Drug may still be viable as CMV prophylaxis

HSCT preparation

Photo by Chad McNeeley

HONOLULU—Despite disappointing results in a phase 3 trial, investigators believe the oral nucleotide analog brincidofovir may still be viable as cytomegalovirus (CMV) prophylaxis in patients undergoing hematopoietic stem cell transplant (HSCT).

As reported last December, brincidofovir did not meet the primary endpoint of the phase 3 SUPPRESS trial, which was to prevent clinically significant CMV infection at week 24 after HSCT.

However, trial investigators said the drug did prevent CMV through week 14, which was the end of the treatment period.

The team believes they have an explanation for these findings, which were presented at the 2016 BMT Tandem Meetings (abstract 5). The trial was supported by Chimerix, the company developing brincidofovir.

The SUPPRESS trial included 452 subjects at high risk for CMV who were randomized to receive brincidofovir or placebo twice weekly for up to 14 weeks following allogeneic HSCT. They were then followed for 10 weeks after treatment.

Baseline characteristics were similar between the treatment arms, although there were more males in the placebo arm than the brincidofovir arm—66% and 54%, respectively. The median age was 56 in the brincidofovir arm and 54 in the placebo arm (overall range, 18-77).

Key results

The primary endpoint was assessed at week 24. At that time, the proportion of patients with clinically significant CMV infection was similar in the brincidofovir and placebo arms—51% and 52%, respectively.

However, the investigators did note that brincidofovir exhibited an antiviral effect during the trial. At the end of the on-treatment period at week 14, patients who received brincidofovir had fewer clinically significant CMV infections than patients in the placebo group—24% and 38%, respectively (P=0.002).

The investigators said the failure to meet the primary endpoint at week 24 appears to be associated with CMV events in the post-treatment period among subjects on the brincidofovir arm, driven by higher use of corticosteroids and other immunosuppressive therapies for the treatment of presumptive graft-versus-host disease (GVHD).

Diarrhea can be a symptom of GVHD in the gut and is also a known side effect of brincidofovir that can be managed by a temporary dose interruption, as described in the safety monitoring and management plan (SMMP) developed during the phase 2 trial of the drug (then known as CMX001).

In the SUPPRESS trial, diarrhea in brincidofovir-treated patients was more frequent and often presumed to be gut GVHD. So patients were treated with corticosteroids rather than undergoing temporary treatment interruption according to the SMMP. Among patients who were managed according to the SMMP, the investigators observed significantly fewer CMV infections (P=0.03) and lower mortality (P<0.001).

There was an 8-fold increase in the use of corticosteroids through week 14 in the brincidofovir arm compared to the placebo arm. The median cumulative dose of prednisone-equivalent corticosteroids was 26 mg/kg and 3 mg/kg, respectively.

The use of corticosteroids and other immunosuppressive therapies for the treatment of GVHD is known to increase the risk of infections, including CMV infections that occur when patients discontinue antiviral therapy.

Among patients who either underwent T-cell depletion or received alemtuzumab/ATG to decrease the risk of GVHD, those who were randomized to receive brincidofovir showed a lower incidence of CMV when compared to placebo, at a rate consistent with what was observed in the phase 2 study.

Additional endpoints

Brincidofovir did not prevent infection with non-CMV DNA viruses, such as BK virus.

And there was no significant difference between the treatment arms with regard to all-cause mortality. The rate was 15.5% in the brincidofovir arm and 10.1% in the placebo arm (P=0.12).

The investigators said the numerical differences in mortality appear to be driven by higher use of corticosteroids and other immunosuppressive therapies in the subjects who received brincidofovir.

The rate of treatment-emergent adverse events (AEs) was 100% in the brincidofovir arm and 98% in the placebo arm. The rate of grade 3 or higher AEs was 67% and 38%, respectively. The rate of serious AEs was 57% and 38%, respectively.

The rate of AEs leading to treatment discontinuation was 26% and 7%, respectively. And the rate of AEs leading to treatment change or interruption was 45% and 15%, respectively.

