Drug can fight adenovirus in HSCT recipients

Adenovirus infection

Image by Yale Rosen

NEW ORLEANS—Interim results of a phase 3 trial suggest brincidofovir can treat adenovirus (AdV) infection in recipients of allogeneic hematopoietic stem cell transplant (HSCT).

Both pediatric and adult patients experienced a decline in AdV viral load after brincidofovir treatment, but pediatric patients were more likely to respond.

Overall survival rates were better for patients who had a rapid response and were therefore better among pediatric patients than adults.

Investigators said the adverse events (AEs) in this study were consistent with the known safety profile of brincidofovir.

Michael Grimley, MD, of Cincinnati Children’s Hospital in Ohio, and his colleagues presented these results at IDWeek 2016 (abstract 2339). The research was supported by Chimerix, the company developing brincidofovir.

This trial, known as AdVise, was designed to evaluate brincidofovir for the treatment of AdV infection in pediatric and adult patients divided into 3 cohorts:

• Cohort A consists of allogeneic HSCT recipients with asymptomatic or limited AdV infection
• Cohort B consists of allogeneic HSCT recipients with disseminated AdV disease
• Cohort C consists of autologous HSCT recipients, solid organ transplant recipients, and other immunocompromised patients.

All patients were assigned to 12 weeks of oral brincidofovir, administered twice weekly. An additional 12 weeks of treatment was allowed in patients with ongoing or recurrent infection. After completing treatment, all patients were followed until week 36.

Interim analysis

The investigators examined outcomes at 24 weeks after the first brincidofovir dose (12 weeks after prescribed dosing duration) in 158 patients, including:

• Cohort A—23 adults and 43 pediatric patients
• Cohort B—35 adults and 57 pediatric patients.

The investigators noted that many of the patients did not complete the study. The team said this is a reflection of the significant mortality risk of AdV because most of these patients died before they could finish.

Sixty-five percent of adults and 33% of children in Cohort A did not complete the study. The same was true for 71% of adults and 49% of children in Cohort B.

Mortality

The study’s primary efficacy endpoint is all-cause mortality at day 60 after the first brincidofovir dose in allogeneic HSCT recipients with disseminated AdV disease (Cohort B). All-cause mortality at day 60 in this cohort was 19% in pediatric patients and 43% in adults.

In Cohorts A and B, all-cause mortality at 24 weeks was lower in children than adults.

At 24 weeks, pediatric all-cause mortality was 33% in Cohort A and 42% in Cohort B. Adult all-cause mortality was 48% in Cohort A and 71% in Cohort B.

AdV-related mortality at 24 weeks in pediatric patients was 9% in Cohort A and 14% in Cohort B. AdV-related mortality in adults was 4% in Cohort A and 46% in Cohort B.

Declines in viremia

In Cohort A, 61% of patients achieved undetectable viremia at the end of treatment—43% of adults and 70% of children.

In Cohort B, 49% of patients achieved undetectable viremia at the end of treatment—29% of adults and 63% of children.

The median time to undetectable AdV viremia was 43 days (range, 8 to non-estimable) for adults in Cohort A, 14 days (range, 5 to 23) for children in Cohort A, non-estimable (range, 29 days to non-estimable) for adults in Cohort B, and 22 days (range, 15 to 36) for children in Cohort B.

Link between response and survival

The investigators conducted post-hoc analyses to assess the correlation between rapid virologic response to brincidofovir and time to subsequent mortality.

The team compared patients who responded to treatment—defined as achieving a ≥ 2-log₁₀ copies/mL decline, undetectable AdV viremia at week 4, or undetectable AdV viremia at week 6—with non-responders.

Fifty percent of adults and 84% of children who were still alive at week 4 had achieved a ≥ 2 log decline or undetectable AdV viremia at that time.

This type of response was associated with improved survival at week 24. In adults, the mortality rate was 46% in responders and 85% in non-responders (P=0.03). In pediatric patients, the mortality rate was 25% in responders and 71% in non-responders (P=0.01).

