Tradipitant for the treatment of lower respiratory tract infections

Abstract

For example, disclosed herein are methods for treating lower respiratory tract infections caused by coronavirus disease (COVID-19), influenza, or other viruses, comprising treatment with the NK-1 receptor antagonist, tradipitant.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 000,477, filed March 26, 2020; U.S. Provisional Patent Application No. 63 / 001,248, filed March 27, 2020; U.S. Provisional Patent Application No. 63 / 002,323, filed March 30, 2020; and U.S. Provisional Patent Application No. 63 / 067,298, filed August 18, 2020.

[0002] The present invention relates to a method for treating lower respiratory tract infections, including associated symptoms, with tradipitant. More particularly, the present invention relates to a method for treating patients suffering from viral pneumonia, e.g., caused by COVID-19, influenza, or another respiratory virus. Such treatment offers such patients an opportunity for accelerated improvement in clinical outcomes associated with severe or critical COVID-19 infection. [Background technology]

[0003] Severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) is a novel coronavirus that causes coronavirus disease (COVID-19), a highly contagious respiratory illness. COVID-19 was declared a pandemic by the World Health Organization (WHO) on March 11, 2020, and has a mortality rate that may exceed 1%. The virus is understood to be transmitted from person to person via droplets or contact. Common symptoms include fever, chills, cough, shortness of breath or difficulty breathing, fatigue, muscle or body aches, headache, new loss of taste or smell, sore throat, nasal congestion, nausea or vomiting, and diarrhea. Symptoms in some patients, including headache, nausea, and vomiting, have raised concerns about the potential neuroinvasive potential of COVID-19.

[0004] In addition, many hospitalized patients experience severe pneumonia accompanied by acute respiratory distress syndrome (ARDS), which can lead to respiratory failure. Cytokine storm has been observed as a complication of COVID-19, and pulmonary fibrosis has also been observed after recovery from COVID-19. The disease pattern is similar to that observed in disease caused by SARS-CoV (Severe Acute Respiratory Syndrome). There is an urgent need for COVID-19 treatments that confer improved patient outcomes, including potentially reduced morbidity and mortality. Successful treatments for COVID-19 have been achieved through the use of the antimalarial drugs chloroquine and hydroxychloroquine, as well as remdesivir. However, there is a need for treatments that can prevent or treat cytokine storm and ARDS, which can lead to respiratory failure and high mortality in patients with COVID-19, as well as reduce the inflammatory lung injury and fibrosis that can persist after recovery from COVID-19 infection.

[0005] Mammalian tachykinins (neurokinins [NK]) are a family of peptide neurotransmitters that share a common C-terminal sequence. This group includes substance P (SP), neurokinin-A (NKA), and neurokinin-B (NKB). SP is the most abundant NK, preferentially binds to the neurokinin type-1 (NK-1) receptor, and is involved in the regulation of many physiological processes, including pulmonary neurogenic inflammation.

[0006] NK-1 receptors have been mapped to the central nervous system and have been found to have a wide distribution in the brain, including the midbrain, basal ganglia, hypothalamus, and limbic system. Neurokinin receptors are also widely distributed in the gastrointestinal tract, bronchial tree, and vasculature.

[0007] Tradipitant is a highly potent, selective, centrally penetrating, orally active NK-1 receptor antagonist and has the structure shown below as Formula I.

[0008] [ka]

[0009] Tradipitant, disclosed in U.S. Patent No. 7,320,994, has six main structural components: a 3,5-bis-trifluoromethylphenyl moiety, two pyridine rings, a triazole ring, a chlorophenyl ring, and methanone. Tradipitant is known by the chemical names 2-[1-[[3,5-bis(trifluoromethyl)phenyl]methyl]-5-(4-pyridinyl)-1H-1,2,3-triazol-4-yl]-3-pyridinyl](2-chlorophenyl)-methanone and {2-[1-(3,5-bistrifluoromethylbenzyl)-5-pyridin-4-yl-1H-[1,2,3]triazol-4-yl]-pyridin-3-yl}-(2-chlorophenyl)-methanone, and is also known as VLY-6868, formerly LY686017. Crystalline Form IV and Form V of tradipitant are disclosed in U.S. Pat. No. 7,381,826, and processes for preparing crystalline {2-[1-(3,5-bistrifluoromethylbenzyl)-5-pyridin-4-yl-1H-[1,2,3]triazol-4-yl]-pyridin-3-yl}-(2-chlorophenyl)-methanone, Form IV, are disclosed in U.S. Pat. Nos. 8,772,496 and 9,708,291.