The most common AEs in the brincidofovir arm were diarrhea (61%), acute GVHD (57%), abdominal pain (34%), nausea (31%), vomiting (24%), peripheral edema (17%), hyperglycemia (16%), hypokalemia (16%), hypomagnesemia (13%), and ALT elevation (11%). There was no evidence of bone marrow toxicity, kidney toxicity, or viral resistance to brincidofovir.

Brincidofovir development

Chimerix said it will discuss the SUPPRESS data in full with the US Food and Drug Administration and other regulators, including the benefit-to-risk profile in specific subpopulations, as well as the current adenovirus and smallpox data, to determine next steps for the brincidofovir clinical programs.

The development of an intravenous (IV) formulation of brincidofovir is progressing toward clinical testing and has the potential to avoid the gastrointestinal side effects of orally administered brincidofovir.

Preclinical studies of IV brincidofovir have shown a lower risk of gastrointestinal effects based on maintained body weight during dosing and no evidence of injury in preliminary review of the gastrointestinal tract.

If human studies continue to support these findings, IV dosing during the first few weeks after transplant when patients are recovering from conditioning chemotherapy could be explored, with oral brincidofovir therapy available as patients are discharged home.

As there is no preventive therapy approved for CMV in HSCT recipients, Chimerix said it is committed to moving brincidofovir forward in this indication. Plans for brincidofovir in HSCT recipients will be the subject of further discussions with regulators.

HSCT preparation

Photo by Chad McNeeley

HONOLULU—Despite disappointing results in a phase 3 trial, investigators believe the oral nucleotide analog brincidofovir may still be viable as cytomegalovirus (CMV) prophylaxis in patients undergoing hematopoietic stem cell transplant (HSCT).

As reported last December, brincidofovir did not meet the primary endpoint of the phase 3 SUPPRESS trial, which was to prevent clinically significant CMV infection at week 24 after HSCT.

However, trial investigators said the drug did prevent CMV through week 14, which was the end of the treatment period.

The team believes they have an explanation for these findings, which were presented at the 2016 BMT Tandem Meetings (abstract 5). The trial was supported by Chimerix, the company developing brincidofovir.

The SUPPRESS trial included 452 subjects at high risk for CMV who were randomized to receive brincidofovir or placebo twice weekly for up to 14 weeks following allogeneic HSCT. They were then followed for 10 weeks after treatment.

Baseline characteristics were similar between the treatment arms, although there were more males in the placebo arm than the brincidofovir arm—66% and 54%, respectively. The median age was 56 in the brincidofovir arm and 54 in the placebo arm (overall range, 18-77).

Key results

The primary endpoint was assessed at week 24. At that time, the proportion of patients with clinically significant CMV infection was similar in the brincidofovir and placebo arms—51% and 52%, respectively.

However, the investigators did note that brincidofovir exhibited an antiviral effect during the trial. At the end of the on-treatment period at week 14, patients who received brincidofovir had fewer clinically significant CMV infections than patients in the placebo group—24% and 38%, respectively (P=0.002).

The investigators said the failure to meet the primary endpoint at week 24 appears to be associated with CMV events in the post-treatment period among subjects on the brincidofovir arm, driven by higher use of corticosteroids and other immunosuppressive therapies for the treatment of presumptive graft-versus-host disease (GVHD).

Diarrhea can be a symptom of GVHD in the gut and is also a known side effect of brincidofovir that can be managed by a temporary dose interruption, as described in the safety monitoring and management plan (SMMP) developed during the phase 2 trial of the drug (then known as CMX001).

In the SUPPRESS trial, diarrhea in brincidofovir-treated patients was more frequent and often presumed to be gut GVHD. So patients were treated with corticosteroids rather than undergoing temporary treatment interruption according to the SMMP. Among patients who were managed according to the SMMP, the investigators observed significantly fewer CMV infections (P=0.03) and lower mortality (P<0.001).

There was an 8-fold increase in the use of corticosteroids through week 14 in the brincidofovir arm compared to the placebo arm. The median cumulative dose of prednisone-equivalent corticosteroids was 26 mg/kg and 3 mg/kg, respectively.

