease State with Profound Consequences).

[0008] Although the definition specifies a minimum duration of three (3) months to qualify as Long COVID, a clinician could recognize, acknowledge, and monitor concerning symptoms before the three-months mark. Previous COVID-19 infections may have been recognized or unrecognized. Long COVID can be continuous from the time of acute SARS-CoV-2 infection or can be delayed in onset for weeks or months following what had appeared to be full recovery from acute infection. Long COVID can affect children and adults, regardless of health, disability, or socioeconomic status, age, sex, gender, sexual orientation, race, ethnicity, or geographic location. Long COVID can exacerbate pre-existing health conditions or present as new conditions. Long COVID can range from mild to severe. It can resolve over a period of months or can persist for months or years. Long COVID can be diagnosed on clinical grounds. No biomarker is currently available that demonstrates conclusively the presence of Long COVID (NASEM 2024-A Long COVID Definition- A Chronic, Systemic Disease State with Profound Consequences).

[0009] An important feature of Long COVID is the functional impairment, ranging from mild to severe, daily activity limitations, and quality of life impacts. Long COVID can impair individuals’ ability to work, attend school, take care of family, and care for themselves. This can have a profound emotional and physical impact on patients and their families and caregivers (NASEM 2024-A Long COVID Definition- A Chronic, Systemic Disease State with Profound Consequences).

[0010] Long COVID shares many features with other complex multisystem infection-associated chronic conditions. The term “infection-associated chronic condition” applies to a variety of chronic conditions that can be triggered by viruses, bacteria, fungi, or parasites. Use of this term highlights the ongoing nature of the medical condition and its association with a triggering infection without conveying any unwarranted conclusions about pathobiological mechanisms. (NASEM 2024-A Long COVID Definition- A Chronic, Systemic Disease State with Profound Consequences). Post-viral syndrome (also known in the art as post-viral fatigue syndrome) is an example of such infection-associated chronic condition that shares similarities with Long COVID and can be triggered by almost any viral infection, including common cold, flu, herpes virus, HIV, West Nile virus, COVID-19, etc. (What to know about post-viral syndrome [online], [retrieved August 82024], retrieved from the lnternet:<URL: https: / / www.medicalnewstoday.eom / articles / 326619#what-is-it; Glick, R. An Overview of Post-viral Syndrome [online], [retrieved August 92024], retrieved from the lnternet:<URL https: / / sma.org / post-viral-syndrome / >; Gandhi et al, Lancet, https: / / doi.org / 10.1016 / S1473- 3099(23)00762-4 (2024)). Furthermore, there is an increasing recognition of chronic diseases associated with prior infectious disease, such as myalgic encephalomyelitis / chronic fatigue syndrome (ME / CFS), fibromyalgia, persistent Lyme disease (aka post-Lyme disease), and multiple sclerosis occurring with Epstein-Barr virus (EBV). Al these infection-associated chronic conditions described above may be associated with, or triggered by COVID-19, and can present as diagnosable conditions in the context of Long COVID, or as a single condition that shares similarities to Long COVID, in terms of symptomatology and functional impairment. (Infection-Associated Chronic Illnesses: Data Drive solutions for diagnosis [online], [retrieved August 82024], retrieved from the Internet: <URL: https: / / healthdata.goV / stories / s / lnfection-Associated-Chronic-lllnesses-2023- / giix-q93k / >; NASEM 2024-Long-Term Health Effects of COVID-19- Disability and Function Following SARS-CoV-2 Infection, 2024; What to know about post-viral syndrome [online], [retrieved August 82024], Retrieved from the Internet: <URL: https: / / www.medicalnewstoday.eom / articles / 326619#symptoms>) The links between infection and lasting symptoms are poorly understood yet serious, potentially triggering longterm problems in many body systems, similar to Long COVID. Patients experiencing these diseases sometimes face barriers in seeking diagnoses, treatment, and care.

[0011] At the present time there are no specific, approved therapies for Long COVID, and patients rely mostly on symptomatic relief. While some diagnosable conditions that fall within the definition of Long COVID, such as diabetes, hypertension, POTS, and Sjogren’s syndrome; are treatable within existing evidence-based guidelines, other manifestations of Long COVID have no approved treatment. At this time, no biomarker exists to clearly ascribe symptoms and diagnosable conditions to Long COVID rather than to other causes. Management for single or multiple symptoms are usually holistic and use a multidisciplinary, patient-centered approach (NASEM 2024-A Long COVID Definition- A Chronic, Systemic Disease State with Profound Consequences).

[0012] Fenretinide is a small molecule synthetic retinoid derivative, with well-documented history of safety in non-clinical and clinical studies. Initially explored for prevention and treatment of cancer, fenretinide was also studied for non-oncological indications such as age-related macular degeneration, cystic fibrosis and COVID-19.

[0013] PCT Patent Application WO 2021 / 189153 discloses fenretinide for the prevention and / or treatment of SARS-coronavirus infection and its associated consequences. However, the use of fenretinide in the context of this disclosure is intended essentially to prevent and / or treat an acute COVID-19 infection and its infection-associated acute conditions related to inflammation of the lung, such as pneumonia and acute respiratory distress syndrome (ARDS). While the use of fenretinide for COVID-19 infection and its associated acute pulmonary conditions (pneumonia and ARDS) has been disclosed to date, fenretinide’s use in treating multisystem infection-associated chronic conditions, such as Long COVID and other similar chronic conditions, has not been disclosed in the art.

[0014] SUMMARY OF THE INVENTION

[0015] In one aspect, the present invention provides for a method of treating Long COVID in a patient in need thereof comprising, consisting essentially of, or consisting of administering to said patient of a therapeutically effective amount of fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof. In one embodiment, Long COVID comprises one or more conditions selected from functional impairment in performing daily activities, fatigue, post-exertional malaise, trouble sleeping, shortness of breath, general pain and discomfort, cognitive problems (memory loss, difficulty thinking or concentrating), mental health symptoms (anxiety, depression), fibromyalgia, and myalgic encephalomyelitis / chronic fatigue syndrome (ME / CFS). In another embodiment, the therapeutically effective amount of fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof comprises 1 mg to 1000 mg of fenretinide. In a further embodiment, the therapeutically effective amount of fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof comprises 10 mg to 300 mg of fenretinide. In an alternative embodiment the therapeutically effective amount of fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof gives rise to a plasma concentration in said human of 0.5 pM to about 5 pM of fenretinide. In a further embodiment the therapeutically effective amount of fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof gives rise to a plasma concentration in said human of 1 pM to about 3 pM of fenretinide. In an alternative embodiment the fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administered orally, once daily, for 14 days or more. In an alternative embodiment the fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administered orally, once daily, for at least three months. In an alternative embodiment the fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is in amount of 200mg administrated orally as LAU-7b, once per day for fourteen (14) days. In an alternative embodiment the fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administrated orally as LAU-7b, in three (3) or more consecutive treatment cycles, each cycle consisting of 200 mg of fenretinide administrated as LAU-7b once per day for fourteen (14) days, followed by a drug-free interval of fourteen (14) days. In an alternative embodiment the fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administered to patient with at least one other active agent. In a further embodiment the at least one other active agent comprises an NSAID (non-steroidal anti-inflammatory drug), a corticosteroid, a COX-2 (cyclooxvgenase-2) inhibitor, an antidepressant, or a combination of two or more thereof.

[0016] In another aspect, the present invention provides for a pharmaceutical composition comprising a therapeutically effective amount of fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof for treating Long COVID in a human. In one embodiment the Long COVID comprise one or more conditions selected from functional impairment in performing daily activities, fatigue, post-exertional malaise, trouble sleeping, shortness of breath, general pain and discomfort, cognitive problems (memory loss, difficulty thinking or concentrating), mental health symptoms (anxiety, depression), fibromyalgia, and myalgic encephalomyelitis / chronic fatigue syndrome (ME / CFS). In another embodiment fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof comprises 1 mg to 1000 mg of fenretinide. In a further embodiment the fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof comprises 10 mg to 300 mg of fenretinide. In an alternative embodiment the fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof results in a plasma concentration of a human of 0.5 pM to 5 pM of fenretinide. In a further embodiment the fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof results in a plasma concentration of a human of 1 pM to 3 pM of fenretinide. In another embodiment the fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administered orally, once daily, for 14 days or more. In another embodiment the fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administered orally, once daily, for at least three months. In another embodiment the fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is in amount of 200mg administrated orally as LAU-7b, once per day for fourteen (14) days. In another embodiment the fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administrated orally as LAU-7b, in three (3) or more consecutive treatment cycles, each cycle consisting of 200 mg of fenretinide administrated as LAU-7b once per day for fourteen (14) days, followed by a drug-free interval of fourteen (14) days. In another embodiment the fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administered to patient with at least one other active agent. In a further embodiment the at least one other active agent comprises an NSAID (non-steroidal anti-inflammatory drug), a corticosteroid, a COX-2 (cyclooxvgenase-2) inhibitor, an antidepressant, or a combination of two or more thereof.

[0017] In another aspect, the present invention provides for a method of treating an infection- associated chronic condition in a human comprising, consisting essentially of, or consisting of administering to said human of a therapeutically effective amount of fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof. In one embodiment the therapeutically effective amount of fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof comprises 1 mg to 1000 mg of fenretinide. In a further embodiment the therapeutically effective amount of fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof comprises 10 mg to 300 mg of fenretinide. In an alternative embodiment the therapeutically effective amount of fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof gives rise to a plasma concentration in said human of 0.5 pM to about 5 pM of fenretinide. In a further embodiment the therapeutically effective amount of fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof gives rise to a plasma concentration in said human of 1 pM to about 3 pM of fenretinide. In another embodiment the fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administered orally, once daily, for 14 days or more. In another embodiment the fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administered orally, once daily, for at least three months. In another embodiment the fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is in amount of 200mg administrated orally as LAU-7b, once per day for fourteen (14) days. In another embodiment the fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administrated orally as LAU-7b, in three (3) or more consecutive treatment cycles, each cycle consisting of 200 mg of fenretinide administrated as l_AU-7b once per day for fourteen (14) days, followed by a drug-free interval of fourteen (14) days. In another embodiment the fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administered to patient with at least one other active agent. In a further embodiment the at least one other active agent comprises an NSAID (non-steroidal antiinflammatory drug), a corticosteroid, a COX-2 (cyclooxvgenase-2) inhibitor, an antidepressant, or a combination of two or more thereof. In an alternative embodiment, the infection-associated chronic condition is post-viral syndrome, myalgic encephalomyelitis / chronic fatigue syndrome (ME / CFS), fibromyalgia, persistent Lyme disease (aka post-Lyme disease), or multiple sclerosis occurring with Epstein-Barr virus (EBV).

[0018] In another aspect, the present invention provides for a pharmaceutical composition comprising a therapeutically effective amount of fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof for treating an infection-associated chronic condition in a human. In one embodiment the fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof comprises 1 mg to 1000 mg of fenretinide. In a further embodiment the fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof comprises 10 mg to 300 mg of fenretinide. In an alternative embodiment the fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof results in a plasma concentration of fenretinide in a human of 0.5 pM to 5 pM. In a further embodiment the fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof results in a plasma concentration of fenretinide in a human of 1 pM to 3 pM. In another embodiment the fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administered orally, once daily, for 14 days or more. In another embodiment the fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administered orally, once daily, for at least three months. In another embodiment the fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is in amount of 200mg administrated orally as LAU-7b, once per day for fourteen (14) days. In another embodiment the fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administrated orally as LAU-7b, in three (3) or more consecutive treatment cycles, each cycle consisting of 200 mg of fenretinide administrated as LAU-7b once per day for fourteen (14) days, followed by a drug-free interval of fourteen (14) days. In another embodiment the fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administered to patient with at least one other active agent. In a further embodiment the at least one other active agent comprises an NSAID (non-steroidal antiinflammatory drug), a corticosteroid, a COX-2 (cyclooxvgenase-2) inhibitor, an antidepressant, or a combination of two or more thereof. In an alternative embodiment, the infection-associated chronic condition is post-viral syndrome, myalgic encephalomyelitis / chronic fatigue syndrome (ME / CFS), fibromyalgia, persistent Lyme disease (aka post-Lyme disease), or multiple sclerosis occurring with Epstein-Barr virus (EBV).

