Brincidofovir promising for adenovirus infection in early data

PHILADELPHIA – Brincidofovir, an orally available lipid conjugate of cidofovir, appears promising for the treatment of adenovirus infection in children and young adults, according to findings from the open-label pilot portion of a phase III study.

Of 26 patients from birth through age 29 years who were enrolled in the study as of July 15, 13 discontinued treatment prematurely, 4 completed treatment, and 9 continued with treatment. Plasma viral load decreased over time in most of the 13 patients who either completed or remained on treatment, Dr. Jo-Anne Young reported at an annual scientific meeting on infectious diseases.

After a median treatment duration of 54 days, clearance of adenovirus from respiratory secretions, urine, and stool among those patients in whom these values were measured at baseline was 42%, 33%, and 27%, respectively. Mortality was 46% among all 26 patients and was 38% among patients with disseminated disease. In a prior expanded-access trial of the drug, mortality was 51% in treated patients with disseminated disease, and in a historical cohort from a 2003 study of patients with disseminated disease, mortality at 1 year was 82%.

Of note, one patient in the current study experienced an increase in viral load; that patient had received prior treatment with brincidofovir, and was found to have a T87I mutation with known resistance to cidofovir and brincidofovir. Six other patients with prior cidofovir exposure reached undetectable levels of adenovirus, and one had a greater than 2-log decline, so the effect of prior exposure on treatment response remains uncertain, Dr. Young of the University of Minnesota Medical Center, Minneapolis, said at the combined annual meetings of the Infectious Diseases Society of America, the Society for Healthcare Epidemiology of America, the HIV Medicine Association, and the Pediatric Infectious Diseases Society.

Another trend that was noted in the current study was a possible increase in viral load prior to a decline in viral load. In one case this occurred in association with treatment interruption due to moderate hyperbilirubinemia, but the viral load declined again once treatment was restarted, and was undetectable by the 8th week of treatment.

Most of the patients in the study to date (80%) were children, 65% were males, 65% were white, and 65% had disseminated infection with two or more body systems affected. Most of those were high-risk patients, who had received hematopoietic stem cell transplants from unrelated donors, Dr. Young noted.

Half of the patients had a high viral copy load in their blood, and many had multiple viruses detected. For example, 27% had BK virus in their urine, 19% had cytomegalovirus detected in their plasma, and 8% had Epstein-Barr virus detected in their plasma .

Treatment was given as a twice-weekly 100-mg dose in adults weighing at least 50 kg, and as a twice-weekly, 2-mg/kg dose in children under age 12 or weighing less than 50 kg. Treatment duration was 12 weeks, and patients were followed for an additional 24 weeks.

Of the 13 patients who discontinued treatment, 4 died, 3 discontinued because of an adverse event (including 2 cases of diarrhea considered treatment related and 1 case of liver function testing abnormalities deemed unrelated to treatment), 2 discontinued on physician advice, 2 started other therapy, 1 experienced progression of transplant qualifying disease, and 1 withdrew consent for study participation. Among those who continued, median treatment duration was 54 days at the time the data were presented.

“Adenovirus is an infection with a high unmet medical treatment need,” Dr. Young said, noting that it is associated with a wide spectrum of disease, ranging from asymptomatic viremia to disseminated disease, particularly among hematopoietic stem cell transplant recipients.

The reported incidence varies from 5% to 50%, and mortality ranges from 26% for untreated symptomatic infection to 80% for disseminated disease.

Risk factors include pediatric age, high-risk types of allogeneic transplants, and the presence of acute graft vs. host disease in any transplant recipient.

Current treatment strategies involve supportive care with a reduction in immune suppression and/or initiation of direct antiviral treatment – typically intravenous cidofovir, which is associated with a risk of significant renal injury, Dr. Young said.

Brincidofovir, however, allows for oral dosing and high intracellular uptake, delivering high intracellular levels of the active antiviral, she noted, adding that there is no evidence of nephrotoxicity or hematologic toxicity associated with brincidofovir.

Antiadenovirus activity was confirmed in a previous study of the drug, and in the expanded-access study, treatment was associated with improved survival vs. historical data.

Up to 100 patients will be enrolled in the current pilot portion of the study, and the findings will be used to guide the second half of the phase III study, she said, noting that as of September, 48 subjects from 17 centers had been enrolled.

“Brincidofovir demonstrated potent virologic activity in patients with adenovirus disease. Subjects treated with brincidofovir appeared to have improved survival vs. historical controls, and there were no new safety signals identified. The data from the pilot portion of this study clearly support progression to the design of the next half of this phase III study for brincidofovir among adenovirus-infected patients,” she concluded.

Dr. Young reported being a clinical investigator and/or receiving research support from Chimerix, GlaxoSmithKline, Merck, and ViroPharma.

