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Repurposed drug could improve HSCT
A medication used to treat joint and skin conditions might also improve allogeneic hematopoietic stem cell transplant (HSCT), according to research published in Science Translational Medicine.
Researchers discovered that, once transplanted, some differentiated cells produce tumor necrosis factor-alpha (TNFα), which impairs cell division and survival of hematopoietic stem and progenitor cells (HSPCs).
This led the researchers to explore whether a drug that blocks TNFα would allow HSPCs to thrive in a new host.
The team administered etanercept, an antibody that binds to and disables TNFα, to mice receiving umbilical cord blood (UCB) transplants.
Mice that received the drug had better bone marrow reconstitution than control mice.
“If this strategy boosts the survival rate of blood stem cells in humans, then we can get away with using smaller grafts,” said study author Peter Zandstra, PhD, of the University of British Columbia in Vancouver, British Columbia, Canada.
“That would vastly increase the pool of usable umbilical cord blood donations, making stem cell transplants more feasible, not only for blood cancers, which we are already doing, but also for auto-immune diseases, like Crohn’s disease, even HIV.”
Dr Zandstra and his colleagues began this research by performing UCB transplants in immunodeficient mice.
The team was surprised to find that mice receiving the highest numbers of UCB cells had the worst outcomes in terms of bone marrow reconstitution. The researchers also found elevated levels of cytokines in the animals’ sera.
The team speculated that mature immune cells within UCB might be producing inflammatory cytokines, thus preventing HSPCs from successfully repopulating the bone marrow.
One molecule in particular, TNFα, inhibited HSPC survival and division.
Treating recipient mice with the TNFα blocker etanercept enhanced short-term HSPC engraftment and accelerated hematopoietic recovery after UCB transplants.
According to the researchers, these results implicate TNFα as a central player in setting off the cytokine storm that can impair donor HSPC survival.
The team also believes their results provide a strong basis for conducting a clinical trial to see whether etanercept or another TNFα blocker would improve outcomes for people receiving HSCTs.
“Failure of the graft after stem cell transplantation is always a potentially life-threatening complication,” said Kirk Schultz, MD, a professor at the University of British Columbia who was not involved in this study.
“This is especially the case when we must use mismatched stem cells derived from umbilical cord blood. This advance may offer a significant advance in making these transplants more successful.” 
A medication used to treat joint and skin conditions might also improve allogeneic hematopoietic stem cell transplant (HSCT), according to research published in Science Translational Medicine.
Researchers discovered that, once transplanted, some differentiated cells produce tumor necrosis factor-alpha (TNFα), which impairs cell division and survival of hematopoietic stem and progenitor cells (HSPCs).
This led the researchers to explore whether a drug that blocks TNFα would allow HSPCs to thrive in a new host.
The team administered etanercept, an antibody that binds to and disables TNFα, to mice receiving umbilical cord blood (UCB) transplants.
Mice that received the drug had better bone marrow reconstitution than control mice.
“If this strategy boosts the survival rate of blood stem cells in humans, then we can get away with using smaller grafts,” said study author Peter Zandstra, PhD, of the University of British Columbia in Vancouver, British Columbia, Canada.
“That would vastly increase the pool of usable umbilical cord blood donations, making stem cell transplants more feasible, not only for blood cancers, which we are already doing, but also for auto-immune diseases, like Crohn’s disease, even HIV.”
Dr Zandstra and his colleagues began this research by performing UCB transplants in immunodeficient mice.
The team was surprised to find that mice receiving the highest numbers of UCB cells had the worst outcomes in terms of bone marrow reconstitution. The researchers also found elevated levels of cytokines in the animals’ sera.
The team speculated that mature immune cells within UCB might be producing inflammatory cytokines, thus preventing HSPCs from successfully repopulating the bone marrow.
One molecule in particular, TNFα, inhibited HSPC survival and division.
Treating recipient mice with the TNFα blocker etanercept enhanced short-term HSPC engraftment and accelerated hematopoietic recovery after UCB transplants.
According to the researchers, these results implicate TNFα as a central player in setting off the cytokine storm that can impair donor HSPC survival.
The team also believes their results provide a strong basis for conducting a clinical trial to see whether etanercept or another TNFα blocker would improve outcomes for people receiving HSCTs.
“Failure of the graft after stem cell transplantation is always a potentially life-threatening complication,” said Kirk Schultz, MD, a professor at the University of British Columbia who was not involved in this study.
“This is especially the case when we must use mismatched stem cells derived from umbilical cord blood. This advance may offer a significant advance in making these transplants more successful.”
A medication used to treat joint and skin conditions might also improve allogeneic hematopoietic stem cell transplant (HSCT), according to research published in Science Translational Medicine.
Researchers discovered that, once transplanted, some differentiated cells produce tumor necrosis factor-alpha (TNFα), which impairs cell division and survival of hematopoietic stem and progenitor cells (HSPCs).
This led the researchers to explore whether a drug that blocks TNFα would allow HSPCs to thrive in a new host.
The team administered etanercept, an antibody that binds to and disables TNFα, to mice receiving umbilical cord blood (UCB) transplants.
Mice that received the drug had better bone marrow reconstitution than control mice.
“If this strategy boosts the survival rate of blood stem cells in humans, then we can get away with using smaller grafts,” said study author Peter Zandstra, PhD, of the University of British Columbia in Vancouver, British Columbia, Canada.
“That would vastly increase the pool of usable umbilical cord blood donations, making stem cell transplants more feasible, not only for blood cancers, which we are already doing, but also for auto-immune diseases, like Crohn’s disease, even HIV.”
Dr Zandstra and his colleagues began this research by performing UCB transplants in immunodeficient mice.
The team was surprised to find that mice receiving the highest numbers of UCB cells had the worst outcomes in terms of bone marrow reconstitution. The researchers also found elevated levels of cytokines in the animals’ sera.
The team speculated that mature immune cells within UCB might be producing inflammatory cytokines, thus preventing HSPCs from successfully repopulating the bone marrow.
One molecule in particular, TNFα, inhibited HSPC survival and division.
Treating recipient mice with the TNFα blocker etanercept enhanced short-term HSPC engraftment and accelerated hematopoietic recovery after UCB transplants.
According to the researchers, these results implicate TNFα as a central player in setting off the cytokine storm that can impair donor HSPC survival.
The team also believes their results provide a strong basis for conducting a clinical trial to see whether etanercept or another TNFα blocker would improve outcomes for people receiving HSCTs.
“Failure of the graft after stem cell transplantation is always a potentially life-threatening complication,” said Kirk Schultz, MD, a professor at the University of British Columbia who was not involved in this study.
“This is especially the case when we must use mismatched stem cells derived from umbilical cord blood. This advance may offer a significant advance in making these transplants more successful.”
Allo-HSCT leads to long-term survival in MF
ATLANTA—One of the largest single-center studies of fludarabine/melphalan-based allogeneic hematopoietic stem cell transplant (allo-HSCT) for patients with myelofibrosis (MF) shows excellent overall survival (OS) with a low risk of relapse, according to investigators.
Allo-HSCT is the only potential curative treatment modality for MF.
However, it is associated with risks of transplant-related morbidity and mortality from graft-versus-host disease (GVHD), infection, graft rejection, and regimen-related toxicities.
This necessitates careful patient selection and intense peri-transplant management, said study investigator Haris Ali, MD, of the City of Hope Medical Center in Duarte, California.
He noted that there has been a 5-fold increase in allo-HSCT in the last 2 decades, mainly among older patients, due to the increase in reduced-intensity conditioning.
At the 2017 ASH Annual Meeting (in abstract 199), Dr Ali reported on a cohort of 110 MF patients who underwent allo-HSCT with fludarabine/melphalan conditioning at City of Hope between 2004 and 2017.
The patients, 58 with primary MF and 52 with secondary MF, were without prior acute leukemic transformation. They were a median age of 58.5 at the time of transplant, with a median interval of 15.2 months from MF diagnosis.
Virtually all (n=107) received peripheral blood stem cells, and 3 were transplanted with bone marrow as the stem cell source. Forty-nine allo-HSCT donors were matched related, 32 were matched unrelated, 27 were mismatched unrelated, 1 was mismatched relative, and 1 was haploidentical family.
Three-quarters of the patients had intermediate-2 or high-risk disease. Of the 110 patients, 16 had splenectomy prior to allo-HSCT. All but 2 patients engrafted.
After a median follow-up of 56.8 months, the 2-year OS rate was 74%, and the 5-year OS rate was 65%.
Non-relapse mortality at 2 years was 12%. At 5 years, it was 24%.
“The risk of non-relapse mortality was acceptable, considering the relatively older age of a large subset of patients; nearly half were over age 60 at allo-HSCT,” Dr Ali said.
In a univariate analysis, mismatched donors and matched unrelated donors were significantly associated with worse OS compared with matched related donors.
The cumulative incidence of relapse was 17% at 2 years and 5 years.
Splenectomy prior to transplant was associated with higher relapse risk, Dr Ali noted.
“Cytogenetic abnormalities were not associated with transplant relapse or other outcomes in our cohort,” he added.
Mutational changes are being tested in pre-transplant samples and will be reported at a later date.
The incidence of grade 2-4 and 3-4 acute GVHD at 100 days was 45% and 17%, respectively.
At 36 months, the cumulative incidence of all chronic GVHD was 66%. For extensive chronic GVHD, it was 59%.
“Interestingly, prior use of ruxolitinib increased the risk of grade 3-4 acute GVHD, possibly due to known inflammatory cytokine rebound,” Dr Ali said.
Extended use of ruxolitinib until day 30 or longer is currently being evaluated in a prospective trial at City of Hope (NCT02917096).
Dr Ali disclosed consulting fees from Incyte.
ATLANTA—One of the largest single-center studies of fludarabine/melphalan-based allogeneic hematopoietic stem cell transplant (allo-HSCT) for patients with myelofibrosis (MF) shows excellent overall survival (OS) with a low risk of relapse, according to investigators.
Allo-HSCT is the only potential curative treatment modality for MF.
