Treatment of adenovirus infection or disease associated with adenovirus infection

Abstract

The present invention provides a method for treating an adenovirus infection or a disease associated with an adenovirus infection.　The present invention provides a pharmaceutical composition for the treatment of an adenovirus infection or a disease associated with an adenovirus infection, said pharmaceutical composition comprising a brincidofovir, a pharmaceutically acceptable salt thereof, or a solvate thereof. The treatment comprises: (i) intravenously administering 0.38-0.42 mg / kg of brincidofovir, a pharmaceutically acceptable salt thereof, or a solvate thereof to a human subject twice per week; or (ii) intravenously administering 18-22 mg / administration of brincidofovir, a pharmaceutically acceptable salt thereof, or a solvate thereof to a human subject twice per week.

Description

Treatment of adenovirus infection or diseases associated with adenovirus infection

[0001] The technical field of the invention relates to the treatment of adenoviral infections or diseases associated with adenoviral infections.

[0002] Brincidofovir (BCV) was approved by the U.S. Food and Drug Administration (FDA) in 2021 as a treatment for smallpox. Non-Patent Document 1 describes a benefit-risk assessment of BCV in smallpox treatment. Non-Patent Document 2 also describes that monkeypox epidemics have begun in May 2022, and that the use of BCV is recommended for the management of confirmed cases.

[0003] "Benefit-risk assessment for brincidofovir for the treatment of smallpox: US Food and Drug Administration's Evaluation" Chan-Tack et al., Antiviral Res. 2021 Nov;195:105182. "Monkeypox: A Mini-Review on the Globally Emerging Orthopoxvirus" Evans et al., Int J Environ Res Public Health. 2022 Nov 25;19(23):15684.

[0004] Many unknowns remain regarding the therapeutic effects and methods of using BCV for adenovirus infection or diseases associated with adenovirus infection.

[0005] On the other hand, the inventors of the present application have demonstrated that intravenous administration of BCV using a specific method and dosage exhibits particularly excellent therapeutic effects against adenovirus infection or diseases associated with adenovirus infection, as described in the Examples below.

[0006] According to one aspect of the present invention, there is provided a pharmaceutical composition for treating adenovirus infection or a disease associated with adenovirus infection, the pharmaceutical composition comprising brincidofovir, a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the treatment comprises (i) intravenously administering 0.38 to 0.42 mg / kg of brincidofovir, a pharmaceutically acceptable salt thereof, or a solvate thereof twice weekly to a human subject, or (ii) intravenously administering 18 to 22 mg of brincidofovir, a pharmaceutically acceptable salt thereof, or a solvate thereof twice weekly to a human subject. Use of this pharmaceutical composition provides particularly excellent therapeutic effects against adenovirus infection or a disease associated with adenovirus infection.

[0007] Shows the results of the study for Cohort 1. Shows the results of the study for Cohort 2. Shows the results of the study for Cohort 3. Shows the results of examining AdV in the stool of patients in Cohorts 1 to 3. Shows the results of examining lymphocyte counts of patients in Cohort 3. Shows the results of examining absolute lymphocyte counts of patients in Cohorts 1 to 3. "Cleared" indicates patients whose AdV levels reached below the detection limit (same as in Figures 7 to 9). Shows the results of examining absolute lymphocyte counts at baseline of patients in Cohorts 1 to 3. Shows the results of examining absolute lymphocyte counts on day 1 of week 3 of patients in Cohorts 1 to 3. Shows the results of examining absolute lymphocyte counts on day 1 of week 5 of patients in Cohorts 1 to 3. Shows the results of the study for Cohort 4. Shows the results of examining the relationship between blood AdV levels and AdV disease symptoms at the end of the clinical trial of patients in Cohorts 1 to 4.

[0008] Hereinafter, embodiments of the present invention will be described in detail, with the same contents omitted as appropriate to avoid repetition.

[0009] (1) Methods According to one embodiment of the present invention, there is provided a method for treating an adenovirus (AdV) infection or a disease associated with AdV infection, comprising the step of administering brincidofovir (BCV), a pharmaceutically acceptable salt thereof, or a solvate thereof to a subject. In this method, the administering step may comprise (i) administering 0.38 to 0.42 mg / kg of BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof intravenously twice weekly to the subject, or (ii) administering 18 to 22 mg of BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof intravenously twice weekly to the subject. Use of this method can reduce the incidence of treatment failure in patients, shorten the time until AdV levels reach below the limit of detection (LOD), shorten the treatment period, and provide a treatment with excellent safety.

[0010] (2) Methods According to one embodiment of the present invention, there is provided a method for treating AdV infection or a disease associated with AdV infection, comprising the step of administering BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof to a subject, wherein the administration step comprises (i) administering 0.38 to 0.42 mg / kg of BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof twice weekly to a subject below a specific body weight, or (ii) administering 18 to 22 mg of BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof twice weekly to a subject at or above a specific body weight, wherein the specific body weights in (i) and (ii) are the same, 48 to 52 kg. Use of this method can reduce the incidence of treatment failure in patients, shorten the time until the AdV load reaches below the LOD, shorten the treatment period, and enable treatment with excellent safety.

[0011] (3) Methods According to one embodiment of the present invention, there is provided a method for treating AdV infection or a disease associated with AdV infection, comprising the step of administering BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof to a subject, wherein the administration step comprises: (i) intravenously administering 0.38 to 0.42 mg / kg of BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof twice weekly to a subject (provided that, in the context of co-administration with cyclosporine, the dose of BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof is reduced by 55 to 65%); or (ii) intravenously administering 18 to 22 mg of BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof twice weekly to a subject (provided that, in the context of co-administration with cyclosporine, the dose of BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof is reduced by 55 to 65%). By using this method, it is possible to suppress the occurrence of patients who do not respond to treatment, shorten the time until the AdV amount reaches below the LOD, shorten the treatment period, or provide treatment with excellent safety.

[0012] (4) Method According to one embodiment of the present invention, there is provided a method for treating AdV infection or a disease associated with AdV infection, comprising the step of administering BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof to a subject, wherein the administering step, when not performed in the context of co-administration of cyclosporine and BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof, is: (i) administering BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof intravenously to a subject at 0.38 to 0.42 mg / kg twice a week; or (ii) administering BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof to a subject. and (ii) administering to a subject intravenously 9.9 to 14.3 mg twice a week of BCV, a pharmaceutically acceptable salt or a solvate thereof, wherein the administering step is carried out in the context of co-administration of cyclosporine and BCV, a pharmaceutically acceptable salt or a solvate thereof, the method comprising the steps of (i) administering to a subject intravenously 0.21 to 0.27 mg / kg of BCV, a pharmaceutically acceptable salt or a solvate thereof twice a week, or (ii) administering to a subject intravenously 9.9 to 14.3 mg of BCV, a pharmaceutically acceptable salt or a solvate thereof twice a week. Use of this method can reduce the incidence of treatment failure in patients, shorten the time until the AdV level reaches below the LOD, shorten the treatment period, or provide a treatment with excellent safety.

[0013] (5) Method According to one embodiment of the present invention, there is provided a method for treating AdV infection or a disease associated with AdV infection, comprising a step of administering BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof to a subject, wherein the administering step comprises (i) intravenously administering 0.38 to 0.42 mg / kg of BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof twice weekly to the subject, or (ii) intravenously administering 18 to 22 mg of BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof twice weekly to the subject, wherein the subject is a patient not receiving cyclosporine; or the administering step comprises (i) intravenously administering 0.21 to 0.27 mg / kg of BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof twice weekly to the subject, or (ii) intravenously administering 9.9 to 14.3 mg of BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof twice weekly to the subject, wherein the subject is a patient receiving cyclosporine. By using this method, it is possible to suppress the occurrence of patients who do not respond to treatment, shorten the time until the AdV amount reaches below the LOD, shorten the treatment period, or provide treatment with excellent safety.

[0014] (6) Methods According to one embodiment of the present invention, there is provided a method for treating AdV infection or a disease associated with AdV infection, comprising administering BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof to a subject, wherein the administering step comprises (i) administering 0.38 to 0.42 mg / kg of BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof twice weekly to the subject, or (ii) administering 18 to 22 mg of BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof twice weekly to the subject, the administration period being terminated based on treatment discontinuation criteria, including multiple measurements of AdV levels in the subject's blood samples, and two consecutive measurements showing AdV levels below the LOD. This method allows for early termination of administration, taking into account the patient's predicted response based on the specific dosage and administration regimen, thereby particularly shortening the treatment period. "Below the LOD" may also be substituted with "less than the lower limit of quantification (LLOQ) and undetectable," for example.

[0015] (7) Methods According to one embodiment of the present invention, there is provided a method for treating AdV infection or a disease associated with AdV infection, comprising the step of administering BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof to a subject, wherein the administering step comprises (i) administering 0.38 to 0.42 mg / kg of BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof twice weekly to the subject, or (ii) administering 18 to 22 mg of BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof twice weekly to the subject, the administration period being terminated based on treatment discontinuation criteria, including two consecutive negative results for AdV after multiple determinations of AdV levels in the subject's blood samples. This method allows for early termination of administration, taking into account the patient's predicted response based on the specific dosage and administration regimen, thereby particularly shortening the treatment period.

[0016] (8) Methods According to one embodiment of the present invention, there is provided a method for treating AdV infection or a disease associated with AdV infection, comprising the step of administering BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof to a subject, wherein the administering step comprises (i) administering 0.38 to 0.42 mg / kg of BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof twice weekly to the subject, or (ii) administering 18 to 22 mg of BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof twice weekly to the subject, wherein the administration period is terminated based on treatment discontinuation criteria, which include the completion of a specific period of treatment, the specific period being selected from the range of 4 to 13 weeks. Use of this method allows for early determination of the termination of administration in consideration of the patient's response predicted from the specific dosage and administration regimen, thereby particularly shortening the treatment period.

[0017] (9) Methods According to one embodiment of the present invention, there is provided a method for treating AdV infection or a disease associated with AdV infection, comprising the step of administering BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof to a subject, wherein the administering step comprises (i) administering 0.38 to 0.42 mg / kg of BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof twice weekly to the subject, or (ii) administering 18 to 22 mg of BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof twice weekly to the subject, wherein the administration period is terminated based on treatment discontinuation criteria, including the completion of the fourth week of treatment. Use of this method allows for early determination of the termination of administration in consideration of the patient's response predicted from the specific dosage and administration method, thereby particularly shortening the treatment period.

[0018] (10) Methods According to one embodiment of the present invention, there is provided a method for treating AdV infection or a disease associated with AdV infection, comprising the step of administering BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof to a subject, wherein the administering step comprises (i) administering 0.38 to 0.42 mg / kg of BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof twice weekly to the subject, or (ii) administering 18 to 22 mg of BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof twice weekly to the subject intravenously, wherein the administration period is terminated when both of the following conditions are satisfied: (a) the amount of AdV in a subject's sample is measured multiple times and the AdV is below the LOD in two consecutive measurements, and (b) a specific period of treatment has elapsed, wherein the specific period is selected from the range of 4 to 13 weeks. Use of this method allows for early determination of the end of administration, taking into account the patient's response predicted by the specific dosage and administration method, thereby particularly shortening the treatment period.

[0019] (11) Methods According to one embodiment of the present invention, there is provided a method for treating AdV infection or a disease associated with AdV infection, comprising the step of administering BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof to a subject, wherein the administering step comprises (i) administering 0.38 to 0.42 mg / kg of BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof twice weekly to the subject, or (ii) administering 18 to 22 mg of BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof twice weekly to the subject intravenously, wherein the administration period is terminated based on the fulfillment of both of the following conditions: (a) the amount of AdV in a sample from the subject is measured multiple times and the AdV is below the LOD in two consecutive measurements, and (b) the fourth week of treatment has elapsed. This method allows for the termination of administration to be determined at an early stage, taking into account the patient's response predicted from the specific dosage and administration method, thereby particularly shortening the treatment period.

[0020] (12) Methods According to one embodiment of the present invention, there is provided a method for treating AdV infection or a disease associated with AdV infection, comprising the step of administering BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof to a subject, wherein the administering step comprises (i) administering 0.38 to 0.42 mg / kg of BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof twice weekly to the subject, or (ii) administering 18 to 22 mg of BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof twice weekly to the subject intravenously, wherein the administration period is terminated when both of the following conditions are satisfied: (a) AdV levels in the subject's samples are measured multiple times and two consecutive AdV-negative results are obtained, and (b) a specific period of treatment has elapsed, wherein the specific period is selected from the range of 4 to 13 weeks. Use of this method allows for early determination of the end of administration, taking into account the patient's response predicted by the specific dosage and administration method, thereby particularly shortening the treatment period.