[0010] U.S. Patent No. 7,320,994 describes the use of compounds such as tradipitant to treat conditions associated with excess tachykinins, most particularly depression and anxiety. U.S. Patent No. 7,320,994 further describes the use of compounds such as tradipitant in other such diseases, because these compounds inhibit the physiological effects associated with excess tachykinins. The patent describes the use of compounds such as tradipitant in other such diseases, namely, psychosis, schizophrenia, and other psychotic disorders; neurodegenerative disorders such as dementia, including Alzheimer's disease, AIDS-related dementia, and Down's syndrome; demyelinating diseases such as multiple sclerosis and amyotrophic lateral sclerosis, and other neuropathological diseases such as peripheral neuropathy, diabetes, and chemotherapy-induced neuropathy, as well as post-herpetic and other neuralgias; adult respiratory distress syndrome, bronchopneumonia, bronchospasm, Acute and chronic obstructive airway diseases such as chronic bronchitis, drivercough, and asthma; inflammatory diseases such as inflammatory bowel disease, psoriasis, fibrositis, osteoarthritis, and rheumatoid arthritis; musculoskeletal disorders such as osteoporosis; allergies such as eczema and rhinitis; hypersensitivity disorders such as poison ivy; eye diseases such as conjunctivitis and vernal conjunctivitis; skin diseases such as contact dermatitis, atopic dermatitis, hives, and other eczema-like dermatitis; and alcoholism. and vomiting, including chemotherapy-induced nausea and vomiting; and a number of other disorders related to tachykinin receptor activation, including, for example, pain or nociception caused by any of the above conditions.Finally, the patent states that such compounds are effective in amounts that are expected to vary from about 0.001 mg / kg / day to about 100 mg / kg / day.

[0011] Tradipitant is known to be administered therapeutically via various routes of administration where it is bioavailable. U.S. Patent No. 7,320,994 discloses oral and parenteral administration of tradipitant, e.g., oral, inhalation, subcutaneous, intramuscular, intravenous, transdermal, intranasal, rectal, ocular, topical, sublingual, and buccal, with oral administration generally being preferred for treatment. In addition, the use of tradipitant in the treatment of pruritus and atopic dermatitis is disclosed in WO 2016 / 141341, in gastric motility disorders including gastroparesis in WO 2019 / 099883, and in motion sickness in WO 2020 / 069092. Summary of the Invention

[0012] Embodiments of the present invention provide methods of treating a patient diagnosed with a lower respiratory tract infection, comprising administering to the patient tradipitant in an amount effective to treat the lower respiratory tract infection or at least one symptom thereof. The lower respiratory tract infection may be a viral infection and may further be viral pneumonia, which may be acute in appearance. The viral pneumonia may be caused by or associated with SARS-CoV2 infection, i.e., COVID-19 infection, influenza infection, or other viral respiratory diseases. According to some embodiments, in addition to tradipitant treatment, the patient may be hospitalized and treated according to the standard of care for the specific lower respiratory tract infection diagnosed, including the use of invasive mechanical ventilation, extracorporeal membrane oxygenation (ECMO), non-invasive ventilation, high-flow oxygen devices, or supplemental oxygen, if indicated. Symptoms of such lower respiratory tract infections can include, for example, fever, shortness of breath, cough, pneumonia, evidence of inflammatory lung damage, and other symptoms.

[0013] Treatment of the patient may involve oral administration of a solid immediate release form containing tradipitant and one or more pharmaceutically acceptable excipients, where the tradipitant dose is 100-400 mg / day, 100-300 mg / day, or 100-200 mg / day; 150-400 mg / day, 150-300 mg / day, or 150-200 mg / day; about 170 mg / day; or about 85 mg twice daily (bid). Alternatively, the tradipitant may be administered orally in a solid controlled release form containing tradipitant and one or more pharmaceutically acceptable excipients, or may be administered orally or intravenously in a liquid suspension form. Treatment may continue for 7 days, 14 days, or longer, for example, in cases requiring hospitalization for more than 14 days. Treatment may further include co-administration with an antiviral therapeutic agent, such as, for example, remdesivir.

[0014] With respect to aspects of the present invention, treating the lower respiratory tract infection includes, but is not limited to: shortening the duration until the patient achieves clinical improvement, accelerating recovery from the lower respiratory tract infection, preventing, slowing, or reducing the progression of the lower respiratory tract infection in the patient, complete resolution of symptoms, preventing respiratory deterioration in the patient, and / or preventing lung damage in the patient after recovery from the lower respiratory tract infection.

[0015] A second aspect of the present invention provides tradipitant for use in any of the above methods of treatment.

[0016] A third aspect of the present invention provides a pharmaceutical composition comprising tradipitant for use in any of the above methods of treatment.

[0017] A fourth aspect of the present invention provides tradipitant for use in the manufacture of a pharmaceutical composition comprising tradipitant for use in any of the above methods of treatment.