However, it is associated with risks of transplant-related morbidity and mortality from graft-versus-host disease (GVHD), infection, graft rejection, and regimen-related toxicities.
This necessitates careful patient selection and intense peri-transplant management, said study investigator Haris Ali, MD, of the City of Hope Medical Center in Duarte, California.
He noted that there has been a 5-fold increase in allo-HSCT in the last 2 decades, mainly among older patients, due to the increase in reduced-intensity conditioning.
At the 2017 ASH Annual Meeting (in abstract 199), Dr Ali reported on a cohort of 110 MF patients who underwent allo-HSCT with fludarabine/melphalan conditioning at City of Hope between 2004 and 2017.
The patients, 58 with primary MF and 52 with secondary MF, were without prior acute leukemic transformation. They were a median age of 58.5 at the time of transplant, with a median interval of 15.2 months from MF diagnosis.
Virtually all (n=107) received peripheral blood stem cells, and 3 were transplanted with bone marrow as the stem cell source. Forty-nine allo-HSCT donors were matched related, 32 were matched unrelated, 27 were mismatched unrelated, 1 was mismatched relative, and 1 was haploidentical family.
Three-quarters of the patients had intermediate-2 or high-risk disease. Of the 110 patients, 16 had splenectomy prior to allo-HSCT. All but 2 patients engrafted.
After a median follow-up of 56.8 months, the 2-year OS rate was 74%, and the 5-year OS rate was 65%.
Non-relapse mortality at 2 years was 12%. At 5 years, it was 24%.
“The risk of non-relapse mortality was acceptable, considering the relatively older age of a large subset of patients; nearly half were over age 60 at allo-HSCT,” Dr Ali said.
In a univariate analysis, mismatched donors and matched unrelated donors were significantly associated with worse OS compared with matched related donors.
The cumulative incidence of relapse was 17% at 2 years and 5 years.
Splenectomy prior to transplant was associated with higher relapse risk, Dr Ali noted.
“Cytogenetic abnormalities were not associated with transplant relapse or other outcomes in our cohort,” he added.
Mutational changes are being tested in pre-transplant samples and will be reported at a later date.
The incidence of grade 2-4 and 3-4 acute GVHD at 100 days was 45% and 17%, respectively.
At 36 months, the cumulative incidence of all chronic GVHD was 66%. For extensive chronic GVHD, it was 59%.
“Interestingly, prior use of ruxolitinib increased the risk of grade 3-4 acute GVHD, possibly due to known inflammatory cytokine rebound,” Dr Ali said.
Extended use of ruxolitinib until day 30 or longer is currently being evaluated in a prospective trial at City of Hope (NCT02917096).
Dr Ali disclosed consulting fees from Incyte.
ATLANTA—One of the largest single-center studies of fludarabine/melphalan-based allogeneic hematopoietic stem cell transplant (allo-HSCT) for patients with myelofibrosis (MF) shows excellent overall survival (OS) with a low risk of relapse, according to investigators.
Allo-HSCT is the only potential curative treatment modality for MF.
However, it is associated with risks of transplant-related morbidity and mortality from graft-versus-host disease (GVHD), infection, graft rejection, and regimen-related toxicities.
This necessitates careful patient selection and intense peri-transplant management, said study investigator Haris Ali, MD, of the City of Hope Medical Center in Duarte, California.
He noted that there has been a 5-fold increase in allo-HSCT in the last 2 decades, mainly among older patients, due to the increase in reduced-intensity conditioning.
At the 2017 ASH Annual Meeting (in abstract 199), Dr Ali reported on a cohort of 110 MF patients who underwent allo-HSCT with fludarabine/melphalan conditioning at City of Hope between 2004 and 2017.
The patients, 58 with primary MF and 52 with secondary MF, were without prior acute leukemic transformation. They were a median age of 58.5 at the time of transplant, with a median interval of 15.2 months from MF diagnosis.
Virtually all (n=107) received peripheral blood stem cells, and 3 were transplanted with bone marrow as the stem cell source. Forty-nine allo-HSCT donors were matched related, 32 were matched unrelated, 27 were mismatched unrelated, 1 was mismatched relative, and 1 was haploidentical family.
Three-quarters of the patients had intermediate-2 or high-risk disease. Of the 110 patients, 16 had splenectomy prior to allo-HSCT. All but 2 patients engrafted.
After a median follow-up of 56.8 months, the 2-year OS rate was 74%, and the 5-year OS rate was 65%.
Non-relapse mortality at 2 years was 12%. At 5 years, it was 24%.
“The risk of non-relapse mortality was acceptable, considering the relatively older age of a large subset of patients; nearly half were over age 60 at allo-HSCT,” Dr Ali said.
In a univariate analysis, mismatched donors and matched unrelated donors were significantly associated with worse OS compared with matched related donors.
The cumulative incidence of relapse was 17% at 2 years and 5 years.
Splenectomy prior to transplant was associated with higher relapse risk, Dr Ali noted.
“Cytogenetic abnormalities were not associated with transplant relapse or other outcomes in our cohort,” he added.
Mutational changes are being tested in pre-transplant samples and will be reported at a later date.
The incidence of grade 2-4 and 3-4 acute GVHD at 100 days was 45% and 17%, respectively.
At 36 months, the cumulative incidence of all chronic GVHD was 66%. For extensive chronic GVHD, it was 59%.
“Interestingly, prior use of ruxolitinib increased the risk of grade 3-4 acute GVHD, possibly due to known inflammatory cytokine rebound,” Dr Ali said.
Extended use of ruxolitinib until day 30 or longer is currently being evaluated in a prospective trial at City of Hope (NCT02917096).
Dr Ali disclosed consulting fees from Incyte.
Method may improve HSC mobilization, engraftment
New research suggests a 2-drug combination might improve hematopoietic stem cell transplant (HSCT) for donors and recipients.
Researchers found that a single dose of the drugs provides HSC mobilization that rivals 5-day treatment with granulocyte colony-stimulating factor (G-CSF).
And the combination mobilizes HSCs that have higher engraftment efficiency than HSCs mobilized by G-CSF.
Jonathan Hoggatt, PhD, of Massachusetts General Hospital in Boston, and his colleagues reported these findings in Cell.
“Our new method of harvesting stem cells requires only a single injection and mobilizes the cells needed in 15 minutes,” Dr Hoggatt said. “So in the time it takes to boil an egg, we are able to acquire the number of stem cells produced by the current standard 5-day protocol. This means less pain, time off work, and lifestyle disruption for the donor, more convenience for the clinical staff, and more predictability for the harvesting procedure.”
Dr Hoggatt and his colleagues have investigated ways to enhance HSC donation for several years. In a previous study, the researchers found that a CXCR2 agonist called GRO-beta induced rapid movement of HSCs from the marrow into the blood in animal models.
Initial experiments in the current study revealed that GRO-beta injections were safe and well tolerated in human volunteers but had only a modest effect in mobilizing HSCs. Therefore, the team tried combining GRO-beta with the CXCR4 antagonist AMD3100 (plerixafor).
The researchers found that simultaneous administration of both drugs rapidly (within 15 minutes) produced a quantity of HSCs equal to that provided by the 5-day G-CSF protocol.
When transplanted in mice, the HSCs mobilized by AMD3100 and GRO-beta prompted faster reconstitution of bone marrow and recovery of immune cell populations than HSCs mobilized by G-CSF.
The HSCs mobilized by AMD3100 and GRO-beta showed patterns of gene expression similar to those of fetal HSCs.
“These highly engraftable hematopoietic stem cells produced by our new strategy are essentially the A+ students of bone marrow stem cells,” Dr Hoggatt said. “Finding that they express genes similar to those of fetal liver HSCs . . . suggests that they will be very good at moving into an empty bone marrow space and rapidly dividing to fill the marrow and produce blood. Now, we need to test the combination in a clinical trial to confirm its safety and effectiveness in humans.”
New research suggests a 2-drug combination might improve hematopoietic stem cell transplant (HSCT) for donors and recipients.
Researchers found that a single dose of the drugs provides HSC mobilization that rivals 5-day treatment with granulocyte colony-stimulating factor (G-CSF).
And the combination mobilizes HSCs that have higher engraftment efficiency than HSCs mobilized by G-CSF.
Jonathan Hoggatt, PhD, of Massachusetts General Hospital in Boston, and his colleagues reported these findings in Cell.
“Our new method of harvesting stem cells requires only a single injection and mobilizes the cells needed in 15 minutes,” Dr Hoggatt said. “So in the time it takes to boil an egg, we are able to acquire the number of stem cells produced by the current standard 5-day protocol. This means less pain, time off work, and lifestyle disruption for the donor, more convenience for the clinical staff, and more predictability for the harvesting procedure.”
Dr Hoggatt and his colleagues have investigated ways to enhance HSC donation for several years. In a previous study, the researchers found that a CXCR2 agonist called GRO-beta induced rapid movement of HSCs from the marrow into the blood in animal models.
Initial experiments in the current study revealed that GRO-beta injections were safe and well tolerated in human volunteers but had only a modest effect in mobilizing HSCs. Therefore, the team tried combining GRO-beta with the CXCR4 antagonist AMD3100 (plerixafor).
The researchers found that simultaneous administration of both drugs rapidly (within 15 minutes) produced a quantity of HSCs equal to that provided by the 5-day G-CSF protocol.
When transplanted in mice, the HSCs mobilized by AMD3100 and GRO-beta prompted faster reconstitution of bone marrow and recovery of immune cell populations than HSCs mobilized by G-CSF.
The HSCs mobilized by AMD3100 and GRO-beta showed patterns of gene expression similar to those of fetal HSCs.
“These highly engraftable hematopoietic stem cells produced by our new strategy are essentially the A+ students of bone marrow stem cells,” Dr Hoggatt said. “Finding that they express genes similar to those of fetal liver HSCs . . . suggests that they will be very good at moving into an empty bone marrow space and rapidly dividing to fill the marrow and produce blood. Now, we need to test the combination in a clinical trial to confirm its safety and effectiveness in humans.”