[0021] (13) Methods According to one embodiment of the present invention, there is provided a method for treating AdV infection or a disease associated with AdV infection, comprising the step of administering BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof to a subject, wherein the administering step comprises (i) administering 0.38 to 0.42 mg / kg of BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof twice weekly to the subject, or (ii) administering 18 to 22 mg of BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof twice weekly to the subject intravenously, wherein the administration period is terminated when both of the following conditions are met: (a) the amount of AdV in a sample from the subject is measured multiple times and two consecutive AdV-negative results are obtained, and (b) the fourth week of treatment has elapsed. Use of this method allows for early determination of the end of administration, taking into account the patient's response predicted from the specific dosage and administration method, thereby particularly shortening the treatment period.

[0022] (14) Methods According to one embodiment of the present invention, there is provided a method for treating AdV infection or a disease associated with AdV infection, comprising the step of administering to a subject a pharmaceutical composition containing BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the administering step comprises: (i) administering to the subject twice weekly an amount of the pharmaceutical composition corresponding to 0.38 to 0.42 mg / kg of BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof, or (ii) administering to the subject twice weekly an amount of the pharmaceutical composition corresponding to 18 to 22 mg / dose of BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof. Use of this method can reduce the incidence of treatment failure in patients, shorten the time until the AdV level reaches below the LOD, shorten the treatment period, and enable treatment with excellent safety. From another aspect, according to one embodiment of the present invention, there is provided a method for treating AdV infection or a disease associated with AdV infection, comprising the step of administering to a subject a pharmaceutical composition comprising BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the administering step comprises: (i) administering to the subject an amount of the pharmaceutical composition equivalent to 0.38 to 0.42 mg / kg of BCV twice weekly, or (ii) administering to the subject an amount of the pharmaceutical composition equivalent to 18 to 22 mg / dose of BCV twice weekly intravenously. From another aspect, according to one embodiment of the present invention, there is provided a method for treating AdV infection or a disease associated with AdV infection, comprising the steps of administering to a subject a pharmaceutical composition comprising BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof, and measuring the amount of AdV in a sample (e.g., blood or stool) from the subject. From another aspect, according to one embodiment of the present invention, there is provided a method for reducing the amount of AdV in a sample (e.g., blood or stool) from a subject, comprising the step of administering to the subject a pharmaceutical composition comprising BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0023] (15) Method According to one embodiment of the present invention, there is provided a method for treating AdV infection or a disease associated with AdV infection, comprising the step of administering BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof to a subject, wherein the administration suppresses recurrence of AdV infection or a disease associated with AdV infection in the subject, and the administering step may comprise (i) intravenously administering 0.38 to 0.42 mg / kg of BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof to the subject twice a week, or (ii) intravenously administering 18 to 22 mg of BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof to the subject twice a week. This method can be used to treat AdV infection or a disease associated with AdV infection.

[0024] (16) Methods According to one embodiment of the present invention, there is provided a method for treating AdV infection or a disease associated with AdV infection, comprising administering BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof to a human subject, wherein the administering step comprises (i) administering BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof intravenously at 0.4 mg / kg twice a week to a subject weighing less than 50 kg (provided that in the context of co-administration with cyclosporine, the BCV dose is reduced to 60%), or (ii) administering BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof to a subject weighing 50 kg or more. and (b) administering a commercially acceptable salt or solvate thereof intravenously at 20 mg twice weekly (provided that in the presence of cyclosporine, the BCV dose is reduced by 60%), wherein the administration period is terminated when the AdV level in a sample from the subject is less than the LOD in two consecutive measurements, the administration is by intravenous infusion (e.g., continuous intravenous infusion) over a two-hour period, and the human subject is an immunosuppressed or immunocompromised patient. Use of this method can reduce the incidence of treatment failure, shorten the time until the AdV level reaches less than the LOD, shorten the treatment period, or provide a treatment with excellent safety.

[0025] (17) Methods According to one embodiment of the present invention, there is provided a method for treating AdV infection or a disease associated with AdV infection, comprising administering BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof to a human subject, wherein the administering step is (i) administering BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof intravenously at 0.4 mg / kg twice a week to a subject weighing less than 50 kg (however, in the case of co-administration with cyclosporine, the BCV dose is reduced to 60%), or (ii) administering BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof intravenously at 20 mg twice a week to a subject weighing 50 kg or more. and (b) a specific period of treatment has elapsed, the specific period being selected from 4 to 13 weeks. The administration is by intravenous infusion (e.g., continuous intravenous infusion) over a period of 2 hours, and the human subject is an immunosuppressed or immunocompromised patient. This method can be used to reduce the incidence of treatment failure, shorten the time it takes for AdV levels to reach below the LOD, shorten the treatment period, or provide a safer treatment.

[0026] (18) Methods According to one embodiment of the present invention, there is provided a method for treating AdV infection or a disease associated with AdV infection, comprising administering BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof to a human subject, wherein the administering step comprises (i) administering BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof intravenously at 0.4 mg / kg twice weekly to a subject weighing less than 50 kg (provided that in the case of co-administration with cyclosporine, the BCV dose is reduced to 60%), or (ii) administering BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof intravenously to a subject weighing 50 kg or more. (c) administering intravenously 20 mg twice weekly (provided that in the presence of cyclosporine, the BCV dose is reduced by 60%), the administration period being terminated when two consecutive AdV measurements in the subject's sample show that the AdV is below the LOD, and (b) the fourth week of treatment has elapsed, the administration being administered by intravenous infusion (e.g., continuous intravenous infusion) over two hours, and the human subject is an immunosuppressed or immunocompromised patient. Use of this method can reduce the incidence of treatment failure, shorten the time until the AdV level reaches below the LOD, shorten the treatment period, and provide a safer treatment.

[0027] (19) Methods According to one embodiment of the present invention, there is provided a method for eliminating or ameliorating AdV infection or a disease associated with AdV infection, the method comprising the steps of transferring BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof into a container containing a diluent; measuring or determining the body weight of an immunosuppressed or immunocompromised human subject who has developed AdV infection or a disease associated with AdV infection; and administering the BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof to the immunosuppressed or immunocompromised human subject who has developed AdV infection or a disease associated with AdV infection, wherein the administering step comprises: (i) administering BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof by continuous intravenous infusion at 0.4 mg / kg twice a week to the human subject weighing less than 50 kg, or (ii) administering BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof by continuous intravenous infusion at 20 mg twice a week to the human subject weighing 50 kg or more. By using this method, it is possible to suppress the occurrence of patients who do not respond to treatment, shorten the time until the AdV amount reaches below the LOD, shorten the treatment period, or provide treatment with excellent safety. From another perspective, one embodiment of the present invention provides a method for eliminating or ameliorating AdV infection or a disease associated with AdV infection, comprising the steps of transferring BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof into a container containing a diluent, and administering the BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof to an immunosuppressed or immunocompromised human subject who has developed the AdV infection or a disease associated with AdV infection, wherein the administering step comprises the steps of (i) identifying a human subject weighing less than 50 kg and administering BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof by continuous intravenous infusion at 0.4 mg / kg twice a week to the human subject weighing less than 50 kg, or (ii) identifying a human subject weighing 50 kg or more and administering BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof by continuous intravenous infusion at 20 mg twice a week to the human subject weighing 50 kg or more. By using this method, it is possible to suppress the occurrence of patients who do not respond to treatment, shorten the time until the AdV amount reaches below the LOD, shorten the treatment period, or provide treatment with excellent safety.

[0028] (20) Method According to one embodiment of the present invention, there is provided a method for treating AdV infection or a disease associated with AdV infection, comprising the step of administering BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof to a subject, wherein the administering step may comprise (i) administering 0.38 to 0.42 mg / kg of BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof intravenously once a week to the subject, or (ii) administering 18 to 22 mg of BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof intravenously once a week to the subject. This method can be used to treat AdV infection or a disease associated with AdV infection.

[0029] (21) Method According to one embodiment of the present invention, there is provided a method for treating AdV infection or a disease associated with AdV infection, comprising the step of administering BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof to a subject, wherein the administering step may comprise (i) administering 0.58 to 0.62 mg / kg of BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof intravenously once a week to the subject, or (ii) administering 28 to 32 mg of BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof intravenously once a week to the subject. This method can be used to treat AdV infection or a disease associated with AdV infection.

[0030] (22) Method According to one embodiment of the present invention, there is provided a method for treating AdV infection or a disease associated with AdV infection, comprising the step of administering BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof to a subject, wherein the administering step may comprise (i) administering 0.78 to 0.82 mg / kg of BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof intravenously once a week to the subject, or (ii) administering 38 to 42 mg of BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof intravenously once a week to the subject. This method can be used to treat AdV infection or a disease associated with AdV infection.

[0031] (23) Method According to one embodiment of the present invention, there is provided a method for treating AdV infection or a disease associated with AdV infection, comprising the step of administering BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof to a subject, wherein the administering step may comprise (i) administering 0.38 to 0.82 mg / kg of BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof intravenously once a week to the subject, or (ii) administering 18 to 42 mg of BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof intravenously once a week to the subject. This method can be used to treat AdV infection or a disease associated with AdV infection.

[0032] (24) Methods According to one embodiment of the present invention, there is provided a method for suppressing the recurrence of AdV infection or a disease associated with AdV infection, or a method for treating and suppressing the recurrence of AdV infection or a disease associated with AdV infection, comprising the step of administering BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof to a human subject. This method can suppress the recurrence of AdV infection or a disease associated with AdV infection. The administering step may comprise (i) intravenously administering 0.38 to 0.42 mg / kg of BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof to the subject twice a week, or (ii) intravenously administering 18 to 22 mg of BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof to the subject twice a week. Recurrence may be a phenomenon in which the AdV level in the subject increases after a decrease in the AdV level. Recurrence may also be a phenomenon in which the AdV level in the subject decreases after a decrease in the AdV level, and the AdV infection or the disease associated with AdV infection worsens. Recurrence may also be a recurrence after treatment of AdV infection or a disease associated with AdV infection. The subject may be a subject who has been administered BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof. The subject may be a subject whose AdV infection or a disease associated with AdV infection has been improved by administration of BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof. Relapse may include a situation in which the AdV amount is higher after one additional dose during the treatment period than before. Relapse may also include a situation in which the AdV infection or a disease associated with AdV infection is worse after one additional dose during the treatment period than before. Relapse may also include a situation in which the AdV amount changes over time from a state in which the AdV amount was below the LOD in a subject who has been administered BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof to a state in which the AdV amount is equal to or greater than the LOD. The subject may be a subject who has been administered BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof using the dosage or administration method described in (1) to (23) above. From another perspective, one embodiment of the present invention provides a method for reducing the likelihood of recurrence of AdV infection or a disease associated with AdV infection, the method comprising administering BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof to a subject. This method can reduce the likelihood of recurrence of AdV infection or a disease associated with AdV infection.

[0033] (25) Methods According to one embodiment of the present invention, there is provided a method for suppressing an increase in AdV levels, the method comprising the step of administering BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof to a human subject. This method can suppress an increase in AdV levels. The administering step may comprise (i) intravenously administering 0.38 to 0.42 mg / kg of BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof to the subject twice a week, or (ii) intravenously administering 18 to 22 mg of BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof to the subject twice a week. The increase may be a phenomenon in which the AdV level in the subject increases after a decrease in the AdV level. The subject may be a subject who has been administered BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof. The subject may be a subject whose AdV level has decreased as a result of being administered BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof. The increase may also include a situation in which the AdV level increases after one additional administration during a treatment period. The increase may include a state in which the AdV amount changes over time from a state where the AdV amount was below the LOD in a subject administered BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof to a state where the AdV amount is equal to or greater than the LOD. The subject may be a subject administered BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof using the method or dosage described in (1) to (23) above.

[0034] (26) Methods According to one embodiment of the present invention, there is provided a method for evaluating the effect of administration of BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof using the amount of lymphocytes as an index. This method may be, for example, a method for evaluating the effect of administration of BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof, comprising a step of detecting the amount of lymphocytes in a human subject. This method, for example, allows the effect of BCV to be confirmed. This method, for example, allows a subject to be treated with BCV while anticipating that an effective therapeutic effect will be observed. The amount of lymphocytes may be, for example, the amount of lymphocytes in a sample from the subject. The detection step or evaluation method may be performed, for example, after a step of administering BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof to a subject. The subject may, for example, have AdV infection or a disease associated with AdV infection, or may have been administered BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof because of AdV infection or a disease associated with AdV infection. Detection may be performed, for example, in vitro, ex vivo, or in vivo. This method may include, for example, a step in which an increase in lymphocytes indicates that BCV administration was effective. This method may include, for example, a step in which an increase in lymphocytes indicates that BCV administration was effective. This method may include, for example, a step in which a lack of increase in lymphocytes indicates that BCV administration was ineffective. This method may include, for example, a step in which a lack of increase in lymphocytes indicates that BCV administration was not effective. This method may include, for example, a step in which continuing BCV administration if lymphocytes increase. This method may include, for example, a step in which discontinuing BCV administration if lymphocytes do not increase. The increase in lymphocyte count may be, for example, an increase with an increase in the number of administrations. If specifically specified, the increase in lymphocyte count does not need to include a decrease in lymphocyte count before and after a single increase in the number of administrations during the treatment period. The lymphocyte count in a sample may be measured by an electrical resistance method or an optical method. In the electrical resistance method, the blood cell count can be measured by measuring the change in resistance between electrodes that occurs when blood cells pass through a pore.In optical methods, blood cell counts can be measured by passing cells through a flow cell irradiated with laser light and measuring the resulting scattered light or fluorescence. Lymphocyte counts may also be measured by the method described in Upadhyay et al., J Immunol Methods. 2000 Oct 20;244(1-2):133-7.