[0018] These and other aspects, advantages and salient features of the present invention will become apparent from the following detailed description, which discloses embodiments of the invention. [Brief explanation of the drawings]

[0019] [Figure 1] FIG. 1 shows a plot of time to 2 or more point improvement at day 7 in the intent-to-treat (ITT) population described in Example 1 herein. [Figure 2] FIG. 2 shows a plot of time to 2 or more point improvement at day 28 in the intent-to-treat (ITT) population described in Example 1 herein. DETAILED DESCRIPTION OF THE INVENTION

[0020] The figures are intended to depict only typical aspects of the disclosure, and therefore should not be considered as limiting the scope of the disclosure.

[0021] In various embodiments of the present invention, the methods described herein include methods for treating patients diagnosed with a lower respiratory tract infection, i.e., an infectious disease that causes lung damage. Causes of lower respiratory tract infections are known in the art. However, in various embodiments, the lower respiratory tract infection is a viral disease or infection, or more specifically, a viral respiratory infection. Such viral infections can include, for example, coronavirus disease (COVID-19) and associated pneumonia, as well as pneumonia caused by or associated with infection with other viruses, e.g., severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV), influenza, and pneumonia secondary to the common cold, such as that caused by rhinovirus, coronavirus, or respiratory syncytial virus (RSV). In other embodiments, the lower respiratory tract infection can be bacterial pneumonia, including, for example, that caused by Streptococcus pneumoniae infection. The methods described herein can be applicable to treating patients who have been confirmed to have or are suspected of having an infectious disease, e.g., COVID-19, SARS, influenza, etc.

[0022] As used herein, treatment of a lower respiratory tract infection may be considered to include reducing the severity of symptoms, preventing or alleviating progression, or completely resolving one or more symptoms of the lower respiratory tract infection, e.g., COVID-19, acute pneumonia, and other infections after such symptom(s) appear in a patient. For example, reducing severity may include successfully transitioning from invasive mechanical ventilation to non-invasive ventilation or a high-flow oxygen device, successfully transitioning from these forms of respiratory support to simply supplemental oxygen, successfully removing supplemental oxygen, and being discharged from the hospital. Preventing or alleviating progression may include, for example, avoiding the need for supplemental oxygen from escalating to the need for more invasive ventilation and respiratory support. Treatment may particularly include preventing or reducing inflammatory lung injury caused by the infectious diseases described above, including the resolution of acute respiratory distress syndrome (ARDS).

[0023] Treatment is also considered to include accelerating the achievement of clinical improvement. Such acceleration may shorten the time course of the disease and result in earlier recovery than would be achieved in the absence of such treatment. Such acceleration may also shorten the duration for which specific respiratory support, such as mechanical ventilation, is required. Such treatment with tradipitant may include reducing total hospital stay, reducing intensive care unit (ICU) time, reducing the period for which a patient requires oxygen support, including, for example, cannula, high-flow, mechanical ventilator, etc., and preventing escalation resulting in hospitalization in patients whose illness is not severe enough to warrant hospitalization.

[0024] Treatment may further include exerting an antiviral effect in vivo by interfering with either viral entry or viral assembly after entry, or by exposing the virus to other antiviral agents. For example, antiviral agents such as remdesivir and others known in the art may be further administered to patients in combination with tradipitant.

[0025] In other embodiments, treatment may include improving long-term lung function or preventing long-term lung function loss after recovery from viral pneumonia, such as that caused by infection with COVID-19. It is known in the art that long-term lung function loss associated with acute viral pneumonia, and that it persists significantly after recovery from such pneumonia.

[0026] In some embodiments of the present invention, treatment may or may not improve a patient's clinical findings during an infectious disease, e.g., COVID-19. For example, treatment may reduce the time course or duration of the illness, but may or may not reduce the severity of the illness prior to recovery. Nevertheless, such treatment may have an effect in preventing long-term lung damage caused by viral pneumonia. As such, treatment may include use in preventing post-viral lung function loss and pulmonary fibrosis.

[0027] In one embodiment, a method for treating a patient diagnosed with an infectious disease that can cause inflammatory lung injury, such as COVID-19, is provided, comprising administering tradipitant to the patient. The tradipitant may be orally administered in a solid immediate-release form containing tradipitant and one or more pharmaceutically acceptable excipients. Alternatively, the tradipitant may be orally administered in a solid controlled-release form containing tradipitant and one or more pharmaceutically acceptable excipients. The solid controlled-release form may contain a relatively higher amount of tradipitant than the solid immediate-release form and may be administered less frequently, for example, once daily (qd), rather than twice daily (bid). Furthermore, the tradipitant may be administered either orally or intravenously in a liquid suspension form. The tradipitant administered to a patient, regardless of dosage form or route of administration, may be crystalline Form IV or crystalline Form V.