New research suggests a 2-drug combination might improve hematopoietic stem cell transplant (HSCT) for donors and recipients.
Researchers found that a single dose of the drugs provides HSC mobilization that rivals 5-day treatment with granulocyte colony-stimulating factor (G-CSF).
And the combination mobilizes HSCs that have higher engraftment efficiency than HSCs mobilized by G-CSF.
Jonathan Hoggatt, PhD, of Massachusetts General Hospital in Boston, and his colleagues reported these findings in Cell.
“Our new method of harvesting stem cells requires only a single injection and mobilizes the cells needed in 15 minutes,” Dr Hoggatt said. “So in the time it takes to boil an egg, we are able to acquire the number of stem cells produced by the current standard 5-day protocol. This means less pain, time off work, and lifestyle disruption for the donor, more convenience for the clinical staff, and more predictability for the harvesting procedure.”
Dr Hoggatt and his colleagues have investigated ways to enhance HSC donation for several years. In a previous study, the researchers found that a CXCR2 agonist called GRO-beta induced rapid movement of HSCs from the marrow into the blood in animal models.
Initial experiments in the current study revealed that GRO-beta injections were safe and well tolerated in human volunteers but had only a modest effect in mobilizing HSCs. Therefore, the team tried combining GRO-beta with the CXCR4 antagonist AMD3100 (plerixafor).
The researchers found that simultaneous administration of both drugs rapidly (within 15 minutes) produced a quantity of HSCs equal to that provided by the 5-day G-CSF protocol.
When transplanted in mice, the HSCs mobilized by AMD3100 and GRO-beta prompted faster reconstitution of bone marrow and recovery of immune cell populations than HSCs mobilized by G-CSF.
The HSCs mobilized by AMD3100 and GRO-beta showed patterns of gene expression similar to those of fetal HSCs.
“These highly engraftable hematopoietic stem cells produced by our new strategy are essentially the A+ students of bone marrow stem cells,” Dr Hoggatt said. “Finding that they express genes similar to those of fetal liver HSCs . . . suggests that they will be very good at moving into an empty bone marrow space and rapidly dividing to fill the marrow and produce blood. Now, we need to test the combination in a clinical trial to confirm its safety and effectiveness in humans.”
Antibody prevents GVHD in mice
Preclinical research suggests PRO 140, a humanized anti-CCR5 monoclonal antibody, can prevent graft-versus-host disease (GVHD) in mice.
Mice that received 2 mg of PRO 140 twice weekly showed no signs of GVHD throughout the study period.
On the other hand, all control mice exhibited signs of GVHD, starting 25 days after engraftment, and had to be sacrificed early.
Researchers reported these results in Biology of Blood and Marrow Transplantation.
The study’s lead author, Denis R. Burger, PhD, is chief science officer of CytoDyn, the company developing PRO 140.
PRO 140 targets the CCR5 receptor, a molecule that modulates the immune cell trafficking crucial for the development of acute GVHD.
Previous clinical studies have shown that inhibiting CCR5 can reduce the clinical impact of acute GVHD without significantly affecting the engraftment of transplanted hematopoietic stem cells (HSCs).
This new study supports the idea that the CCR5 receptor on engrafted cells is critical for the development of acute GVHD and that preventing this receptor from recognizing certain immune signaling molecules is a viable approach to mitigating acute GVHD.
Dr Burger and his colleagues tested PRO 140 in NOD-scid IL-2Rynull mice transplanted with human HSCs.
Mice received 2 different doses of PRO 140 or a control antibody—2 mg or 0.2 mg—twice weekly and were followed for a maximum of 75 days.
Engraftment at the higher dose
Mice that received the 2 mg dose of PRO 140 or the control antibody had received HSCs from a 56-year-old donor.
Engraftment was similar between control and PRO 140-treated mice for the first 30+ days. However, at day 50, there were significantly fewer human CD45+ cells in the PRO 140-treated mice (P=0.034).
At 54 days, control mice had greater engraftment of mature T cells than treated mice in the peripheral blood (63.2% vs 49.8%) and bone marrow (40.2% vs 26.4%).
GVHD at the higher dose
Throughout the study period, there were no physical signs of GVHD in the PRO 140-treated mice.
However, control mice exhibited signs of GVHD starting at day 25 after bone marrow engraftment. Signs included ruffled fur, lethargy, hunching, and weight loss.
There was a significant difference in survival between the 2 groups (P<0.01). All of the control mice had to be sacrificed early, by day 56, whereas all of the PRO 140-treated animals were alive until planned sacrifice at day 75.
Engraftment at the low dose
Mice that received the 0.2 mg dose of PRO 140 or the control antibody had received HSCs from a 26-year-old donor.
Mice in the treatment and control groups achieved the same percentage of CD45+ engraftment. However, PRO 140-treated mice achieved engraftment about 20 days later than control mice (P<0.01).
GVHD at the low dose
Both control and PRO 140-treated mice showed signs of GVHD. However, weight loss was significantly greater among control mice (P<0.05).
Survival was significantly worse among control mice as well (P<0.05). All control mice were dead by 31 days, and all PRO 140-treated mice were dead by 54 days.
The researchers said the difference in survival times between these mice and the mice treated with the higher dose of antibody suggest the younger HSC donor produced more aggressive GVHD.
“This research provided CytoDyn with strong rationale for exploring the use of PRO 140 in . . . the prevention of GVHD,” Dr Burger said.
“The potential of PRO 140 to prevent this life-threatening condition could help extend the use of [HSC] transplantation, an important and effective therapy, to more patients.”
CytoDyn is currently enrolling patients in a phase 2 trial of PRO 140 in leukemia patients undergoing transplant.
Preclinical research suggests PRO 140, a humanized anti-CCR5 monoclonal antibody, can prevent graft-versus-host disease (GVHD) in mice.
Mice that received 2 mg of PRO 140 twice weekly showed no signs of GVHD throughout the study period.
On the other hand, all control mice exhibited signs of GVHD, starting 25 days after engraftment, and had to be sacrificed early.
Researchers reported these results in Biology of Blood and Marrow Transplantation.
The study’s lead author, Denis R. Burger, PhD, is chief science officer of CytoDyn, the company developing PRO 140.
PRO 140 targets the CCR5 receptor, a molecule that modulates the immune cell trafficking crucial for the development of acute GVHD.
Previous clinical studies have shown that inhibiting CCR5 can reduce the clinical impact of acute GVHD without significantly affecting the engraftment of transplanted hematopoietic stem cells (HSCs).
This new study supports the idea that the CCR5 receptor on engrafted cells is critical for the development of acute GVHD and that preventing this receptor from recognizing certain immune signaling molecules is a viable approach to mitigating acute GVHD.
Dr Burger and his colleagues tested PRO 140 in NOD-scid IL-2Rynull mice transplanted with human HSCs.
Mice received 2 different doses of PRO 140 or a control antibody—2 mg or 0.2 mg—twice weekly and were followed for a maximum of 75 days.
Engraftment at the higher dose
Mice that received the 2 mg dose of PRO 140 or the control antibody had received HSCs from a 56-year-old donor.
Engraftment was similar between control and PRO 140-treated mice for the first 30+ days. However, at day 50, there were significantly fewer human CD45+ cells in the PRO 140-treated mice (P=0.034).
At 54 days, control mice had greater engraftment of mature T cells than treated mice in the peripheral blood (63.2% vs 49.8%) and bone marrow (40.2% vs 26.4%).
GVHD at the higher dose
Throughout the study period, there were no physical signs of GVHD in the PRO 140-treated mice.
However, control mice exhibited signs of GVHD starting at day 25 after bone marrow engraftment. Signs included ruffled fur, lethargy, hunching, and weight loss.
There was a significant difference in survival between the 2 groups (P<0.01). All of the control mice had to be sacrificed early, by day 56, whereas all of the PRO 140-treated animals were alive until planned sacrifice at day 75.
Engraftment at the low dose
Mice that received the 0.2 mg dose of PRO 140 or the control antibody had received HSCs from a 26-year-old donor.
Mice in the treatment and control groups achieved the same percentage of CD45+ engraftment. However, PRO 140-treated mice achieved engraftment about 20 days later than control mice (P<0.01).
GVHD at the low dose
Both control and PRO 140-treated mice showed signs of GVHD. However, weight loss was significantly greater among control mice (P<0.05).
Survival was significantly worse among control mice as well (P<0.05). All control mice were dead by 31 days, and all PRO 140-treated mice were dead by 54 days.
The researchers said the difference in survival times between these mice and the mice treated with the higher dose of antibody suggest the younger HSC donor produced more aggressive GVHD.
“This research provided CytoDyn with strong rationale for exploring the use of PRO 140 in . . . the prevention of GVHD,” Dr Burger said.
“The potential of PRO 140 to prevent this life-threatening condition could help extend the use of [HSC] transplantation, an important and effective therapy, to more patients.”
CytoDyn is currently enrolling patients in a phase 2 trial of PRO 140 in leukemia patients undergoing transplant.
Preclinical research suggests PRO 140, a humanized anti-CCR5 monoclonal antibody, can prevent graft-versus-host disease (GVHD) in mice.
Mice that received 2 mg of PRO 140 twice weekly showed no signs of GVHD throughout the study period.
On the other hand, all control mice exhibited signs of GVHD, starting 25 days after engraftment, and had to be sacrificed early.
Researchers reported these results in Biology of Blood and Marrow Transplantation.
The study’s lead author, Denis R. Burger, PhD, is chief science officer of CytoDyn, the company developing PRO 140.
PRO 140 targets the CCR5 receptor, a molecule that modulates the immune cell trafficking crucial for the development of acute GVHD.
Previous clinical studies have shown that inhibiting CCR5 can reduce the clinical impact of acute GVHD without significantly affecting the engraftment of transplanted hematopoietic stem cells (HSCs).
This new study supports the idea that the CCR5 receptor on engrafted cells is critical for the development of acute GVHD and that preventing this receptor from recognizing certain immune signaling molecules is a viable approach to mitigating acute GVHD.