PHILADELPHIA – Brincidofovir, an orally available lipid conjugate of cidofovir, appears promising for the treatment of adenovirus infection in children and young adults, according to findings from the open-label pilot portion of a phase III study.

Of 26 patients from birth through age 29 years who were enrolled in the study as of July 15, 13 discontinued treatment prematurely, 4 completed treatment, and 9 continued with treatment. Plasma viral load decreased over time in most of the 13 patients who either completed or remained on treatment, Dr. Jo-Anne Young reported at an annual scientific meeting on infectious diseases.

After a median treatment duration of 54 days, clearance of adenovirus from respiratory secretions, urine, and stool among those patients in whom these values were measured at baseline was 42%, 33%, and 27%, respectively. Mortality was 46% among all 26 patients and was 38% among patients with disseminated disease. In a prior expanded-access trial of the drug, mortality was 51% in treated patients with disseminated disease, and in a historical cohort from a 2003 study of patients with disseminated disease, mortality at 1 year was 82%.

Of note, one patient in the current study experienced an increase in viral load; that patient had received prior treatment with brincidofovir, and was found to have a T87I mutation with known resistance to cidofovir and brincidofovir. Six other patients with prior cidofovir exposure reached undetectable levels of adenovirus, and one had a greater than 2-log decline, so the effect of prior exposure on treatment response remains uncertain, Dr. Young of the University of Minnesota Medical Center, Minneapolis, said at the combined annual meetings of the Infectious Diseases Society of America, the Society for Healthcare Epidemiology of America, the HIV Medicine Association, and the Pediatric Infectious Diseases Society.

Another trend that was noted in the current study was a possible increase in viral load prior to a decline in viral load. In one case this occurred in association with treatment interruption due to moderate hyperbilirubinemia, but the viral load declined again once treatment was restarted, and was undetectable by the 8th week of treatment.

Most of the patients in the study to date (80%) were children, 65% were males, 65% were white, and 65% had disseminated infection with two or more body systems affected. Most of those were high-risk patients, who had received hematopoietic stem cell transplants from unrelated donors, Dr. Young noted.

Half of the patients had a high viral copy load in their blood, and many had multiple viruses detected. For example, 27% had BK virus in their urine, 19% had cytomegalovirus detected in their plasma, and 8% had Epstein-Barr virus detected in their plasma .

Treatment was given as a twice-weekly 100-mg dose in adults weighing at least 50 kg, and as a twice-weekly, 2-mg/kg dose in children under age 12 or weighing less than 50 kg. Treatment duration was 12 weeks, and patients were followed for an additional 24 weeks.

Of the 13 patients who discontinued treatment, 4 died, 3 discontinued because of an adverse event (including 2 cases of diarrhea considered treatment related and 1 case of liver function testing abnormalities deemed unrelated to treatment), 2 discontinued on physician advice, 2 started other therapy, 1 experienced progression of transplant qualifying disease, and 1 withdrew consent for study participation. Among those who continued, median treatment duration was 54 days at the time the data were presented.

“Adenovirus is an infection with a high unmet medical treatment need,” Dr. Young said, noting that it is associated with a wide spectrum of disease, ranging from asymptomatic viremia to disseminated disease, particularly among hematopoietic stem cell transplant recipients.

The reported incidence varies from 5% to 50%, and mortality ranges from 26% for untreated symptomatic infection to 80% for disseminated disease.

Risk factors include pediatric age, high-risk types of allogeneic transplants, and the presence of acute graft vs. host disease in any transplant recipient.

Current treatment strategies involve supportive care with a reduction in immune suppression and/or initiation of direct antiviral treatment – typically intravenous cidofovir, which is associated with a risk of significant renal injury, Dr. Young said.

Brincidofovir, however, allows for oral dosing and high intracellular uptake, delivering high intracellular levels of the active antiviral, she noted, adding that there is no evidence of nephrotoxicity or hematologic toxicity associated with brincidofovir.

Antiadenovirus activity was confirmed in a previous study of the drug, and in the expanded-access study, treatment was associated with improved survival vs. historical data.

Up to 100 patients will be enrolled in the current pilot portion of the study, and the findings will be used to guide the second half of the phase III study, she said, noting that as of September, 48 subjects from 17 centers had been enrolled.

“Brincidofovir demonstrated potent virologic activity in patients with adenovirus disease. Subjects treated with brincidofovir appeared to have improved survival vs. historical controls, and there were no new safety signals identified. The data from the pilot portion of this study clearly support progression to the design of the next half of this phase III study for brincidofovir among adenovirus-infected patients,” she concluded.

Dr. Young reported being a clinical investigator and/or receiving research support from Chimerix, GlaxoSmithKline, Merck, and ViroPharma.

