Drug disappoints in phase 3 HSCT trial

The antiviral drug brincidofovir did not meet the primary endpoint of the phase 3 SUPPRESS trial, according to the drug’s developer, Chimerix.

Brincidofovir did not prevent clinically significant cytomegalovirus (CMV) infection through week 24 after hematopoietic stem cell transplant (HSCT).

However, the president and CEO of Chimerix said the company still believes there is a “viable path forward” for the drug.

Brincidofovir is an oral nucleotide analog that has shown in vitro antiviral activity against all 5 families of DNA viruses that affect humans, including herpes viruses and adenovirus.

The SUPPRESS trial, which was initiated in August 2013 and fully enrolled in June 2015, was informed by a successful phase 2 trial conducted in HSCT recipients.

The SUPPRESS trial enrolled and treated 452 adults who received allogeneic HSCTs from more than 40 transplant centers in the US, Canada, and Europe.

Subjects received twice-weekly brincidofovir or placebo (2:1 ratio) from the early post-transplant period through week 14 post-transplant, the period of highest risk for viral infections.

All patients in the trial were CMV-seropositive, placing them at high risk of CMV infection. The most common indications leading to HSCT were acute myelogenous leukemia (43% of patients), myelodysplasia (17%), non-Hodgkin lymphoma (10%), and acute lymphocytic leukemia (9%).

During the on-treatment period through week 14 after HSCT, fewer patients in the brincidofovir arm had a CMV infection, which was consistent with results from the phase 2 study of the drug.

However, during the 10 weeks off treatment from week 14 to week 24, there was an increase in CMV infections in the brincidofovir arm compared to the control arm. And there was a non-statistically significant increase in mortality in the brincidofovir arm compared to the control arm.

Preliminary analysis suggests the failure in preventing CMV infections and the increased mortality in the brincidofovir arm were driven by confirmed cases of graft-versus-host-disease (GVHD), which resulted in a significantly higher use of corticosteroids than in the control arm.

Both GVHD and the use of corticosteroids are risk factors for “late” CMV infection that occurs after the discontinuation of the antiviral in HSCT recipients.

The rate of study drug discontinuation for gastrointestinal events was less than 10% in this study, which is comparable to that observed in the phase 2 trial of brincidofovir in a similar HSCT population.

“While we are clearly disappointed in the top-line results from SUPPRESS, we remain committed to better understanding the full data set as we consider potential paths forward for brincidofovir,” said M. Michelle Berrey, MD, president and CEO of Chimerix.

“We will be evaluating the subgroups of patients within SUPPRESS, such as T-cell-depleted transplant recipients who have a lower risk of GVHD, to better understand these results and inform our next steps,” said W. Garrett Nichols, MD, Chimerix’s chief medical officer.

“We are reaching out to investigators and other experts to help us assess the complete data set to understand what may have caused the results of the SUPPRESS trial to differ substantially from those seen in the phase 2 study. Additionally, we are in communication with the US Food and Drug Administration and other regulatory bodies and will share any updates on the brincidofovir clinical program when we can.”

“With data currently in hand, we believe that brincidofovir may ultimately demonstrate a positive risk-benefit profile for the treatment of adenovirus and smallpox, as well as use in other populations in need of a novel compound for DNA viral infections.”

Chimerix plans to continue the programs testing brincidofovir in serious adenovirus infections and in smallpox. Pending the availability of complete data from SUPPRESS, including secondary endpoints in other dsDNA viral infections, Chimerix has elected to pause further enrollment in the phase 3 SUSTAIN and SURPASS trials in kidney transplant recipients.

A full analysis of the SUPPRESS trial results is ongoing. The data are scheduled to be presented at the BMT Tandem Meetings in Honolulu, Hawaii, in February.

The antiviral drug brincidofovir did not meet the primary endpoint of the phase 3 SUPPRESS trial, according to the drug’s developer, Chimerix.

Brincidofovir did not prevent clinically significant cytomegalovirus (CMV) infection through week 24 after hematopoietic stem cell transplant (HSCT).

However, the president and CEO of Chimerix said the company still believes there is a “viable path forward” for the drug.

Brincidofovir is an oral nucleotide analog that has shown in vitro antiviral activity against all 5 families of DNA viruses that affect humans, including herpes viruses and adenovirus.

The SUPPRESS trial, which was initiated in August 2013 and fully enrolled in June 2015, was informed by a successful phase 2 trial conducted in HSCT recipients.

The SUPPRESS trial enrolled and treated 452 adults who received allogeneic HSCTs from more than 40 transplant centers in the US, Canada, and Europe.

Subjects received twice-weekly brincidofovir or placebo (2:1 ratio) from the early post-transplant period through week 14 post-transplant, the period of highest risk for viral infections.

All patients in the trial were CMV-seropositive, placing them at high risk of CMV infection. The most common indications leading to HSCT were acute myelogenous leukemia (43% of patients), myelodysplasia (17%), non-Hodgkin lymphoma (10%), and acute lymphocytic leukemia (9%).

During the on-treatment period through week 14 after HSCT, fewer patients in the brincidofovir arm had a CMV infection, which was consistent with results from the phase 2 study of the drug.

However, during the 10 weeks off treatment from week 14 to week 24, there was an increase in CMV infections in the brincidofovir arm compared to the control arm. And there was a non-statistically significant increase in mortality in the brincidofovir arm compared to the control arm.

Preliminary analysis suggests the failure in preventing CMV infections and the increased mortality in the brincidofovir arm were driven by confirmed cases of graft-versus-host-disease (GVHD), which resulted in a significantly higher use of corticosteroids than in the control arm.