Dr Burger and his colleagues tested PRO 140 in NOD-scid IL-2Rynull mice transplanted with human HSCs.
Mice received 2 different doses of PRO 140 or a control antibody—2 mg or 0.2 mg—twice weekly and were followed for a maximum of 75 days.
Engraftment at the higher dose
Mice that received the 2 mg dose of PRO 140 or the control antibody had received HSCs from a 56-year-old donor.
Engraftment was similar between control and PRO 140-treated mice for the first 30+ days. However, at day 50, there were significantly fewer human CD45+ cells in the PRO 140-treated mice (P=0.034).
At 54 days, control mice had greater engraftment of mature T cells than treated mice in the peripheral blood (63.2% vs 49.8%) and bone marrow (40.2% vs 26.4%).
GVHD at the higher dose
Throughout the study period, there were no physical signs of GVHD in the PRO 140-treated mice.
However, control mice exhibited signs of GVHD starting at day 25 after bone marrow engraftment. Signs included ruffled fur, lethargy, hunching, and weight loss.
There was a significant difference in survival between the 2 groups (P<0.01). All of the control mice had to be sacrificed early, by day 56, whereas all of the PRO 140-treated animals were alive until planned sacrifice at day 75.
Engraftment at the low dose
Mice that received the 0.2 mg dose of PRO 140 or the control antibody had received HSCs from a 26-year-old donor.
Mice in the treatment and control groups achieved the same percentage of CD45+ engraftment. However, PRO 140-treated mice achieved engraftment about 20 days later than control mice (P<0.01).
GVHD at the low dose
Both control and PRO 140-treated mice showed signs of GVHD. However, weight loss was significantly greater among control mice (P<0.05).
Survival was significantly worse among control mice as well (P<0.05). All control mice were dead by 31 days, and all PRO 140-treated mice were dead by 54 days.
The researchers said the difference in survival times between these mice and the mice treated with the higher dose of antibody suggest the younger HSC donor produced more aggressive GVHD.
“This research provided CytoDyn with strong rationale for exploring the use of PRO 140 in . . . the prevention of GVHD,” Dr Burger said.
“The potential of PRO 140 to prevent this life-threatening condition could help extend the use of [HSC] transplantation, an important and effective therapy, to more patients.”
CytoDyn is currently enrolling patients in a phase 2 trial of PRO 140 in leukemia patients undergoing transplant.
CHMP recommends letermovir as CMV prophylaxis
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended marketing authorization for letermovir (Prevymis), which belongs to a class of non-nucleoside CMV inhibitors known as 3,4 dihydro-quinazolines.
The CHMP is advocating that letermovir be approved as prophylaxis for cytomegalovirus (CMV) reactivation and disease in patients who receive immunosuppressants after allogeneic hematopoietic stem cell transplant (HSCT).
The CHMP’s opinion will be reviewed by the European Commission (EC).
If the EC agrees with the CHMP, the commission will grant a centralized marketing authorization that will be valid in the European Union. Norway, Iceland, and Liechtenstein will make corresponding decisions on the basis of the EC’s decision.
The EC typically makes a decision within 67 days of the CHMP’s recommendation.
Letermovir previously received an orphan designation from the European Medicines Agency’s Committee for Orphan Medicinal Products in June 2012. Now, the committee will assess whether the orphan designation should be maintained.
Phase 3 trial
The CHMP’s recommendation to authorize use of letermovir is based on data from a phase 3 trial. Results from this trial were presented at the 2017 BMT Tandem Meetings.
The trial enrolled adult recipients of allogeneic HSCTs who were CMV-seropositive. Patients were randomized (2:1) to receive either letermovir (at a dose of 480 mg once-daily, adjusted to 240 mg when co-administered with cyclosporine) or placebo.
Study drug was initiated after HSCT (at any time from day 0 to 28 post-transplant) and continued through week 14 post-transplant. Patients were monitored through week 24 post-HSCT for the primary efficacy endpoint, with continued follow-up through week 48.
Among the 565 treated patients, 34% were engrafted at baseline, and 30% had one or more factors associated with additional risk for CMV reactivation. The most common primary reasons for transplant were acute myeloid leukemia (38%), myelodysplastic syndromes (16%), and lymphoma (12%).
Thirty eight percent of patients in the letermovir arm and 61% in the placebo arm failed prophylaxis.
Reasons for failure (in the letermovir and placebo arms, respectively) included:
- Clinically significant CMV infection—18% vs 42%
- Initiation of PET based on documented CMV viremia—16% vs 40%
- CMV end-organ disease—2% for both
- Study discontinuation before week 24—17% vs 16%
- Missing outcome in week 24 visit window—3% for both.
The stratum-adjusted treatment difference for letermovir vs placebo was -23.5 (95% CI, -32.5, -14.6, P<0.0001).
The Kaplan-Meier event rate for all-cause mortality in the letermovir and placebo arms, respectively, was 12% and 17% at week 24 and 24% and 28% at week 48.
Common adverse events (in the letermovir and placebo arms, respectively) were nausea (27% vs 23%), diarrhea (26% vs 24%), vomiting (19% vs 14%), peripheral edema (14% vs 9%), cough (14% vs 10%), headache (14% vs 9%), fatigue (13% vs 11%), and abdominal pain (12% vs 9%).
The cardiac adverse event rate (regardless of investigator-assessed causality) was 13% in the letermovir arm and 6% in the placebo arm. The most common cardiac adverse events (in the letermovir and placebo arms, respectively) were tachycardia (4% vs 2%) and atrial fibrillation (3% vs 1%).
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended marketing authorization for letermovir (Prevymis), which belongs to a class of non-nucleoside CMV inhibitors known as 3,4 dihydro-quinazolines.
The CHMP is advocating that letermovir be approved as prophylaxis for cytomegalovirus (CMV) reactivation and disease in patients who receive immunosuppressants after allogeneic hematopoietic stem cell transplant (HSCT).
The CHMP’s opinion will be reviewed by the European Commission (EC).
If the EC agrees with the CHMP, the commission will grant a centralized marketing authorization that will be valid in the European Union. Norway, Iceland, and Liechtenstein will make corresponding decisions on the basis of the EC’s decision.
The EC typically makes a decision within 67 days of the CHMP’s recommendation.
Letermovir previously received an orphan designation from the European Medicines Agency’s Committee for Orphan Medicinal Products in June 2012. Now, the committee will assess whether the orphan designation should be maintained.
Phase 3 trial
The CHMP’s recommendation to authorize use of letermovir is based on data from a phase 3 trial. Results from this trial were presented at the 2017 BMT Tandem Meetings.
The trial enrolled adult recipients of allogeneic HSCTs who were CMV-seropositive. Patients were randomized (2:1) to receive either letermovir (at a dose of 480 mg once-daily, adjusted to 240 mg when co-administered with cyclosporine) or placebo.
Study drug was initiated after HSCT (at any time from day 0 to 28 post-transplant) and continued through week 14 post-transplant. Patients were monitored through week 24 post-HSCT for the primary efficacy endpoint, with continued follow-up through week 48.
Among the 565 treated patients, 34% were engrafted at baseline, and 30% had one or more factors associated with additional risk for CMV reactivation. The most common primary reasons for transplant were acute myeloid leukemia (38%), myelodysplastic syndromes (16%), and lymphoma (12%).
Thirty eight percent of patients in the letermovir arm and 61% in the placebo arm failed prophylaxis.
Reasons for failure (in the letermovir and placebo arms, respectively) included:
- Clinically significant CMV infection—18% vs 42%
- Initiation of PET based on documented CMV viremia—16% vs 40%
- CMV end-organ disease—2% for both
- Study discontinuation before week 24—17% vs 16%
- Missing outcome in week 24 visit window—3% for both.
The stratum-adjusted treatment difference for letermovir vs placebo was -23.5 (95% CI, -32.5, -14.6, P<0.0001).
The Kaplan-Meier event rate for all-cause mortality in the letermovir and placebo arms, respectively, was 12% and 17% at week 24 and 24% and 28% at week 48.
Common adverse events (in the letermovir and placebo arms, respectively) were nausea (27% vs 23%), diarrhea (26% vs 24%), vomiting (19% vs 14%), peripheral edema (14% vs 9%), cough (14% vs 10%), headache (14% vs 9%), fatigue (13% vs 11%), and abdominal pain (12% vs 9%).
The cardiac adverse event rate (regardless of investigator-assessed causality) was 13% in the letermovir arm and 6% in the placebo arm. The most common cardiac adverse events (in the letermovir and placebo arms, respectively) were tachycardia (4% vs 2%) and atrial fibrillation (3% vs 1%).
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended marketing authorization for letermovir (Prevymis), which belongs to a class of non-nucleoside CMV inhibitors known as 3,4 dihydro-quinazolines.
The CHMP is advocating that letermovir be approved as prophylaxis for cytomegalovirus (CMV) reactivation and disease in patients who receive immunosuppressants after allogeneic hematopoietic stem cell transplant (HSCT).
The CHMP’s opinion will be reviewed by the European Commission (EC).
If the EC agrees with the CHMP, the commission will grant a centralized marketing authorization that will be valid in the European Union. Norway, Iceland, and Liechtenstein will make corresponding decisions on the basis of the EC’s decision.
The EC typically makes a decision within 67 days of the CHMP’s recommendation.
Letermovir previously received an orphan designation from the European Medicines Agency’s Committee for Orphan Medicinal Products in June 2012. Now, the committee will assess whether the orphan designation should be maintained.
Phase 3 trial
The CHMP’s recommendation to authorize use of letermovir is based on data from a phase 3 trial. Results from this trial were presented at the 2017 BMT Tandem Meetings.
The trial enrolled adult recipients of allogeneic HSCTs who were CMV-seropositive. Patients were randomized (2:1) to receive either letermovir (at a dose of 480 mg once-daily, adjusted to 240 mg when co-administered with cyclosporine) or placebo.
Study drug was initiated after HSCT (at any time from day 0 to 28 post-transplant) and continued through week 14 post-transplant. Patients were monitored through week 24 post-HSCT for the primary efficacy endpoint, with continued follow-up through week 48.