[0019] In another aspect, the present invention provides a method of treating or attenuating functional impairment in performing daily activities in a patient with Long COVID, comprising, consisting essentially of, or consisting of administering to said human of a therapeutically effective amount of fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof. In one embodiment the therapeutically effective amount of fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof comprises 1 mg to 1000 mg of fenretinide. In a further embodiment the therapeutically effective amount of fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof comprises 10 mg to 300 mg of fenretinide. In an alternative embodiment the therapeutically effective amount of fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof gives rise to a plasma concentration of fenretinide in said human of 0.5 pM to about 5 pM. In another embodiment the fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administered orally, once daily, for 14 days or more. In another embodiment the fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administered orally, once daily, for at least three months. In another embodiment the fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is in amount of 200mg administrated orally as LAU-7b, once per day for fourteen (14) days. In another embodiment the fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administrated orally as LAU-7b, in three (3) or more consecutive treatment cycles, each cycle consisting of 200 mg of fenretinide administrated as LAU-7b once per day for fourteen (14) days, followed by a drug-free interval of fourteen (14) days. In another embodiment the fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administered to patient with at least one other active agent. In a further embodiment the at least one other active agent comprises an NSAID (non-steroidal anti-inflammatory drug), a corticosteroid, a COX-2 (cyclooxvgenase-2) inhibitor, an antidepressant, or a combination of two or more thereof. In a further embodiment the therapeutically effective amount of fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof gives rise to a plasma concentration of fenretinide in said human of 1 pM to about 3 pM.

[0020] In another aspect, the present invention provides for a pharmaceutical composition comprising a therapeutically effective amount of fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof for treating or attenuating functional impairment in performing daily activities in a patient with Long COVID. In one embodiment the fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof comprises 1 mg to 1000 mg of fenretinide. In a further embodiment the fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof comprises 10 mg to 300 mg of fenretinide. In an alternative embodiment the fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof results in a plasma concentration of fenretinide in a human of 0.5 pM to 5 pM. In a further embodiment the fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof results in a plasma concentration of fenretinide in a human of 1 pM to 3 pM. In another embodiment the fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administered orally, once daily, for 14 days or more. In another embodiment the fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administered orally, once daily, for at least three months. In another embodiment the fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is in amount of 200mg administrated orally as LAU- 7b, once per day for fourteen (14) days. In another embodiment the fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administrated orally as LAU-7b, in three (3) or more consecutive treatment cycles, each cycle consisting of 200 mg of fenretinide administrated as LAU-7b once per day for fourteen (14) days, followed by a drug- free interval of fourteen (14) days. In another embodiment the fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administered to patient with at least one other active agent. In a further embodiment the at least one other active agent comprises an NSAID (non-steroidal anti-inflammatory drug), a corticosteroid, a COX-2 (cyclooxvgenase-2) inhibitor, an antidepressant, or a combination of two or more thereof.

[0021] In another aspect, the present invention provides a method of treating or attenuating functional impairment in performing daily activities in a patient with an infection-associated chronic condition, comprising, consisting essentially of, or consisting of administering to said human of a therapeutically effective amount of fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof. In one embodiment the therapeutically effective amount of fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof comprises 1 mg to 1000 mg of fenretinide. In a further embodiment the therapeutically effective amount of fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof comprises 10 mg to 300 mg of fenretinide. In an alternative embodiment the therapeutically effective amount of fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof gives rise to a plasma concentration of fenretinide in said human of 0.5 pM to about 5 pM. In a further embodiment the therapeutically effective amount of fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof gives rise to a plasma concentration of fenretinide in said human of 1 pM to about 3 pM. In another embodiment the fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administered orally, once daily, for 14 days or more. In another embodiment the fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administered orally, once daily, for at least three months. In another embodiment the fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is in amount of 200mg administrated orally as LAU-7b, once per day for fourteen (14) days. In another embodiment the fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administrated orally as LAU-7b, in three (3) or more consecutive treatment cycles, each cycle consisting of 200 mg of fenretinide administrated as LAU-7b once per day for fourteen (14) days, followed by a drug-free interval of fourteen (14) days. In another embodiment the fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administered to patient with at least one other active agent. In a further embodiment the at least one other active agent comprises an NSAID (non-steroidal antiinflammatory drug), a corticosteroid, a COX-2 (cyclooxvgenase-2) inhibitor, an antidepressant, or a combination of two or more thereof.

[0022] In another aspect, the present invention provides for a pharmaceutical composition comprising a therapeutically effective amount of fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof for treating or attenuating functional impairment in performing daily activities in a patient with an infection-associated chronic condition. In one embodiment the therapeutically effective amount of fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof comprises 1 mg to 1000 mg of fenretinide. In a further embodiment the therapeutically effective amount of fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof comprises 10 mg to 300 mg of fenretinide. In an alternative embodiment the therapeutically effective amount of fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof gives rise to a plasma concentration of fenretinide in said human of 0.5 pM to about 5 pM. In a further embodiment the therapeutically effective amount of fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof gives rise to a plasma concentration of fenretinide in said human of 1 piM to about 3 pM. In an alternative embodiment the fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administered orally, once daily, for 14 days or more. In an alternative embodiment the fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administered orally, once daily, for at least three months. In an alternative embodiment the fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is in amount of 200mg administrated orally as LAU-7b, once per day for fourteen (14) days. In an alternative embodiment the fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administrated orally as LAU-7b, in three (3) or more consecutive treatment cycles, each cycle consisting of 200 mg of fenretinide administrated as LAU-7b once per day for fourteen (14) days, followed by a drug-free interval of fourteen (14) days. In an alternative embodiment the fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administered to patient with at least one other active agent. In a further embodiment the at least one other active agent comprises an NSAID (non-steroidal anti-inflammatory drug), a corticosteroid, a COX-2 (cyclooxvgenase-2) inhibitor, an antidepressant, or a combination of two or more thereof.

[0023] In another aspect, the present invention provides a method of treating or attenuating one or more symptoms of Long COVID in a human, selected from fatigue, post-exertional malaise, trouble sleeping, shortness of breath, general pain and discomfort, cognitive problems (memory loss, difficulty thinking or concentrating) and mental health symptoms (anxiety, depression), comprising, consisting essentially of, or consisting of administering to said human of a therapeutically effective amount of fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof. In one embodiment the therapeutically effective amount of fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof comprises 1 mg to 1000 mg of fenretinide. In a further embodiment the therapeutically effective amount of fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof comprises 10 mg to 300 mg of fenretinide. In an alternative embodiment the therapeutically effective amount of fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof gives rise to a plasma concentration of fenretinide in said human of 0.5 pM to about 5 pM. In a further embodiment the therapeutically effective amount of fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof gives rise to a plasma concentration of fenretinide in said human of 1 pM to about 3 pM. In an alternative embodiment the fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administered orally, once daily, for 14 days or more. In an alternative embodiment the fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administered orally, once daily, for at least three months. In an alternative embodiment the fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is in amount of 200mg administrated orally as LAU-7b, once per day for fourteen (14) days. In an alternative embodiment the fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administrated orally as LAU-7b, in three (3) or more consecutive treatment cycles, each cycle consisting of 200 mg of fenretinide administrated as LAU-7b once per day for fourteen (14) days, followed by a drug-free interval of fourteen (14) days. In an alternative embodiment the fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administered to patient with at least one other active agent. In a further embodiment the at least one other active agent comprises an NSAID (non-steroidal anti-inflammatory drug), a corticosteroid, a COX-2 (cyclooxvgenase-2) inhibitor, an antidepressant, or a combination of two or more thereof.

[0024] In another aspect, the present invention provides for the use of fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof for the preparation of a pharmaceutical composition for treating or attenuating one or more symptoms of Long COVID in a human, selected from fatigue, post-exertional malaise, trouble sleeping, shortness of breath, general pain and discomfort, cognitive problems (memory loss, difficulty thinking or concentrating) and mental health symptoms (anxiety, depression). In one embodiment the fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof comprises 1 mg to 1000 mg of fenretinide. In a further embodiment the fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof comprises 10 mg to 300 mg of fenretinide. In an alternative embodiment the fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof results in a plasma concentration of fenretinide in a human of 0.5 pM to 5 pM. In a further embodiment the fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof results in a plasma concentration of fenretinide in a human of 1 pM to 3 pM. In an alternative embodiment the fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administered orally, once daily, for 14 days or more. In an alternative embodiment the fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administered orally, once daily, for at least three months. In an alternative embodiment the fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is in amount of 200mg administrated orally as LAU-7b, once per day for fourteen (14) days. In an alternative embodiment the fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administrated orally as LAU-7b, in three (3) or more consecutive treatment cycles, each cycle consisting of 200 mg of fenretinide administrated as LAU-7b once per day for fourteen (14) days, followed by a drug-free interval of fourteen (14) days. In an alternative embodiment the fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administered to patient with at least one other active agent. In a further embodiment the at least one other active agent comprises an NSAID (non-steroidal anti-inflammatory drug), a corticosteroid, a COX-2 (cyclooxvgenase-2) inhibitor, an antidepressant, or a combination of two or more thereof.

[0025] In another aspect, the present invention provides a method of treating or attenuating one or more symptoms of an infection-associated chronic condition in a human, selected from fatigue, post-exertional malaise, trouble sleeping, shortness of breath, general pain and discomfort, cognitive problems (memory loss, difficulty thinking or concentrating) and mental health symptoms (anxiety, depression), comprising, consisting essentially of, or consisting of administering to said human of a therapeutically effective amount of fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof. In one embodiment the therapeutically effective amount of fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof comprises 1 mg to 1000 mg of fenretinide. In a further embodiment the therapeutically effective amount of fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof comprises 10 mg to 300 mg of fenretinide. In an alternative embodiment the therapeutically effective amount of fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof gives rise to a plasma concentration of fenretinide in said human of 0.5 pM to about 5 pM. In a further embodiment the therapeutically effective amount of fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof gives rise to a plasma concentration of fenretinide in said human of 1 pM to about 3 pM. In an alternative embodiment the fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administered orally, once daily, for 14 days or more. In an alternative embodiment the fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administered orally, once daily, for at least three months. In an alternative embodiment the fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is in amount of 200mg administrated orally as LAU-7b, once per day for fourteen (14) days. In an alternative embodiment the fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administrated orally as LAU-7b, in three (3) or more consecutive treatment cycles, each cycle consisting of 200 mg of fenretinide administrated as LAU-7b once per day for fourteen (14) days, followed by a drug-free interval of fourteen (14) days. In an alternative embodiment the fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administered to patient with at least one other active agent. In a further embodiment the at least one other active agent comprises an NSAID (non-steroidal anti-inflammatory drug), a corticosteroid, a COX-2 (cyclooxvgenase-2) inhibitor, an antidepressant, or a combination of two or more thereof. In an alternative embodiment, the infection-associated chronic condition is post-viral syndrome, myalgic encephalomyelitis / chronic fatigue syndrome (ME / CFS), fibromyalgia, persistent Lyme disease (aka post-Lyme disease), or multiple sclerosis occurring with Epstein-Barr virus (EBV).

[0026] In another aspect, the present invention provides for a pharmaceutical composition comprising a therapeutically effective amount of fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof for treating or attenuating one or more symptoms of an infection-associated chronic condition in a human, selected from fatigue, post-exertional malaise, trouble sleeping, shortness of breath, general pain and discomfort, cognitive problems (memory loss, difficulty thinking or concentrating) and mental health symptoms (anxiety, depression). In one embodiment the therapeutically effective amount of fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof comprises 1 mg to 1000 mg of fenretinide. In a further embodiment the therapeutically effective amount of fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof comprises 10 mg to 300 mg of fenretinide. In an alternative embodiment the therapeutically effective amount of fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof gives rise to a plasma concentration of fenretinide in said human of 0.5 pM to about 5 pM. In a further embodiment the therapeutically effective amount of fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof gives rise to a plasma concentration of fenretinide in said human of 1 pM to about 3 pM. In an alternative embodiment the fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administered orally, once daily, for 14 days or more. In an alternative embodiment the fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administered orally, once daily, for at least three months. In an alternative embodiment the fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is in amount of 200mg administrated orally as LAU-7b, once per day for fourteen (14) days. In an alternative embodiment the fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administrated orally as LAU-7b, in three (3) or more consecutive treatment cycles, each cycle consisting of 200 mg of fenretinide administrated as LAU-7b once per day for fourteen (14) days, followed by a drug-free interval of fourteen (14) days. In an alternative embodiment the fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administered to patient with at least one other active agent. In a further embodiment the at least one other active agent comprises an NSAID (non-steroidal anti-inflammatory drug), a corticosteroid, a COX-2 (cyclooxvgenase-2) inhibitor, an antidepressant, or a combination of two or more thereof. In an alternative embodiment, the infection-associated chronic condition is, myalgic encephalomyelitis / chronic fatigue syndrome (ME / CFS), fibromyalgia, persistent Lyme disease (aka post-Lyme disease), or multiple sclerosis occurring with Epstein-Barr virus (EBV).