[0035] (27) Methods According to one embodiment of the present invention, there is provided a method for evaluating the effect of administration of BCV, its pharmaceutically acceptable salt, or a solvate thereof, using lymphocytes as a biomarker. This method may, for example, comprise a step of detecting lymphocytes as a biomarker. This step may, for example, detect the amount of lymphocytes in a subject's sample. The detection step or evaluation method may be performed after the step of administering BCV to a subject. This method may comprise one or more of the steps or embodiments of the methods described above in (1) to (26). According to one embodiment of the present invention, there is provided a biomarker for evaluating the effect of BCV administration, comprising lymphocytes. The above method or biomarker can be used, for example, to confirm the effect of BCV. The above method or biomarker can be used, for example, to treat a subject while anticipating that BCV will have an effective therapeutic effect.

[0036] (28) Methods According to one embodiment of the present invention, there is provided a method for detecting lymphocyte levels in a human subject administered BCV, its pharmaceutically acceptable salt, or a solvate thereof. This method includes, for example, (a) obtaining a sample from the subject, or (b) measuring the number of lymphocytes in the sample. This method allows detection of lymphocyte levels from a patient after BCV administration. This allows, for example, confirmation of the effectiveness of BCV. This also allows treatment of the subject while anticipating an effective therapeutic effect of BCV. For example, detection of a high lymphocyte level may indicate a favorable effect of BCV. For example, detection of a high lymphocyte level may indicate the appropriateness of continued administration of BCV. The sample may be, for example, a blood sample (e.g., plasma, serum, or whole blood).

[0037] (29) Methods According to one embodiment of the present invention, there is provided a method for detecting an indicator for identifying a human subject who is likely to have Adv infection or a disease associated with Adv infection improved by administration of BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof, the method comprising a step of examining lymphocyte levels in a sample from a subject administered BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof. This method can be used to identify subjects who are likely to have their disease improved by BCV using the lymphocyte level as an indicator. Therefore, use of this method allows for more appropriate BCV treatment to be implemented.

[0038] (30) Method According to one embodiment of the present invention, there is provided a method for increasing lymphocytes, comprising the step of administering BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof to a human subject. This method can restore or activate the subject's immune system. The lymphocytes may be lymphocytes in the subject. The increase may be compared to the increase before administration of BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0039] (31) Method According to one embodiment of the present invention, there is provided a method for restoring or activating the immune system, comprising the step of administering BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof to a human subject. This method can restore or activate the immune system of a subject. The lymphocytes may be lymphocytes in the subject. The restoration or activation may be restoration or activation compared to before administration of BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof. The restoration or activation may occur in a subject whose immune system has been weakened due to transplantation.

[0040] (32) Methods The methods of the embodiments of the present invention (e.g., (1) to (31) above) may include, for example, (i) testing a subject for the presence or absence of AdV infection or a disease associated with AdV infection, (ii) identifying a subject with AdV infection or a disease associated with AdV infection, (iii) identifying a subject in need of treatment for AdV infection or a disease associated with AdV infection, (iv) identifying a subject in need of prevention of AdV infection or a disease associated with AdV infection, (v) identifying a subject after allogeneic or autologous transplantation (e.g., hematopoietic cell transplantation), (vi) identifying a subject in an immunosuppressed or immunodeficient state, (vii) identifying a subject after administration of an immunosuppressant, (viii) identifying a patient with an immunodeficiency syndrome, or (ix) transferring BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof, or a pharmaceutical composition comprising same to a container. Additionally, the methods of the embodiments of the present invention (e.g., (1) to (31) above) may or may not include, for example, the following, if specified: a step of identifying a subject with cytomegalovirus (CMV), BK virus (BKV), Epstein-Barr virus (EBV), or variola virus (VaV) infection, a method for the prevention or treatment of a disease associated with CMV, BKV, EBV, or VaV infection.

[0041] (33) Composition According to one embodiment of the present invention, there is provided a pharmaceutical composition for treating AdV infection or a disease associated with AdV infection, the pharmaceutical composition comprising BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof, and the treatment comprising (i) intravenously administering 0.38 to 0.42 mg / kg of BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof twice weekly to a subject, or (ii) intravenously administering 18 to 22 mg of BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof twice weekly to a subject. Use of this pharmaceutical composition can reduce the incidence of treatment failure in patients, shorten the time until the AdV load reaches below the LOD, or shorten the treatment period.

[0042] (34) Composition According to one embodiment of the present invention, there is provided a pharmaceutical composition for treating AdV infection or a disease associated with AdV infection, the composition comprising BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the treatment comprises (i) intravenously administering 0.38 to 0.42 mg / kg of BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof twice weekly to a subject below a specific weight, or (ii) intravenously administering 18 to 22 mg of BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof twice weekly to a subject above a specific weight, wherein the specific weights in (i) and (ii) are the same, 48 to 52 kg. Use of this pharmaceutical composition can reduce the incidence of treatment failure in patients, shorten the time until the AdV load reaches below the LOD, or shorten the treatment period.

[0043] (35) Compositions According to one embodiment of the present invention, there is provided a pharmaceutical composition for treating AdV infection or a disease associated with AdV infection, comprising BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the treatment comprises (i) intravenously administering to a subject 0.38 to 0.42 mg / kg of BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof twice weekly (provided that, in combination with cyclosporine, the BCV dose is reduced by 55 to 65%), or (ii) intravenously administering to a subject 18 to 22 mg of BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof twice weekly (provided that, in combination with cyclosporine, the BCV dose is reduced by 55 to 65%). Use of this pharmaceutical composition can reduce the incidence of treatment failure in patients, shorten the time until the AdV load reaches below the LOD, or shorten the treatment period.

[0044] (36) Composition According to one embodiment of the present invention, there is provided a pharmaceutical composition for treating AdV infection or a disease associated with AdV infection, the pharmaceutical composition comprising BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the treatment comprises (i) administering 0.38 to 0.42 mg / kg of BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof intravenously twice weekly to a subject, or (ii) administering 18 to 22 mg of BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof intravenously twice weekly to a subject, wherein the administration period of BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof intravenously to a subject is terminated based on treatment discontinuation criteria, which include multiple measurements of AdV levels in the subject's blood samples, and two consecutive measurements showing that the AdV level is below the LOD. Use of this pharmaceutical composition allows for early determination of the termination of administration, taking into account the patient's response predicted by the specific dosage and administration method, thereby particularly shortening the treatment period.

[0045] (37) Composition According to one embodiment of the present invention, there is provided a pharmaceutical composition for treating AdV infection or a disease associated with AdV infection, the pharmaceutical composition comprising BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the treatment comprises (i) administering 0.38 to 0.42 mg / kg of BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof intravenously twice weekly to a subject, or (ii) administering 18 to 22 mg of BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof intravenously twice weekly to a subject, wherein the administration period of BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof is terminated based on a treatment discontinuation criterion, which includes the elapse of a specific period of treatment, the specific period being selected from 4 to 13 weeks. Use of this pharmaceutical composition allows for early determination of the termination of administration, taking into account the patient's response predicted by the specific dosage and administration method, thereby particularly shortening the treatment period.

[0046] (38) Composition According to one embodiment of the present invention, there is provided a pharmaceutical composition for treating AdV infection or a disease associated with AdV infection, comprising BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the treatment comprises (i) administering 0.38 to 0.42 mg / kg of BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof intravenously twice weekly to a subject, or (ii) administering 18 to 22 mg of BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof intravenously twice weekly to a subject, wherein the administration period of BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof intravenously is terminated based on treatment discontinuation criteria, including the completion of the fourth week of treatment. Use of this pharmaceutical composition allows for early determination of the termination of administration in consideration of the patient's response predicted from the specific dosage and administration method, thereby particularly shortening the treatment period.

[0047] (39) Composition According to one embodiment of the present invention, there is provided a pharmaceutical composition for treating AdV infection or a disease associated with AdV infection, comprising BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the treatment comprises (i) administering 0.38 to 0.42 mg / kg of BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof intravenously twice weekly to a subject, or (ii) administering 18 to 22 mg of BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof intravenously twice weekly to a subject, wherein the administration period of BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof is terminated when both of the following conditions are satisfied: (a) the amount of AdV in a sample from the subject is measured multiple times and the AdV is below the LOD in two consecutive measurements, and (b) the fourth week of treatment has elapsed. Use of this pharmaceutical composition allows for early determination of the termination of administration, taking into account the patient's response predicted from the specific dosage and administration method, thereby particularly shortening the treatment period.

[0048] (40) Composition According to one embodiment of the present invention, there is provided a pharmaceutical composition for treating AdV infection or a disease associated with AdV infection, the pharmaceutical composition comprising BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the treatment comprises (i) administering to a human subject intravenously twice weekly an amount of the pharmaceutical composition equivalent to 0.38 to 0.42 mg / kg of BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof, or (ii) administering to a human subject intravenously twice weekly an amount of the pharmaceutical composition equivalent to 18 to 22 mg / dose of BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof. Use of this pharmaceutical composition can reduce the occurrence of treatment failure in patients, shorten the time until the AdV load reaches below the LOD, or shorten the treatment period. From another perspective, one embodiment of the present invention provides a pharmaceutical composition for treating AdV infection or a disease associated with AdV infection, the pharmaceutical composition comprising BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof, and the treatment comprises (i) administering the pharmaceutical composition intravenously to a human subject twice weekly in an amount equivalent to 0.38 to 0.42 mg / kg of BCV, or (ii) administering the pharmaceutical composition intravenously to a human subject twice weekly in an amount equivalent to 18 to 22 mg / dose of BCV.

[0049] (41) Composition According to one embodiment of the present invention, there is provided a pharmaceutical composition for treating AdV infection or a disease associated with AdV infection, comprising BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the treatment comprises (i) administering BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof intravenously at 0.4 mg / kg twice weekly to a subject weighing less than 50 kg (provided that in the case of co-administration with cyclosporine, the BCV dose is reduced to 60%), or (ii) administering BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof intravenously at 0.4 mg / kg twice weekly to a subject weighing 50 kg or more. and a solvate thereof at 20 mg twice weekly intravenously (provided that, in the presence of coadministration with cyclosporine, the BCV dose is reduced by 60%), wherein the administration period of BCV, its pharmaceutically acceptable salt, or a solvate thereof is terminated when the AdV level in a subject's sample is measured multiple times and the AdV level is below the LOD in two consecutive measurements, and the BCV, its pharmaceutically acceptable salt, or a solvate thereof is administered by continuous intravenous infusion over two hours. Use of this pharmaceutical composition can reduce the incidence of treatment failure in patients, shorten the time until the AdV level reaches below the LOD, or shorten the treatment period.

[0050] (42) Composition According to one embodiment of the present invention, there is provided a pharmaceutical composition for treating AdV infection or a disease associated with AdV infection, comprising BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the treatment comprises (i) administering BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof intravenously at 0.4 mg / kg twice weekly to a subject weighing less than 50 kg (provided that in the context of co-administration with cyclosporine, the BCV dose is reduced to 60%), or (ii) administering BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof intravenously at 20 mg twice weekly to a subject weighing 50 kg or more (provided that in the context of co-administration with cyclosporine, the BCV dose is reduced to 60%). The pharmaceutical composition includes a BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof, which comprises administering BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof in combination with a porin, the BCV dose being reduced by 60% (in the presence of a porin, the BCV dose is reduced by 60%), wherein the treatment is terminated based on the following two conditions being satisfied: (a) the amount of AdV in a subject's sample is measured multiple times and the AdV is below the LOD on two consecutive measurements, and (b) a specific period of treatment has elapsed, wherein the specific period is selected from the range of 4 to 13 weeks, and the BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof is administered by continuous intravenous infusion over 2 hours. Use of this pharmaceutical composition can reduce the occurrence of treatment failure in patients, shorten the time until the AdV amount reaches below the LOD, or shorten the treatment period.

[0051] (43) Composition According to one embodiment of the present invention, there is provided a pharmaceutical composition for treating AdV infection or a disease associated with AdV infection, comprising BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the treatment comprises (i) intravenous administration of BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof at 0.4 mg / kg twice weekly to a subject weighing less than 50 kg (however, in the case of co-administration with cyclosporine, the BCV dose is reduced to 60%), or (ii) intravenous administration of BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof at 20 mg twice weekly to a subject weighing 50 kg or more. (However, when administered in combination with cyclosporine, the BCV dose is reduced by 60%), and the administration period of BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof is terminated based on the following two conditions being met: (a) the amount of AdV in a subject's sample is measured multiple times and the AdV is below the LOD on two consecutive measurements, and (b) four weeks of treatment have elapsed. The BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof is administered by continuous intravenous infusion over two hours. Use of this pharmaceutical composition can reduce the incidence of treatment failure in patients, shorten the time until the AdV amount reaches below the LOD, or shorten the treatment period.