Both GVHD and the use of corticosteroids are risk factors for “late” CMV infection that occurs after the discontinuation of the antiviral in HSCT recipients.

The rate of study drug discontinuation for gastrointestinal events was less than 10% in this study, which is comparable to that observed in the phase 2 trial of brincidofovir in a similar HSCT population.

“While we are clearly disappointed in the top-line results from SUPPRESS, we remain committed to better understanding the full data set as we consider potential paths forward for brincidofovir,” said M. Michelle Berrey, MD, president and CEO of Chimerix.

“We will be evaluating the subgroups of patients within SUPPRESS, such as T-cell-depleted transplant recipients who have a lower risk of GVHD, to better understand these results and inform our next steps,” said W. Garrett Nichols, MD, Chimerix’s chief medical officer.

“We are reaching out to investigators and other experts to help us assess the complete data set to understand what may have caused the results of the SUPPRESS trial to differ substantially from those seen in the phase 2 study. Additionally, we are in communication with the US Food and Drug Administration and other regulatory bodies and will share any updates on the brincidofovir clinical program when we can.”

“With data currently in hand, we believe that brincidofovir may ultimately demonstrate a positive risk-benefit profile for the treatment of adenovirus and smallpox, as well as use in other populations in need of a novel compound for DNA viral infections.”

Chimerix plans to continue the programs testing brincidofovir in serious adenovirus infections and in smallpox. Pending the availability of complete data from SUPPRESS, including secondary endpoints in other dsDNA viral infections, Chimerix has elected to pause further enrollment in the phase 3 SUSTAIN and SURPASS trials in kidney transplant recipients.

A full analysis of the SUPPRESS trial results is ongoing. The data are scheduled to be presented at the BMT Tandem Meetings in Honolulu, Hawaii, in February.

The antiviral drug brincidofovir did not meet the primary endpoint of the phase 3 SUPPRESS trial, according to the drug’s developer, Chimerix.

Brincidofovir did not prevent clinically significant cytomegalovirus (CMV) infection through week 24 after hematopoietic stem cell transplant (HSCT).

However, the president and CEO of Chimerix said the company still believes there is a “viable path forward” for the drug.

Brincidofovir is an oral nucleotide analog that has shown in vitro antiviral activity against all 5 families of DNA viruses that affect humans, including herpes viruses and adenovirus.

The SUPPRESS trial, which was initiated in August 2013 and fully enrolled in June 2015, was informed by a successful phase 2 trial conducted in HSCT recipients.

The SUPPRESS trial enrolled and treated 452 adults who received allogeneic HSCTs from more than 40 transplant centers in the US, Canada, and Europe.

Subjects received twice-weekly brincidofovir or placebo (2:1 ratio) from the early post-transplant period through week 14 post-transplant, the period of highest risk for viral infections.

All patients in the trial were CMV-seropositive, placing them at high risk of CMV infection. The most common indications leading to HSCT were acute myelogenous leukemia (43% of patients), myelodysplasia (17%), non-Hodgkin lymphoma (10%), and acute lymphocytic leukemia (9%).

During the on-treatment period through week 14 after HSCT, fewer patients in the brincidofovir arm had a CMV infection, which was consistent with results from the phase 2 study of the drug.

However, during the 10 weeks off treatment from week 14 to week 24, there was an increase in CMV infections in the brincidofovir arm compared to the control arm. And there was a non-statistically significant increase in mortality in the brincidofovir arm compared to the control arm.

Preliminary analysis suggests the failure in preventing CMV infections and the increased mortality in the brincidofovir arm were driven by confirmed cases of graft-versus-host-disease (GVHD), which resulted in a significantly higher use of corticosteroids than in the control arm.

Both GVHD and the use of corticosteroids are risk factors for “late” CMV infection that occurs after the discontinuation of the antiviral in HSCT recipients.

The rate of study drug discontinuation for gastrointestinal events was less than 10% in this study, which is comparable to that observed in the phase 2 trial of brincidofovir in a similar HSCT population.

“While we are clearly disappointed in the top-line results from SUPPRESS, we remain committed to better understanding the full data set as we consider potential paths forward for brincidofovir,” said M. Michelle Berrey, MD, president and CEO of Chimerix.

“We will be evaluating the subgroups of patients within SUPPRESS, such as T-cell-depleted transplant recipients who have a lower risk of GVHD, to better understand these results and inform our next steps,” said W. Garrett Nichols, MD, Chimerix’s chief medical officer.

“We are reaching out to investigators and other experts to help us assess the complete data set to understand what may have caused the results of the SUPPRESS trial to differ substantially from those seen in the phase 2 study. Additionally, we are in communication with the US Food and Drug Administration and other regulatory bodies and will share any updates on the brincidofovir clinical program when we can.”

“With data currently in hand, we believe that brincidofovir may ultimately demonstrate a positive risk-benefit profile for the treatment of adenovirus and smallpox, as well as use in other populations in need of a novel compound for DNA viral infections.”

Chimerix plans to continue the programs testing brincidofovir in serious adenovirus infections and in smallpox. Pending the availability of complete data from SUPPRESS, including secondary endpoints in other dsDNA viral infections, Chimerix has elected to pause further enrollment in the phase 3 SUSTAIN and SURPASS trials in kidney transplant recipients.

A full analysis of the SUPPRESS trial results is ongoing. The data are scheduled to be presented at the BMT Tandem Meetings in Honolulu, Hawaii, in February.