[0027] In another aspect, the present invention provides a method of treating or attenuating one or more symptoms of Long COVID in a human, selected from fatigue, post-exertional malaise, trouble sleeping, shortness of breath, general pain and discomfort, cognitive problems (memory loss, difficulty thinking or concentrating) and mental health symptoms (anxiety, depression), comprising, consisting essentially of, or consisting of administering to said human of a therapeutically effective amount of fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof. In one embodiment the therapeutically effective amount of fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof comprises 1 mg to 1000 mg of fenretinide. In a further embodiment the therapeutically effective amount of fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof comprises 10 mg to 300 mg of fenretinide. In an alternative embodiment the therapeutically effective amount of fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof gives rise to a plasma concentration of fenretinide in said human of 0.5 pM to about 5 pM. In a further embodiment the therapeutically effective amount of fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof gives rise to a plasma concentration of fenretinide in said human of 1 pM to about 3 pM. In an alternative embodiment the fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administered orally, once daily, for 14 days or more. In an alternative embodiment the fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administered orally, once daily, for at least three months. In an alternative embodiment the fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is in amount of 200mg administrated orally as LAU-7b, once per day for fourteen (14) days. In an alternative embodiment the fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administrated orally as LAU-7b, in three (3) or more consecutive treatment cycles, each cycle consisting of 200 mg of fenretinide administrated as LAU-7b once per day for fourteen (14) days, followed by a drug-free interval of fourteen (14) days. In an alternative embodiment the fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administered to patient with at least one other active agent. In a further embodiment the at least one other active agent comprises an NSAID (non-steroidal anti-inflammatory drug), a corticosteroid, a COX-2 (cyclooxvgenase-2) inhibitor, an antidepressant, or a combination of two or more thereof. In an alternative embodiment, the infection-associated chronic condition is post-viral syndrome, myalgic encephalomyelitis / chronic fatigue syndrome (ME / CFS), fibromyalgia, persistent Lyme disease (aka post-Lyme disease), or multiple sclerosis occurring with Epstein-Barr virus (EBV).

[0028] In another aspect, the present invention provides for a pharmaceutical composition comprising a therapeutically effective amount of fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof for treating or attenuating one or more symptoms of Long COVID in a human, selected from fatigue, post-exertional malaise, trouble sleeping, shortness of breath, general pain and discomfort, cognitive problems (memory loss, difficulty thinking or concentrating) and mental health symptoms (anxiety, depression). In one embodiment the therapeutically effective amount of fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof comprises 1 mg to 1000 mg of fenretinide. In a further embodiment the therapeutically effective amount of fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof comprises 10 mg to 300 mg of fenretinide. In an alternative embodiment the therapeutically effective amount of fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof gives rise to a plasma concentration of fenretinide in said human of 0.5 pM to about 5 pM. In a further embodiment the therapeutically effective amount of fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof gives rise to a plasma concentration of fenretinide in said human of 1 pM to about 3 pM. In an alternative embodiment the fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administered orally, once daily, for 14 days or more. In an alternative embodiment the fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administered orally, once daily, for at least three months. In an alternative embodiment the fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is in amount of 200mg administrated orally as LAU-7b, once per day for fourteen (14) days. In an alternative embodiment the fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administrated orally as LAU-7b, in three (3) or more consecutive treatment cycles, each cycle consisting of 200 mg of fenretinide administrated as LAU-7b once per day for fourteen (14) days, followed by a drug-free interval of fourteen (14) days. In an alternative embodiment the fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administered to patient with at least one other active agent. In a further embodiment the at least one other active agent comprises an NSAID (non-steroidal anti-inflammatory drug), a corticosteroid, a COX-2 (cyclooxvgenase-2) inhibitor, an antidepressant, or a combination of two or more thereof. In an alternative embodiment, the infection-associated chronic condition is, myalgic encephalomyelitis / chronic fatigue syndrome (ME / CFS), fibromyalgia, persistent Lyme disease (aka post-Lyme disease), or multiple sclerosis occurring with Epstein-Barr virus (EBV).

[0029] DETAILED DESCRIPTION OF THE PRESENT INVENTION

[0030] The present invention provides for novel methods and compositions useful for the treatment of Long COVID and other similar infection-associated chronic conditions. The term “infection- associated chronic condition” applies to a variety of chronic conditions that can be triggered by viruses, bacteria, fungi, or parasites. Long COVID shares many features with other multisystem infection-associated chronic conditions, such as post-viral syndrome, myalgic encephalomyelitis and chronic fatigue syndrome (ME / CFS), fibromyalgia, persistent Lyme disease (aka post-Lyme disease), and multiple sclerosis occurring with Epstein-Barr virus (EBV) (NASEM 2024-A Long COVID Definition- A Chronic, Systemic Disease State with Profound Consequences; NASEM 2024-Long-Term Health Effects of COVID-19- Disability and Function Following SARS-CoV-2 Infection, 2024).

[0031] As used herein, the term “infection-associated” means the ongoing nature of the medical condition and its association with a triggering infection without conveying any unwarranted conclusions about pathobiological mechanisms. The term “comprising” or “comprises” is intended to mean that the compositions and methods include the recited elements, but not excluding others. “Consisting essentially of” when used to define compositions and methods, shall mean excluding other elements of any essential significance to the combination for the stated purpose, and not exclude other steps that do not materially affect the basis and novelty of the claimed invention. “Consisting of” shall mean excluding more than trace elements of other ingredients and substantial methods steps. Embodiments defined by each of these terms are within the scope of the invention. When an embodiment is defined by one of these terms (e.g., “comprising”) it should be understood that this disclosure also included alternative embodiments, such as “consisting essentially of” and “consisting of’ for said embodiment.

[0032] In one aspect of the invention, fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof is the sole active agent administered to the patient.

[0033] In other aspects of the present invention, “co-administered” and “co-administration” as relating to a patient, refer to administering to the subject a compound and / or composition of the present invention, or salt thereof, along with a compound and / or composition that may also treat any of the diseases or disorders contemplated within the invention. In some embodiments, the co-administered compounds and / or compositions comprises or consists of an NSAID (non-steroidal anti-inflammatory drug), a corticosteroid, a COX-2 (cyclooxvgenase- 2) inhibitor, an antidepressant, or a combination of two or more thereof. In one embodiment, the co-administered compounds and / or compositions are administered separately, or in any kind of combination as part of a single therapeutic approach. The co-administered compound and / or composition may be formulated in any kind of combination as mixtures of solids and liquids under a variety of solid, gel, and liquid formulations, and as a solution.

[0034] As used herein, the term “about” will be understood by one skilled in the art to vary to some extent by the context under which it is used. As used herein, when referring to a measurable value such as an amount, time duration, and the like; the term “about” shall encompass variations of + / -20%, or + / -10%, more preferably + / -5%, even more preferably + / -1%, and still more preferably + / -0.1 % from the specified value, as such variations are appropriate to perform the disclosed methods.

[0035] As used herein, “administration”, means providing a compound and / or composition of the present invention to a subject by any suitable method.

[0036] As used herein, “alkyl”, by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain hydrocarbon having the number of carbon atoms designated and includes straight, branched chain, or cyclic substituent groups. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyls, pentyl, neopentyl, hexyl and cyclopropylmethyl.

[0037] As used herein, “ameliorate” means to decrease, suppress, attenuate, diminish, arrest, or stabilize the development or progression of a disease or disorder.

[0038] As used herein, an “amorphous solid dispersion” means a dispersion in which at least a major portion (i.e. , more than 50%) of the fenretinide, fenretinide analog, or salt thereof in the dispersion is in amorphous form. By "amorphous" is meant that the fenretinide, fenretinide analog, or salt thereof is in a non-crystalline state. In embodiments, at least 55, 60, 65, 70, 75, 80, 85, 90% or 95% of the fenretinide, fenretinide analog, or salt thereof (by weight) in the dispersion is in the amorphous form.

[0039] As used herein, the term “composition” or “pharmaceutical composition” refers to a mixture of at least one compound useful within the invention with a pharmaceutically acceptable carrier. The pharmaceutical composition facilitates administration of the compound to a subject.

[0040] As used herein, an “effective amount” means the amount of a compound that is required to ameliorate the symptom of a disease, prevent the worsening of the disease, or reduce viral load, as appropriate, relative to an untreated patient. The effective amount of active compound(s) used to practise the present invention for therapeutic treatment of a disease varies depending upon the manner of administration, the age, body weight, and general health of the subject. Ultimately, the attending physician will decide the appropriate amount and dosage regimen. Such amount is therefore referred to as an “effective amount”.

[0041] As used herein, "excipient" has its normal meaning in the art and is any ingredient that is not an active ingredient (drug) itself. Excipients include for example binders, lubricants, diluents, fillers, thickening agents, disintegrants, plasticizers, coatings, barrier layer formulations, lubricants, stabilizing agent, release-delaying agents and other components. "Pharmaceutically acceptable excipient" as used herein refers to any excipient that does not interfere with effectiveness of the biological activity of the active ingredients and that is not toxic to the subject, i.e., is a type of excipient and / or is for use in an amount which is not toxic to the subject. Excipients are well known in the art, and the present system is not limited in these respects. In certain embodiments, the composition includes excipients, including for example and without limitation, one or more binders (binding agents), thickening agents, surfactants, diluents, release-delaying agents, colorants, flavoring agents, fillers, disintegrants / dissolution promoting agents, lubricants, plasticizers, silica flow conditioners, glidants, anti-caking agents, anti-tacking agents, stabilizing agents, anti-static agents, swelling agents and any combinations thereof. As those of skill would recognize, a single excipient can fulfill more than two functions at once, e.g., can act as both a binding agent and a thickening agent. As those of skill will also recognize, these terms are not necessarily mutually exclusive.

[0042] As used herein, “pharmaceutically acceptable” means a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound useful within the present invention and is relatively non-toxic. It is intended that “pharmaceutically acceptable” materials may be administered to a subject without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

[0043] As used herein, “pharmaceutically acceptable salt” means a salt of the administered compounds prepared from pharmaceutically acceptable non-toxic acids, including inorganic acids, organic acids, inorganic bases, organic bases, solvates, hydrates, or clathrates thereof. The compounds described herein may form salts with acids or bases, and such salts are included in the present invention. In one embodiment, the salts are pharmaceutically acceptable salt. The term “salts” includes addition of free acids or bases that are useful within the methods of the present invention. The term “pharmaceutically acceptable salt” refers to salts that possess toxicity profiles within a range that affords utility in pharmaceutical and disease and disorder treatment of patient applications.

[0044] Pharmaceutically unacceptable salts may nonetheless possess properties which have utility in the practise of the present invention, and one skilled in the art would be capable of identifying and using a pharmaceutically unacceptable salt as part of the treatment of a disease or disorder of patients, as contemplated herein, or as part of the manufacturing of a compound of the present invention.

[0045] As used herein, "solid dispersion" means a solid material, in which a drug (e.g., fenretinide) is dispersed in the solid matrix polymer. Such solid dispersions are also referred to in the art as "molecular dispersions" or "solid solutions" of the drug in the polymer. Solid dispersions may be obtained by various techniques, for example fast evaporation, spray-drying, precipitation or melt extrusion (e.g., hot melt extrusion, HME). In an embodiment, the solid dispersion is obtained by spray-drying (spray-dried solid dispersion).

[0046] As used herein, “LAU-7b” means an improved oral formulation of fenretinide, formulated as spray dried solid amorphous dispersion. l_AU-7b SDI is a spray dry intermediate of LAU-7b, with each 2.5mg of l_AU-7b-SDI containing 1 mg fenretinide, 1.49 mg povidone, 0.006 mg butylated-hydroxyanisole, and 0.004 mg butylated hydroxytoluene.