[0028] When a solid immediate-release form is used, the dosage of tradipitant can be, for example, about 100-400 mg / day, about 150-400 mg / day, about 100-300 mg / day, about 150-300 mg / day, about 100-200 mg / day, about 170-340 mg / day, or about 170-255 mg / day. In certain embodiments, the amount can be about 170 mg / day of tradipitant. More specifically, the dosage can be 85 mg twice daily (bid) or 85 mg every 12 hours (Q12H). The dosage of tradipitant is known, for example, from International Publication Nos. WO 2016 / 141341 and WO 2019 / 055225, which are incorporated herein by reference as if fully set forth, to be an amount and frequency sufficient to provide a tradipitant exposure consistent with achieving and maintaining a tradipitant plasma concentration level of at least about 100 ng / mL, at least about 125 ng / mL, at least about 150 ng / mL, at least about 175 ng / mL, at least about 200 ng / mL, or about 225 ng / mL or greater for the duration of the treatment regimen, which may be up to and including 7 days, 14 days, or may exceed such a period if the patient is hospitalized, for example, until discharge from the hospital.

[0029] Tradipitant administered as described herein may confer beneficial anti-inflammatory effects and be useful in preventing, slowing, or reducing the progression of COVID-19-associated inflammatory lung injury in patients with COVID-19 and / or accelerating the time to recovery from such infection.

[0030] In another embodiment, a method is provided for treating a patient suffering from or experiencing symptoms of suspected or confirmed infectious disease, e.g., pneumonia associated with COVID-19. Such symptoms may include, for example, fever (defined as a temperature of ≥36.6°C (axillary), ≥37.2°C (oral), or ≥37.8°C (rectal)), cough, pneumonia confirmed by chest x-ray or CT scan, low oxygen saturation (defined as <92%), or evidence of inflammatory lung injury. Alternatively, the patient may have a confirmed laboratory diagnosis of COVID-19 infection by RT-PCR and / or may be determined to meet severe or critical criteria for COVID-19 infection as defined by the treating hospital.

[0031] In this embodiment, the method comprises orally administering tradipitant to the patient, for example, in crystalline Form IV or crystalline Form V. In some embodiments, the tradipitant may be orally administered in a solid immediate release form containing about 100-400 mg / day, about 150-400 mg / day, about 100-300 mg / day, about 150-300 mg / day, about 100-200 mg / day, about 170-340 mg / day, or about 170-255 mg / day of tradipitant, about 170 mg / day of tradipitant, about 85 mg bid, or 85 mg Q12H. The duration of the treatment regimen may be up to and including 7 days, 14 days, or may exceed such a period if the patient is hospitalized, for example, until discharge from the hospital.

[0032] As described above, tradipitant may be orally administered in a solid immediate-release form containing tradipitant and one or more pharmaceutically acceptable excipients, or alternatively, in a solid controlled-release form containing tradipitant and one or more pharmaceutically acceptable excipients. Furthermore, tradipitant may be administered orally or intravenously in a liquid suspension. Regardless of the form or route of administration, such administration may have the effect of reducing inflammation and preventing, delaying, or ameliorating the progression of disease-related inflammatory lung damage, and may further include exerting an antiviral effect in vivo by interfering with either viral entry or viral assembly after entry, or by exposing the virus to other antiviral agents.

[0033] In a further aspect of the present invention, there is provided a method for reducing inflammation, preventing inflammatory lung injury, or slowing or attenuating the progression of inflammatory lung injury in a patient suffering from an infectious disease, which may be, for example, COVID-19. In this embodiment, the method comprises orally administering to the patient tradipitant, e.g., in crystalline Form IV or crystalline Form V. In some embodiments, the tradipitant may be orally administered in a solid immediate-release form containing about 100-400 mg / day, about 150-400 mg / day, about 100-300 mg / day, about 150-300 mg / day, about 100-200 mg / day, about 170-340 mg / day, or about 170-255 mg / day of tradipitant, about 170 mg / day of tradipitant, about 85 mg bid, or 85 mg Q12H. The duration of the treatment regimen may be up to and including 7 days, 14 days, or may exceed such a period if the patient is hospitalized, for example, until discharge from the hospital.

[0034] As described above, the tradipitant may be administered orally in a solid immediate-release form comprising tradipitant and one or more pharmaceutically acceptable excipients, or alternatively, in a solid controlled-release form comprising tradipitant and one or more pharmaceutically acceptable excipients. Additionally, the tradipitant may be administered either orally or intravenously in a liquid suspension form.

[0035] Further embodiments provide methods of treating a patient suffering from an infectious disease, e.g., COVID-19, and preventing a decline in respiratory function in the patient. In such embodiments, a decline in respiratory function is defined as having an oxygen saturation of less than 92%. In this embodiment, the method includes orally administering tradipitant to the patient, e.g., in crystalline Form IV or crystalline Form V. In some embodiments, the tradipitant may be orally administered in a solid immediate-release form containing a dose of about 100-400 mg / day, about 150-400 mg / day, about 100-300 mg / day, about 150-300 mg / day, about 100-200 mg / day, about 170-340 mg / day, or about 170-255 mg / day of tradipitant, about 170 mg / day of tradipitant, about 85 mg bid, or 85 mg Q12H of tradipitant. The duration of the treatment regimen may be up to and including 7 days, 14 days, or may exceed such a period if the patient is hospitalized, for example, until discharge from the hospital.