Among the 565 treated patients, 34% were engrafted at baseline, and 30% had one or more factors associated with additional risk for CMV reactivation. The most common primary reasons for transplant were acute myeloid leukemia (38%), myelodysplastic syndromes (16%), and lymphoma (12%).
Thirty eight percent of patients in the letermovir arm and 61% in the placebo arm failed prophylaxis.
Reasons for failure (in the letermovir and placebo arms, respectively) included:
- Clinically significant CMV infection—18% vs 42%
- Initiation of PET based on documented CMV viremia—16% vs 40%
- CMV end-organ disease—2% for both
- Study discontinuation before week 24—17% vs 16%
- Missing outcome in week 24 visit window—3% for both.
The stratum-adjusted treatment difference for letermovir vs placebo was -23.5 (95% CI, -32.5, -14.6, P<0.0001).
The Kaplan-Meier event rate for all-cause mortality in the letermovir and placebo arms, respectively, was 12% and 17% at week 24 and 24% and 28% at week 48.
Common adverse events (in the letermovir and placebo arms, respectively) were nausea (27% vs 23%), diarrhea (26% vs 24%), vomiting (19% vs 14%), peripheral edema (14% vs 9%), cough (14% vs 10%), headache (14% vs 9%), fatigue (13% vs 11%), and abdominal pain (12% vs 9%).
The cardiac adverse event rate (regardless of investigator-assessed causality) was 13% in the letermovir arm and 6% in the placebo arm. The most common cardiac adverse events (in the letermovir and placebo arms, respectively) were tachycardia (4% vs 2%) and atrial fibrillation (3% vs 1%).
FDA approves letermovir as CMV prophylaxis
The US Food and Drug Administration (FDA) has approved the oral and intravenous formulations of letermovir (PREVYMIS™).
Letermovir is a member of a new class of non-nucleoside CMV inhibitors known as 3,4 dihydro-quinazolines.
The FDA approved letermovir as prophylaxis for cytomegalovirus (CMV) infection and disease in adult recipients of allogeneic hematopoietic stem cell transplants (HSCTs) who are CMV-seropositive.
“PREVYMIS is the first new medicine for CMV infection approved in the US in 15 years,” said Roy Baynes, senior vice president, head of clinical development, and chief medical officer of Merck Research Laboratories, the company marketing letermovir.
Letermovir is expected to be available in December. The list price (wholesaler acquisition cost) per day is $195.00 for letermovir tablets and $270.00 for letermovir injections. (Wholesaler acquisition costs do not include discounts that may be paid on the product.)
The recommended dosage of letermovir is 480 mg once daily, initiated as early as day 0 and up to day 28 post-transplant (before or after engraftment) and continued through day 100. If letermovir is co-administered with cyclosporine, the dosage of letermovir should be decreased to 240 mg once daily.
Letermovir is available as 240 mg and 480 mg tablets, which may be administered with or without food. Letermovir is also available as a 240 mg and 480 mg injection for intravenous infusion via a peripheral catheter or central venous line at a constant rate over 1 hour.
For more details on letermovir, see the full prescribing information.
Trial results
The FDA’s approval of letermovir was supported by results of a phase 3 trial of adult recipients of allogeneic HSCTs who were CMV-seropositive. Patients were randomized (2:1) to receive either letermovir (at a dose of 480 mg once-daily, adjusted to 240 mg when co-administered with cyclosporine) or placebo.
Study drug was initiated after HSCT (at any time from day 0 to 28 post-transplant) and continued through week 14 post-transplant. Patients were monitored through week 24 post-HSCT for the primary efficacy endpoint, with continued follow-up through week 48.
Among the 565 treated patients, 34% were engrafted at baseline, and 30% had one or more factors associated with additional risk for CMV reactivation. The most common primary reasons for transplant were acute myeloid leukemia (38%), myelodysplastic syndromes (16%), and lymphoma (12%).
Thirty eight percent of patients in the letermovir arm and 61% in the placebo arm failed prophylaxis.
Reasons for failure (in the letermovir and placebo arms, respectively) included:
- Clinically significant CMV infection—18% vs 42%
- Initiation of PET based on documented CMV viremia—16% vs 40%
- CMV end-organ disease—2% for both
- Study discontinuation before week 24—17% vs 16%
- Missing outcome in week 24 visit window—3% for both.
The stratum-adjusted treatment difference for letermovir vs placebo was -23.5 (95% CI, -32.5, -14.6, P<0.0001).
The Kaplan-Meier event rate for all-cause mortality in the letermovir and placebo arms, respectively, was 12% and 17% at week 24 and 24% and 28% at week 48.
Common adverse events (in the letermovir and placebo arms, respectively) were nausea (27% vs 23%), diarrhea (26% vs 24%), vomiting (19% vs 14%), peripheral edema (14% vs 9%), cough (14% vs 10%), headache (14% vs 9%), fatigue (13% vs 11%), and abdominal pain (12% vs 9%).
The cardiac adverse event rate (regardless of investigator-assessed causality) was 13% in the letermovir arm and 6% in the placebo arm. The most common cardiac adverse events (in the letermovir and placebo arms, respectively) were tachycardia (4% vs 2%) and atrial fibrillation (3% vs 1%).
Results from this trial were presented at the 2017 BMT Tandem Meetings.
The US Food and Drug Administration (FDA) has approved the oral and intravenous formulations of letermovir (PREVYMIS™).
Letermovir is a member of a new class of non-nucleoside CMV inhibitors known as 3,4 dihydro-quinazolines.
The FDA approved letermovir as prophylaxis for cytomegalovirus (CMV) infection and disease in adult recipients of allogeneic hematopoietic stem cell transplants (HSCTs) who are CMV-seropositive.
“PREVYMIS is the first new medicine for CMV infection approved in the US in 15 years,” said Roy Baynes, senior vice president, head of clinical development, and chief medical officer of Merck Research Laboratories, the company marketing letermovir.
Letermovir is expected to be available in December. The list price (wholesaler acquisition cost) per day is $195.00 for letermovir tablets and $270.00 for letermovir injections. (Wholesaler acquisition costs do not include discounts that may be paid on the product.)
The recommended dosage of letermovir is 480 mg once daily, initiated as early as day 0 and up to day 28 post-transplant (before or after engraftment) and continued through day 100. If letermovir is co-administered with cyclosporine, the dosage of letermovir should be decreased to 240 mg once daily.
Letermovir is available as 240 mg and 480 mg tablets, which may be administered with or without food. Letermovir is also available as a 240 mg and 480 mg injection for intravenous infusion via a peripheral catheter or central venous line at a constant rate over 1 hour.
For more details on letermovir, see the full prescribing information.
Trial results
The FDA’s approval of letermovir was supported by results of a phase 3 trial of adult recipients of allogeneic HSCTs who were CMV-seropositive. Patients were randomized (2:1) to receive either letermovir (at a dose of 480 mg once-daily, adjusted to 240 mg when co-administered with cyclosporine) or placebo.
Study drug was initiated after HSCT (at any time from day 0 to 28 post-transplant) and continued through week 14 post-transplant. Patients were monitored through week 24 post-HSCT for the primary efficacy endpoint, with continued follow-up through week 48.
Among the 565 treated patients, 34% were engrafted at baseline, and 30% had one or more factors associated with additional risk for CMV reactivation. The most common primary reasons for transplant were acute myeloid leukemia (38%), myelodysplastic syndromes (16%), and lymphoma (12%).
Thirty eight percent of patients in the letermovir arm and 61% in the placebo arm failed prophylaxis.
Reasons for failure (in the letermovir and placebo arms, respectively) included:
- Clinically significant CMV infection—18% vs 42%
- Initiation of PET based on documented CMV viremia—16% vs 40%
- CMV end-organ disease—2% for both
- Study discontinuation before week 24—17% vs 16%
- Missing outcome in week 24 visit window—3% for both.
The stratum-adjusted treatment difference for letermovir vs placebo was -23.5 (95% CI, -32.5, -14.6, P<0.0001).
The Kaplan-Meier event rate for all-cause mortality in the letermovir and placebo arms, respectively, was 12% and 17% at week 24 and 24% and 28% at week 48.
Common adverse events (in the letermovir and placebo arms, respectively) were nausea (27% vs 23%), diarrhea (26% vs 24%), vomiting (19% vs 14%), peripheral edema (14% vs 9%), cough (14% vs 10%), headache (14% vs 9%), fatigue (13% vs 11%), and abdominal pain (12% vs 9%).
The cardiac adverse event rate (regardless of investigator-assessed causality) was 13% in the letermovir arm and 6% in the placebo arm. The most common cardiac adverse events (in the letermovir and placebo arms, respectively) were tachycardia (4% vs 2%) and atrial fibrillation (3% vs 1%).
Results from this trial were presented at the 2017 BMT Tandem Meetings.
The US Food and Drug Administration (FDA) has approved the oral and intravenous formulations of letermovir (PREVYMIS™).
Letermovir is a member of a new class of non-nucleoside CMV inhibitors known as 3,4 dihydro-quinazolines.
The FDA approved letermovir as prophylaxis for cytomegalovirus (CMV) infection and disease in adult recipients of allogeneic hematopoietic stem cell transplants (HSCTs) who are CMV-seropositive.
“PREVYMIS is the first new medicine for CMV infection approved in the US in 15 years,” said Roy Baynes, senior vice president, head of clinical development, and chief medical officer of Merck Research Laboratories, the company marketing letermovir.
Letermovir is expected to be available in December. The list price (wholesaler acquisition cost) per day is $195.00 for letermovir tablets and $270.00 for letermovir injections. (Wholesaler acquisition costs do not include discounts that may be paid on the product.)
The recommended dosage of letermovir is 480 mg once daily, initiated as early as day 0 and up to day 28 post-transplant (before or after engraftment) and continued through day 100. If letermovir is co-administered with cyclosporine, the dosage of letermovir should be decreased to 240 mg once daily.