[0047] Fenretinide and analogs thereof

[0048] Fenretinide (4-hydroxyphenyl retinamide; also referred to as 4-HPR, which has CAS registry number 65646-68-6, is a synthetic retinoid of the following formula II:

[0049] Formula II

[0050] Functional analogs (and / or metabolites) of fenretinide (i.e. , which exhibit the same biological activity as fenretinide) may also be used according to the present disclosure. As used herein, a "fenretinide analog" refers to a compound that shares certain chemical structural features with fenretinide but at the same time comprises one or more modifications thereto, and which exhibits similar biological activity as fenretinide (but may exhibit such activity to a different extent). Examples of analogs of fenretinide that may be used include, but are not limited to, 4-oxo-N-(4-hydroxyphenyl)retinamide (4-oxo-4-HPR), N-(4-methoxyphenyl)retinamide (4- MPR), 4-Hydroxybenzylretinone, C-glycoside and arylamide analogues of N-(4- hydroxyphenyl) retinamide-O-glucuronide, including but not limited to 4-(retinamido)phenyl- C-glucuronide, 4-(retinamido)phenyl-C-glucoside, 4-(retinamido)benzyl-C-xyloside; and retinoyl p-glucuronide analogues such as, for example, 1-(£-D-glucopyranosyl) retinamide, 1- (D-glucopyranosyluronosyl) retinamide and bexarotene, described in WO 07 / 136636, U.S. Patent Application No. 2006 / 0264514, U.S. Patent Nos. 5,516,792, 5,663,377, 5,599,953, 5,574,177, Anding et al. (Anding, A.L. et al., Cancer Research, https: / / doi.org / 10.1158 / 0008- 5472. CAN-07-0727, 2007) and Bhatnagar et al. (Bhatnagar, R., et al., Biochemical Pharmacology, https: / / doi.org / 10.1016 / 0006-2952(91)90563-K, 1991). In an embodiment, the fenretinide / fenretinide analog is represented by formula I:

[0051] R is OH, COOH, CH2OH, CH2CH2OH, or CH2COOH; carbons a-d and f-i are optionally substituted with one or more groups selected from CH3, OH, COOH, (CHs)2 and CH2OH, or any combination thereof, and carbon e is optionally substituted with a C1-C3 alkyl group that is optionally substituted with CH3 and / or OH.

[0052] Any salts of fenretinide or fenretinide analogs may also be used in the method or use described herein.

[0053] The method or use comprises the administration or use of fenretinide or an analog of fenretinide, or a pharmaceutically acceptable salt thereof.

[0054] Fenretinide is a small molecule synthetic retinoid derivative, with well-documented history of safety in non-clinical and clinical studies. Initially explored for prevention and treatment of cancer, fenretinide was also studied for non-oncological indications such as age-related macular degeneration, cystic fibrosis and COVID-19.

[0055] Dosage

[0056] Any suitable amount of fenretinide, fenretinide analog or salt thereof may be administered to a subject. The dosages will depend on many factors including the mode of administration. Typically, the amount of fenretinide, fenretinide analog or salt thereof, contained within a single dose will be an amount that effectively prevents, delays or treats the SARS- coronavirus associated pneumonia without inducing significant toxicity.

[0057] For prophylaxis, treatment or reduction in the severity of SARS-coronavirus infection, the appropriate dosage of the compound / composition depends on the severity of the pneumonia, whether the compound / composition is administered for preventive or therapeutic purposes, previous or concomitant therapy, the patient's clinical history and response to the compound / composition, and the discretion of the attending physician. The fenretinide, fenretinide analog or salt thereof, is / are suitably administered to the patient at one time or over a series of treatments.

[0058] The present invention provides dosages for the compounds and compositions comprising same. For example, depending on the severity of the disease, the effective dose may be 0.5 mg / kg, 1 mg / kg, 1.5 mg / kg, 2 mg / kg, 2.5 mg / kg, 3 mg / Kg, 4 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 35 mg / kg, 40 mg / kg, 45 mg / kg, and up to 100 mg / kg of fenretinide. A typical daily dosage might range from about 1 mg / kg to 20 mg / kg or more, depending on the factors mentioned above; provided by way of administration to a patient of fenretinide, fenretinide analog or salt thereof that is administered in an amount of 1 mg to about 1000 mg, preferably about 10 mg to 300 mg. For repeated administrations over several days or longer, the treatment is sustained until the desired suppression of disease symptoms occurs. The present invention contemplates establishing a plasma concentration in the patient of fenretinide, fenretinide analog or salt thereof of about 0.5 pM to about 5 pM, preferably of about 1 pM to about 3 pM.

[0059] However, other dosage regimens may be useful. The progress of this therapy is easily monitored by conventional techniques and assays. These are simply guidelines since the actual dose must be carefully selected and titrated by the attending physician based upon clinical factors unique to each patient or by a nutritionist. The optimal daily dose will be determined by methods known in the art and will be influenced by factors such as the age of the patient and other clinically relevant factors. In addition, patients may be taking medications for other diseases or conditions. The other medications may be continued during the time that fenretinide, fenretinide analog or salt thereof, is given to the patient, but it is particularly advisable in such cases to begin with lower doses to determine if adverse side effects are experienced. Compositions

[0060] The fenretinide, fenretinide analog or salt thereof, may be combined with one or more optional carriers or excipients to formulate the compound(s) into suitable dosage formulations, such as tablets, capsules (e.g., hard gelatine capsules), caplets, suspensions, powders for suspensions, and the like. Such compositions may be prepared by mixing the active ingredient (e.g., fenretinide) having the desired degree of purity; with one or more optional pharmaceutically acceptable carriers, excipients and / or stabilizers in a manner well known in the pharmaceutical art. Supplementary active compounds can also be incorporated into the compositions. The carrier / excipient can be suitable, for example, for oral, intravenous, parenteral, subcutaneous, intramuscular, intranasal or pulmonary (e.g., aerosol) administration (see Remington: The Science and Practice of Pharmacy, by Loyd V Allen, Jr, 2012, 22nd edition, Pharmaceutical Press; Handbook of Pharmaceutical Excipients, by Rowe et al., 2012, 7th edition, Pharmaceutical Press). Therapeutic formulations are prepared using standard methods known in the art.

[0061] Examples of matrix materials, fillers, or diluents include, without limitation, lactose, mannitol, xylitol, microcrystalline cellulose, dibasic calcium phosphate (anhydrous and dihydrate), starch, and any combination thereof.

[0062] Examples of disintegrants include, without limitation, sodium starch glycolate, sodium alginate, carboxy methyl cellulose sodium, methyl cellulose, and croscarmellose sodium, and crosslinked forms of polyvinyl pyrrolidone such as those sold under the trade name CROSPOVIDONE® (available from BASF Corporation), and any combination thereof.

[0063] Examples of binders include, without limitation, methyl cellulose, microcrystalline cellulose, starch, and gums such as guar gum, tragacanth, and any combination thereof.

[0064] Examples of lubricants include, without limitation, magnesium stearate, calcium stearate, stearic acid, and any combination thereof.

[0065] Examples of glidants include, without limitation, metal silicates, silicon dioxides, higher fatty acid metal salts, metal oxides, alkaline earth metal salts, and metal hydroxides. Examples of preservatives include, without limitation, sulfites (an antioxidant), benzalkonium chloride, methyl paraben, propyl paraben, benzyl alcohol, sodium benzoate, and any combination thereof.

[0066] Examples of suspending agents or thickeners, without limitation, include xanthan gum, starch, guar gum, sodium alginate, carboxymethyl cellulose, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, polyacrylic acid, silica gel, aluminum silicate, magnesium silicate, titanium dioxide, and any combination thereof.

[0067] Examples of anti-caking agents or fillers, without limitation, include silicon oxide, lactose, and any combination thereof.

[0068] Examples of solubilizers include, without limitation, ethanol, propylene glycol, polyethylene glycol, and any combination thereof.

[0069] Examples of antioxidants include, without limitation, phenolic-based antioxidants such as butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), tert-butyl-hydroquinone (TBHQ), 4-hydroxymethyl-2,6-di-tert-butylphenol (HMBP), 2,4,5-trihydroxy-butyrophenone (THBP), propyl gallate (PG), triamyl gallate, gallic acid (GA), a-Tocopherol (vitamin E), tocopherol acetate, reducing agents such as L-ascorbic acid (vitamin C), L-ascorbyl palmitate, L-ascorbyl stearate, thioglycolic acid (TGA), ascorbyl palmitate (ASP), sulphite- based antioxidants such as sodium sulphite, sodium metabisulphite, sodium bisulphite and thioglycerol and other agents such as disodium ethylenediamine tetraacetate (EDTA), sodium pyrophosphate, sodium metaphosphate, methionine, erythorbic acid and lecithin, and any combination thereof. In an embodiment, the formulation comprises a combination of antioxidants. In an embodiment, the formulation comprises a combination of BHA and BHT. In an embodiment, the formulation comprises ascorbic acid.

[0070] Another class of excipients is surfactants, optionally present from about 0 to about 10 wt %. Suitable surfactants include, without limitation, fatty acid and alkyl sulfonates; commercial surfactants such as benzalkonium chloride (HYAMINE® 1622, available from Lonza, Inc., Fairlawn, N.J.); dioctyl sodium sulfosuccinate (DOCUSATE SODIUM, available from Mallinckrodt Spec. Chem., St. Louis, Mo.); polyoxyethylene sorbitan fatty acid esters (TWEEN®, available from ICI Americas Inc., Wilmington, Del.; LIPOSORB® 0-20, available from Lipochem Inc., Patterson N.J.; CAPMUL.TM. POE-0, available from Abitec Corp., Janesville, Wis.); and natural surfactants such as sodium taurocholic acid, 1-palmitoyl-2- oleoyl-sn-glycero-3-phosphocholine, lecithin, and other phospholipids and mono- and diglycerides, and any combination thereof. Such materials can be employed to increase the rate of dissolution by, for example, facilitating wetting, or otherwise increase the rate of drug release from the dosage form.

[0071] Other conventional excipients, including pigments, lubricants, flavorants, humectants, solution retarding agents, absorption accelerators, wetting agents, absorbents, and other ones well-known in the art, may be employed in the compositions of this invention. For example, excipients such as pigments, lubricants, flavorants, and so forth may be used for customary purposes and in typical amounts without adversely affecting the properties of the compositions.

[0072] Other components commonly added to pharmaceutical compositions include, e.g., inorganic salts such as sodium chloride, potassium chloride, calcium chloride, sodium phosphate, potassium phosphate, sodium bicarbonate; and organic salts such as sodium citrate, potassium citrate, sodium acetate, etc.

[0073] In an embodiment, the fenretinide, fenretinide analog or salt thereof is present in the composition as an amorphous solid dispersion as described in U.S. Patent Publication No. 2017 / 0189356 A1, which is incorporated by reference in its entirety.

[0074] Examples of "matrix polymers", also referred to in the field as "concentration-enhancing polymers" or "dispersion polymers", which may be suitable for use in the present invention, are discussed in detail in for example U.S. Patent Nos. 7,780,988 and 7,887,840. The matrix polymer can be any pharmaceutically acceptable polymer that, once co-processed with the fenretinide, fenretinide analog, or salt thereof, functions to maintain the fenretinide / fenretinide analog in amorphous form.

[0075] Examples of polymers that may be suitable for use with the present invention comprise non- ionizable (neutral) non-cellulosic polymers. Exemplary polymers include: vinyl polymers and copolymers having at least one substituent selected from hydroxyl, alkylacyloxy, and cyclicamido; polyvinyl alcohols that have at least a portion of their repeat units in the unhydrolyzed (vinyl acetate) form; polyvinyl alcohol polyvinyl acetate copolymers; polyvinyl pyrrolidone; and polyethylene polyvinyl alcohol copolymers; and polyoxyethylenepolyoxypropylene copolymers. Other examples of polymers that may be suitable for use with the present invention comprise ionizable non-cellulosic polymers. Exemplary polymers include: carboxylic acid- functionalized vinyl polymers, such as the carboxylic acid functionalized polymethacrylates and carboxylic acid functionalized polyacrylates such as the EUDRAGIT® series, amine- functionalized polyacrylates and polymethacrylates; proteins such as gelatin and albumin; and carboxylic acid functionalized starches such as starch glycolate.

[0076] Other examples polymers that may be suitable for use with the present invention comprise nonionizable cellulosic polymers that may be used as the polymer include: hydroxypropyl methyl cellulose acetate, hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose, methyl cellulose, hydroxyethyl methyl cellulose, hydroxyethyl cellulose acetate, hydroxyethyl ethyl cellulose, and the like.