[0036] As described above, the tradipitant may be administered orally in a solid immediate-release form comprising tradipitant and one or more pharmaceutically acceptable excipients, or alternatively, in a solid controlled-release form comprising tradipitant and one or more pharmaceutically acceptable excipients. Additionally, the tradipitant may be administered either orally or intravenously in a liquid suspension form.

[0037] In a further embodiment, a method is provided for preventing lung damage after recovery from an infectious disease, such as COVID-19, by administering tradipitant to a patient. In such an embodiment, the lung damage can manifest as a decrease in lung capacity, i.e., lung loss. These losses can be, for example, a decrease relative to pre-disease lung function or lung capacity. In particular, the lung damage can be pulmonary fibrosis.

[0038] In this embodiment, the method comprises orally administering tradipitant to the patient, for example, in crystalline Form IV or crystalline Form V. In some embodiments, the tradipitant may be orally administered in a solid immediate release form containing about 100-400 mg / day, about 150-400 mg / day, about 100-300 mg / day, about 150-300 mg / day, about 100-200 mg / day, about 170-340 mg / day, or about 170-255 mg / day of tradipitant, about 170 mg / day of tradipitant, about 85 mg bid, or 85 mg Q12H. The duration of the treatment regimen may be up to and including 7 days, 14 days, or may exceed such a period if the patient is hospitalized, for example, until discharge from the hospital.

[0039] As described above, the tradipitant may be administered orally in a solid immediate-release form comprising tradipitant and one or more pharmaceutically acceptable excipients, or alternatively, in a solid controlled-release form comprising tradipitant and one or more pharmaceutically acceptable excipients. Additionally, the tradipitant may be administered either orally or intravenously in a liquid suspension form.

[0040] Further embodiments provide tradipitant for use in any of the aforementioned methods of treatment, pharmaceutical compositions comprising tradipitant for use in any of the aforementioned methods of treatment, and tradipitant for use in the manufacture of a medicament comprising tradipitant for use in any of the aforementioned methods of treatment.

[0041] In any of the above embodiments, the patient's symptoms of COVID-19 may include a diagnosis of inflammatory lung injury, pneumonia, and / or a severe or critical COVID-19 infection, either with or without inflammatory lung injury. The patient's symptoms of COVID-19 may further include symptoms of fever and / or cough. Moreover, the patient may have a diagnosis of COVID-19 that may be confirmed by a diagnostic test or may be suspected based on, for example, one or more of symptoms, medical history, and travel and / or exposure history.

[0042] Those skilled in the art will recognize that further embodiments may be selected by combining the above embodiments or by reference to the examples provided herein.

[0043] Example 1 The randomized, double-blind, placebo-controlled trial will investigate the efficacy of tradipitant in treating inflammatory lung injury and pneumonia associated with severe or critical COVID-19 infection and improving clinical outcomes associated with severe or critical COVID-19 infection, including reducing long-term lung function loss and pulmonary fibrosis.

[0044] Methods: Potential participants will attend a screening visit on study days -1 to 0 to assess prospective patient eligibility. All enrolled patients will undergo an initial physical examination and must meet inclusion and exclusion criteria before enrolling in the study. A total sample size of 300 patients (150 / arm) will provide approximately 93% power to detect a 20% normalization difference in fever and oxygen saturation, assuming normalization rates of 50% and 70% in the placebo and tradipitant treatment groups, respectively, based on a two-sided Fisher's exact test at a 5% significance level.

[0045] Inclusion criteria included: adults aged 18-90 years; laboratory-confirmed COVID-19 infection by RT-PCR; pneumonia confirmed by chest radiography or computed tomography; fever defined as a temperature of ≥36.6°C (axillary), ≥37.2°C (oral), or ≥37.8°C (rectal); and oxygen saturation less than 92% on room air, mechanical ventilation, or increased work of breathing (WOB) at the time of testing, without respiratory assistance or a respiratory rate greater than 20 bpm. Exclusion criteria included recent illicit drug use or alcoholism; history of allergy to tradipitant or other neurokinin-1 antagonists; pregnancy; history of HIV, HBV, or HCV infection; malignancy or other serious systemic disease; and inability to give informed consent, or lack of a relative or designated person authorized to give informed consent, or inability to comply with protocol requirements.