In patients who were alive at week 6, 42% of adults and 68% of children achieved undetectable AdV viremia by that time.

This response was associated with improved survival at week 24. In adults, the mortality rate was 30% in responders and 86% in non-responders (P=0.001). In pediatric patients, the mortality rate was 18% in responders and 54% in non-responders (P=0.01).

Safety

All adults had treatment-emergent AEs, as did all pediatric patients in Cohort B and 95% of pediatric patients in Cohort A.

The most common treatment-emergent AEs were gastrointestinal (GI) events, which occurred in 70% of adults and 81% of children in Cohort A, as well as 83% of adults and 74% of children in Cohort B.

Acute graft-versus-host disease (GVHD) was also common, occurring in 22% of adults and 37% of children in Cohort A and 43% of adults and 40% of children in Cohort B. Some patients did have acute GVHD at baseline, however—22%, 26%, 34%, and 19%, respectively.

The percentage of patients with AEs leading to treatment discontinuation was 26% for adults and 28% for children in Cohort A and 31% for adults and 14% for children in Cohort B.

Overall, 20% of pediatric patients and 29% of adults discontinued brincidofovir due to AEs. GI events were cited as the most common reason—5% and 14%, respectively.

The investigators said there were no events reported that were suggestive of drug-related nephrotoxicity or myelosuppression.

Adenovirus infection

Image by Yale Rosen

NEW ORLEANS—Interim results of a phase 3 trial suggest brincidofovir can treat adenovirus (AdV) infection in recipients of allogeneic hematopoietic stem cell transplant (HSCT).

Both pediatric and adult patients experienced a decline in AdV viral load after brincidofovir treatment, but pediatric patients were more likely to respond.

Overall survival rates were better for patients who had a rapid response and were therefore better among pediatric patients than adults.

Investigators said the adverse events (AEs) in this study were consistent with the known safety profile of brincidofovir.

Michael Grimley, MD, of Cincinnati Children’s Hospital in Ohio, and his colleagues presented these results at IDWeek 2016 (abstract 2339). The research was supported by Chimerix, the company developing brincidofovir.

This trial, known as AdVise, was designed to evaluate brincidofovir for the treatment of AdV infection in pediatric and adult patients divided into 3 cohorts:

• Cohort A consists of allogeneic HSCT recipients with asymptomatic or limited AdV infection
• Cohort B consists of allogeneic HSCT recipients with disseminated AdV disease
• Cohort C consists of autologous HSCT recipients, solid organ transplant recipients, and other immunocompromised patients.

All patients were assigned to 12 weeks of oral brincidofovir, administered twice weekly. An additional 12 weeks of treatment was allowed in patients with ongoing or recurrent infection. After completing treatment, all patients were followed until week 36.

Interim analysis

The investigators examined outcomes at 24 weeks after the first brincidofovir dose (12 weeks after prescribed dosing duration) in 158 patients, including:

• Cohort A—23 adults and 43 pediatric patients
• Cohort B—35 adults and 57 pediatric patients.

The investigators noted that many of the patients did not complete the study. The team said this is a reflection of the significant mortality risk of AdV because most of these patients died before they could finish.

Sixty-five percent of adults and 33% of children in Cohort A did not complete the study. The same was true for 71% of adults and 49% of children in Cohort B.

Mortality

The study’s primary efficacy endpoint is all-cause mortality at day 60 after the first brincidofovir dose in allogeneic HSCT recipients with disseminated AdV disease (Cohort B). All-cause mortality at day 60 in this cohort was 19% in pediatric patients and 43% in adults.

In Cohorts A and B, all-cause mortality at 24 weeks was lower in children than adults.

At 24 weeks, pediatric all-cause mortality was 33% in Cohort A and 42% in Cohort B. Adult all-cause mortality was 48% in Cohort A and 71% in Cohort B.

AdV-related mortality at 24 weeks in pediatric patients was 9% in Cohort A and 14% in Cohort B. AdV-related mortality in adults was 4% in Cohort A and 46% in Cohort B.