Letermovir is available as 240 mg and 480 mg tablets, which may be administered with or without food. Letermovir is also available as a 240 mg and 480 mg injection for intravenous infusion via a peripheral catheter or central venous line at a constant rate over 1 hour.
For more details on letermovir, see the full prescribing information.
Trial results
The FDA’s approval of letermovir was supported by results of a phase 3 trial of adult recipients of allogeneic HSCTs who were CMV-seropositive. Patients were randomized (2:1) to receive either letermovir (at a dose of 480 mg once-daily, adjusted to 240 mg when co-administered with cyclosporine) or placebo.
Study drug was initiated after HSCT (at any time from day 0 to 28 post-transplant) and continued through week 14 post-transplant. Patients were monitored through week 24 post-HSCT for the primary efficacy endpoint, with continued follow-up through week 48.
Among the 565 treated patients, 34% were engrafted at baseline, and 30% had one or more factors associated with additional risk for CMV reactivation. The most common primary reasons for transplant were acute myeloid leukemia (38%), myelodysplastic syndromes (16%), and lymphoma (12%).
Thirty eight percent of patients in the letermovir arm and 61% in the placebo arm failed prophylaxis.
Reasons for failure (in the letermovir and placebo arms, respectively) included:
- Clinically significant CMV infection—18% vs 42%
- Initiation of PET based on documented CMV viremia—16% vs 40%
- CMV end-organ disease—2% for both
- Study discontinuation before week 24—17% vs 16%
- Missing outcome in week 24 visit window—3% for both.
The stratum-adjusted treatment difference for letermovir vs placebo was -23.5 (95% CI, -32.5, -14.6, P<0.0001).
The Kaplan-Meier event rate for all-cause mortality in the letermovir and placebo arms, respectively, was 12% and 17% at week 24 and 24% and 28% at week 48.
Common adverse events (in the letermovir and placebo arms, respectively) were nausea (27% vs 23%), diarrhea (26% vs 24%), vomiting (19% vs 14%), peripheral edema (14% vs 9%), cough (14% vs 10%), headache (14% vs 9%), fatigue (13% vs 11%), and abdominal pain (12% vs 9%).
The cardiac adverse event rate (regardless of investigator-assessed causality) was 13% in the letermovir arm and 6% in the placebo arm. The most common cardiac adverse events (in the letermovir and placebo arms, respectively) were tachycardia (4% vs 2%) and atrial fibrillation (3% vs 1%).
Results from this trial were presented at the 2017 BMT Tandem Meetings.
Protein may be target for enhancing HSC transplants
Targeting the protein Del-1 could potentially improve hematopoietic stem cell (HSC) transplants, according to researchers.
The team found that Del-1 promoted engraftment in murine transplant recipients, but the protein also promoted the retention of hematopoietic progenitors in the bone marrow of mice that received granulocyte colony-stimulating factor (G-CSF).
The researchers therefore believe that enhancing Del-1 in HSC transplant recipients might improve engraftment.
And inhibiting Del-1 could increase progenitor mobilization in transplant donors.
The researchers detailed these findings and theories in The Journal of Clinical Investigation.
“Because the hematopoietic stem cell niche is so important for the creation of bone marrow and blood cells and because Del-1 is a soluble protein and easily manipulated, one can see that it could be a target in many potential applications,” said study author George Hajishengallis, DDS, PhD, of Penn Dental Medicine in Philadelphia, Pennsylvania.
For Dr Hajishengallis, the route to studying Del-1 in the bone marrow began in his field of dental medicine.
Dr Hajishengallis and Triantafyllos Chavakis, Dr med, of Technische Universität Dresden in Germany, identified Del-1 as a potential drug target for gum disease. (Del-1 prevents inflammatory cells from moving into the gums.)
Both of the researchers’ labs also discovered that Del-1 is expressed in bone marrow, so the groups began following up to examine the protein’s function there.
Their work revealed that Del-1 is a key regulator of the HSC niche.
Del-1 is expressed by cells that promote HSC maintenance under steady-state conditions. This includes arteriolar endothelial cells, CXCL12-abundant reticular cells, and cells of the osteoblastic lineage.
The researchers also found that Del-1 regulates long-term HSC proliferation and differentiation toward the myeloid lineage.
In mice that received HSC transplants, Del-1 promoted progenitor engraftment and the generation of both progenitors and mature myeloid cells. The researchers noted that this was dependent upon β3 integrin expression in hematopoietic cells.
The team also found that Del-1 promotes hematopoietic progenitors’ response to systemic inflammation (induced by lipopolysaccharide). And the protein promotes the retention of hematopoietic progenitors in the bone marrow after G-CSF administration.
Taken together, these findings suggest that manipulating Del-1 might enhance HSC transplants.
“It’s easy to think of practical applications,” Dr Hajishengallis said. “Now, we need to find out whether it works in practice, so our studies continue.”
Targeting the protein Del-1 could potentially improve hematopoietic stem cell (HSC) transplants, according to researchers.
The team found that Del-1 promoted engraftment in murine transplant recipients, but the protein also promoted the retention of hematopoietic progenitors in the bone marrow of mice that received granulocyte colony-stimulating factor (G-CSF).
The researchers therefore believe that enhancing Del-1 in HSC transplant recipients might improve engraftment.
And inhibiting Del-1 could increase progenitor mobilization in transplant donors.
The researchers detailed these findings and theories in The Journal of Clinical Investigation.
“Because the hematopoietic stem cell niche is so important for the creation of bone marrow and blood cells and because Del-1 is a soluble protein and easily manipulated, one can see that it could be a target in many potential applications,” said study author George Hajishengallis, DDS, PhD, of Penn Dental Medicine in Philadelphia, Pennsylvania.
For Dr Hajishengallis, the route to studying Del-1 in the bone marrow began in his field of dental medicine.
Dr Hajishengallis and Triantafyllos Chavakis, Dr med, of Technische Universität Dresden in Germany, identified Del-1 as a potential drug target for gum disease. (Del-1 prevents inflammatory cells from moving into the gums.)
Both of the researchers’ labs also discovered that Del-1 is expressed in bone marrow, so the groups began following up to examine the protein’s function there.
Their work revealed that Del-1 is a key regulator of the HSC niche.
Del-1 is expressed by cells that promote HSC maintenance under steady-state conditions. This includes arteriolar endothelial cells, CXCL12-abundant reticular cells, and cells of the osteoblastic lineage.
The researchers also found that Del-1 regulates long-term HSC proliferation and differentiation toward the myeloid lineage.
In mice that received HSC transplants, Del-1 promoted progenitor engraftment and the generation of both progenitors and mature myeloid cells. The researchers noted that this was dependent upon β3 integrin expression in hematopoietic cells.
The team also found that Del-1 promotes hematopoietic progenitors’ response to systemic inflammation (induced by lipopolysaccharide). And the protein promotes the retention of hematopoietic progenitors in the bone marrow after G-CSF administration.
Taken together, these findings suggest that manipulating Del-1 might enhance HSC transplants.
“It’s easy to think of practical applications,” Dr Hajishengallis said. “Now, we need to find out whether it works in practice, so our studies continue.”
Targeting the protein Del-1 could potentially improve hematopoietic stem cell (HSC) transplants, according to researchers.
The team found that Del-1 promoted engraftment in murine transplant recipients, but the protein also promoted the retention of hematopoietic progenitors in the bone marrow of mice that received granulocyte colony-stimulating factor (G-CSF).
The researchers therefore believe that enhancing Del-1 in HSC transplant recipients might improve engraftment.
And inhibiting Del-1 could increase progenitor mobilization in transplant donors.
The researchers detailed these findings and theories in The Journal of Clinical Investigation.
“Because the hematopoietic stem cell niche is so important for the creation of bone marrow and blood cells and because Del-1 is a soluble protein and easily manipulated, one can see that it could be a target in many potential applications,” said study author George Hajishengallis, DDS, PhD, of Penn Dental Medicine in Philadelphia, Pennsylvania.
For Dr Hajishengallis, the route to studying Del-1 in the bone marrow began in his field of dental medicine.
Dr Hajishengallis and Triantafyllos Chavakis, Dr med, of Technische Universität Dresden in Germany, identified Del-1 as a potential drug target for gum disease. (Del-1 prevents inflammatory cells from moving into the gums.)
Both of the researchers’ labs also discovered that Del-1 is expressed in bone marrow, so the groups began following up to examine the protein’s function there.
Their work revealed that Del-1 is a key regulator of the HSC niche.
Del-1 is expressed by cells that promote HSC maintenance under steady-state conditions. This includes arteriolar endothelial cells, CXCL12-abundant reticular cells, and cells of the osteoblastic lineage.
The researchers also found that Del-1 regulates long-term HSC proliferation and differentiation toward the myeloid lineage.
In mice that received HSC transplants, Del-1 promoted progenitor engraftment and the generation of both progenitors and mature myeloid cells. The researchers noted that this was dependent upon β3 integrin expression in hematopoietic cells.
The team also found that Del-1 promotes hematopoietic progenitors’ response to systemic inflammation (induced by lipopolysaccharide). And the protein promotes the retention of hematopoietic progenitors in the bone marrow after G-CSF administration.
Taken together, these findings suggest that manipulating Del-1 might enhance HSC transplants.
“It’s easy to think of practical applications,” Dr Hajishengallis said. “Now, we need to find out whether it works in practice, so our studies continue.”
Team identifies HSCs that rapidly reconstitute hematopoiesis
Researchers say they have identified a subpopulation of hematopoietic stem cells (HSCs) that immediately contributes to long-term, multilineage hematopoietic reconstitution after transplant.
These HSCs were discovered in macaques, but the cells are similar to a subset of HSCs found in humans.
The researchers found the 2 sets of cells behaved identically when tested in vitro.
The team believes their findings will increase the efficiency of future efforts for HSC transplants, gene therapies, and gene editing.
Hans-Peter Kiem, MD, PhD, of the Fred Hutchinson Cancer Research Center in Seattle, Washington, and his colleagues reported these findings in Science Translational Medicine.