[0046] Patients who met the inclusion and exclusion criteria were randomized 1:1 to receive either 85 mg of tradipitant twice daily (bid) orally (PO, i.e., orally) or a matching placebo under double-blind conditions, in addition to standard treatment for COVID-19 infection according to the treating hospital's protocol. In both study arms, treatment with the study drug will continue for 14 days or until discharge from the hospital. In both the tradipitant treatment and placebo study arms, patients will receive one capsule of study drug orally daily at or before 9:00 AM in the morning and one capsule of study drug orally daily approximately 12 hours later (±1 hour) in the afternoon. Patients in the tradipitant treatment arm will receive a capsule containing 85 mg of tradipitant and the following excipients: spray-dried lactose monohydrate, microcrystalline cellulose (Avicel PH102 and PH200), povidone, croscarmellose sodium, sodium lauryl sulfate, and magnesium stearate. The tradipitant capsules will be milky white, hard gelatin capsules. Placebo capsules will be provided in the same size and appearance as those containing tradipitant.

[0047] For patients requiring administration via nasogastric tube, the following procedure is used: 1) empty the contents of one 85 mg capsule into a glass mortar and crush using a pestle until all granules are completely crushed; 2) add 10 mL of water while continuing to crush to obtain a uniform dispersion; 3) draw up the entire dispersion into a suitable syringe; 4) connect the syringe tip to the nasogastric tube and compress the entire syringe contents; and 5) rinse the mortar and pestle with 5 mL of water and repeat steps 3) and 4). The crushing procedure results in the preparation of a uniform dispersion in water that can then be administered through the nasogastric tube without obstruction.

[0048] Patient assessments will be performed according to the schedule of evaluations detailed in Table 1 below.

[0049] [Table 1]

[0050] EOS = End of Study; ET = Early Termination; WOCBP = Women of Childbearing Potential; PG = Pharmacogenetics; NEWS2 = National Instantaneous Alert Score 2; CT = Computed Tomography 1 Informed consent for the study will be explained to subjects at the screening visit and must be signed before any procedures are performed. 2 Laboratory tests will be repeated as necessary to follow up any abnormal changes. 3 Height will be recorded at screening only. Weight will be collected at screening and EOS / ET only. 4 Determine any cardiac abnormalities using automated interpretation from a given ECG machine 5 Only if possible, do not intubate the subject.

[0051] Oxygen saturation will be measured daily using a pulse oximeter as specified in Table 1. Blood oxygen concentration (SpO2) will be measured by pulse oximeter. The criterion for oxygen normalization is peripheral capillary oxygen saturation (SpO2) >94% sustained for at least 24 hours.

[0052] Body temperature is measured daily as specified in Table 1. Criteria for fever normalization include a temperature of less than 36.6°C (axillary), less than 37.2°C (oral), or less than 37.8°C (rectal) sustained for at least 24 hours.

[0053] Nasopharyngeal swabs will be collected to detect COVID-19 viral load by polymerase chain reaction (PCR). This daily assessment is part of markers of infection and inflammation and will be performed as indicated in the assessment schedule (Table 1).

[0054] The NEWS is a tool developed by the Royal College of Physicians and later updated to the NEWS2 in 2017. The NEWS2 score identifies acute deterioration, including sepsis, in hospitalized patients. It is based on a simple summative scoring system of six physiological parameters: respiratory rate, oxygen saturation, systolic blood pressure, pulse rate, level of consciousness or new disturbances, and temperature. The NEWS2 is assessed at the intervals shown in Table 1.

[0055] Mortality will be assessed as the proportion of participants with in-hospital mortality and will be evaluated by treatment arm.

[0056] Cough severity will be assessed using the Numerical Cough Scale (NRS), in which the physician or designee rates the participant's cough from 0 (no cough) to 10 (most severe cough). Assessments will be performed as indicated in the Schedule of Assessments (Table 1).

[0057] Clinical status will be assessed daily during hospitalization using a 7-point ordinal scale with scores defined as follows: 1) dead; 2) hospitalized on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 3) hospitalized on noninvasive ventilation or high-flow oxygen device; 4) hospitalized requiring supplemental oxygen; 5) hospitalized without requiring supplemental oxygen; 6) not hospitalized with activity limitations; and 7) not hospitalized.

[0058] Markers of infection and inflammation will be collected daily (Table 1), including ferritin; CRP; CBC with differential; IL-1 beta, IL-2, IL-4, IL-6, IL-7, IL-10, IL-37; granulocyte colony-stimulating factor; interferon-gamma; COVID-19 viral load; PT / PTT / INR; D-Dimer, BNP, ESR; troponin-1 and T; TNF-alpha; and inducible protein 10, and will be used to quantify and assess the reduction in inflammation and inflammatory lung injury.