[0052] (44) Composition According to one embodiment of the present invention, there is provided a pharmaceutical composition for treating AdV infection or a disease associated with AdV infection, the pharmaceutical composition comprising BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the treatment comprises (i) intravenously administering 0.39 to 0.41 mg / kg of BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof twice weekly to a subject, or (ii) intravenously administering 19 to 21 mg of BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof twice weekly to a subject. Use of this pharmaceutical composition can reduce the incidence of treatment failure in patients, shorten the time until the AdV load reaches below the LOD, or shorten the treatment period.

[0053] (45) Composition According to one embodiment of the present invention, there is provided a composition for suppressing the recurrence of AdV infection or a disease associated with AdV infection in a subject, or a composition for treating and suppressing the recurrence of AdV infection or a disease associated with AdV infection, the composition comprising BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof. This composition can suppress the recurrence of AdV infection or a disease associated with AdV infection. Recurrence may be a phenomenon in which the AdV level in a subject increases after a decrease in the AdV level. Recurrence may be a phenomenon in which AdV infection or a disease associated with AdV infection worsens after a decrease in the AdV level in a subject. Recurrence may be a recurrence after treatment of AdV infection or a disease associated with AdV infection. The subject may be a subject to whom BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof has been administered. The subject may be a subject to whom AdV infection or a disease associated with AdV infection has improved as a result of administration of BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof. Recurrence may also include a situation in which the AdV level is higher after one additional administration during the treatment period. Relapse may also include a subsequent AdV infection or a worsening of a disease associated with AdV infection when the number of doses is increased by one during the treatment period. Relapse may also include a state in which the AdV amount in a subject administered BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof changes over time from a state in which the AdV amount was below the LOD to a state in which the AdV amount is equal to or greater than the LOD. The subject may be a subject administered BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof using the dosage or method described in (33) to (44) above.

[0054] (46) Composition According to one embodiment of the present invention, a composition for suppressing an increase in AdV levels in a subject is provided, the composition comprising BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof. This composition can suppress an increase in AdV levels. The increase may be a phenomenon in which the AdV level in a subject increases after the AdV level in the subject decreases. The subject may be a subject administered with BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof. The subject may be a subject whose AdV level has decreased as a result of administration of BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof. The increase may include a situation in which the AdV level increases after one additional administration during a treatment period compared to before. The increase may also include a situation in which the AdV level in a subject administered with BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof changes over time from a state in which the AdV level was below the LOD to a state in which the AdV level is equal to or greater than the LOD. The subject may be a subject who has been administered the BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof in the composition described in (33) to (44) above by the method or dosage.

[0055] (47) Composition According to one embodiment of the present invention, a composition for evaluating the effect of administration of BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof, comprising lymphocytes from a subject is provided. The subject may be, for example, a subject with AdV infection or a disease associated with AdV infection, or a subject who has been administered BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof due to AdV infection or a disease associated with AdV infection. Measuring the amount of lymphocytes in this composition can, for example, confirm the effect of BCV. Measuring the amount of lymphocytes in this composition can, for example, allow the subject to be treated with BCV, anticipating that an effective therapeutic effect will be observed. The composition may, for example, be a sample from the subject. The sample may, for example, be a blood sample (e.g., plasma, serum, or whole blood).

[0056] (48) Composition According to one embodiment of the present invention, there is provided a composition for increasing lymphocytes in a subject, the composition comprising BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof. This composition can restore or activate the immune system of a subject. The increase may be compared to before administration of BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0057] (49) Composition According to one embodiment of the present invention, there is provided a composition for restoring or activating the immune system in a subject, the composition comprising BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof. This composition can restore or activate the immune system of a subject. The restoration or activation may be restoration or activation compared to the state before administration of BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof. The restoration or activation may occur in a subject whose immune system has been weakened due to transplantation.

[0058] (50) Composition According to one embodiment of the present invention, there is provided a pharmaceutical composition comprising BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof, for use in the methods described in (1) to (32) above.

[0059] (51) Container According to one embodiment of the present invention, there is provided a container containing the composition described in (33) to (50) above. The container may be, for example, a medical container. The container includes, for example, a bag or a syringe. The bag may be, for example, a medical bag (e.g., an intravenous injection bag, a bag with a sterile content). The syringe may be, for example, equipped with a needle. The composition in the container may be a liquid.

[0060] (52) Container According to one embodiment of the present invention, there is provided a container containing a pharmaceutical composition for treating AdV infection or a disease associated with AdV infection, the container comprising BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the treatment comprises (i) intravenously administering 0.38 to 0.42 mg / kg of BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof twice weekly to a subject, or (ii) intravenously administering 18 to 22 mg of BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof twice weekly to a subject. Use of this container can reduce the occurrence of treatment failure in patients, shorten the time until the AdV load reaches below the LOD, or shorten the treatment period.

[0061] (53) Kit According to one embodiment of the present invention, there is provided a kit comprising the composition described in any one of (33) to (50) above. The kit may also include, for example, an instruction manual, a buffer solution, a container, packaging, a bag, a tube, a pump, a syringe, or an injection needle.

[0062] (54) Use According to one embodiment of the present invention, there is provided a use of BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof for producing the composition according to any one of (33) to (50) above.

[0063] In embodiments of the present invention (e.g., (1) to (54) above), brincidofovir (BCV) includes a compound having the structure shown in the following formula: BCV can also be referred to by its IUPAC name, [(2S)-1-(4-amino-2-oxopyrimidin-1-yl)-3-hydroxypropan-2-yl]oxymethyl-(3-hexadecoxypropoxy)phosphinic acid. BCV includes the compound represented by the CAS registry number 444805-28-1. As used herein, BCV is an abbreviation for brincidofovir, and the two terms have the same meaning.

[0064] In embodiments of the present invention (e.g., (1) to (54) above), adenovirus (AdV) refers to, for example, a type of DNA virus, including viruses capable of causing AdV infection. In this specification, AdV is an abbreviation for adenovirus, and the terms have the same meaning. AdV includes viruses of the Adenoviridae family. Viruses of the Adenoviridae family include, for example, viruses of the Mastadenovirus genus. The therapeutic effect on AdV infection or diseases associated with AdV infection may be evaluated, for example, by observing the change in AdV level over time in a subject's sample after administration of a pharmaceutical composition. In this case, the therapeutic effect may be assessed based on a trend toward a decrease in AdV level. Furthermore, the therapeutic effect may be determined when the AdV level is significantly reduced compared to before administration of the pharmaceutical composition or after administration of a negative control. The AdV level may be measured, for example, by a method for measuring AdV DNA level (e.g., quantitative polymerase chain reaction (PCR) or immunochromatography). The measurement may be quantitative or qualitative.

[0065] In embodiments of the present invention (e.g., (1) to (54) above), diseases associated with AdV infection include diseases caused by AdV infection, such as AdV viremia, fever associated with AdV infection, symptomatic or asymptomatic AdV infection accompanied by organ dysfunction as described below, disseminated AdV infection accompanied by dysfunction of multiple organs or systemic symptoms, deterioration of the general condition due to AdV infection or death associated therewith, AdV myocarditis, AdV central nervous system infection, AdV kidney infection, gastrointestinal diseases associated with AdV infection (e.g., hepatitis or gastroenteritis), respiratory infections associated with AdV infection (e.g., respiratory tract infections (e.g., rhinitis, pharyngitis, or tonsillitis) or pneumonia), eye diseases associated with AdV infection (e.g., epidemic keratoconjunctivitis), pharyngoconjunctival fever associated with AdV infection, and AdV hemorrhagic cystitis.

[0066] In embodiments of the present invention (e.g., (1) to (54) above), the amount of BCV, its pharmaceutically acceptable salt, or a solvate thereof is 0.38 to 0.42 mg / kg, more preferably 0.39 to 0.41 mg / kg, and most preferably 0.4 mg / kg, from the viewpoint of more effective treatment of AdV infection or a disease associated with AdV infection. Effective treatment includes, for example, suppression of the occurrence of treatment failure in patients, shortening of the time until the AdV amount reaches below the LOD, shortening of the treatment period, or treatment with excellent safety. 0.38 to 0.42 mg / kg may be 0.38, 0.39, 0.4, 0.41, or 0.42 mg / kg, or may be within a range of any two of these values.

[0067] In embodiments of the present invention (e.g., (1) to (54) above), 0.58 to 0.62 mg / kg as the amount of BCV, its pharmaceutically acceptable salt, or a solvate thereof may be 0.59 to 0.61 mg / kg or 0.6 mg / kg. 0.58 to 0.62 mg / kg may be 0.58, 0.59, 0.6, 0.61, or 0.62 mg / kg, or may be within a range between any two of these values. 0.78 to 0.82 mg / kg may be 0.79 to 0.81 mg / kg or may be 0.8 mg / kg. 0.78 to 0.82 mg / kg may be 0.78, 0.79, 0.8, 0.81, or 0.82 mg / kg, or may be within a range between any two of these values. 0.38 to 0.82 mg / kg may be 0.39 to 0.81 mg / kg, 0.4 to 0.8 mg / kg, or 0.4, 0.6, or 0.8 mg / kg. 0.38 to 0.82 mg / kg may be 0.38, 0.4, 0.42, 0.5, 0.58, 0.6, 0.62, 0.7, 0.78, 0.8, or 0.82 mg / kg, or may be within a range of any two of these values.

[0068] In embodiments of the present invention (e.g., (1) to (54) above), the amount of BCV, its pharmaceutically acceptable salt, or a solvate thereof is 18 to 22 mg / dose, more preferably 19 to 21 mg / dose, and most preferably 20 mg / dose, from the viewpoint of more effective treatment of AdV infection or diseases associated with AdV infection. Effective treatment includes, for example, suppression of the occurrence of treatment failure in patients, shortening of the time until the AdV amount reaches below the LOD, shortening of the treatment period, or treatment with excellent safety. 18 to 22 mg / dose may be 18, 19, 20, 21, or 22 mg / dose, or may be within a range of any two of these values. mg / dose can also be expressed in mg / body.

[0069] In embodiments of the present invention (e.g., (1) to (54) above), the amount of 28 to 32 mg / dose of BCV, its pharmaceutically acceptable salt, or a solvate thereof may be 29 to 31 mg / dose or 30 mg / dose. 28 to 32 mg / dose may be 28, 29, 30, 31, or 32 mg / dose, or may be within a range between any two of these values. 38 to 42 mg / dose may be 39 to 41 mg / dose or 40 mg / dose. 38 to 42 mg / dose may be 38, 39, 40, 41, or 42 mg / dose, or may be within a range between any two of these values. 18 to 42 mg / dose may be 19 to 41 mg / dose, 20 to 40 mg / dose, or 20, 30, or 40 mg / dose. The 18 to 42 mg / dose may be 18, 20, 22, 25, 28, 30, 32, 35, 38, 40, or 42 mg / dose, or may be within a range of any two of these values.

[0070] In embodiments of the present invention (e.g., (1) to (54) above), the phrase "as an amount of BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof" can refer to, for example, the amount of BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof contained in a specific amount of a pharmaceutical composition when the specific amount of the pharmaceutical composition is administered to a subject. For example, if an amount A (mg / kg or mg / dose) of a pharmaceutical composition contains an amount B of BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof, and an amount C of an additive, the amount of BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof is amount B. Here, an amount of a pharmaceutical composition equivalent to amount B of BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof is amount A of a pharmaceutical composition. Furthermore, the phrase "as an amount of BCV" can refer to the amount of the BCV portion contained in a specific amount of a pharmaceutical composition when the specific amount of the pharmaceutical composition is administered to a subject. For example, if an amount D (mg / kg or mg / dose) of a pharmaceutical composition contains an amount E of BCV and an amount F of an additive, the amount E is the BCV portion. Here, a pharmaceutical composition in an amount equivalent to E in terms of the amount of BCV is an amount D of the pharmaceutical composition. For example, if a pharmaceutical composition in an amount G (mg / kg or mg / dose) contains a pharmaceutically acceptable salt of BCV in an amount H and an additive in an amount I, the amount of BCV is the amount of the free form of BCV in the amount H (in other words, the amount obtained by subtracting the salt portion combined with the free form of BCV from the amount H). Here, a pharmaceutical composition in an amount equivalent to the amount of the free form of BCV in the amount H is an amount G of the pharmaceutical composition. Expressing dosages based on the amount of components, rather than the amount of the final formulation, is common practice in the pharmaceutical field. Therefore, those skilled in the art will understand embodiments of pharmaceutical compositions or treatment methods in which dosages are expressed based on the amount of components.

[0071] In embodiments of the present invention (e.g., (1) to (54) above), twice-weekly administration includes administration once on any one of days 1, 2, 3, 4, 5, 6, and 7, and once on another day, when a week is divided into days 1 to 7. From the viewpoint of more effective treatment of AdV infection or a disease associated with AdV infection, twice-weekly administration is preferably on days 1 and 3, 4, or 5, and most preferably on days 1 and 4. Day 1 may be the start day of treatment, the first day of administration, or the first day of the week, and the day of the week may be Sunday, Monday, Tuesday, Wednesday, Thursday, Friday, or Saturday.