The researchers performed HSC transplants in pig-tailed macaques, following hundreds of thousands of cells immediately after transplant and over the course of 7.5 years.
Previous reports had suggested that successive waves of progenitor cells expand and contract to establish the new bone marrow after transplant.
However, Dr Kiem and his colleagues homed in on a distinct group of HSCs that took hold early after transplant and went on to produce all cell lineages that constitute a complete blood system.
“These findings came as a surprise,” Dr Kiem said. “We had thought that there were multiple types of blood stem cells that take on different roles in rebuilding a blood and immune system. This population does it all.”
The population is a subset of CD34+ cells expressing CD90 and lacking CD45RA markers.
“The gold standard target cell population for stem cell gene therapy are cells with the marker CD34,” said study author Stefan Radtke, PhD, of the Fred Hutchinson Cancer Research Center.
“But we used 2 additional markers to further distinguish the population from the other blood stem cells.”
The researchers noted that the CD34+ CD45RA- CD90+ HSCs started repopulating the hematopoietic system within 10 days of being infused in macaques undergoing transplant.
A year later, the researchers found strong molecular traces of the cells, suggesting they were responsible for the ongoing maintenance of the newly transplanted system.
The team also determined the minimum numbers of CD34+ CD45RA- CD90+ HSCs that were necessary for successful transplant (defined as sustained neutrophil and platelet recovery).
And the researchers found similar gene expression profiles between macaque and human CD34+ CD45RA- CD90+ HSCs.
The team therefore believes these findings could have implications for HSC transplants in humans.
The researchers are now working to move their findings into the clinic with the hopes of integrating them in ongoing clinical trials. The team is currently looking for commercial partners.
Researchers say they have identified a subpopulation of hematopoietic stem cells (HSCs) that immediately contributes to long-term, multilineage hematopoietic reconstitution after transplant.
These HSCs were discovered in macaques, but the cells are similar to a subset of HSCs found in humans.
The researchers found the 2 sets of cells behaved identically when tested in vitro.
The team believes their findings will increase the efficiency of future efforts for HSC transplants, gene therapies, and gene editing.
Hans-Peter Kiem, MD, PhD, of the Fred Hutchinson Cancer Research Center in Seattle, Washington, and his colleagues reported these findings in Science Translational Medicine.
The researchers performed HSC transplants in pig-tailed macaques, following hundreds of thousands of cells immediately after transplant and over the course of 7.5 years.
Previous reports had suggested that successive waves of progenitor cells expand and contract to establish the new bone marrow after transplant.
However, Dr Kiem and his colleagues homed in on a distinct group of HSCs that took hold early after transplant and went on to produce all cell lineages that constitute a complete blood system.
“These findings came as a surprise,” Dr Kiem said. “We had thought that there were multiple types of blood stem cells that take on different roles in rebuilding a blood and immune system. This population does it all.”
The population is a subset of CD34+ cells expressing CD90 and lacking CD45RA markers.
“The gold standard target cell population for stem cell gene therapy are cells with the marker CD34,” said study author Stefan Radtke, PhD, of the Fred Hutchinson Cancer Research Center.
“But we used 2 additional markers to further distinguish the population from the other blood stem cells.”
The researchers noted that the CD34+ CD45RA- CD90+ HSCs started repopulating the hematopoietic system within 10 days of being infused in macaques undergoing transplant.
A year later, the researchers found strong molecular traces of the cells, suggesting they were responsible for the ongoing maintenance of the newly transplanted system.
The team also determined the minimum numbers of CD34+ CD45RA- CD90+ HSCs that were necessary for successful transplant (defined as sustained neutrophil and platelet recovery).
And the researchers found similar gene expression profiles between macaque and human CD34+ CD45RA- CD90+ HSCs.
The team therefore believes these findings could have implications for HSC transplants in humans.
The researchers are now working to move their findings into the clinic with the hopes of integrating them in ongoing clinical trials. The team is currently looking for commercial partners.
Researchers say they have identified a subpopulation of hematopoietic stem cells (HSCs) that immediately contributes to long-term, multilineage hematopoietic reconstitution after transplant.
These HSCs were discovered in macaques, but the cells are similar to a subset of HSCs found in humans.
The researchers found the 2 sets of cells behaved identically when tested in vitro.
The team believes their findings will increase the efficiency of future efforts for HSC transplants, gene therapies, and gene editing.
Hans-Peter Kiem, MD, PhD, of the Fred Hutchinson Cancer Research Center in Seattle, Washington, and his colleagues reported these findings in Science Translational Medicine.
The researchers performed HSC transplants in pig-tailed macaques, following hundreds of thousands of cells immediately after transplant and over the course of 7.5 years.
Previous reports had suggested that successive waves of progenitor cells expand and contract to establish the new bone marrow after transplant.
However, Dr Kiem and his colleagues homed in on a distinct group of HSCs that took hold early after transplant and went on to produce all cell lineages that constitute a complete blood system.
“These findings came as a surprise,” Dr Kiem said. “We had thought that there were multiple types of blood stem cells that take on different roles in rebuilding a blood and immune system. This population does it all.”
The population is a subset of CD34+ cells expressing CD90 and lacking CD45RA markers.
“The gold standard target cell population for stem cell gene therapy are cells with the marker CD34,” said study author Stefan Radtke, PhD, of the Fred Hutchinson Cancer Research Center.
“But we used 2 additional markers to further distinguish the population from the other blood stem cells.”
The researchers noted that the CD34+ CD45RA- CD90+ HSCs started repopulating the hematopoietic system within 10 days of being infused in macaques undergoing transplant.
A year later, the researchers found strong molecular traces of the cells, suggesting they were responsible for the ongoing maintenance of the newly transplanted system.
The team also determined the minimum numbers of CD34+ CD45RA- CD90+ HSCs that were necessary for successful transplant (defined as sustained neutrophil and platelet recovery).
And the researchers found similar gene expression profiles between macaque and human CD34+ CD45RA- CD90+ HSCs.
The team therefore believes these findings could have implications for HSC transplants in humans.
The researchers are now working to move their findings into the clinic with the hopes of integrating them in ongoing clinical trials. The team is currently looking for commercial partners.
Ibrutinib approved to treat cGVHD in Canada
Health Canada has approved the BTK inhibitor ibrutinib (IMBRUVICA®) for the treatment of patients with steroid-dependent or -refractory chronic graft-versus-host disease (cGVHD).
This is the sixth approval for ibrutinib in Canada.
The drug is approved as monotherapy for patients with previously untreated chronic lymphocytic leukemia (CLL), CLL patients who have received at least 1 prior therapy, patients with Waldenström’s macroglobulinemia, and patients with relapsed or refractory mantle cell lymphoma.
Ibrutinib is also approved for use in combination with bendamustine and rituximab for the treatment of CLL patients who have received at least 1 prior therapy.
Ibrutinib is co-developed by Cilag GmbH International (a member of the Janssen Pharmaceutical Companies) and Pharmacyclics LLC, an AbbVie company. Janssen Inc. markets ibrutinib in Canada.
The approval of ibrutinib to treat cGVHD is based on results of a phase 2 trial, which were presented at the 2016 ASH Annual Meeting.
The trial included 42 patients with a median age of 56 (range, 19 to 74). The most common underlying malignancies that led to patients’ transplants were acute lymphocytic leukemia, acute myeloid leukemia, and CLL.
At baseline, the patients had persistent cGVHD symptoms despite receiving standard treatment with corticosteroids. Most patients’ symptoms included mouth ulcers and skin rashes, and more than 50% had 2 or more organs affected by cGVHD.
The median time since cGVHD diagnosis was 14 months, the median number of prior cGVHD treatments was 2 (range, 1 to 3), and 60% of patients had a Karnofsky performance score of ≤ 80.
Fifty-two percent of patients were receiving ongoing immunosuppressants and systemic corticosteroids at baseline.
Sixty-seven percent of patients responded to treatment with ibrutinib, and 21% had a complete response. In 48% of patients, responses lasted for 5 months or longer. Responses were seen across all organs affected by cGVHD (ie, skin, mouth, gastrointestinal tract, and liver).
The patients’ median steroid dose was reduced over time, from 0.31 mg/kg/day at baseline to 0.14 mg/kg/day at week 48. Five patients were able to completely discontinue corticosteroids while in response.
The most common (≥20%) adverse events (AEs) of all grades were fatigue (57%), bruising (40%), diarrhea (36%), stomatitis (29%), muscle spasms (29%), nausea (26%), hemorrhage (26%), and pneumonia (21%).
Atrial fibrillation (grade 3) occurred in 1 patient (2%). Serious AEs occurred in 52% of patients. The most common serious AEs (2 or more patients) were pneumonia, sepsis (septic shock), cellulitis, headache, and pyrexia.
There were 2 fatal events, a case of pneumonia and a case of pulmonary aspergillosis.
Twenty-four percent of patients discontinued ibrutinib due to AEs. The most common AEs leading to discontinuation were fatigue and pneumonia. AEs leading to dose reductions occurred in 26% of patients.
The recommended dose of ibrutinib for cGVHD is 420 mg (three 140 mg capsules) once daily.
Health Canada has approved the BTK inhibitor ibrutinib (IMBRUVICA®) for the treatment of patients with steroid-dependent or -refractory chronic graft-versus-host disease (cGVHD).
This is the sixth approval for ibrutinib in Canada.
The drug is approved as monotherapy for patients with previously untreated chronic lymphocytic leukemia (CLL), CLL patients who have received at least 1 prior therapy, patients with Waldenström’s macroglobulinemia, and patients with relapsed or refractory mantle cell lymphoma.
Ibrutinib is also approved for use in combination with bendamustine and rituximab for the treatment of CLL patients who have received at least 1 prior therapy.
Ibrutinib is co-developed by Cilag GmbH International (a member of the Janssen Pharmaceutical Companies) and Pharmacyclics LLC, an AbbVie company. Janssen Inc. markets ibrutinib in Canada.
The approval of ibrutinib to treat cGVHD is based on results of a phase 2 trial, which were presented at the 2016 ASH Annual Meeting.