Declines in viremia

In Cohort A, 61% of patients achieved undetectable viremia at the end of treatment—43% of adults and 70% of children.

In Cohort B, 49% of patients achieved undetectable viremia at the end of treatment—29% of adults and 63% of children.

The median time to undetectable AdV viremia was 43 days (range, 8 to non-estimable) for adults in Cohort A, 14 days (range, 5 to 23) for children in Cohort A, non-estimable (range, 29 days to non-estimable) for adults in Cohort B, and 22 days (range, 15 to 36) for children in Cohort B.

Link between response and survival

The investigators conducted post-hoc analyses to assess the correlation between rapid virologic response to brincidofovir and time to subsequent mortality.

The team compared patients who responded to treatment—defined as achieving a ≥ 2-log₁₀ copies/mL decline, undetectable AdV viremia at week 4, or undetectable AdV viremia at week 6—with non-responders.

Fifty percent of adults and 84% of children who were still alive at week 4 had achieved a ≥ 2 log decline or undetectable AdV viremia at that time.

This type of response was associated with improved survival at week 24. In adults, the mortality rate was 46% in responders and 85% in non-responders (P=0.03). In pediatric patients, the mortality rate was 25% in responders and 71% in non-responders (P=0.01).

In patients who were alive at week 6, 42% of adults and 68% of children achieved undetectable AdV viremia by that time.

This response was associated with improved survival at week 24. In adults, the mortality rate was 30% in responders and 86% in non-responders (P=0.001). In pediatric patients, the mortality rate was 18% in responders and 54% in non-responders (P=0.01).

Safety

All adults had treatment-emergent AEs, as did all pediatric patients in Cohort B and 95% of pediatric patients in Cohort A.

The most common treatment-emergent AEs were gastrointestinal (GI) events, which occurred in 70% of adults and 81% of children in Cohort A, as well as 83% of adults and 74% of children in Cohort B.

Acute graft-versus-host disease (GVHD) was also common, occurring in 22% of adults and 37% of children in Cohort A and 43% of adults and 40% of children in Cohort B. Some patients did have acute GVHD at baseline, however—22%, 26%, 34%, and 19%, respectively.

The percentage of patients with AEs leading to treatment discontinuation was 26% for adults and 28% for children in Cohort A and 31% for adults and 14% for children in Cohort B.

Overall, 20% of pediatric patients and 29% of adults discontinued brincidofovir due to AEs. GI events were cited as the most common reason—5% and 14%, respectively.

The investigators said there were no events reported that were suggestive of drug-related nephrotoxicity or myelosuppression.

Adenovirus infection

Image by Yale Rosen

NEW ORLEANS—Interim results of a phase 3 trial suggest brincidofovir can treat adenovirus (AdV) infection in recipients of allogeneic hematopoietic stem cell transplant (HSCT).

Both pediatric and adult patients experienced a decline in AdV viral load after brincidofovir treatment, but pediatric patients were more likely to respond.

Overall survival rates were better for patients who had a rapid response and were therefore better among pediatric patients than adults.

Investigators said the adverse events (AEs) in this study were consistent with the known safety profile of brincidofovir.

Michael Grimley, MD, of Cincinnati Children’s Hospital in Ohio, and his colleagues presented these results at IDWeek 2016 (abstract 2339). The research was supported by Chimerix, the company developing brincidofovir.

This trial, known as AdVise, was designed to evaluate brincidofovir for the treatment of AdV infection in pediatric and adult patients divided into 3 cohorts:

• Cohort A consists of allogeneic HSCT recipients with asymptomatic or limited AdV infection
• Cohort B consists of allogeneic HSCT recipients with disseminated AdV disease
• Cohort C consists of autologous HSCT recipients, solid organ transplant recipients, and other immunocompromised patients.