[0059] The efficacy of tradipitant in treating COVID-19 will be assessed by the following scales: improvement in clinical status and time to improvement, assessed on a 7-point ordinal scale compared to baseline; proportion of participants who normalized fever and oxygen saturation at day 14; change from baseline in pulmonary markers of inflammation, including interleukin-6 (IL-6), collected once daily in the morning; percentage reduction in COVID-19 viral load, assessed by RT-PCR from nasopharyngeal samples; proportion of participants with in-hospital mortality; mean change from baseline in NEWS2 score, assessed daily at screening after randomization; and, if available, reduction in cough from baseline, measured by NRS (Nutrient Rating Scale) for cough, assessed daily at screening after randomization in the morning.

[0060] Results: An interim analysis of the first 60 enrolled patients will assess the safety and efficacy of tradipitant in this COVID-19 patient population. The demographics of this intention-to-treat population are shown in Table 2.

[0061] [Table 2]

[0062] Clinical status is assessed on a 7-point ordinal scale. Clinical improvement is defined as an improvement of at least 2 points on the 7-point ordinal scale. 57% of patients in the tradipitant arm show clinical improvement, while 50% of patients in the placebo arm show clinical improvement. The tradipitant arm has a mortality rate of 14.2%, while the placebo arm has a mortality rate of 16.6%. On each of these scales, patients in the tradipitant arm show superior results, although not by a statistically significant margin.

[0063] During the improvement analysis period, patients treated with tradipitant recovered more quickly than patients receiving placebo (Figure 1). As shown in Table 3, this difference was statistically significant at Day 7 of treatment (HR = 2.55, p = 0.0375) and was generally consistent across patients with varying baseline severity. Table 3 presents overall results at Day 7 and results by baseline ordinal scale score (baseline ordinal scale scores of 4, 3, and 2).

[0064] [Table 3-1]

[0065] [Table 3-2]

[0066] Table 4 and Figure 2 show that at Day 28, tradipitant demonstrated a numerical benefit over placebo, with a faster median time to recovery (HR=1.55, p=0.2254, median time to improvement 10 days for tradipitant and 28 days for placebo). This benefit was generally consistent across patients with varying baseline severity. Table 4 shows the overall results at Day 28 and the results by baseline ordinal scale score (baseline ordinal scale scores of 4, 3, and 2).

[0067] [Table 4-1]

[0068] [Table 4-2]

[0069] These data indicate that tradipitant accelerates the time to clinical improvement in patients with severe or critical COVID-19 infection, and that hospitalized patients with COVID-19 pneumonia improve more quickly when treated with tradipitant compared with placebo. Given the relatively low mortality associated with COVID-19, significantly larger study populations are needed to assess the effect of treatment on mortality.