The trial included 42 patients with a median age of 56 (range, 19 to 74). The most common underlying malignancies that led to patients’ transplants were acute lymphocytic leukemia, acute myeloid leukemia, and CLL.
At baseline, the patients had persistent cGVHD symptoms despite receiving standard treatment with corticosteroids. Most patients’ symptoms included mouth ulcers and skin rashes, and more than 50% had 2 or more organs affected by cGVHD.
The median time since cGVHD diagnosis was 14 months, the median number of prior cGVHD treatments was 2 (range, 1 to 3), and 60% of patients had a Karnofsky performance score of ≤ 80.
Fifty-two percent of patients were receiving ongoing immunosuppressants and systemic corticosteroids at baseline.
Sixty-seven percent of patients responded to treatment with ibrutinib, and 21% had a complete response. In 48% of patients, responses lasted for 5 months or longer. Responses were seen across all organs affected by cGVHD (ie, skin, mouth, gastrointestinal tract, and liver).
The patients’ median steroid dose was reduced over time, from 0.31 mg/kg/day at baseline to 0.14 mg/kg/day at week 48. Five patients were able to completely discontinue corticosteroids while in response.
The most common (≥20%) adverse events (AEs) of all grades were fatigue (57%), bruising (40%), diarrhea (36%), stomatitis (29%), muscle spasms (29%), nausea (26%), hemorrhage (26%), and pneumonia (21%).
Atrial fibrillation (grade 3) occurred in 1 patient (2%). Serious AEs occurred in 52% of patients. The most common serious AEs (2 or more patients) were pneumonia, sepsis (septic shock), cellulitis, headache, and pyrexia.
There were 2 fatal events, a case of pneumonia and a case of pulmonary aspergillosis.
Twenty-four percent of patients discontinued ibrutinib due to AEs. The most common AEs leading to discontinuation were fatigue and pneumonia. AEs leading to dose reductions occurred in 26% of patients.
The recommended dose of ibrutinib for cGVHD is 420 mg (three 140 mg capsules) once daily.
Health Canada has approved the BTK inhibitor ibrutinib (IMBRUVICA®) for the treatment of patients with steroid-dependent or -refractory chronic graft-versus-host disease (cGVHD).
This is the sixth approval for ibrutinib in Canada.
The drug is approved as monotherapy for patients with previously untreated chronic lymphocytic leukemia (CLL), CLL patients who have received at least 1 prior therapy, patients with Waldenström’s macroglobulinemia, and patients with relapsed or refractory mantle cell lymphoma.
Ibrutinib is also approved for use in combination with bendamustine and rituximab for the treatment of CLL patients who have received at least 1 prior therapy.
Ibrutinib is co-developed by Cilag GmbH International (a member of the Janssen Pharmaceutical Companies) and Pharmacyclics LLC, an AbbVie company. Janssen Inc. markets ibrutinib in Canada.
The approval of ibrutinib to treat cGVHD is based on results of a phase 2 trial, which were presented at the 2016 ASH Annual Meeting.
The trial included 42 patients with a median age of 56 (range, 19 to 74). The most common underlying malignancies that led to patients’ transplants were acute lymphocytic leukemia, acute myeloid leukemia, and CLL.
At baseline, the patients had persistent cGVHD symptoms despite receiving standard treatment with corticosteroids. Most patients’ symptoms included mouth ulcers and skin rashes, and more than 50% had 2 or more organs affected by cGVHD.
The median time since cGVHD diagnosis was 14 months, the median number of prior cGVHD treatments was 2 (range, 1 to 3), and 60% of patients had a Karnofsky performance score of ≤ 80.
Fifty-two percent of patients were receiving ongoing immunosuppressants and systemic corticosteroids at baseline.
Sixty-seven percent of patients responded to treatment with ibrutinib, and 21% had a complete response. In 48% of patients, responses lasted for 5 months or longer. Responses were seen across all organs affected by cGVHD (ie, skin, mouth, gastrointestinal tract, and liver).
The patients’ median steroid dose was reduced over time, from 0.31 mg/kg/day at baseline to 0.14 mg/kg/day at week 48. Five patients were able to completely discontinue corticosteroids while in response.
The most common (≥20%) adverse events (AEs) of all grades were fatigue (57%), bruising (40%), diarrhea (36%), stomatitis (29%), muscle spasms (29%), nausea (26%), hemorrhage (26%), and pneumonia (21%).
Atrial fibrillation (grade 3) occurred in 1 patient (2%). Serious AEs occurred in 52% of patients. The most common serious AEs (2 or more patients) were pneumonia, sepsis (septic shock), cellulitis, headache, and pyrexia.
There were 2 fatal events, a case of pneumonia and a case of pulmonary aspergillosis.
Twenty-four percent of patients discontinued ibrutinib due to AEs. The most common AEs leading to discontinuation were fatigue and pneumonia. AEs leading to dose reductions occurred in 26% of patients.
The recommended dose of ibrutinib for cGVHD is 420 mg (three 140 mg capsules) once daily.
Therapy receives rare pediatric disease designation
The US Food and Drug Administration (FDA) has granted rare pediatric disease designation to ATA230 for the treatment of congenital cytomegalovirus (CMV) infection.
ATA230 is an allogeneic T-cell immunotherapy targeting antigens expressed by CMV.
Rare pediatric disease designation is granted to drugs that show promise to treat orphan diseases affecting fewer than 200,000 patients in the US, primarily patients age 18 and younger.
The designation provides incentives to advance the development of drugs for rare disease, including access to the FDA’s expedited review and approval programs.
Under the FDA’s Rare Pediatric Disease Priority Review Voucher Program, a drug developer with rare pediatric disease designation that receives an approval of a new drug application is eligible for a voucher that can be redeemed to obtain priority review for any subsequent marketing application.
The company developing ATA230 is Atara Biotherapeutics, Inc. The company also received orphan designation for ATA230.
ATA230 trials
ATA230 has been investigated in phase 1 and 2 studies of immunocompromised patients with CMV viremia or disease who are refractory or resistant to antiviral drug treatment in the post-transplant setting.
Researchers reported phase 2 results with ATA230 at the 2016 ASH Annual Meeting.
The data encompassed 15 patients with documented CMV mutations conferring resistance to antiviral therapies. The patients had received a median of 3 prior therapies.
Eleven of the 15 patients (73.3%) responded to ATA230, 6 with complete responses and 5 with partial responses.
At 6 months, the overall survival was 72.7% in responders and 25% in non-responders.
Within the 6 months of follow-up, 1 of the 11 responders died of CMV, and 3 of the 4 non-responders died of CMV.
Adverse events occurred in 6 patients. One grade 3 event and 1 grade 4 event were considered possibly related to ATA230.
The US Food and Drug Administration (FDA) has granted rare pediatric disease designation to ATA230 for the treatment of congenital cytomegalovirus (CMV) infection.
ATA230 is an allogeneic T-cell immunotherapy targeting antigens expressed by CMV.
Rare pediatric disease designation is granted to drugs that show promise to treat orphan diseases affecting fewer than 200,000 patients in the US, primarily patients age 18 and younger.
The designation provides incentives to advance the development of drugs for rare disease, including access to the FDA’s expedited review and approval programs.
Under the FDA’s Rare Pediatric Disease Priority Review Voucher Program, a drug developer with rare pediatric disease designation that receives an approval of a new drug application is eligible for a voucher that can be redeemed to obtain priority review for any subsequent marketing application.
The company developing ATA230 is Atara Biotherapeutics, Inc. The company also received orphan designation for ATA230.
ATA230 trials
ATA230 has been investigated in phase 1 and 2 studies of immunocompromised patients with CMV viremia or disease who are refractory or resistant to antiviral drug treatment in the post-transplant setting.
Researchers reported phase 2 results with ATA230 at the 2016 ASH Annual Meeting.
The data encompassed 15 patients with documented CMV mutations conferring resistance to antiviral therapies. The patients had received a median of 3 prior therapies.
Eleven of the 15 patients (73.3%) responded to ATA230, 6 with complete responses and 5 with partial responses.
At 6 months, the overall survival was 72.7% in responders and 25% in non-responders.
Within the 6 months of follow-up, 1 of the 11 responders died of CMV, and 3 of the 4 non-responders died of CMV.
Adverse events occurred in 6 patients. One grade 3 event and 1 grade 4 event were considered possibly related to ATA230.
The US Food and Drug Administration (FDA) has granted rare pediatric disease designation to ATA230 for the treatment of congenital cytomegalovirus (CMV) infection.
ATA230 is an allogeneic T-cell immunotherapy targeting antigens expressed by CMV.
Rare pediatric disease designation is granted to drugs that show promise to treat orphan diseases affecting fewer than 200,000 patients in the US, primarily patients age 18 and younger.
The designation provides incentives to advance the development of drugs for rare disease, including access to the FDA’s expedited review and approval programs.
Under the FDA’s Rare Pediatric Disease Priority Review Voucher Program, a drug developer with rare pediatric disease designation that receives an approval of a new drug application is eligible for a voucher that can be redeemed to obtain priority review for any subsequent marketing application.
The company developing ATA230 is Atara Biotherapeutics, Inc. The company also received orphan designation for ATA230.
ATA230 trials
ATA230 has been investigated in phase 1 and 2 studies of immunocompromised patients with CMV viremia or disease who are refractory or resistant to antiviral drug treatment in the post-transplant setting.
Researchers reported phase 2 results with ATA230 at the 2016 ASH Annual Meeting.
The data encompassed 15 patients with documented CMV mutations conferring resistance to antiviral therapies. The patients had received a median of 3 prior therapies.
Eleven of the 15 patients (73.3%) responded to ATA230, 6 with complete responses and 5 with partial responses.
At 6 months, the overall survival was 72.7% in responders and 25% in non-responders.
Within the 6 months of follow-up, 1 of the 11 responders died of CMV, and 3 of the 4 non-responders died of CMV.
Adverse events occurred in 6 patients. One grade 3 event and 1 grade 4 event were considered possibly related to ATA230.