[0077] While specific polymers have been discussed as being suitable for use in the dispersions formable by the present invention, blends of such polymers may also be suitable. Thus, the term "matrix polymer" is intended to include blends of polymers in addition to a single species of polymer.

[0078] In an embodiment, the matrix polymer comprises polyvinylpyrrolidone. In another embodiment, the matrix polymer is a polyvinylpyrrolidone, for example polymers sold under the trade-name Plasdone® (povidones), polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, polyvinylpyrrolidone K30 or polyvinylpyrrolidone K90.

[0079] In an embodiment, the ratio of the fenretinide, fenretinide analog, or salt thereof / matrix polymer is from about 1:5 to about 5:1 , in further embodiments about 1 :4 to about 4:1 , about 1 :3 to about 3:1 , about 1:2 to about 2:1 or about 1.5:1 to about 1:1.5, by weight. In an embodiment, the solid dispersion comprises between about 30 to about 50% of the fenretinide, fenretinide analog, or salt thereof, and between about 50 to about 70% of matrix polymer. In another embodiment, the solid dispersion comprises between about 40% of the fenretinide, fenretinide analog, or salt thereof, and about 60% of matrix polymer, by weight.

[0080] In an embodiment, the solid dispersion comprises one or more additives. Additives that may be suitable for use with the present invention comprise antioxidant agents. Exemplary antioxidants include: L-ascorbic acid (vitamin C), propyl gallate, sodium sulfite, sodium metabisulfite, sodium bisulfite, thioglycerol, thioglycollic acid, tocopherols and tocotrienols, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT) or any combination thereof. In an embodiment, the matrix polymer or solid dispersion comprises BHA and / or BHT as antioxidant agent(s). In an embodiment, the matrix polymer or solid dispersion comprises BHA and BHT as antioxidant agents. In an embodiment, the matrix polymer comprises L- ascorbic acid as antioxidant agent. In an embodiment, the antioxidant agent(s) is / are present in an amount of about 0.01% to about 5%, in further embodiments in an amount of about 0.1% to about 5%, about 0.2% to about 4%, 0.5% to about 3% or 0.5% to about 2%.

[0081] The amorphous solid dispersion of fenretinide, fenretinide analog, or salt thereof may be combined with one or more optional excipients as described above.

[0082] In an embodiment, the amorphous solid dispersion of fenretinide, fenretinide analog, or salt thereof is combined with a disintegrant, for example a cross-linked sodium carboxymethylcellulose e.g., croscarmellose (Solutab®). Other examples of disintegrants include corn starch, potato starch, sodium carboxymethylcellulose, sodium starch glycolate, sodium croscarmellose, crospovidone, and any combination thereof. In an embodiment, the disintegrant is present in an amount from about 2% to about 10% by weight, for example from about 3% to about 8% or about 4% to about 6% by weight.

[0083] In an embodiment, the amorphous solid dispersion of fenretinide, fenretinide analog, or salt thereof is combined with a lubricant, for example magnesium stearate. Other examples of lubricants include talc, silicon dioxide, stearic acid, and sodium stearyl fumarate. In an embodiment, the lubricant is present in an amount from about 0.5 to about 2% by weight, for example from about 0.8 to about 1.2% or about 1% by weight.

[0084] In an embodiment, the amorphous solid dispersion of fenretinide, fenretinide analog, or 30 salt thereof is combined with a filler or diluent, for example microcrystalline cellulose (Avicel®, such as Avicel®PH-102) and / or calcium hydrogen phosphate dehydrate (Encompress®). Other examples of fillers or diluents include crystalline cellulose, cellulose derivatives, acacia, corn starch, lactose, mannitol, sugars, calcium phosphate, calcium carbonate, gelatins, and any combination thereof. In an embodiment, the filler or diluent is present in an amount from about 35 20 to about 45% by weight, for example from about 30% to about 40% by weight, e.g., about 35%. In an embodiment, the amorphous solid dispersion of fenretinide, fenretinide analog, or salt thereof is combined one or more antioxidants, for example butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), citric acid, sodium metabisulfite, alpha-tocopherol and / or L- ascorbic acid.

[0085] In certain embodiments, the amorphous solid dispersion as disclosed herein is formulated as an oral dosage formulation. Formulations suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an elixir or syrup, or as pastilles (using an inert matrix, such as gelatin and glycerin, or sucrose and acacia), and the like, each containing a predetermined amount of an active ingredient. A composition may also be administered as a bolus, electuary, or paste.

[0086] In an embodiment, the oral dosage formulation is a tablet. A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder, lubricant, inert diluent, preservative, disintegrant, surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered inhibitor(s) moistened with an inert liquid diluent.

[0087] In some embodiments of the oral dosage formulation as disclosed herein, the amorphous solid dispersion is present in an amount of from about 10 to about 90%, about 20 to about 80%, about 30 to about 60% or about 45 to about 55% by weight, or another range within the values provided herein.

[0088] Membrane lipids play multiple biological roles ranging from first-line host defense against pathogens, to inflammation signaling, and protein trafficking. Moreover, membrane lipids are crucial in the virus life cycle, and host lipid biogenesis pathways are needed in the propagation of lipid-enveloped viruses, and have been described as key players in coronavirus infection (Casari I et al 2021, https: / / doi.Org / 10.1016 / j.plipres.2021.101092 ; Abu- Farha M et al 2020, http: / / dx.doi.org / 10.3390 / ijms21103544 ).

[0089] At low doses (1-5 pM, preferably 1-3 pM, plasma concentration), fenretinide was shown to have modulating activity on certain bioactive membrane lipids (phospholipids and sphingolipids) that play central roles in the activation / resolution of the inflammation process, as well as in the host defense against pathogens. Although not fully elucidated, fenretinide’s lipid modulating mechanism appears to follow a multi-target pharmacology involving certain desaturases (Poliakov et al 2017, https: / / doi.org / 10.1371 / journal.pone.0176487 ) and ceramide synthase CerS5 (Garic et al 2017, https: / / doi.org / 10.1007 / s00109-017-1564-y ), which play important roles in fatty acids metabolism, and in the modulation of cell membrane lipids fluidity and de-novo lipogenesis. Fenretinide was also associated with the modulation of several molecular pathways involved in inflammation, fibrosis, and host defense, such as MAPK / ERK (Lachance et al 2013, https: / / doi.org / 10.1371 / journal.pone.0074875), cPLA2 (Garic et al 2020, https: / / doi.org / 10.1007 / s00109-017-1564-y ), NF-KB (Vilela RM et al 2006, http: / / dx.doi.Org / 10.1016 / j.intimp.2006.06.012 ), and PPARy (Mcilroy GD et al, https: / / doi.org / 10.2337 / db12-04582013 ).

[0090] Although the antiviral effect of fenretinide was evaluated in the context of acute COVID-19 infection, as disclosed in PCT Patent Application WO 2021 / 189153, it is still unknown if fenretinide’s effect on the virus is uniquely responsible for its efficacy. Furthermore, the disclosed antiviral effect alone may be less relevant for the treatment of Long COVID, a condition in which the pathobiological mechanisms seem to be even more complex and cannot be explained uniquely by the potential presence of the virus reservoirs. Indeed, a recent placebo-controlled clinical study evaluating the effect of a 15-day course of the approved antiviral COVID-19 medication nirmatrelvir-ritonavir (also known as Paxlovid) failed to show benefit in patients with Long COVID (Geng et al 2024 https: / / doi.org / 10.1001%2Fjamainternmed.2024.2007). Paxlovid is the most prescribed antiviral therapeutic for COVID- 19. This example clearly demonstrate that Long COVID is a distinct condition from COVID-19, with multiple proposed pathogenic mechanisms that may contribute to its development.

[0091] Of particular interest in the context of present invention is the multi-target and multi-organ approach conferred by fenretinide’s ability to modulate multiple molecular targets and signaling pathways, some related to the host cell membrane lipids (Hayashi Y. et al 2021, https: / / doi.org / 10.1128 / JVI.00807-21; Hayashi Y. et al 2022, https: / / doi.org / 10.1248 / bpb.b22- 00503; Hayashi Y. et al 2023, https: / / doi.org / 10.1093 / jb / mvad020) and their effect on , inflammation and fibrosis (Konstan et al 2024, https: / / doi.Org / 10.1016 / j.jcf.2024.07.004; Houle 2024 https: / / doi.Org / 10.1164 / ajrccm-conference.2024.209.1_MeetingAbstracts.A1057; WO 2021 / 189153; WO 2022 / 040782; Lachance et al 2013, https: / / doi.org / 10.1371 / journal.pone.0074875), or other mechanisms (Potenza et al 2022, https: / / doi.org / 10.3390 / ijms23137426). Fenretinide also have the ability to penetrate and modulate the blood-brain barrier (BBB), and exert effects on neuroinflammation, as shown in multiple animal models of neurological disorders (spinal cord injury, amyotrophic lateral sclerosis, depression) (Lopez-Vales et al 2010, https: / / doi.org / 10.1523 / jneurosci.5770- 09.2010 ; Orienti et al 2021 , https: / / doi.Org / 10.1016 / j.neuroscience.2021.07.033; Skinner 2008, Molecular and neurological effects of fenretinide on Amyotrophic Lateral Sclerosis (Thesis T Skinner 2008, under supervision of Dr. Radzioch); Li et al 2020, https: / / doi.Org / 10.1016 / j.biopha.2019.109680 ).

[0092] Relevant for its potential benefit against Long COVID neurological conditions, fenretinide has shown ability to cross the blood-brain barrier and exert inflammation-controlling effect in multiple preclinical models of neuro-inflammation in spinal cord (Lopez-Vales et al 2010, https: / / doi.org / 10.1523 / jneurosci.5770-09.2010), and ALS (Orienti et al 2021 , https: / / doi.Org / 10.1016 / j.neuroscience.2021.07.033; Skinner 2008, Molecular and neurological effects of fenretinide on Amyotrophic Lateral Sclerosis, Thesis T Skinner 2008, under supervision of Dr. Radzioch). Oral fenretinide 5mg / kg / day for 28 days after spinal cord contusion injury in female BALB / c mice reduced inflammation and tissue damage in the spinal cord and improved locomotor recovery ((Lopez-Vales et al 2010, https: / / doi.org / 10.1523 / jneurosci.5770-09.2010). In a mouse model of ALS (SOD1-G93), fenretinide altered membrane PUFA concentration and resulted in delayed onset, improved motor coordination, and increased life expectancy (Skinner 2008, Molecular and neurological effects of fenretinide on Amyotrophic Lateral Sclerosis, Thesis T Skinner 2008, under supervision of Dr. Radzioch). Fenretinide was also shown to attenuate lipopolysaccharide (LPS)-induced blood-brain barrier (BBB) and depressive-like behavior in mice by targeting Nrf-2 signaling (Li et al 2020, https: / / doi.Org / 10.1016 / j.biopha.2019.109680). Li et al (2020) explored the regulatory role of fenretinide in LPS-triggered neuroinflammation, and the underlying molecular mechanisms. Results indicated that fenretinide is a potent Nrf2 (nuclear factor erythroid-2 related factor 2) activator, markedly improved Nrf2 expression and nuclear translocation in mouse brain endothelial cell line bEnd.3, and promoted Nrf2-antioxidant responsive element (ARE) transcription activity, as well as its down-streaming signals, which was Nrf2-dependent. Fenretinide also exhibited cytoprotective role in LPS-stimulated bEnd.3 cells through improving anti-oxidant capacity and inhibiting inflammation by the blockage of nuclear factor-kappa B (NF- KB) signaling. In the mouse model with brain injury induced by LPS, fenretinide administration markedly attenuated the behavior impairments, blood-brain- barrier (BBB) damage and the histological changes in hippocampus samples. Additionally, fenretinide attenuated oxidative stress and blunted inflammation in hippocampus of LPS- challenged mice. Overall results in the study highlighted the protective role of fenretinide against LPS-elicited brain injury (Li et al 2020, https: / / doi.Org / 10.1016 / j.biopha.2019.109680).