PHILADELPHIA – Brincidofovir, an orally available lipid conjugate of cidofovir, appears promising for the treatment of adenovirus infection in children and young adults, according to findings from the open-label pilot portion of a phase III study.

Of 26 patients from birth through age 29 years who were enrolled in the study as of July 15, 13 discontinued treatment prematurely, 4 completed treatment, and 9 continued with treatment. Plasma viral load decreased over time in most of the 13 patients who either completed or remained on treatment, Dr. Jo-Anne Young reported at an annual scientific meeting on infectious diseases.

After a median treatment duration of 54 days, clearance of adenovirus from respiratory secretions, urine, and stool among those patients in whom these values were measured at baseline was 42%, 33%, and 27%, respectively. Mortality was 46% among all 26 patients and was 38% among patients with disseminated disease. In a prior expanded-access trial of the drug, mortality was 51% in treated patients with disseminated disease, and in a historical cohort from a 2003 study of patients with disseminated disease, mortality at 1 year was 82%.

Of note, one patient in the current study experienced an increase in viral load; that patient had received prior treatment with brincidofovir, and was found to have a T87I mutation with known resistance to cidofovir and brincidofovir. Six other patients with prior cidofovir exposure reached undetectable levels of adenovirus, and one had a greater than 2-log decline, so the effect of prior exposure on treatment response remains uncertain, Dr. Young of the University of Minnesota Medical Center, Minneapolis, said at the combined annual meetings of the Infectious Diseases Society of America, the Society for Healthcare Epidemiology of America, the HIV Medicine Association, and the Pediatric Infectious Diseases Society.

Another trend that was noted in the current study was a possible increase in viral load prior to a decline in viral load. In one case this occurred in association with treatment interruption due to moderate hyperbilirubinemia, but the viral load declined again once treatment was restarted, and was undetectable by the 8th week of treatment.

Most of the patients in the study to date (80%) were children, 65% were males, 65% were white, and 65% had disseminated infection with two or more body systems affected. Most of those were high-risk patients, who had received hematopoietic stem cell transplants from unrelated donors, Dr. Young noted.

Half of the patients had a high viral copy load in their blood, and many had multiple viruses detected. For example, 27% had BK virus in their urine, 19% had cytomegalovirus detected in their plasma, and 8% had Epstein-Barr virus detected in their plasma .

Treatment was given as a twice-weekly 100-mg dose in adults weighing at least 50 kg, and as a twice-weekly, 2-mg/kg dose in children under age 12 or weighing less than 50 kg. Treatment duration was 12 weeks, and patients were followed for an additional 24 weeks.

Of the 13 patients who discontinued treatment, 4 died, 3 discontinued because of an adverse event (including 2 cases of diarrhea considered treatment related and 1 case of liver function testing abnormalities deemed unrelated to treatment), 2 discontinued on physician advice, 2 started other therapy, 1 experienced progression of transplant qualifying disease, and 1 withdrew consent for study participation. Among those who continued, median treatment duration was 54 days at the time the data were presented.

“Adenovirus is an infection with a high unmet medical treatment need,” Dr. Young said, noting that it is associated with a wide spectrum of disease, ranging from asymptomatic viremia to disseminated disease, particularly among hematopoietic stem cell transplant recipients.

The reported incidence varies from 5% to 50%, and mortality ranges from 26% for untreated symptomatic infection to 80% for disseminated disease.

Risk factors include pediatric age, high-risk types of allogeneic transplants, and the presence of acute graft vs. host disease in any transplant recipient.

Current treatment strategies involve supportive care with a reduction in immune suppression and/or initiation of direct antiviral treatment – typically intravenous cidofovir, which is associated with a risk of significant renal injury, Dr. Young said.

Brincidofovir, however, allows for oral dosing and high intracellular uptake, delivering high intracellular levels of the active antiviral, she noted, adding that there is no evidence of nephrotoxicity or hematologic toxicity associated with brincidofovir.

Antiadenovirus activity was confirmed in a previous study of the drug, and in the expanded-access study, treatment was associated with improved survival vs. historical data.

Up to 100 patients will be enrolled in the current pilot portion of the study, and the findings will be used to guide the second half of the phase III study, she said, noting that as of September, 48 subjects from 17 centers had been enrolled.

“Brincidofovir demonstrated potent virologic activity in patients with adenovirus disease. Subjects treated with brincidofovir appeared to have improved survival vs. historical controls, and there were no new safety signals identified. The data from the pilot portion of this study clearly support progression to the design of the next half of this phase III study for brincidofovir among adenovirus-infected patients,” she concluded.

Dr. Young reported being a clinical investigator and/or receiving research support from Chimerix, GlaxoSmithKline, Merck, and ViroPharma.