The use of corticosteroids and other immunosuppressive therapies for the treatment of GVHD is known to increase the risk of infections, including CMV infections that occur when patients discontinue antiviral therapy.

Among patients who either underwent T-cell depletion or received alemtuzumab/ATG to decrease the risk of GVHD, those who were randomized to receive brincidofovir showed a lower incidence of CMV when compared to placebo, at a rate consistent with what was observed in the phase 2 study.

Additional endpoints

Brincidofovir did not prevent infection with non-CMV DNA viruses, such as BK virus.

And there was no significant difference between the treatment arms with regard to all-cause mortality. The rate was 15.5% in the brincidofovir arm and 10.1% in the placebo arm (P=0.12).

The investigators said the numerical differences in mortality appear to be driven by higher use of corticosteroids and other immunosuppressive therapies in the subjects who received brincidofovir.

The rate of treatment-emergent adverse events (AEs) was 100% in the brincidofovir arm and 98% in the placebo arm. The rate of grade 3 or higher AEs was 67% and 38%, respectively. The rate of serious AEs was 57% and 38%, respectively.

The rate of AEs leading to treatment discontinuation was 26% and 7%, respectively. And the rate of AEs leading to treatment change or interruption was 45% and 15%, respectively.

The most common AEs in the brincidofovir arm were diarrhea (61%), acute GVHD (57%), abdominal pain (34%), nausea (31%), vomiting (24%), peripheral edema (17%), hyperglycemia (16%), hypokalemia (16%), hypomagnesemia (13%), and ALT elevation (11%). There was no evidence of bone marrow toxicity, kidney toxicity, or viral resistance to brincidofovir.

Brincidofovir development

Chimerix said it will discuss the SUPPRESS data in full with the US Food and Drug Administration and other regulators, including the benefit-to-risk profile in specific subpopulations, as well as the current adenovirus and smallpox data, to determine next steps for the brincidofovir clinical programs.

The development of an intravenous (IV) formulation of brincidofovir is progressing toward clinical testing and has the potential to avoid the gastrointestinal side effects of orally administered brincidofovir.

Preclinical studies of IV brincidofovir have shown a lower risk of gastrointestinal effects based on maintained body weight during dosing and no evidence of injury in preliminary review of the gastrointestinal tract.

If human studies continue to support these findings, IV dosing during the first few weeks after transplant when patients are recovering from conditioning chemotherapy could be explored, with oral brincidofovir therapy available as patients are discharged home.

As there is no preventive therapy approved for CMV in HSCT recipients, Chimerix said it is committed to moving brincidofovir forward in this indication. Plans for brincidofovir in HSCT recipients will be the subject of further discussions with regulators.

HSCT preparation

Photo by Chad McNeeley

HONOLULU—Despite disappointing results in a phase 3 trial, investigators believe the oral nucleotide analog brincidofovir may still be viable as cytomegalovirus (CMV) prophylaxis in patients undergoing hematopoietic stem cell transplant (HSCT).

As reported last December, brincidofovir did not meet the primary endpoint of the phase 3 SUPPRESS trial, which was to prevent clinically significant CMV infection at week 24 after HSCT.

However, trial investigators said the drug did prevent CMV through week 14, which was the end of the treatment period.

The team believes they have an explanation for these findings, which were presented at the 2016 BMT Tandem Meetings (abstract 5). The trial was supported by Chimerix, the company developing brincidofovir.

The SUPPRESS trial included 452 subjects at high risk for CMV who were randomized to receive brincidofovir or placebo twice weekly for up to 14 weeks following allogeneic HSCT. They were then followed for 10 weeks after treatment.

Baseline characteristics were similar between the treatment arms, although there were more males in the placebo arm than the brincidofovir arm—66% and 54%, respectively. The median age was 56 in the brincidofovir arm and 54 in the placebo arm (overall range, 18-77).

Key results

The primary endpoint was assessed at week 24. At that time, the proportion of patients with clinically significant CMV infection was similar in the brincidofovir and placebo arms—51% and 52%, respectively.