[0093] Of particular interest for Long COVID potential lung fibrotic sequels, fenretinide (LAU-7b formulation) was also shown to have anti-fibrotic potential as demonstrated in-vitro (human lung fibroblasts, HLF), ex-vivo (lung-on-a-chip microtissue model) and in-vivo in bleomycin- induced lung fibrosis mouse models (https: / / doi.org / 10.1164 / ajrccm- conference.2024.209.1_MeetingAbstracts.A1057; WO 2022 / 040782). Fenretinide was previously shown to inhibit certain membrane lipid desaturases involved in TGF-beta signaling and extracellular matrix deposition in lung fibroblasts. Bleomycin (BLM) model. Two in-vivo studies assessed LAU-7b antifibrotic effect after 14 days of treatment (Day 21 model), and 21 days of treatment (Day 28 model). Male C57BL / 6N mice received 2mg / kg bleomycin by single intratracheal instillation. Oral LAU-7b (12.5 and 25mg / kg per day) started on Day 7 post-bleomycin. Control BLM group received 10mL / kg of vehicle. Pirfenidone 100mg / kg was used as positive control. Fibrosis was evaluated using the Aschroft score (AS), pulmonary foci, collagen content and SpO2. Both BLM studies had similar outcomes, Day 21 data are presented. Compared to vehicle, LAU-7b dose-dependently reduced AS, significantly (p=0.013) with 25mg / kg dose, reduced the percentage of pulmonary foci (p=0.048) and reduced nearly significantly (p=0.057) the lung collagen content. Reduction of AS by pirfenidone was equivalent to 12.5mg / kg LAU-7b. All BLM-treated groups showed similar mild hypoxemia, (https: / / doi.org / 10.1164 / ajrccm- conference.2024.209.1_MeetingAbstracts.A1057; WO 2022 / 040782) In an ex-vivo lung-on-a- chip model, in-vitro 3D lung microtissues suspended over multiple flexible micropillars were used to assess fenretinide effect (2 and 4_,pM) on the inhibition of microtissue contractile force and fibrotic biomarkers expression induced by TGF£1 (5ng / mL).

[0094] (https: / / doi.org / 10.1164 / ajrccm-conference.2024.209.1_MeetingAbstracts.A1057; WO 2022 / 040782) Fenretinide reduced Day 6 TGF£1-induced microtissue stiffness, and SMA and procollagen markers of fibrosis in both preventative (Day 1) and therapeutic (Day 3) interventions. In an in-vitro model, HLF culture was exposed to myoblast differentiation inducer TGF£1 (2ng / mL) in the presence of 1-4pM of fenretinide, pirfenidone 1mg / mL (active control) or vehicle only. SMA and collagen type 1 transcript, protein levels, and endoplasmic reticulum stress markers BiP and CHOP levels were measured. Apoptosis was assessed by flow cytometry. Fenretinide caused exposure-proportional reductions in SMA and collagen type 1 transcript and protein levels (p=0.0001). Pirfenidone was not as effective as fenretinide but both combined resulted in significantly greater response. Fenretinide increased BiP and CHOP compared to TGFbl alone and induced less apoptosis than pirfenidone in the presence of TGFbl . (https: / / doi.org / 10.1164 / ajrccm- conference.2024.209.1_MeetingAbstracts.A1057; WO 2022 / 040782) Overall, fenretinide and l_AU-7b oral formulation showed positive, dose-dependent antifibrotic effect in all models tested, comparable or better than standard-of-care pirfenidone.

[0095] Other mechanisms are also proposed for fenretinide in Long COVID and similar infection- associated chronic diseases. A recent longitudinal case-control study provided new insights into the pathophysiology of post-exertional malaise in patients with Long COVID, showing affected mitochondrial function in skeletal muscles of long COVID patients. (Appelman et al 2024, https: / / doi.org / 10.1038 / s41467-023-44432-3) The data indicate that the lower exercise capacity in Long COVID patients is associated with a greater proportion of high-fatigable glycolytic fibers and lower mitochondrial function. The key metabolites of the tricarboxylic acid cycle (including glutamate, FAD+, alpha-ketoglutarate and citric acid) were lower in skeletal muscle of Long COVID patients. Potenza et al (2022, https: / / doi.org / 10.3390 / ijms23137426 ) describes fenretinide ability to replace retinol in the mitochondrial signalosome and activate the pyruvate dehydrogenase complex (PDHC) that feeds the tricarboxylic acid cycle (TCA) leading to generation of reactive oxygen species (ROS) and adenosine triphosphate (ATP), a nucleotide that provides the energy during muscle contraction. This mechanism can be helpful in Long COVID patients with muscular fatigue, particularly at low fenretinide plasma concentrations (1uM to 3uM). Independent work by Hayashi et al (2022, https: / / doi.org / 10.1093 / jb / mvad020) also showed that the decrease in SARS-CoV-2 spike protein-mediated membrane fusion and membrane fluidity by low-dose fenretinide was due to ROS generation and associated with the fenretinide inhibitory effect on SARS-CoV-2 entry into the host cell.

[0096] The present invention arises from the observed correlation between administration of fenretinide to a human and reduction of inflammation and fibrosis, modulation of cellular membrane lipids physiology, and activation of mitochondrial function at low doses of fenretinide to provides the energy during muscle contraction. Further, oral fenretinide formulations demonstrate the ability to access multiple organ-systems in a human, including crossing the blood-brain barrier. Long COVID patients demonstrate symptoms inconsistent with multi-organ systems negatively affected by and consistent with chronic, organ system localized, inflammation and related tissular damage, as a long-term consequence of the initial infection, which may be or not associated with persistence of virus reservoirs. The present invention provides for a therapeutic intervention for Long COVID patients by means of administration of an effective dose of fenretinide, as described herein.

[0097] While particular embodiments of the present invention have been described in the foregoing, it is to be understood that other embodiments are possible within the scope of the invention and are intended to be included herein. It will be clear to any person skilled in the art that modifications of and adjustments to this invention, not shown, are possible without departing from the spirit of the invention as demonstrated through the exemplary embodiments. The invention is therefore to be considered limited solely by the scope of the appended claims.

[0098] The following examples are given for the purpose of illustrating various embodiments of the disclosure and are not meant to limit the present disclosure in any fashion. The present examples, along with the methods described herein are presently representative of embodiments and are exemplary and are not intended as limitations on the scope of the disclosure.

[0099] EXAMPLES

[0100] Example 1 : Improvement of Quality of Life in COVID-19 patients from administration of fenretinide

[0101] Quality-of-Life (QoL) was evaluated as part of a randomized (1 :1), placebo-controlled Phase 3 RESOLUTION clinical study with LAU-7b in hospitalized adult patients with moderate to severe COVID-19 (Clinicaltrials.gov, #NCT04417257). In this study, 300mg of fenretinide was administered orally as LAU-7b, once-a-day for three (3) days, followed by once-a-day oral administration of LAU-7b fenretinide 200mg dose for eleven (11) days. The change from baseline to Days 14, 29, 45 and 60 in the score obtained on the EuroQol- 5D questionnaire (EQ-5D-5L) index, a well-documented scoring system that has been widely used and validated as a QoL assessment tool, compared between the active and control (placebo) treatment groups of the study, in subjects reaching Days 14, 29, 45 and 60 and able to fill the questionnaire. A longer-term assessment was set around 2 months’ postrandomization.

[0102] For the ITT population (N=119; LAU-7b arm N=57; Placebo arm N=62), mean (SD) EQ-5D- 5L scores ranged changed from 0.597 (0.3083) at screening to 0.830 (0.1803) at Day 60 for the LAU-7b treatment group and from 0.517 (0.3236) at baseline to 0.774 (0.2924) at Day 60 for the placebo treatment group (Table 1).

[0103] TABLE 1 :

[0104] Lau-7b Placebo

[0105] Visit (N=57) (N=62)

[0106] QoL improvement was numerically larger and happened earlier in the LAU-7b treatment group. The change from baseline in EQ-5D-5L score analyzed by Mixed Model Repeated Measures (MMRM). A positive change from baseline value represents an improvement of the quality of life, and a higher value indicates a better health status improvement.

[0107] Of particular interest for Long COVID are the values post Day 29 (at Day 45 and Day 60), where there is a clinically meaningful change in EQ-5D-5L index, LAU-7b relative to placebo. The change from baseline in EQ-5D-5L index is above the threshold of 0.26 representing a minimal clinically important difference (MCID) at 8 weeks, as established for Long COVID patients by Corral et al, 2023.

[0108] Example 2: Improvement of fatigue in COVID-19 patients from administration of fenretinide

[0109] Fatigue / Tiredness symptom was monitored as part of the of a randomized (1:1), placebo- controlled Phase 3 RESOLUTION clinical study with LAU-7b in hospitalized adult patients with moderate to severe COVID-19 (Clinicaltrials.gov, #NCT04417257). In this study, 300mg of fenretinide was administered orally as LAU-7b, once-a-day for three (3) days, followed by once-a-day oral administration of LAU-7b fenretinide 200mg dose for eleven (11) days. This symptom of interest was evaluated at baseline and Day 60 in this Phase 3 study.

[0110] Fatigue is also part of the core symptoms in Long COVID and it’s persistence past Day 30 since initial infection has a particular relevance in this context.

[0111] 44 patients presented with fatigue / tiredness symptom at baseline in the LAU-7b group, versus 53 patients with fatigue / tiredness symptom at baseline in the placebo group. At Day 60, only 9 out of 44 (20.5%) patients reported fatigue / tiredness symptom in the LAU-7b group, versus 18 out of 53 (34%) patients in the placebo group, demonstrating a benefit for fenretinide in addressing persistent fatigue symptom after COVID-19 infection.

[0112] Example 3: Phase 2 / 3 clinical study with LAU-7b in adult patients with Long COVID

[0113] A multi-center, randomized, double-blind, placebo-controlled adaptive Phase 2 / 3 clinical study is conducted to evaluate the efficacy of LAU-7b in non-hospitalized adults with moderate to severe Long COVID symptoms. The goal of the study is to evaluate the efficacy of LAU-7b therapy + stable symptomatic standard-of-care relative to placebo + stable symptomatic standard-of-care at reducing the overall Long COVID burden by improving multiple dimensions of quality-of-life and alleviating the symptoms. Brain and lung are two of the most frequently affected organs in Long COVID, and LAU-7b is demonstrated as a disease-modifying medication for the treatment of Long COVID.

[0114] Up to 270 subjects with Long COVID will be randomized. Subjects will be 18 years and older, of both genders, diagnosed with Long COVID and exhibiting a Long COVID symptomatology including a minimum of one moderate to severe core Long COVID symptom. There is a minimum 12 weeks between the start (test positivity or symptom onset) of the causative COVID-19 infection and screening for this study, to ensure the symptoms are those of Long COVID. Each study arm will consist of three (3) treatment cycles of 14 days of treatment intake each spaced by a drug-free period of 14 days. Eligible subjects will be randomized (1 :1 :1) to receive in a blinded fashion, either:

[0115] ARM 1 (LAU-7b for 3 cycles): Three cycles of 14 days of once-a-day intake of LAU- 7b, each followed by a treatment intake pause of 14 days.

[0116] ARM 2 (l_AU-7b for 1 cycle, placebo for 2 cycles): One cycle of 14 days of once-a-day intake of l_AU-7b followed by a treatment intake pause of 14 days, then two cycles of 14 days of once-a-day intake of placebo, each followed by a treatment intake pause of 14 days.

[0117] ARM 3 (Placebo for 3 cycles): Three cycles of 14 days of once-a-day intake of placebo, each followed by a treatment intake pause of 14 days.