[0072] In embodiments of the present invention (e.g., (1) to (54) above), the body weight of a subject to whom BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof is administered intravenously at 0.38 to 0.42 mg / kg in (i) is less than a specific body weight, and the body weight of a subject to whom BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof is administered intravenously at 18 to 22 mg / dose in (ii) is equal to or greater than a specific body weight. The specific body weights of subjects (i) and (ii) may be the same, 48 to 52 kg. From the viewpoint of more effective treatment of AdV infection or a disease associated with AdV infection, 48 to 52 kg is more preferably 49 to 51 kg, and 50 kg is most preferably 50 kg. 48 to 52 kg may be 48, 49, 50, 51, or 52 kg, or may be within a range of any two of these values. The specific body weight includes the given body weight.

[0073] In embodiments of the present invention (e.g., (1) to (54) above), the administration period of BCV, its pharmaceutically acceptable salt, or a solvate thereof may be terminated based on treatment discontinuation criteria. Use of these treatment discontinuation criteria allows for early determination of the end of administration, taking into account the patient's predicted response from the specific dosage and administration described above, thereby particularly shortening the treatment period. Treatment discontinuation criteria may include, for example, multiple measurements of AdV levels in a subject's blood sample showing that AdV levels are below the LOD in two consecutive measurements, the elapse of a specific treatment period (e.g., 4 to 13 weeks) since the first administration, or the elapse of 4 weeks of treatment since the first administration. The 4 to 13 weeks may be, for example, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 weeks. The specific period may be set with an upper limit of 13 weeks from the viewpoint of safety. From the viewpoint of comprehensive therapeutic efficacy and safety, the specific period is preferably selected from 4 to 13 weeks, and particularly preferably from 4 to 8 weeks. From the viewpoint of life prognosis, the specific period is particularly preferably the fourth week.

[0074] In embodiments of the present invention (e.g., (1) to (54) above), the administration period of BCV, its pharmaceutically acceptable salt, or a solvate thereof may be terminated based on the following two conditions being met: (a) the amount of AdV in a subject's sample is measured multiple times and AdV is below the LOD in two consecutive measurements; and (b) a specific period of treatment has elapsed. The specific period may be selected from 4 to 13 weeks. In this case, the end of administration can be determined early, taking into account the patient's response predicted from the specific dosage and administration method, thereby particularly shortening the treatment period. The measurement in (a) above may be performed multiple times with an interval of 3 days or more. The measurement in (a) above may be performed on the same day as the administration of BCV, its pharmaceutically acceptable salt, or a solvate thereof. The measurement in (a) above may be performed on the same day as the earlier or later administration of twice-weekly administration. The measurement in (a) above may be performed at least once a week or twice a week for at least 13 weeks. The above (a) may be the case where the amount of AdV in a subject sample is measured multiple times and the AdV is below the LOD in the two most recent measurements. The most recent two measurements may be, for example, the two most recent measurements based on the time when the decision to terminate the administration period is made (e.g., the most recent measurement and the measurement immediately before that).

[0075] In embodiments of the present invention (e.g., (1) to (54) above), the administration period of BCV, its pharmaceutically acceptable salt, or solvate thereof may be terminated based on the following two conditions being met: (a) the amount of AdV in a subject's sample is measured multiple times and AdV is below the LOD in two consecutive measurements; and (b) the fourth week of treatment has elapsed. In this case, the end of administration can be determined early, taking into account the patient's expected response based on the specific dosage and administration method, thereby particularly shortening the treatment period. The measurement in (a) above may be performed multiple times, with an interval of at least three days between measurements. The measurement in (a) above may be performed on the same day as the administration of BCV, its pharmaceutically acceptable salt, or solvate thereof. The measurement in (a) above may be performed on the same day as the earlier or later administration of twice-weekly administration. The measurement in (a) above may be performed on one or two of days 1, 2, 3, 4, 5, 6, or 7 of twice-weekly administration. The measurement in (a) above may be performed at least once a week or twice a week for at least four weeks. The multiple measurements may be, for example, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, or 30 or more times, or a number within a range between any two of these values. (a) above may also be performed when the amount of AdV in a subject's sample is measured multiple times and the AdV is below the LOD in the two most recent measurements. The most recent two measurements may be, for example, the most recent two measurements based on the time when the administration period is to be terminated (e.g., the most recent measurement and the measurement immediately before that). For example, if the administration period ends at four weeks, the most recent two measurements may be the last measurement and the penultimate measurement within the four weeks. For example, if the AdV does not reach below the LOD within four weeks of administration, the most recent two measurements may be the first measurement in which the AdV is below the LOD after the fifth week and the measurement immediately following that. For example, if AdV first falls below the LOD at the last measurement within 4 weeks after administration, the most recent two measurements may be the last measurement within 4 weeks after administration and the first measurement at week 5 after administration. The 3 or more days in (a) above is preferably 3 or more days but no more than 14 days."Three days or more" may be, for example, 3, 4, 5, 6, 7, 8, 10, 12, or 14 days, or may be any one or more of these values, or a range between any two of these values. From another perspective, in embodiments of the present invention (e.g., (1) to (54) above), the administration period of BCV, its pharmaceutically acceptable salt, or a solvate thereof may be terminated based on the fulfillment of both of the following conditions: (a) the amount of AdV in a subject's sample is measured multiple times and AdV is negative in two consecutive measurements, and (b) the fourth week of treatment has elapsed. In this case, the termination of administration can be determined at an early stage, taking into account the patient's response predicted from the specific dosage and administration method described above, thereby particularly shortening the treatment period. From another perspective, in embodiments of the present invention (e.g., (1) to (54) above), the administration period of BCV, its pharmaceutically acceptable salt, or a solvate thereof may be terminated based on the fulfillment of both of the following conditions: (a) the amount of AdV in a subject's sample is measured multiple times and AdV is negative in two consecutive measurements. In this case, the end of administration can be determined at an early stage, which in particular makes it possible to shorten the treatment period.

[0076] In embodiments of the present invention (e.g., (1) to (54) above), AdV being below the LOD includes, for example, AdV not reaching the LOD when a PCR method (e.g., quantitative PCR (e.g., real-time quantitative PCR)) is performed. Being below the LOD may also include a negative result. The PCR method described above may have, for example, an LOD of 25 copies / mL, a lower limit of quantification of 190 copies / mL, and an upper limit of quantification of 1×10 9 The LOD of AdV may be, for example, 100, 75, 50, or 25 copies / mL. For methods of detecting AdV, see, for example, Ison et al., Microbiol Spectr. 2016 Aug;4(4).

[0077] In the embodiments of the present invention (e.g., (1) to (54) above), "less than LOD" may include, for example, "less than the lower limit of quantitation (LLOQ) and undetectable." These terms may be used with substantially the same meaning.

[0078] In embodiments of the present invention (e.g., (1) to (54) above), when treatment is performed in the context of coadministration of cyclosporine and BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof, the dose of BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof may be reduced by 55 to 65%. A dose reduced by 55 to 65% is equivalent to a dose that is 0.55 to 0.65 times the original dose. From the viewpoint of more effective treatment of AdV infection or a disease associated with AdV infection, 55 to 65% is more preferably 57 to 63%, even more preferably 59 to 61%, and most preferably 60%. 55 to 65% may be 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, or 65%, or may be within a range of any two of these values. In the above (i), when BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof is administered intravenously at 0.38 to 0.42 mg / kg twice a week, a dose reduced by 55 to 65% includes 0.21 to 0.27 mg / kg. From the viewpoint of more effective treatment of AdV infection or a disease associated with AdV infection, 0.21 to 0.27 mg / kg is more preferably 0.23 to 0.25 mg / kg, and 0.24 mg / kg is most preferably 0.21 to 0.27 mg / kg. 0.21 to 0.27 mg / kg may be 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, or 0.27 mg / kg, or may be within a range between any two of these values. In the above (ii), when BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof is administered intravenously at 18 to 22 mg twice weekly, a dose reduced by 55 to 65% includes 9.9 to 14.3 mg. From the viewpoint of more effective treatment of AdV infection or a disease associated with AdV infection, 9.9 to 14.3 mg is more preferably 11 to 13 mg, and most preferably 12 mg. 9.9 to 14.3 mg may be 9.9, 10, 11, 12, 13, 14, or 14.3 mg, or may be within a range between any two of these values.

[0079] In embodiments of the present invention (e.g., (1) to (54) above), the dosage and administration of cyclosporine when coadministering cyclosporine and BCV, its pharmaceutically acceptable salt, or a solvate thereof may be, for example, those approved by the PMDA or FDA at the time of filing this application or known in the art. For example, to transplant patients, starting on day 1 after transplantation, a dose of 6 to 16 mg / kg / day of cyclosporine may be orally administered twice daily, with subsequent administration of 2 mg / kg / day or gradually reduced. A standard maintenance dose is 2 to 6 mg / kg / day, which may be increased or decreased as appropriate depending on symptoms. Cyclosporine may be administered by continuous intravenous infusion. Administration of cyclosporine does not affect the blood concentration of BCV. Cyclosporine includes the compound designated by CAS Registry Number (R) 59865-13-3.

[0080] In embodiments of the present invention (e.g., (1) to (54) above), when two or more treatments (e.g., administration) are present, combination includes administration of one treatment before, simultaneously with, or after the other treatment.

[0081] In embodiments of the present invention (e.g., (1) to (54) above), the fourth week of treatment includes, for example, the case where four weeks have passed since the first administration or the case where the second administration in the fourth week has been completed.

[0082] In embodiments of the present invention (e.g., (1) to (54) above), the administration period includes, for example, the period from the first administration, after which administration is repeated at a specific frequency (e.g., twice a week), until administration is discontinued. For example, if administration is performed twice a week for four weeks, the administration period may be four weeks. The administration period includes, for example, the period of continuous intravenous infusion and interval periods (e.g., periods without continuous intravenous infusion). The administration period includes the treatment period.

[0083] In the methods of the embodiments of the present invention (e.g., (1) to (32) above), the step of identifying a subject may include a step of identifying a subject as a subject for treatment or a step of identifying a subject as a subject for administration of a pharmaceutical composition. The step of identifying a subject may include a step of selecting a subject or a step of identifying a subject.

[0084] In one embodiment of the present invention (e.g., (1) to (54) above), the time period for a single intravenous administration may be 1.5 to 4 hours. This administration time may be 1.5, 2, 2.5, 3, 3.5, or 4 hours, or may be within a range of any two of these values. Intravenous administration includes, for example, intravenous infusion (e.g., continuous intravenous infusion).

[0085] In embodiments of the present invention (e.g., (1) to (54) above), a subject having AdV infection or a disease associated with AdV infection may be identified based on the detection of AdV DNA in a sample (e.g., blood) from the subject, the amount of AdV DNA in the sample being significantly higher than that of a comparison subject (e.g., a healthy individual), or the amount of AdV DNA in the sample being 1000 copies / ml or more or 10,000 copies / ml or more.

[0086] In embodiments of the present invention (e.g., (1) to (54) above), the sample may include, for example, a biological sample. The sample may include, for example, a body fluid (e.g., blood (e.g., plasma, serum, or whole blood), throat swab, saliva, urine, or cerebrospinal fluid), sputum, or stool. The sample may include, for example, a specimen. In treating a subject, the effectiveness of treatment may be evaluated based on the amount of AdV in the subject's sample, and the amount of AdV may be used as an indicator for discontinuing treatment.

[0087] In embodiments of the present invention (e.g., the above (1) to (54)), BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof, or a pharmaceutical composition containing them may be placed in a container, for example, in the form of a liquid. The container may be, for example, a medical container. The container includes, for example, a bag or a syringe. The bag may be, for example, a medical bag (e.g., an intravenous injection bag, a bag with sterile contents).

[0088] In one embodiment of the present invention (e.g., (1) to (54) above), the diluent may include, for example, a diluent for infusion (e.g., containing a glucose solution or physiological saline). The diluent may be, for example, a solution for diluting or adjusting the concentration of an active ingredient. In one embodiment of the present invention (e.g., (1) to (54) above), the step of identifying a human subject weighing less than 50 kg or the step of identifying a human subject weighing 50 kg or more may include a step of selecting the human subject. In one embodiment of the present invention (e.g., (1) to (54) above), the step of identifying a human subject weighing less than 50 kg, the step of identifying a human subject weighing 50 kg or more, or the step of identifying the body weight of a human subject may be identified by interview. In one embodiment of the method (e.g., (1) to (32) above), the administration may suppress AdV infection or recurrence of a disease associated with AdV infection in the subject. In one embodiment of the method (e.g., (1) to (32) above), the administration may restore or activate the immune system in the subject.