However, the investigators did note that brincidofovir exhibited an antiviral effect during the trial. At the end of the on-treatment period at week 14, patients who received brincidofovir had fewer clinically significant CMV infections than patients in the placebo group—24% and 38%, respectively (P=0.002).

The investigators said the failure to meet the primary endpoint at week 24 appears to be associated with CMV events in the post-treatment period among subjects on the brincidofovir arm, driven by higher use of corticosteroids and other immunosuppressive therapies for the treatment of presumptive graft-versus-host disease (GVHD).

Diarrhea can be a symptom of GVHD in the gut and is also a known side effect of brincidofovir that can be managed by a temporary dose interruption, as described in the safety monitoring and management plan (SMMP) developed during the phase 2 trial of the drug (then known as CMX001).

In the SUPPRESS trial, diarrhea in brincidofovir-treated patients was more frequent and often presumed to be gut GVHD. So patients were treated with corticosteroids rather than undergoing temporary treatment interruption according to the SMMP. Among patients who were managed according to the SMMP, the investigators observed significantly fewer CMV infections (P=0.03) and lower mortality (P<0.001).

There was an 8-fold increase in the use of corticosteroids through week 14 in the brincidofovir arm compared to the placebo arm. The median cumulative dose of prednisone-equivalent corticosteroids was 26 mg/kg and 3 mg/kg, respectively.

The use of corticosteroids and other immunosuppressive therapies for the treatment of GVHD is known to increase the risk of infections, including CMV infections that occur when patients discontinue antiviral therapy.

Among patients who either underwent T-cell depletion or received alemtuzumab/ATG to decrease the risk of GVHD, those who were randomized to receive brincidofovir showed a lower incidence of CMV when compared to placebo, at a rate consistent with what was observed in the phase 2 study.

Additional endpoints

Brincidofovir did not prevent infection with non-CMV DNA viruses, such as BK virus.

And there was no significant difference between the treatment arms with regard to all-cause mortality. The rate was 15.5% in the brincidofovir arm and 10.1% in the placebo arm (P=0.12).

The investigators said the numerical differences in mortality appear to be driven by higher use of corticosteroids and other immunosuppressive therapies in the subjects who received brincidofovir.

The rate of treatment-emergent adverse events (AEs) was 100% in the brincidofovir arm and 98% in the placebo arm. The rate of grade 3 or higher AEs was 67% and 38%, respectively. The rate of serious AEs was 57% and 38%, respectively.

The rate of AEs leading to treatment discontinuation was 26% and 7%, respectively. And the rate of AEs leading to treatment change or interruption was 45% and 15%, respectively.

The most common AEs in the brincidofovir arm were diarrhea (61%), acute GVHD (57%), abdominal pain (34%), nausea (31%), vomiting (24%), peripheral edema (17%), hyperglycemia (16%), hypokalemia (16%), hypomagnesemia (13%), and ALT elevation (11%). There was no evidence of bone marrow toxicity, kidney toxicity, or viral resistance to brincidofovir.

Brincidofovir development

Chimerix said it will discuss the SUPPRESS data in full with the US Food and Drug Administration and other regulators, including the benefit-to-risk profile in specific subpopulations, as well as the current adenovirus and smallpox data, to determine next steps for the brincidofovir clinical programs.

The development of an intravenous (IV) formulation of brincidofovir is progressing toward clinical testing and has the potential to avoid the gastrointestinal side effects of orally administered brincidofovir.

Preclinical studies of IV brincidofovir have shown a lower risk of gastrointestinal effects based on maintained body weight during dosing and no evidence of injury in preliminary review of the gastrointestinal tract.

If human studies continue to support these findings, IV dosing during the first few weeks after transplant when patients are recovering from conditioning chemotherapy could be explored, with oral brincidofovir therapy available as patients are discharged home.

As there is no preventive therapy approved for CMV in HSCT recipients, Chimerix said it is committed to moving brincidofovir forward in this indication. Plans for brincidofovir in HSCT recipients will be the subject of further discussions with regulators.