[0118] Subjects with Long COVID demonstrate a therapeutic benefit from administration of LAU-7b by way of change from baseline in the Medical Outcomes Study Short-Form-36 (SF-36) at Week 4, 8 and 12; patient Global Impression of Change at Week 4, 8 and 12; change from baseline in the FACIT-Fatigue scale at Week 4, 8 and 12; change from baseline in the DePaul Post-Exertional Malaise Questionnaire (DPEMQ) at Week 12; in the Daily Activity Long COVID Impact Score (DALCI Score©), at Week 4, 8, and 12; change from baseline in the EQ-5D-5L score at Week 4, 8 and 12; from baseline in the total number of Long COVID symptoms, at Week 4, 8 and 12; or change relative to baseline (percent change) of systemic biomarkers of hematologic, inflammation and immunologic functions, at Week 2 and 10 Demonstration of therapeutic benefit may also be observed from the proportion of subjects who judge to have regained their daily usual activity level of pre-causative-infection, at Week 4, 8 and 12; proportion of subjects with relief of at least one core Long COVID symptom for a minimum of 2 weeks, from baseline through Week 12; the proportion of subjects with a sustained clinical recovery, meaning a relief of all core Long COVID symptoms, by Week 4, 8 and 12; proportion of subjects with Long COVID-related unplanned medical visits, from Week 0 to Week 12; or time to relief of the first core Long COVID symptom for a minimum of 2 weeks, among those symptoms present at baseline. The core Long COVID symptoms are: fatigue, trouble sleeping, shortness of breath, general pain and discomfort, cognitive problems (most commonly known as brain fog or memory fog) and mental health symptoms (anxiety, depression). Change in the Daily Activity Long COVID Impact Score (DALCI Score©), at Week 4, 8, and 12. The DALCI Score is a novel proposed score that measures the impact of a core Long COVID symptoms on the ability of a subject to perform daily activities, in order to evaluate the overall burden of Long COVID on the subject's life and the impact of the treatment on attenuating such burden. Long COVID affects individuals differently, and there have been reports of over 200 symptoms. The core Long COVID symptoms must have persisted or started since the index infection and at least one of them be moderate or severe, for a minimum of 2 weeks prior to screening. Symptom(s) cannot be explained by an alternative etiology including a COVID re-infection. The core Long COVID symptoms will be assessed at screening and each study visit according to the schedule of events. The symptoms will each be graded for their severity / impact on daily activities, using a standard LIKERT scale shown below: (0) No symptom; (1) Mild symptom (no interference with daily activities); (2) Moderate symptom (interfere and may limit daily activities); (3) Severe symptom (strong interference preventing daily activities. With regards to their overall impact on daily activities, mild symptoms are considered "Non-burdensome", and moderate and severe symptoms are considered "Burdensome". These two encompassing categories, in particular the "Burdensome" category, are descriptors of the impact of the core LONG COVID symptoms on daily activities.

Claims

What is claimed is:

1. A method of treating Long COVID in a patient in need thereof, the method comprising administration to said patient a therapeutically effective amount of fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof.

2. The method of claim 1, wherein Long COVID comprises one or more conditions selected from functional impairment in performing daily activities, fatigue, post- exertional malaise, trouble sleeping, shortness of breath, general pain and discomfort, cognitive problems (memory loss, difficulty thinking or concentrating), mental health symptoms (anxiety, depression), fibromyalgia, and myalgic encephalomyelitis / chronic fatigue syndrome (ME / CFS).

3. The method of claim 1 wherein the therapeutically effective amount of fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof comprises 1 mg to 1000 mg of fenretinide daily.

4. The method of claim 3 wherein the therapeutically effective amount of fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof comprises 10 mg to 300 mg of fenretinide.

5. The method of claim 1 wherein the therapeutically effective amount of fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof gives rise to fenretinide plasma concentration in human of 0.5 pM to about 5 pM.

6. The method of claim 5 wherein the therapeutically effective amount of fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof gives rise to fenretinide plasma concentration in human of 1 pM to about 3 pM.

7. The method of claim 1, wherein fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administered orally, once daily, for 14 days or more.

8. The method of claim 1, wherein fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administered orally, once daily, for at least three months.

9. The method of claim 1, wherein fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is in amount of 200mg administrated orally as LAU-7b, once per day for fourteen (14) days.

10. The method of claim 1, wherein fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administrated orally as LAU-7b, in three (3) or more consecutive treatment cycles, each cycle consisting of 200 mg of fenretinideadministrated as LAU-7b once per day for fourteen (14) days, followed by a drug-free interval of fourteen (14) days.

11. The method of claim 1, wherein fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administered to patient with at least one other active agent.

12. The method of claim 11, wherein the at least one other active agent comprises an NSAID (non-steroidal anti-inflammatory drug), a corticosteroid, a COX-2 (cyclooxvgenase-2) inhibitor, an antidepressant, or a combination of two or more thereof.

13. A method of treating an infection-associated chronic condition in a patient in need thereof, the method comprising administration to said human of a therapeutically effective amount of fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof.

14. The method of claim 13 wherein the infection-associated chronic condition is post- viral syndrome, myalgic encephalomyelitis / chronic fatigue syndrome (ME / CFS), fibromyalgia, persistent Lyme disease (aka post-Lyme disease), or multiple sclerosis occurring with Epstein-Barr virus (EBV).

15. The method of claim 13 wherein the therapeutically effective amount of fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof comprises 1 mg to 1 ,000 mg of fenretinide daily.

16. The method of claim 15 wherein the therapeutically effective amount of fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof comprises 10 mg to 300 mg of fenretinide.

17. The method of claim 13 wherein the therapeutically effective amount of fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof gives rise to fenretinide plasma concentration in human of 0.5 mM to about 5 mM18. The method of claim 17 wherein the therapeutically effective amount of fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof gives rise to fenretinide plasma concentration in human of 1 pM to about 3 pM.

19. The method of claim 13, wherein fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administered orally, once daily, for 14 days or more.

20. The method of claim 13, wherein fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administered orally, once daily, for at least three months.

21. The method of claim 13, wherein fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is in amount of 200mg administrated orally as LAU-7b, once per day for fourteen (14) days.

22. The method of claim 13, wherein fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administrated orally as LAU-7b, in three (3) or more consecutive treatment cycles, each cycle consisting of 200 mg of fenretinide administrated as LAU-7b once per day for fourteen (14) days, followed by a drug-free interval of fourteen (14) days.

23. The method of claim 13, wherein fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administered to patient with at least one other active agent.

24. The method of claim 23, wherein the at least one other active agent comprises an NSAID (non-steroidal anti-inflammatory drug), a corticosteroid, a COX-2 (cyclooxvgenase-2) inhibitor, an antidepressant, or a combination of two or more thereof.

25. A pharmaceutical composition comprising a therapeutically effective amount of fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof for treating Long COVID in a patient in need thereof.

26. The pharmaceutical composition of claim 25 wherein Long COVID comprises one or more conditions selected from functional impairment in performing daily activities, fatigue, post-exertional malaise, trouble sleeping, shortness of breath, general pain and discomfort, cognitive problems (memory loss, difficulty thinking or concentrating), mental health symptoms (anxiety, depression), fibromyalgia, and myalgic encephalomyelitis / chronic fatigue syndrome (ME / CFS).

27. The pharmaceutical composition of claim 25 wherein fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof comprises 1 mg to 1,000 mg of fenretinide daily.

28. The pharmaceutical composition of claim 27 wherein fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof comprises 10 mg to 300 mg of fenretinide.

29. The pharmaceutical composition of claim 25 wherein administration of fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof gives rise to fenretinide plasma concentration in human of 0.5 pM to about 5 pM.

30. The pharmaceutical composition of claim 29 wherein administration of fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof gives rise to fenretinide plasma concentration in human of 1 pM to about 3 pM.

31. The pharmaceutical composition of claim 25, wherein fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administered orally, once daily, for 14 days or more.

32. The pharmaceutical composition of claim 25, wherein fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administered orally, once daily, for at least three months.

33. The pharmaceutical composition of claim 25, wherein fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is in amount of 200mg administrated orally as LAU-7b, once per day for fourteen (14) days.

34. The pharmaceutical composition of claim 25, wherein fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administrated orally as LAU-7b, in three (3) or more consecutive treatment cycles, each cycle consisting of 200 mg of fenretinide administrated as LAU-7b once per day for fourteen (14) days, followed by a drug-free interval of fourteen (14) days.

35. The pharmaceutical composition of claim 25, wherein fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administered to patient with at least one other active agent.

36. The pharmaceutical composition of claim 35, wherein the at least one other active agent comprises an NSAID (non-steroidal anti-inflammatory drug), a corticosteroid, a COX-2 (cyclooxvgenase-2) inhibitor, an antidepressant, or a combination of two or more thereof.

37. The use of fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof for the preparation of a pharmaceutical composition for the treatment of an infection- associated chronic condition in a patient in need thereof.

38. The pharmaceutical composition of claim 37, wherein the infection-associated chronic condition is post-viral syndrome, myalgic encephalomyelitis / chronic fatigue syndrome (ME / CFS), fibromyalgia, persistent Lyme disease (aka post-Lyme disease), or multiple sclerosis occurring with Epstein-Barr virus (EBV).

39. The pharmaceutical composition of claim 37 wherein fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof comprises 1 mg to 1,000 mg of fenretinide.

40. The pharmaceutical composition of claim 39 wherein fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof comprises 10 mg to 300 mg of fenretinide.

41. The pharmaceutical composition of claim 37 wherein administration of fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof gives rise to fenretinide plasma concentration in human of 0.5 pM to about 5 pM.

42. The pharmaceutical composition of claim 41 wherein administration of fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof gives rise to fenretinide plasma concentration in human of 1 pM to about 3 pM.

43. The pharmaceutical composition of claim 37, wherein fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administered orally, once daily, for 14 days or more.

44. The pharmaceutical composition of claim 37, wherein fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administered orally, once daily, for at least three months.

45. The pharmaceutical composition of claim 37, wherein fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is in amount of 200mg administrated orally as LAU-7b, once per day for fourteen (14) days.

46. The pharmaceutical composition of claim 37, wherein fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administrated orally as LAU-7b, in three (3) or more consecutive treatment cycles, each cycle consisting of 200 mg of fenretinide administrated as LAU-7b once per day for fourteen (14) days, followed by a drug-free interval of fourteen (14) days.

47. The pharmaceutical composition of claim 37, wherein fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administered to patient with at least one other active agent.

48. The pharmaceutical composition of claim 47, wherein the at least one other active agent comprises an NSAID (non-steroidal anti-inflammatory drug), a corticosteroid, a COX-2 (cyclooxvgenase-2) inhibitor, an antidepressant, or a combination of two or more thereof.

49. A method of treating or attenuating functional impairment in performing daily activities in a patient with Long COVID, the method comprising administration to said patient a therapeutically effective amount of fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof.

50. The method of claim 49 wherein the therapeutically effective amount of fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof comprises 1 mg to 1000 mg of fenretinide daily.

51. The method of claim 50 wherein the therapeutically effective amount of fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof comprises 10 mg to 300 mg of fenretinide.

52. The method of claim 48 wherein the therapeutically effective amount of fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof gives rise to fenretinide plasma concentration in human of 0.5 pM to about 5 pM.

53. The method of claim 52 wherein the therapeutically effective amount of fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof gives rise to fenretinide plasma concentration in human of 1 pM to about 3 pM.

54. The method of claim 48, wherein fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administered orally, once daily, for 14 days or more.

55. The method of claim 48, wherein fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administered orally, once daily, for at least three months.

56. The method of claim 48, wherein fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is in amount of 200mg administrated orally as LAU-7b, once per day for fourteen (14) days.

57. The method of claim 48, wherein fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administrated orally as LAU-7b, in three (3) or more consecutive treatment cycles, each cycle consisting of 200 mg of fenretinide administrated as LAU-7b once per day for fourteen (14) days, followed by a drug-free interval of fourteen (14) days.

58. The method of claim 48, wherein fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administered to patient with at least one other active agent.

59. The method of claim 58, wherein the at least one other active agent comprises an NSAID (non-steroidal anti-inflammatory drug), a corticosteroid, a COX-2 (cyclooxvgenase-2) inhibitor, an antidepressant, or a combination of two or more thereof.

60. A pharmaceutical composition comprising a therapeutically effective amount of fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof for treatingor attenuating functional impairment in performing daily activities in a patient with Long COVID.

61. The pharmaceutical composition of claim 60 wherein fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof comprises 1 mg to 1,000 mg of fenretinide daily.

62. The pharmaceutical composition of claim 61 wherein fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof comprises 10 mg to 300 mg of fenretinide.

63. The pharmaceutical composition of claim 60 wherein administration of fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof gives rise to fenretinide plasma concentration in human of 0.5 pM to about 5 pM.

64. The pharmaceutical composition of claim 63 wherein administration of fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof gives rise to fenretinide plasma concentration in human of 1 pM to about 3 pM.

65. The pharmaceutical composition of claim 60, wherein fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administered orally, once daily, for 14 days or more.

66. The pharmaceutical composition of claim 60, wherein fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administered orally, once daily, for at least three months.

67. The pharmaceutical composition of claim 60, wherein fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is in amount of 200mg administrated orally as LAU-7b, once per day for fourteen (14) days.