[0089] In embodiments of the present invention (e.g., (1) to (54) above), treatment includes exerting an effect that brings about a beneficial result in a patient with respect to a patient's disease (e.g., AdV infection or a disease associated with AdV infection) or one or more symptoms associated with the disease (e.g., improvement, alleviation, palliation, cure, remission, or suppression (e.g., suppression of onset (e.g., prevention), suppression of progression, or suppression of recurrence). Treatment may be carried out by administering a therapeutically effective amount of BCV, its pharmaceutically acceptable salt, or a solvate thereof to a subject. In embodiments of the present invention (e.g., (1) to (54) above), the pharmaceutical composition may be produced by, for example, mixing an active ingredient with one or more pharmaceutically acceptable carriers using any method known in the technical field of pharmaceuticals. Furthermore, the pharmaceutical composition may be in any form used as long as it is used for treatment, and may contain the active ingredient alone or a mixture of the active ingredient with any ingredient. Furthermore, the form of the carrier is not particularly limited, and may be, for example, a solid or liquid (e.g., a buffer solution). The content of the carrier may be, for example, a pharmaceutically effective amount. An effective amount is, for example, The amount may be sufficient for pharmaceutical stability or delivery of the active ingredient. For example, a buffer is effective for stabilizing the active ingredient in the vial. The pharmaceutical composition may also contain a stabilizer (e.g., mannitol), a buffering agent (e.g., arginine), or a pH adjuster (e.g., NaOH). The pharmaceutical composition may be prepared by mixing the active ingredient with a diluent (e.g., glucose solution or physiological saline). The dosage, administration interval, administration method, and administration route are not particularly limited and can be selected appropriately depending on the patient's age, weight, symptoms, target organ, etc. Furthermore, the pharmaceutical composition preferably contains a therapeutically effective amount, or an effective amount that exerts the desired effect, of the active ingredient. In one embodiment of the present invention, a therapeutically effective amount includes the amount necessary to clinically observe improvement in symptoms in the patient. In one embodiment of the present invention, pharmaceutically acceptable includes a state that is suitable for use within the scope of sound medical judgment and commensurate with a reasonable benefit / risk ratio. The components other than BCV in the pharmaceutical composition are not particularly limited as long as they do not impair the effects of the present invention and can be selected appropriately depending on the purpose.The therapeutic effect on AdV infection or a disease associated with AdV infection may be determined to be effective when the amount of AdV in a patient is significantly reduced after administration of the pharmaceutical composition.

[0090] In embodiments of the present invention (e.g., (1) to (54) above), the subject (including a patient) may be, for example, a subject diagnosed with AdV infection or a disease associated with AdV infection, a subject suspected of having AdV infection or a disease associated with AdV infection, or a subject in need of treatment for AdV infection or a disease associated with AdV infection. The subject may be, for example, a subject in whom AdV is detected in a sample, a subject in whom the amount of AdV in the sample is increased compared to a comparison subject (e.g., a healthy individual), or a subject in whom AdV DNA in the sample is 1,000 copies / ml or more or 10,000 copies / ml or more. The subject may be, for example, a subject who has experienced AdV infection or a disease associated with AdV infection. The subject may be, for example, an allogeneic transplant patient, an autologous transplant patient, or a hematopoietic stem cell transplant patient. The subject may be, for example, a patient with an immunodeficiency disease or condition, including a patient after allogeneic hematopoietic stem cell transplantation. A subject includes a human or a non-human mammal (e.g., one or more of a mouse, guinea pig, hamster, rat, mouse, rabbit, pig, sheep, goat, cow, horse, cat, dog, marmoset, monkey, or chimpanzee). A subject includes a human adult patient or a human pediatric patient (e.g., a patient aged 2 months or older). A subject's age may be, for example, 0, 1, 2, 3, 4, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100, or within a range of any two of these values. A subject includes a population of subjects.

[0091] In embodiments of the present invention (e.g., (1) to (54) above), the subject to be treated with BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof may be, for example, an immunosuppressed subject. From the viewpoint of being particularly effective in treating AdV infection or a disease associated with AdV infection, it is more preferable to treat an immunosuppressed human subject. Immunosuppressed human subjects include, for example, immunocompromised human subjects. Immunosuppressed human subjects may be, for example, patients with primary or acquired immunodeficiency (e.g., allogeneic transplant patients, autologous transplant patients, hematopoietic stem cell transplant patients, patients administered immunosuppressants (e.g., organ transplant patients), or patients with immunodeficiency syndromes).

[0092] In embodiments of the present invention (e.g., (1) to (54) above), the route of administration of BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof (or a pharmaceutical composition containing them) to a subject (including a human subject) is preferably intravenous for effective treatment. The preferred administration form is injection (e.g., intravenous injection) for effective treatment.

[0093] In embodiments of the present invention (e.g., (1) to (54) above), the salt is not particularly limited and includes, for example, inorganic salts or organic salts (see, for example, Bharate et al., Drug Discov Today. 2021 Feb;26(2):384-398 or Berge et al., J Pharm Sci. 1977 Jan;66(1):1-19). Salts include, for example, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like. Metal salts include, for example, alkali metal salts (sodium salts, potassium salts, etc.), alkaline earth metal salts (calcium salts, magnesium salts, barium salts, etc.), aluminum salts, and the like. Salts with organic bases include, for example, salts with trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N,N'-dibenzylethylenediamine, and the like. Salts with inorganic acids include, for example, salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc. Salts with organic acids include, for example, salts with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, mesylic acid, tosylic acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc. Salts with basic amino acids include, for example, salts with arginine, lysine, ornithine, etc. Salts with acidic amino acids include, for example, salts with aspartic acid, glutamic acid, etc. Salts include pharmaceutically acceptable salts. In one embodiment of the present invention, pharmaceutically acceptable includes forms having reasonable benefits for pharmaceutical use. In one embodiment of the present invention, a form of the compound or a salt thereof includes a solvate form thereof. In embodiments of the present invention (e.g., (1) to (54) above), solvates include forms of compounds formed by a solute and a solvent (see, for example, Healy et al., Adv Drug Deliv Rev. 2017 Aug 1;117:25-46).Solvates include, but are not limited to, hydrates (e.g., monohydrates, dihydrates, trihydrates, etc.) or organic solvent solvates (e.g., solvates with alcohols (e.g., methanol, ethanol, propanol, etc.), acetone, dimethylformamide, or ethyl acetate, etc.). Solvents include those that can substantially maintain the physiological activity of the solute after forming the solvate. Solvates include pharmaceutically acceptable solvates.

[0094] In one embodiment of the present invention (e.g., (1) to (54) above), "significantly" may mean, for example, a state where a statistically significant difference is evaluated using a Student's t-test (one-tailed or two-tailed) and p<0.05 or p<0.01. Alternatively, it may mean a state where a substantial difference is present.

[0095] All publications cited herein are incorporated by reference in their entirety. As used herein, "or" is used when "at least one or more" of the items listed in the text can be employed. The same applies to "or." As used herein, a term in the form "at least one or more of A, B, and C" means that any of (A), (B), (C), (A and B), (A and C), (B and C), or (A, B and C) can be employed. As used herein, when it is stated that "within a range of two values," the range also includes the two values ​​themselves. As used herein, "A to B" includes A and B as well as values ​​between A and B. As used herein, "having" when referring to a disease includes being affected. In this specification, "the above (1) to (54)" means (1), (2), (3), (4), (5), (6), (7), (8), (9), (10), (11), (12), (13), (14), (15), (16), (17), (18), (19), (20), (21), (22), (23), (24), (25), (26), (27), (28), (29), (30), (31), (32), (33), (34), (35), (36), (37), (38), (39), (40), (41), (42), (43), (44), (45), (46), (47), (48), (49), (50), (51), (52), (53), (54), (55), (56), (57), (58), (59), (60), (61), (62), (63), (64), (65), (66), (67), (68), (69), (70), (71), (72), (73), (74), (75), (76), (77), (78), (79), (80), (81), (82), (83), (84), (85), (86), (87), (88), (89), (90), (91), (92), (93), (94), (95), (96), (97), (98), (99), (100), (101), (102), (103), (104), (105), (106), (107), (108), (109), (110), (111), (122), (133), (144), (155), (165), (170), (186), (190), (109), (1 8), (29), (30), (31), (32), (33), (34), (35), (36), (37), (38), (39), (40), (41), (42), (43), (44), (45), (46), (47), (48), (49), (50), (51), (52), (53), or (54).

[0096] Although the embodiments of the present invention have been described above, these are merely examples of forms that may be included in the present invention, and the present invention is not limited to these, and various configurations other than those described above may also be adopted. Furthermore, the present invention may be adopted by combining or independently adopting each of the configurations or features described in the above embodiments.

[0097] The present invention will be further explained below with reference to examples, but is not limited to these.

[0098] Example 1: Human clinical trial for treatment of AdV infection A human clinical trial for treatment of adenovirus (AdV) infection was carried out according to the following procedure.

[0099] 1.1 Materials and Methods 1.1.1 Patients Patients aged 2 months or older who are immunosuppressed and have asymptomatic AdV infection or AdV disease, including hematopoietic stem cell transplant patients before immune reconstitution with transplanted cells has been achieved, organ transplant patients receiving immunosuppressants, and patients with immunodeficiency syndrome, and who have high levels of AdV viremia (patients with a single sample of 10,000 copies / ml or more, or two samples of 1000 copies / ml or more, with the second sample showing an increase in viral load compared to the first).

[0100] 1.1.2 Drug Description Brincidofovir (BCV) injection is a sterile aqueous solution containing 10 mg / mL BCV. Drug Overview Product Name: Brincidofovir Dosage Form: Injection Unit Dose: 10 mg / mL (1 mL per vial) Route of Administration: Intravenous Injection Physical Description: Clear, colorless solution in a sterilized glass bottle Storage Method: Refrigerated (2-8°C) Administration Method: Continuous intravenous infusion over 2 hours twice a week (days 1 and 4 of administration).

[0101] 1.1.3 Dosage Cohort 1: 0.2 mg / kg (10 mg / dose if body weight is 50 kg or more) twice weekly Cohort 2: 0.3 mg / kg (15 mg / dose if body weight is 50 kg or more) twice weekly Cohort 3: 0.4 mg / kg (20 mg / dose if body weight is 50 kg or more) twice weekly

[0102] 1.1.4 Drug Administration The dose of BCV 10 mg / mL injection is prepared based on the patient's weight. The following kit is used for preparation and administration of the intravenous solution: Intravenous bag: 5% glucose, 100 mL, non-PVC (polyvinyl chloride), DEHP (diethylhexyl phthalate)-free Intravenous tubing: The tubing does not contain plasticizers and is DEHP-free. Intravenous pump: Use approved tubing. Preparation: Using a sterile syringe and needle, transfer 1 mL of BCV intravenous solution from one vial into a 100 mL glucose 5% intravenous bag to create the diluted administration solution. If the dose exceeds 10 mg, prepare an additional dose of diluted administration solution using the same procedure as above. Gently invert the bag at least five times to mix. Avoid vigorously shaking the solution in the vial or the diluted administration solution in the bag.

[0103] Administer the appropriate volume of diluent based on the patient's weight. Each dose should be administered intravenously at a steady rate over 2 hours. After administration is complete, flush the IV line with 5% glucose or 5% dextrose to ensure all active medication has been removed from the IV line. If required per facility practice, the 5% glucose or 5% dextrose flush may be followed by a normal saline flush. Diluent should generally be prepared at the time of use, not the day before.

[0104] Subjects 101-12 in Cohort 2 and subjects 101-15, 101-18, and 110-06 in Cohort 3 will receive cyclosporine, an immunosuppressant, during the treatment period with intravenous BCV. A preliminary PK study in healthy volunteers showed that coadministration of BCV and cyclosporine significantly increased plasma BCV exposure. When BCV and cyclosporine were administered simultaneously, the AUC inf and C max The AUC of plasma BCV increased approximately 3.4-fold and approximately 2.3-fold compared with BCV alone. When cyclosporine was administered over 2 hours after the end of intravenous BCV injection, the AUC of plasma BCV increased approximately 3.4-fold and approximately 2.3-fold, respectively. inf and C maxThe AUC of plasma BCV after BCV monotherapy increased by approximately 1.8 and 1.3 times, respectively. inf and C max The results were generally similar. Taking the above into consideration, for the above patients taking cyclosporine, all doses shown in 1.1.3 (Cohorts 1-3) above will be reduced by 60%. When cyclosporine is administered as an oral or injection BID (twice daily), it should be administered with a 2-hour interval after the end of the BCV intravenous infusion. When cyclosporine is administered as a 24-hour continuous infusion, there is no interval.