All patients were assigned to 12 weeks of oral brincidofovir, administered twice weekly. An additional 12 weeks of treatment was allowed in patients with ongoing or recurrent infection. After completing treatment, all patients were followed until week 36.

Interim analysis

The investigators examined outcomes at 24 weeks after the first brincidofovir dose (12 weeks after prescribed dosing duration) in 158 patients, including:

• Cohort A—23 adults and 43 pediatric patients
• Cohort B—35 adults and 57 pediatric patients.

The investigators noted that many of the patients did not complete the study. The team said this is a reflection of the significant mortality risk of AdV because most of these patients died before they could finish.

Sixty-five percent of adults and 33% of children in Cohort A did not complete the study. The same was true for 71% of adults and 49% of children in Cohort B.

Mortality

The study’s primary efficacy endpoint is all-cause mortality at day 60 after the first brincidofovir dose in allogeneic HSCT recipients with disseminated AdV disease (Cohort B). All-cause mortality at day 60 in this cohort was 19% in pediatric patients and 43% in adults.

In Cohorts A and B, all-cause mortality at 24 weeks was lower in children than adults.

At 24 weeks, pediatric all-cause mortality was 33% in Cohort A and 42% in Cohort B. Adult all-cause mortality was 48% in Cohort A and 71% in Cohort B.

AdV-related mortality at 24 weeks in pediatric patients was 9% in Cohort A and 14% in Cohort B. AdV-related mortality in adults was 4% in Cohort A and 46% in Cohort B.

Declines in viremia

In Cohort A, 61% of patients achieved undetectable viremia at the end of treatment—43% of adults and 70% of children.

In Cohort B, 49% of patients achieved undetectable viremia at the end of treatment—29% of adults and 63% of children.

The median time to undetectable AdV viremia was 43 days (range, 8 to non-estimable) for adults in Cohort A, 14 days (range, 5 to 23) for children in Cohort A, non-estimable (range, 29 days to non-estimable) for adults in Cohort B, and 22 days (range, 15 to 36) for children in Cohort B.

Link between response and survival

The investigators conducted post-hoc analyses to assess the correlation between rapid virologic response to brincidofovir and time to subsequent mortality.

The team compared patients who responded to treatment—defined as achieving a ≥ 2-log₁₀ copies/mL decline, undetectable AdV viremia at week 4, or undetectable AdV viremia at week 6—with non-responders.

Fifty percent of adults and 84% of children who were still alive at week 4 had achieved a ≥ 2 log decline or undetectable AdV viremia at that time.

This type of response was associated with improved survival at week 24. In adults, the mortality rate was 46% in responders and 85% in non-responders (P=0.03). In pediatric patients, the mortality rate was 25% in responders and 71% in non-responders (P=0.01).

In patients who were alive at week 6, 42% of adults and 68% of children achieved undetectable AdV viremia by that time.

This response was associated with improved survival at week 24. In adults, the mortality rate was 30% in responders and 86% in non-responders (P=0.001). In pediatric patients, the mortality rate was 18% in responders and 54% in non-responders (P=0.01).

Safety

All adults had treatment-emergent AEs, as did all pediatric patients in Cohort B and 95% of pediatric patients in Cohort A.

The most common treatment-emergent AEs were gastrointestinal (GI) events, which occurred in 70% of adults and 81% of children in Cohort A, as well as 83% of adults and 74% of children in Cohort B.

Acute graft-versus-host disease (GVHD) was also common, occurring in 22% of adults and 37% of children in Cohort A and 43% of adults and 40% of children in Cohort B. Some patients did have acute GVHD at baseline, however—22%, 26%, 34%, and 19%, respectively.

The percentage of patients with AEs leading to treatment discontinuation was 26% for adults and 28% for children in Cohort A and 31% for adults and 14% for children in Cohort B.

Overall, 20% of pediatric patients and 29% of adults discontinued brincidofovir due to AEs. GI events were cited as the most common reason—5% and 14%, respectively.

The investigators said there were no events reported that were suggestive of drug-related nephrotoxicity or myelosuppression.