68. The pharmaceutical composition of claim 60, wherein fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administrated orally as LAU-7b, in three (3) or more consecutive treatment cycles, each cycle consisting of 200 mg of fenretinide administrated as LAU-7b once per day for fourteen (14) days, followed by a drug-free interval of fourteen (14) days.

69. The pharmaceutical composition of claim 60, wherein fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administered to patient with at least one other active agent.

70. The pharmaceutical composition of claim 60, wherein the at least one other active agent comprises an NSAID (non-steroidal anti-inflammatory drug), a corticosteroid, aCOX-2 (cyclooxvgenase-2) inhibitor, an antidepressant, or a combination of two or more thereof.

71. A method of treating or attenuating functional impairment in performing daily activities in a patient with an infection-associated chronic condition, the method comprising administration to said patient a therapeutically effective amount of fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof.

72. The method of claim 71 wherein the infection-associated chronic condition is post- viral syndrome, myalgic encephalomyelitis / chronic fatigue syndrome (ME / CFS), fibromyalgia, persistent Lyme disease (aka post-Lyme disease), or multiple sclerosis occurring with Epstein-Barr virus (EBV).

73. The method of claim 71 wherein the therapeutically effective amount of fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof comprises 1 mg to 1000 mg of fenretinide daily.

74. The method of claim 73 wherein the therapeutically effective amount of fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof comprises 10 mg to 300 mg of fenretinide.

75. The method of claim 71 wherein the therapeutically effective amount of fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof gives rise to fenretinide plasma concentration in human of 0.5 pM to about 5 pM.

76. The method of claim 75 wherein the therapeutically effective amount of fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof gives rise to fenretinide plasma concentration in human of 1 pM to about 3 pM.

77. The method of claim 71, wherein fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administered orally, once daily, for 14 days or more.

78. The method of claim 71, wherein fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administered orally, once daily, for at least three months.

79. The method of claim 71, wherein fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is in amount of 200mg administrated orally as LAU-7b, once per day for fourteen (14) days.

80. The method of claim 71, wherein fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administrated orally as LAU-7b, in three (3) or more consecutive treatment cycles, each cycle consisting of 200 mg of fenretinideadministrated as LAU-7b once per day for fourteen (14) days, followed by a drug-free interval of fourteen (14) days.

81. The method of claim 71, wherein fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administered to patient with at least one other active agent.

82. The method of claim 81, wherein the at least one other active agent comprises an NSAID (non-steroidal anti-inflammatory drug), a corticosteroid, a COX-2 (cyclooxvgenase-2) inhibitor, an antidepressant, or a combination of two or more thereof.

83. A pharmaceutical composition comprising a therapeutically effective amount of fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof for treating or attenuating functional impairment in performing daily activities in a patient with an infection-associated chronic condition.

84. The pharmaceutical composition of claim 83 wherein the infection-associated chronic condition is post-viral syndrome, myalgic encephalomyelitis / chronic fatigue syndrome (ME / CFS), fibromyalgia, persistent Lyme disease (aka post-Lyme disease), or multiple sclerosis occurring with Epstein-Barr virus (EBV) and the functional impairment in performing daily activities is selected from fatigue, post-exertional malaise, trouble sleeping, shortness of breath, general pain and discomfort, cognitive problems (memory loss, difficulty thinking or concentrating), mental health symptoms (anxiety, depression).

85. The pharmaceutical composition of claim 83 wherein fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof comprises 1 mg to 1,000 mg of fenretinide daily.

86. The pharmaceutical composition of claim 85 wherein fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof comprises 10 mg to 300 mg of fenretinide.

87. The pharmaceutical composition of claim 83 wherein administration of fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof gives rise to fenretinide plasma concentration in human of 0.5 pM to about 5 pM.

88. The pharmaceutical composition of claim 87 wherein administration of fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof gives rise to fenretinide plasma concentration in human of 1 pM to about 3 pM.

89. The pharmaceutical composition of claim 83, wherein fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administered orally, once daily, for 14 days or more.

90. The pharmaceutical composition of claim 83, wherein fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administered orally, once daily, for at least three months.

91. The pharmaceutical composition of claim 83, wherein fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is in amount of 200mg administrated orally as LAU-7b, once per day for fourteen (14) days.

92. The pharmaceutical composition of claim 83, wherein fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administrated orally as LAU-7b, in three (3) or more consecutive treatment cycles, each cycle consisting of 200 mg of fenretinide administrated as LAU-7b once per day for fourteen (14) days, followed by a drug-free interval of fourteen (14) days.

93. The pharmaceutical composition of claim 83, wherein fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administered to patient with at least one other active agent.

94. The pharmaceutical composition of claim 83, wherein the at least one other active agent comprises an NSAID (non-steroidal anti-inflammatory drug), a corticosteroid, a COX-2 (cyclooxvgenase-2) inhibitor, an antidepressant, or a combination of two or more thereof.

95. A method of treating or attenuating one or more symptoms of an infection associated chronic condition in a human, the method comprising administration to said patient a therapeutically effective amount of fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof.

96. The method of claim 95 wherein the symptoms are selected from fatigue, post- exertional malaise, trouble sleeping, shortness of breath, general pain and discomfort, cognitive problems (memory loss, difficulty thinking or concentrating) and mental health symptoms (anxiety, depression).

97. The method of claim 96 wherein the therapeutically effective amount of fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof comprises 1 mg to98. The method of claim 97 wherein the therapeutically effective amount of fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof comprises 10 mg to 300 mg of fenretinide.

99. The method of claim 96 wherein the therapeutically effective amount of fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof gives rise to fenretinide plasma concentration in human of 0.5 pM to about 5 pM.

100. The method of claim 99 wherein the therapeutically effective amount of fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof gives rise to fenretinide plasma concentration in human of 1 pM to about 3 pM.

101. The method of claim 96, wherein fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administered orally, once daily, for 14 days or more.

102. The method of claim 96, wherein fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administered orally, once daily, for at least three months.

103. The method of claim 96, wherein fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is in amount of 200mg administrated orally as LAU-7b, once per day for fourteen (14) days.

104. The method of claim 96, wherein fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administrated orally as LAU-7b, in three (3) or more consecutive treatment cycles, each cycle consisting of 200 mg of fenretinide administrated as l_AU-7b once per day for fourteen (14) days, followed by a drug-free interval of fourteen (14) days.

105. The method of claim 96, wherein fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administered to patient with at least one other active agent.

106. The method of claim 105, wherein the at least one other active agent comprises an NSAID (non-steroidal anti-inflammatory drug), a corticosteroid, a COX- 2 (cyclooxvgenase-2) inhibitor, an antidepressant, or a combination of two or more thereof.

107. A pharmaceutical composition comprising a therapeutically effective amount of fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof fortreating or attenuating one or more symptoms of an infection associated chronic condition in a human.

108. The pharmaceutical composition of claim 107 wherein the symptoms are selected from fatigue, post-exertional malaise, trouble sleeping, shortness of breath, general pain and discomfort, cognitive problems (memory loss, difficulty thinking or concentrating) and mental health symptoms (anxiety, depression).

109. The pharmaceutical composition of claim 108 wherein fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof comprises 1 mg to 1,000 mg of fenretinide daily.

110. The pharmaceutical composition of claim 109 wherein fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof comprises 10 mg to 300 mg of fenretinide.

111. The pharmaceutical composition of claim 108 wherein administration of fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof gives rise to fenretinide plasma concentration in human of 0.5 pM to about 5 pM.

112. The pharmaceutical composition of claim 111 wherein administration of fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof gives rise to fenretinide plasma concentration in human of 1 pM to about 3 pM.

113. The pharmaceutical composition of claim 108, wherein fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administered orally, once daily, for 14 days or more.

114. The pharmaceutical composition of claim 108, wherein fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administered orally, once daily, for at least three months.

115. The pharmaceutical composition of claim 108, wherein fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is in amount of 200mg administrated orally as LAU-7b, once per day for fourteen (14) days.

116. The pharmaceutical composition of claim 108, wherein fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administrated orally as LAU-7b, in three (3) or more consecutive treatment cycles, each cycle consisting of 200 mg of fenretinide administrated as LAU-7b once per day for fourteen (14) days, followed by a drug-free interval of fourteen (14) days.

117. The pharmaceutical composition of claim 108, wherein fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administered to patient with at least one other active agent.

118. The pharmaceutical composition of claim 108, wherein the at least one other active agent comprises an NSAID (non-steroidal anti-inflammatory drug), a corticosteroid, a COX-2 (cyclooxvgenase-2) inhibitor, an antidepressant, or a combination of two or more thereof.

119. A method of treating or attenuating one or more symptoms of Long COVID in a human, the method comprising administration to said patient a therapeutically effective amount of fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof.

120. The method of claim 119 wherein the symptoms are selected from fatigue, post-exertional malaise, trouble sleeping, shortness of breath, general pain and discomfort, cognitive problems (memory loss, difficulty thinking or concentrating) and mental health symptoms (anxiety, depression).

121. The method of claim 120 wherein the therapeutically effective amount of fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof comprises 1 mg to 1000 mg of fenretinide daily.

122. The method of claim 121 wherein the therapeutically effective amount of fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof comprises 10 mg to 300 mg of fenretinide.

123. The method of claim 120 wherein the therapeutically effective amount of fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof gives rise to fenretinide plasma concentration in human of 0.5 pM to about 5 pM.

124. The method of claim 123 wherein the therapeutically effective amount of fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof gives rise to fenretinide plasma concentration in human of 1 pM to about 3 pM.

125. The method of claim 120, wherein fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administered orally, once daily, for 14 days or more.

126. The method of claim 120, wherein fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administered orally, once daily, for at least three months.

127. The method of claim 120, wherein fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is in amount of 200mg administrated orally as LAU-7b, once per day for fourteen (14) days.

128. The method of claim 120, wherein fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administrated orally as LAU-7b, in three (3) or more consecutive treatment cycles, each cycle consisting of 200 mg of fenretinide administrated as l_AU-7b once per day for fourteen (14) days, followed by a drug-free interval of fourteen (14) days.

129. The method of claim 120, wherein fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administered to patient with at least one other active agent.

130. The method of claim 129, wherein the at least one other active agent comprises an NSAID (non-steroidal anti-inflammatory drug), a corticosteroid, a COX- 2 (cyclooxvgenase-2) inhibitor, an antidepressant, or a combination of two or more thereof.

131. A pharmaceutical composition comprising a therapeutically effective amount of fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof for treating or attenuating one or more symptoms of Long COVID in a human.

132. The pharmaceutical composition of claim 131 wherein the symptoms are selected from fatigue, post-exertional malaise, trouble sleeping, shortness of breath, general pain and discomfort, cognitive problems (memory loss, difficulty thinking or concentrating) and mental health symptoms (anxiety, depression).

133. The pharmaceutical composition of claim 132 wherein fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof comprises 1 mg to 1,000 mg of fenretinide daily.

134. The pharmaceutical composition of claim 133 wherein fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof comprises 10 mg to 300 mg of fenretinide.

135. The pharmaceutical composition of claim 132 wherein administration of fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof gives rise to fenretinide plasma concentration in human of 0.5 pM to about 5 pM.

136. The pharmaceutical composition of claim 135 wherein administration of fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof gives rise to fenretinide plasma concentration in human of 1 pM to about 3 pM.

137. The pharmaceutical composition of claim 132, wherein fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administered orally, once daily, for 14 days or more.

138. The pharmaceutical composition of claim 132, wherein fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administered orally, once daily, for at least three months.

139. The pharmaceutical composition of claim 132, wherein fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is in amount of 200mg administrated orally as LAU-7b, once per day for fourteen (14) days.

140. The pharmaceutical composition of claim 132, wherein fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administrated orally as LAU-7b, in three (3) or more consecutive treatment cycles, each cycle consisting of 200 mg of fenretinide administrated as LAU-7b once per day for fourteen (14) days, followed by a drug-free interval of fourteen (14) days.

141. The pharmaceutical composition of claim 132, wherein fenretinide, fenretinide analog or pharmaceutically acceptable salt thereof, is administered to patient with at least one other active agent.

142. The pharmaceutical composition of claim 132, wherein the at least one other active agent comprises an NSAID (non-steroidal anti-inflammatory drug), a corticosteroid, a COX-2 (cyclooxvgenase-2) inhibitor, an antidepressant, or a combination of two or more thereof.

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