[0105] 1.1.5 Study Duration The study duration will be at least 9 weeks, based on a 1-week screening period, a treatment period of at least 4 weeks, and a 30-day post-treatment follow-up period. After patients provide informed consent, screening assessments will be conducted to determine study eligibility. On the first day of the first week of treatment, patients will be assigned a dose based on their appropriate cohort (see 1.1.3, Cohorts 1-3, above). Treatment will last a minimum of 4 weeks and a maximum of 14 weeks, with termination based on the treatment discontinuation criteria described below. For patients assessed by the physician as being at high risk for AdV infection / disease recurrence, even after completing the 4-week treatment period, treatment may be extended for up to 10 weeks if AdV load is not confirmed on two consecutive measurements taken at least 3 days apart. All patients will be followed for 30 days after the final dose. Adverse events will be assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0 (Grades 1-5). The decision to start Cohort 2 will be based on the results of a review of the safety data from Cohort 1. Similarly, the decision to start Cohort 3 will be based on the results of a review of the safety data from Cohort 2. If grade 3 or higher adverse events are observed in more than 25% of all subjects in the previous cohort, enrollment in the new cohort will be immediately halted.

[0106] The treatment stopping criteria for the end of the treatment period are as follows: AdV levels in the subject's sample are measured multiple times, and treatment is discontinued when the two most recent measurements show AdV levels below the LOD on both consecutive occasions, and after four weeks of treatment. To confirm clearance of AdV viremia, two consecutive plasma viral load test results below the LOD are required. After the initial result is reported as below the LOD, a confirmatory blood draw must be performed at least three days (two full days) but within 14 days (thirteen full days) after the initial sample was collected. Patients receiving intravenous BCV treatment will continue treatment for four weeks, even if AdV viremia is confirmed to have cleared, unless excluded by guidelines for managing BCV-specific adverse events. If two consecutive plasma AdV levels below the LOD are confirmed before the completion of four weeks of BCV treatment, patients will continue the designated BCV treatment for up to four weeks. If AdV viremia is present by week 5, day 1, and confirmed by serial weekly viral load testing, BCV treatment may be continued for up to 14 weeks. Patients receiving BCV for 4 weeks may discontinue intravenous BCV treatment and proceed to post-treatment follow-up once AdV viremia has resolved as confirmed by two consecutive plasma viral load measurements.

[0107] 1.1.6 Blood samples for viremia analysis Blood from each patient was collected into a K2EDTA (dipotassium dihydrogen ethylenediaminetetraacetate) tube, mixed by inversion 8-10 times, and centrifuged at 1100-1300 × g for 10 minutes. Plasma was isolated immediately after collection or within 30 minutes after collection. Plasma was frozen and stored at -70°C and analyzed for AdV viremia using real-time qPCR (LOD: 25 copies / mL, lower limit of quantification: 190 copies / mL, upper limit of quantification: 1 × 10 10 copies / mL).

[0108] 1.2 Clinical Trial Data Figures 1 to 3 show the study results for Cohorts 1 to 3. In Figures 1 to 3, the horizontal axis, W in W1D1, stands for week, and D stands for day (i.e., W1D1 is week 1, day 1). The same applies to W2D1 and onward. The vertical axis in Figures 1 to 3 shows the amount of AdV in plasma. The LLOQ line is the lower limit of quantitation. Cohorts 1 to 3 include male or female patients aged 0 to 80 years and weighing 5.4 to 82.4 kg. Cohort 1 included one patient weighing 50 kg or more, and Cohorts 2 and 3 each included two patients.

[0109] In cohort 1, two patients achieved AdV levels below the LOD. One of the two patients relapsed, and one patient died. In cohort 2, five patients achieved AdV levels below the LOD. In these five patients, it took a long time for AdV levels to reach below the LOD. One patient died.

[0110] In Cohort 3, all patients (10) achieved AdV levels below the LOD. None of the patients experienced recurrence or death. Furthermore, the 10 patients generally achieved a short time to reach levels below the LOD. Eight patients in Cohort 3 achieved levels below the LOD within 4 weeks, and the remaining two patients achieved levels below the LOD by weeks 5 and 6. These findings suggest that Cohort 3 can reduce the incidence of treatment failures. Furthermore, the short time to reach levels below the LOD in Cohort 3 suggests that the treatment period can be shortened. Furthermore, the treatment period can be terminated based on the above-mentioned treatment discontinuation criteria, suggesting that the treatment period can be particularly shortened in Cohort 3.

[0111] BCV-related adverse events were as follows: Cohort 1: 110-01: diarrhea, grade 2 (possible); Cohort 2: 101-09: diarrhea, grade 3 (possible); Cohort 3: 109-03: nausea, grade 1 (possible); Cohort 3: 102-02: increased ALT, grade 3 (possible); Cohort 3: increased AST, grade 3 (possible); Cohort 4: palpitations, grade 1 (possible); Cohort 5: nausea, grade 1 (possible); Cohort 6: palpitations, grade 1 (possible); Cohort 7: nausea, grade 1 (possible); Cohort 8: palpitations, grade 1 (possible); Cohort 9: diarrhea, grade 2 (possible); Cohort 10: nausea, grade 1 (possible); Cohort 11: nausea, grade 1 (possible); Cohort 12: diarrhea, grade 3 (possible); Cohort 13: elevated ALT, grade 3 (possible); Cohort 14: palpitations, grade 1 (possible); Cohort 15: nausea, grade 1 (possible). There were 0 grade 3 adverse events in Cohort 1, 2 in Cohort 2, and 1 in Cohort 3. Although Cohort 3 received a higher dose than Cohort 2, the incidence of grade 3 adverse events was lower.

[0112] 1.3. Discussion BCV injection is effective for the treatment of AdV infection and for the prevention of AdV infection in immunocompromised patients. Intravenous administration of 0.4 mg / kg twice weekly (20 mg for patients weighing 50 kg or more) demonstrated significantly superior therapeutic efficacy. This administration method can reduce the occurrence of treatment failures. This administration method shortens the treatment period because it shortens the time until AdV levels reach below the LOD and also suppresses recurrence. This administration method can particularly shorten the treatment period by applying the above-mentioned treatment discontinuation criteria. Furthermore, shortening the treatment period has benefits such as suppressing the emergence of resistant strains, reducing the physical burden on patients, reducing the incidence of adverse events, and reducing treatment costs. This administration method is also safe because of its low incidence of adverse events.

[0113] Example 2: Analysis of AdV in Feces In the clinical trial of Example 1, AdV was examined in the feces of patients. As shown in Figure 4, feces of patients were collected and tested. In the figure, D means detected, ND means not detected, and NP means not performed. A qualitative PCR method was used to detect AdV.

[0114] In Cohort 1, AdV was not detected in 0 of 8 patients during the study period. In Cohort 2, AdV was not detected in 2 of 9 patients during the study period. In 1 of the 2 patients, AdV was detected the following week.

[0115] In Cohort 3, AdV was undetectable in 5 of 8 patients during the study period. Although there were no drugs that could eliminate AdV in stool, the administration method used in Cohort 3 demonstrated that AdV could be effectively eliminated from stool.

[0116] Example 3: Lymphocyte Analysis In the clinical trial described in Example 1, the absolute lymphocyte count in the plasma of patient 110-05 in Cohort 3 was examined. Figure 5 shows the measurement results of the absolute lymphocyte count, AdV load, and ALT value. While the AdV load fell below the LOD at week 3, the lymphocyte count tended to increase. The increase in lymphocyte count suggested that the lymphocyte-related immune system had recovered, making the recurrence of AdV viremia less likely.

[0117] Example 4: Lymphocyte analysis In the clinical trial of Example 1, blood samples were collected from patients in Cohorts 1 to 3 and examined and evaluated at the clinical trial site. The absolute lymphocyte count (ALC) was calculated from the white blood cell count and lymphocyte percentage (%).

[0118] Figures 6–9 show the results of ALC measurements. Because ALC did not necessarily increase in patients in whom circulating AdV disappeared, it is believed that AdV disappearance is due to the antiviral effect of BCV, rather than immune system reconstitution after hematopoietic stem cell transplantation. Furthermore, a tendency for ALC to increase was observed in Cohort 3, which received the most effective dose. AdV has been reported to suppress lymphocyte proliferation, particularly T cell proliferation (Wang et al., Front Immunol. 2023 Oct 17:14:1286622). These findings suggest that the mechanism of action of BCV administration is that the reduction in AdV levels by optimal administration promotes the recovery of lymphocyte counts, further eliminating AdV-infected cells.

[0119] Example 5: Human clinical trial for treatment of AdV infection A human clinical trial for treatment of adenovirus (AdV) infection was carried out according to the following procedure.

[0120] 5.1 Materials and Methods 5.1.1 Patients Patients aged 2 months or older who are immunosuppressed and have asymptomatic AdV infection or AdV disease, including hematopoietic stem cell transplant patients before immune reconstitution with transplanted cells has been achieved, organ transplant patients receiving immunosuppressants, and patients with immunodeficiency syndromes, and who have high levels of AdV viremia (≥10,000 copies / ml in one sample, or ≥1000 copies / ml in two samples with an increased viral load in the second sample compared to the first).

[0121] 5.1.2 Drug Description Brincidofovir (BCV) injection is a sterile aqueous solution containing 10 mg / mL BCV. Drug Overview Product Name: Brincidofovir Dosage Form: Injection Unit Dose: 10 mg / mL (1 mL per vial) Route of Administration: Intravenous Injection Physical Description: Clear, colorless solution in a sterilized glass bottle Storage Method: Refrigerated (2-8°C) Administration Method: Continuous intravenous infusion over 2 hours once weekly.

[0122] 5.1.3 Dose Cohort 4: 0.4 mg / kg (20 mg / dose if body weight is 50 kg or more) administered once weekly

[0123] 5.1.4 Drug Administration The dose of BCV 10 mg / mL injection is prepared based on the patient's weight. Use the following kit for preparation and administration of the intravenous solution: Intravenous bag: 5% glucose, 100 mL, non-PVC, DEHP-free Intravenous tubing: The tubing does not contain plasticizers and is DEHP-free. Intravenous pump: Use approved tubing. Preparation: Using a sterile syringe and needle, transfer 1 mL of BCV intravenous solution from one vial into a 100 mL intravenous bag containing 5% glucose to create the diluted administration solution. If the dose exceeds 10 mg, prepare an additional dose of diluted administration solution using the same procedure as above. Gently invert the bag at least five times to mix. Avoid vigorously shaking the solution in the vial or the diluted administration solution in the bag.

[0124] Administer the appropriate volume of diluent based on the patient's weight. Each dose should be administered intravenously at a steady rate over 2 hours. After administration is complete, flush the IV line with 5% glucose or 5% dextrose to ensure all active medication has been removed from the IV line. If required per facility practice, the 5% glucose or 5% dextrose flush may be followed by a normal saline flush. Diluent should generally be prepared at the time of use, not the day before.

[0125] 5.1.5 Study Duration The study duration will be at least 9 weeks, based on a 1-week screening period, a treatment period of at least 4 weeks, and a 30-day post-treatment follow-up period. After providing informed consent, patients will undergo screening assessments to determine study eligibility. On the first day of the first week of treatment, patients will be assigned a dose based on their appropriate cohort (see 5.1.3, Cohort 4 above). Treatment will last a minimum of 4 weeks and a maximum of 14 weeks, with termination based on the treatment discontinuation criteria described below. For patients assessed by the physician as being at high risk for AdV infection / disease recurrence, even after completing the 4-week treatment period, treatment may be extended for up to 10 weeks if AdV load is not confirmed on two consecutive measurements taken at least 3 days apart. All patients will be followed for 30 days after the final dose. Adverse events will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0 (Grades 1-5). In Cohort 4, patients will be enrolled to receive the initially planned dosing regimen of 0.4 mg / kg or 20 mg intravenously once weekly.

[0126] The end of the treatment period based on the treatment discontinuation criteria is explained below. Treatment discontinuation criteria are met when AdV levels in the subject's sample are measured multiple times and the most recent two measurements are below the LOD, or when four weeks of treatment have been completed. To confirm the resolution of AdV viremia, two consecutive plasma viral load results below the LOD are required. After the initial result is reported as below the LOD, a confirmatory blood draw must be performed at least three days (two full days) but within 14 days (thirteen full days) after the initial sample was collected. Patients receiving intravenous BCV treatment will continue treatment for four weeks, even if AdV viremia is confirmed to have resolved, unless excluded by guidelines for managing BCV-specific adverse events. If two consecutive plasma AdV levels below the LOD are confirmed before the completion of four weeks of BCV treatment, the patient will continue the designated BCV treatment for up to four weeks. If AdV viremia is present by day 1 of week 5 and confirmed by weekly serial viral load testing, BCV treatment can be continued for up to 14 weeks. Patients who received BCV for 4 weeks were discontinued on intravenous BCV therapy and transitioned to post-treatment follow-up once AdV viremia was confirmed to have disappeared as determined by two consecutive measurements of plasma viral load.

[0127] 5.1.6 Blood samples for viremia analysis Blood from each patient was collected in a K2EDTA tube, mixed by inversion 8-10 times, and centrifuged at 1100-1300 × g for 10 minutes. Plasma was isolated immediately after collection or within 30 minutes after collection. Plasma was frozen and stored at -70°C and analyzed for AdV viremia using real-time qPCR (LOD: 25 copies / mL, lower limit of quantification: 190 copies / mL, upper limit of quantification: 1 × 10 9 copies / mL).