[0070] The foregoing detailed description of various aspects of the present invention has been presented for purposes of illustration and description. It is not intended to be exhaustive or to limit the invention to the precise form disclosed, and modifications and variations are possible. Such modifications and variations that may be apparent to those skilled in the art are intended to be included within the scope of the invention as defined by the appended claims. <Additional Notes> The present invention includes the following aspects. <Section 1> 1. A method of treating a patient diagnosed with a lower respiratory tract infection, comprising: administering to said patient tradipitant in an amount effective to treat said lower respiratory tract infection or at least one symptom thereof. The method comprising: <Section 2> The method according to <Item 1>, wherein the lower respiratory tract infection is a viral infection. <Section 3> The method according to <Item 2>, wherein the lower respiratory tract infection is viral pneumonia. <Section 4> The method according to <Item 3>, wherein the viral pneumonia is acute. <Section 5> The method according to <Item 4>, wherein the viral pneumonia is caused by or occurs in association with COVID-19 infection. <Section 6> The method according to <Item 4>, wherein the viral pneumonia is caused by or occurs in association with influenza infection. <Section 7> The method according to <Item 4>, wherein the viral pneumonia is caused by or occurs in association with infection with SARS-CoV, rhinovirus, a coronavirus other than SARS-CoV, or respiratory syncytial virus (RSV). <Section 8> The method according to <Item 1>, wherein the lower respiratory tract infection is a bacterial infection. <Section 9> The method according to <Item 8>, wherein the bacterial infection is caused by Streptococcus pneumoniae. <Section 10> The method according to <Item 1>, wherein the patient is hospitalized. <Section 11> The method of <Item 10>, wherein the treatment of the patient further includes one or more of invasive mechanical ventilation, extracorporeal membrane oxygenation (ECMO), non-invasive ventilation, a high-flow oxygen device, or supplemental oxygen. <Section 12> The method of <Item 1>, wherein the at least one symptom of the lower respiratory tract infection is selected from the group consisting of fever, shortness of breath, cough, pneumonia, oxygen saturation less than 92%, and evidence of inflammatory lung injury. <Section 13> The method according to <Item 1>, wherein treating the lower respiratory tract infection comprises shortening the duration until the patient achieves clinical improvement. <Section 14> The method according to <Item 1>, wherein the treatment of the lower respiratory tract infection comprises accelerating recovery from the lower respiratory tract infection. <Section 15> 10. The method of claim 1, wherein treating the lower respiratory tract infection prevents, slows, or reduces the progression of the lower respiratory tract infection in the patient. <Section 16> The method according to <Item 1>, wherein the treatment of the lower respiratory tract infection comprises preventing respiratory deterioration in the patient. <Section 17> The method according to <Item 1>, wherein the treatment of the lower respiratory tract infection comprises preventing lung damage after recovery from the lower respiratory tract infection. <Section 18> The method according to <Item 1>, wherein the treatment of the lower respiratory tract infection includes resolution of the lower respiratory tract infection or one or more symptoms thereof. <Section 19> The method according to <Item 1>, wherein the tradipitant is orally administered to the patient in a solid immediate-release form containing tradipitant and one or more pharmaceutically acceptable excipients, and the dose of tradipitant is 100 to 400 mg / day, 100 to 300 mg / day, or 100 to 200 mg / day. <Section 20> The method according to <Item 1>, wherein the tradipitant is orally administered to the patient in a solid immediate-release form containing tradipitant and one or more pharmaceutically acceptable excipients, and the dose of tradipitant is 150 to 400 mg / day, 150 to 300 mg / day, or 150 to 200 mg / day. <Section 21> The method according to <Item 20>, wherein the dose of tradipitant is 170 mg / day. <Section 22> The method according to <Item 21>, wherein the dose of tradipitant is 85 mg twice a day (bid). <Section 23> The method according to <Item 1>, wherein the tradipitant is orally administered in a solid controlled-release form comprising tradipitant and one or more pharmaceutically acceptable excipients. <Section 24> The method according to <Item 1>, wherein the tradipitant is orally administered in the form of a liquid suspension. <Section 25> The method according to <Item 1>, wherein the tradipitant is administered intravenously in the form of a liquid suspension. <Section 26> The method according to item 1, wherein the tradipitant is administered to the patient for a period of 14 days. <Section 27> The method according to item 1, wherein the tradipitant is administered to the patient for a period of 7 days. <Section 28> The method according to <Item 1>, further comprising administering the tradipitant to the patient in combination with an antiviral drug. <Section 29> Tradipitant for use in any of the aforementioned methods of treatment. <Section 30> A pharmaceutical composition comprising tradipitant for use in any of the aforementioned methods of treatment. <Section 31> Tradipitant for use in the manufacture of a pharmaceutical composition comprising tradipitant for use in any of the aforementioned methods of treatment. <Section 32> The method, tradipitant, or pharmaceutical composition according to any one of <Item 1> to <Item 31>, wherein the tradipitant is crystalline form IV or crystalline form V.

Claims

1. A solid immediate release form for oral administration for treating viral pneumonia caused by or associated with COVID-19 infection in a patient, comprising tradipitant at a dose of 150 to 400 mg / day and one or more pharmaceutically acceptable excipients; The pharmaceutical composition, wherein the dose is effective to treat the viral pneumonia caused by or associated with COVID-19 infection or at least one symptom thereof.

2. 2. The pharmaceutical composition of claim 1, wherein the viral pneumonia is acute.

3. 10. The pharmaceutical composition of claim 1, wherein the treatment comprises one or more of invasive mechanical ventilation, extracorporeal membrane oxygenation (ECMO), non-invasive ventilation, a high-flow oxygen device, or supplemental oxygen.

4. The pharmaceutical composition of claim 1, wherein the at least one symptom is selected from the group consisting of fever, shortness of breath, cough, pneumonia, oxygen saturation less than 92%, and evidence of inflammatory lung injury.

5. 10. The pharmaceutical composition of claim 1, wherein the treatment comprises reducing the duration until the patient achieves clinical improvement.

6. 10. The pharmaceutical composition of claim 1, wherein the treatment comprises accelerating recovery from the viral pneumonia.

7. 10. The pharmaceutical composition of claim 1, wherein the treatment prevents, slows, or reduces the progression of the viral pneumonia in the patient.

8. 10. The pharmaceutical composition of claim 1, wherein the treatment comprises preventing respiratory deterioration in the patient.

9. 10. The pharmaceutical composition of claim 1, wherein the treatment comprises preventing lung damage after recovery from the viral pneumonia.

10. 10. The pharmaceutical composition of claim 1, wherein the treatment comprises resolution of the viral pneumonia or one or more symptoms thereof.

11. The pharmaceutical composition of claim 1, wherein the dose of tradipitant is 150 to 300 mg / day.

12. The pharmaceutical composition described in claim 11, wherein the dose of tradipitant is 150 to 200 mg / day.

13. 13. The pharmaceutical composition of claim 12, wherein the dose of tradipitant is 170 mg / day.

14. 14. The method of claim 13, wherein the dose of tradipitant is 85 mg twice daily (bid).

15. The pharmaceutical composition of any one of claims 1 to 14, wherein the tradipitant is crystalline form IV or crystalline form V.

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