[0128] 5.2 Clinical Trial Data Figure 10 shows the results of the Cohort 4 study. In the horizontal axis of Figure 10, W1D1 stands for week and D stands for day (i.e., W1D1 is week 1, day 1). The same applies to W2D1 and onwards. The vertical axis of Figure 10 shows the amount of AdV in plasma. The LLOQ line is the lower limit of quantitation. Cohort 4 included male or female patients aged 0-62 years, weighing 6.6-96.1 kg. Four patients weighed 50 kg or more.

[0129] In Cohort 4, five patients achieved AdV levels below the LOD. Two of the five patients relapsed. Cohort 4 had a higher proportion of patients with AdV levels below the LOD than Cohorts 1 and 2.

[0130] Example 6: Human clinical trial for treatment of AdV infection A human clinical trial for treatment of adenovirus (AdV) infection is conducted as follows.

[0131] 6.1 Materials and Methods 6.1.1 Patients Immunosuppressed patients aged 2 months or older with asymptomatic AdV infection or AdV disease, including hematopoietic stem cell transplant patients before immune reconstitution with transplanted cells has been achieved, organ transplant patients receiving immunosuppressants, and patients with immunodeficiency syndromes.

[0132] 6.1.2 Drug Description Brincidofovir (BCV) injection is a sterile aqueous solution containing 10 mg / mL BCV. Drug Description Product Name: Brincidofovir Dosage Form: Injection Unit Dose: 10 mg / mL (1 mL per vial) Route of Administration: Intravenous Injection Physical Description: Clear, colorless solution in a sterilized glass bottle Storage Method: Refrigerated (2-8°C) Administration Method: Continuous intravenous infusion over 2 hours once weekly.

[0133] 6.1.3 Dosage Cohort 5: 0.6 mg / kg (30 mg / dose if body weight is 50 kg or more) administered once weekly Cohort 6: 0.8 mg / kg (40 mg / dose if body weight is 50 kg or more) administered once weekly

[0134] 6.1.4 Drug Administration The dose of BCV 10 mg / mL injection is prepared based on the patient's weight. Use the following kit for preparation and administration of the intravenous solution: Intravenous bag: 5% glucose, 100 mL, non-PVC, DEHP-free Intravenous tubing: The tubing does not contain plasticizers and is DEHP-free. Intravenous pump: Use approved tubing. Preparation: Using a sterile syringe and needle, transfer 1 mL of BCV intravenous solution from one vial into a 100 mL intravenous bag containing 5% glucose to create the diluted administration solution. If the dose exceeds 10 mg, prepare an additional dose of diluted administration solution using the same procedure as above. Gently invert the bag at least five times to mix. Avoid vigorously shaking the solution in the vial or the diluted administration solution in the bag.

[0135] Administer the appropriate volume of diluent based on the patient's weight. Each dose should be administered intravenously at a steady rate over 2 hours. After administration is complete, flush the IV line with 5% glucose or 5% dextrose to ensure all active medication has been removed from the IV line. If required per facility practice, the 5% glucose or 5% dextrose flush may be followed by a normal saline flush. Diluent should generally be prepared at the time of use, not the day before.

[0136] Previous PK studies in healthy volunteers have shown that coadministration of BCV and cyclosporine significantly increases plasma BCV exposure. inf and C max The AUC of plasma BCV increased approximately 3.4-fold and approximately 2.3-fold compared with BCV alone. When cyclosporine was administered over 2 hours after the end of intravenous BCV injection, the AUC of plasma BCV increased approximately 3.4-fold and approximately 2.3-fold, respectively. inf and C max The AUC of plasma BCV after BCV monotherapy increased by approximately 1.8 and 1.3 times, respectively. inf and C maxThe results were generally similar. Taking the above into consideration, for the above patients taking cyclosporine, all doses shown in 6.1.3 (Cohorts 5-6) will be reduced by 60%. When cyclosporine is administered as an oral or injection BID (twice daily), it should be administered with a 2-hour interval after the end of the BCV intravenous infusion. When cyclosporine is administered as a 24-hour continuous infusion, there is no interval.

[0137] 6.1.5 Study Duration The study duration will be at least 9 weeks, based on a 1-week screening period, a treatment period of at least 4 weeks, and a 30-day post-treatment follow-up period. After patients provide informed consent, screening assessments will be conducted to determine study eligibility. On the first day of the first week of treatment, patients will be assigned a dose based on their appropriate cohort (see 6.1.3, Cohorts 5-6, above). Treatment will last a minimum of 4 weeks and a maximum of 14 weeks, with termination based on the treatment discontinuation criteria described below. For patients assessed by the physician as being at high risk for AdV infection / disease recurrence, even after completing the 4-week treatment period, treatment may be extended for up to 10 weeks if AdV load is not confirmed on two consecutive measurements taken at least 3 days apart. All patients will be followed for 30 days after the final dose. Adverse events will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0 (Grades 1-5). In Cohort 5, patients will be enrolled in the initially planned dosing regimen of 0.6 mg / kg or 30 mg intravenously once weekly. If tolerability is confirmed in n=3 patients in Cohort 5, Cohort 6 will be initiated, and the BCV will be increased to 0.8 mg / kg or 40 mg intravenously once weekly.

[0138] The end of the treatment period based on the treatment discontinuation criteria is explained below. Treatment discontinuation criteria are met when AdV levels in the subject's sample are measured multiple times and the most recent two measurements are below the LOD, and 4 weeks have passed since the first dose. To confirm the resolution of AdV viremia, two consecutive plasma viral load results below the LOD are required. After the initial result is reported as below the LOD, a confirmatory blood draw must be performed at least 3 days (2 full days) but within 14 days (13 full days) after the initial sample was collected. Patients receiving intravenous BCV treatment will continue treatment for 4 weeks, even if AdV viremia is confirmed to have resolved, unless excluded by guidelines for managing BCV-specific adverse events. If two consecutive plasma AdV levels below the LOD are confirmed before the completion of 4 weeks of BCV treatment, patients will continue their designated BCV treatment for up to 4 weeks. If AdV viremia is present by day 1 of week 5 and confirmed by weekly serial viral load testing, BCV treatment can be continued for up to 14 weeks. Patients who received BCV for 4 weeks should be followed up after treatment and discontinued intravenous BCV treatment once AdV viremia has been confirmed by two consecutive measurements of plasma viral load.

[0139] 6.1.6 Blood Samples for Viremia Analysis Blood samples from each patient were collected in K2EDTA tubes, mixed by inversion 8-10 times, and centrifuged at 1100-1300 x g for 10 minutes. Plasma was isolated immediately or within 30 minutes of collection. The plasma was frozen and stored at -70°C and analyzed for AdV viremia using real-time qPCR.

[0140] 6.2 Clinical Trial Data Patients in cohorts 5-6 will achieve AdV loads below the LOD during the study period.

[0141] Example 7: Evaluation of disease symptoms associated with AdV infection In the clinical trials of Examples 1 and 5, the enrolled AdV viremia patients were evaluated for the presence or absence of symptomatic infection (disease) prior to the start of BCV administration. Of the patients enrolled in cohorts 1 to 4, 31 patients were found to have symptomatic AdV infection, including gastrointestinal disease, respiratory disease, renal disease, and hepatic disease. These disease symptoms were reevaluated by the Endpoint Adjudication Committee (EAC) at the end of the study (EoS), and their association with improvement in blood AdV levels was analyzed.

[0142] Figure 11 shows the results of investigating the relationship between blood AdV levels and AdV disease symptoms at the end of the study. Patients whose blood AdV levels were below the LOD (<LOD) at EoS tended to have disappearance / improvement of AdV disease symptoms compared with patients whose AdV viremia persisted, and this trend was statistically significant (Fisher's exact test). These results demonstrate that reducing blood AdV levels through BCV administration can eliminate / improve disease symptoms associated with AdV infection.

[0143] The present invention has been described above based on the embodiments. However, these embodiments are merely illustrative, and it will be understood by those skilled in the art that various modifications are possible and that such modifications are also within the scope of the present invention.

Claims

1. A pharmaceutical composition for treating an adenovirus infection or a disease associated with an adenovirus infection, comprising brincidofovir, a pharma- ceutical acceptable salt or solvate thereof, said treatment comprising (i) administering 0.38-0.42 mg / kg of brincidofovir, a pharma-ceutical acceptable salt or solvate thereof intravenously to a human subject twice weekly, or (ii) administering 18-22 mg of brincidofovir, a pharma-ceutical acceptable salt or solvate thereof intravenously to a human subject twice weekly.

2. The pharmaceutical composition according to claim 1, wherein said 0.38 to 0.42 mg / kg is 0.4 mg / kg, and said 18 to 22 mg / dose is 20 mg / dose.

3. The pharmaceutical composition according to claim 1 or 2, wherein the body weight of the subject in (i) is less than a specific body weight, the body weight of the subject in (ii) is equal to or greater than a specific body weight, and the specific body weights of (i) and (ii) are the same, being between 48 kg and 52 kg.

4. The pharmaceutical composition of claim 2, wherein the subject in (i) has a body weight less than a specific body weight, the subject in (ii) has a body weight equal to or greater than a specific body weight, and the specific body weights of (i) and (ii) are the same, 50 kg.

5. A pharmaceutical composition according to any one of claims 1 to 4, comprising brincidofovir.

6. A pharmaceutical composition according to any one of claims 1 to 5 for treating an adenovirus infection or an adenovirus infectious disease.

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein the administration period of brincidofovir, a pharma- ceutically acceptable salt thereof, or a solvate thereof is terminated based on a treatment discontinuation criterion.

8. The pharmaceutical composition of claim 7, wherein the criteria for discontinuing treatment include multiple measurements of the amount of adenovirus in the subject's blood sample and two consecutive measurements showing that the adenovirus is below the limit of detection.

9. The pharmaceutical composition according to claim 8, wherein the measurement is performed multiple times at intervals of not less than 3 days and not more than 14 days.

10. The pharmaceutical composition according to claim 9, wherein the measurements are the most recent two measurements when the amount of adenovirus in a subject's sample is measured multiple times.

11. The pharmaceutical composition of claim 7, wherein the treatment discontinuation criteria include having completed 4 to 13 weeks of treatment.

12. The pharmaceutical composition of claim 7, wherein the criteria for discontinuing treatment include having completed the fourth week of treatment.

13. The pharmaceutical composition of any one of claims 1 to 11, wherein the administration period of brincidofovir, a pharma- ceutically acceptable salt thereof, or a solvate thereof is terminated based on the fact that both of the following conditions are met: (a) the amount of adenovirus in a blood sample from the subject is measured multiple times, and the amount of adenovirus is below the limit of detection in two consecutive measurements; and (b) 4 to 13 weeks of treatment have elapsed.

14. The pharmaceutical composition of claim 4, wherein the treatment is terminated based on the administration period of brincidofovir, a pharma- ceutically acceptable salt thereof, or a solvate thereof satisfying both of the following conditions: (a) the amount of adenovirus in the subject's blood sample is measured multiple times and the adenovirus is below the limit of detection in two consecutive measurements; and (b) 4 to 13 weeks of treatment have elapsed.

15. The pharmaceutical composition of any one of claims 1 to 14, wherein the administration period of brincidofovir, a pharma- ceutically acceptable salt, or a solvate thereof is terminated based on the fact that both of the following conditions are met: (a) the amount of adenovirus in a blood sample from the subject is measured multiple times, and the amount of adenovirus is below the limit of detection in two consecutive blood samples; and (b) the fourth week of treatment has elapsed.

16. The pharmaceutical composition of claim 4, wherein the administration period of brincidofovir, a pharma- ceutically acceptable salt, or a solvate thereof is terminated based on the satisfaction of both of the following conditions: (a) the amount of adenovirus in a subject's sample is measured multiple times and the adenovirus is below the limit of detection in two consecutive measurements; and (b) the fourth week of treatment has elapsed.

17. The pharmaceutical composition according to claim 15 or 16, wherein the measurement (a) is carried out multiple times at intervals of not less than 3 days and not more than 14 days.

18. The pharmaceutical composition of claim 17, wherein (a) is a case in which the amount of adenovirus in a subject's sample is measured multiple times and the adenovirus is below the detection limit in two consecutive measurements in the most recent two measurements.

19. The pharmaceutical composition according to any one of claims 1 to 18, wherein when the treatment is carried out in the context of concomitant administration of cyclosporine and brincidofovir, a pharma- ceutically acceptable salt thereof, or a solvate thereof, the dosage of brincidofovir, a pharma- ceutically acceptable salt thereof, or a solvate thereof in (i) and (ii) is reduced by 55-65%.

20. The pharmaceutical composition of claim 19, wherein the 55-65% is 60%.

21. The pharmaceutical composition according to any one of claims 1 to 20, wherein the treatment is administered by intravenous infusion of brincidofovir, a pharma- ceutically acceptable salt thereof, or a solvate thereof over a period of 1.5 to 4 hours.

22. The pharmaceutical composition of claim 21, wherein the 1.5 to 4 hours is 2 hours.

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