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Predicting outcomes in relapsed BCP-ALL
Image by Vashi Donsk
Screening for genetic abnormalities can provide a more accurate prediction of outcomes in children with relapsed B-cell precursor acute lymphoblastic leukemia (BCP-ALL), according to a study published in Blood.
Researchers found that mutations or deletions in TP53, NR3C1, BTG1, and NRAS were associated with inferior outcomes in relapsed BCP-ALL.
And screening for these abnormalities could improve upon the predictive accuracy of clinical risk factors.
“Current methods used to guide treatment for relapsed leukemia are not accurate enough, with some children believed to have a good chance of survival actually responding very poorly to chemotherapy,” said study author Anthony Moorman, PhD, of Newcastle University in Newcastle upon Tyne, UK.
“Screening patients at relapse for key genetic abnormalities that influence outcome will ensure that treatment can be personalized, thereby improving their chances of survival.”
For this study, Dr Moorman and his colleagues analyzed cytogenetic data from 427 children with relapsed BCP-ALL and screened 238 patients with a marrow relapse for certain copy number alterations and mutations.
According to univariate analysis, alterations in TP53, NR3C1 deletions, and BTG1 deletions were significantly associated with patient outcomes.
Patients with TP53 alterations had a higher risk of progression (hazard ratio [HR]=2.36, P<0.001) and death (HR=2.56, P<0.001), as did patients with deletions in NR3C1 and BTG1.
Because both NR3C1 and BTG1 are implicated in resistance to glucocorticoids and the deletions are mutually exclusive, the researchers considered the effect of the deletions together. So for patients with NR3C1 and BTG1 deletions, the HR for progression was 2.15 (P=0.002), and the HR for death was 1.91 (P=0.015).
Patients with NRAS mutations had an increased risk of progression and death as well, but this did not reach statistical significance.
The researchers also found that patients who were standard risk according to clinical characteristics but, at the time of relapse, had one or more high-risk genetic abnormalities had poorer outcomes.
Standard-risk patients with a TP53 alteration had an increased risk of death (HR=2.56, P<0.001), as did standard-risk patients with NR3C1 and BTG1 deletions (HR=1.91, P=0.015).
Standard-risk patients with NRAS mutations and high hyperdiploidy had an increased risk of progression (HR=3.17, P=0.026) and death (HR=3.41, P=0.032).
The researchers concluded that the outcomes of clinical standard-risk patients with high-risk cytogenetics were equivalent to outcomes of clinical high-risk patients.
The team therefore believes that screening BCP-ALL patients for the aforementioned genetic abnormalities at relapse will improve patient stratification and outcomes. 
Image by Vashi Donsk
Screening for genetic abnormalities can provide a more accurate prediction of outcomes in children with relapsed B-cell precursor acute lymphoblastic leukemia (BCP-ALL), according to a study published in Blood.
Researchers found that mutations or deletions in TP53, NR3C1, BTG1, and NRAS were associated with inferior outcomes in relapsed BCP-ALL.
And screening for these abnormalities could improve upon the predictive accuracy of clinical risk factors.
“Current methods used to guide treatment for relapsed leukemia are not accurate enough, with some children believed to have a good chance of survival actually responding very poorly to chemotherapy,” said study author Anthony Moorman, PhD, of Newcastle University in Newcastle upon Tyne, UK.
“Screening patients at relapse for key genetic abnormalities that influence outcome will ensure that treatment can be personalized, thereby improving their chances of survival.”
For this study, Dr Moorman and his colleagues analyzed cytogenetic data from 427 children with relapsed BCP-ALL and screened 238 patients with a marrow relapse for certain copy number alterations and mutations.
According to univariate analysis, alterations in TP53, NR3C1 deletions, and BTG1 deletions were significantly associated with patient outcomes.
Patients with TP53 alterations had a higher risk of progression (hazard ratio [HR]=2.36, P<0.001) and death (HR=2.56, P<0.001), as did patients with deletions in NR3C1 and BTG1.
Because both NR3C1 and BTG1 are implicated in resistance to glucocorticoids and the deletions are mutually exclusive, the researchers considered the effect of the deletions together. So for patients with NR3C1 and BTG1 deletions, the HR for progression was 2.15 (P=0.002), and the HR for death was 1.91 (P=0.015).
Patients with NRAS mutations had an increased risk of progression and death as well, but this did not reach statistical significance.
The researchers also found that patients who were standard risk according to clinical characteristics but, at the time of relapse, had one or more high-risk genetic abnormalities had poorer outcomes.
Standard-risk patients with a TP53 alteration had an increased risk of death (HR=2.56, P<0.001), as did standard-risk patients with NR3C1 and BTG1 deletions (HR=1.91, P=0.015).
Standard-risk patients with NRAS mutations and high hyperdiploidy had an increased risk of progression (HR=3.17, P=0.026) and death (HR=3.41, P=0.032).
The researchers concluded that the outcomes of clinical standard-risk patients with high-risk cytogenetics were equivalent to outcomes of clinical high-risk patients.
The team therefore believes that screening BCP-ALL patients for the aforementioned genetic abnormalities at relapse will improve patient stratification and outcomes.
Image by Vashi Donsk
Screening for genetic abnormalities can provide a more accurate prediction of outcomes in children with relapsed B-cell precursor acute lymphoblastic leukemia (BCP-ALL), according to a study published in Blood.
Researchers found that mutations or deletions in TP53, NR3C1, BTG1, and NRAS were associated with inferior outcomes in relapsed BCP-ALL.
And screening for these abnormalities could improve upon the predictive accuracy of clinical risk factors.
“Current methods used to guide treatment for relapsed leukemia are not accurate enough, with some children believed to have a good chance of survival actually responding very poorly to chemotherapy,” said study author Anthony Moorman, PhD, of Newcastle University in Newcastle upon Tyne, UK.
“Screening patients at relapse for key genetic abnormalities that influence outcome will ensure that treatment can be personalized, thereby improving their chances of survival.”
For this study, Dr Moorman and his colleagues analyzed cytogenetic data from 427 children with relapsed BCP-ALL and screened 238 patients with a marrow relapse for certain copy number alterations and mutations.
According to univariate analysis, alterations in TP53, NR3C1 deletions, and BTG1 deletions were significantly associated with patient outcomes.
Patients with TP53 alterations had a higher risk of progression (hazard ratio [HR]=2.36, P<0.001) and death (HR=2.56, P<0.001), as did patients with deletions in NR3C1 and BTG1.
Because both NR3C1 and BTG1 are implicated in resistance to glucocorticoids and the deletions are mutually exclusive, the researchers considered the effect of the deletions together. So for patients with NR3C1 and BTG1 deletions, the HR for progression was 2.15 (P=0.002), and the HR for death was 1.91 (P=0.015).
Patients with NRAS mutations had an increased risk of progression and death as well, but this did not reach statistical significance.
The researchers also found that patients who were standard risk according to clinical characteristics but, at the time of relapse, had one or more high-risk genetic abnormalities had poorer outcomes.
Standard-risk patients with a TP53 alteration had an increased risk of death (HR=2.56, P<0.001), as did standard-risk patients with NR3C1 and BTG1 deletions (HR=1.91, P=0.015).
Standard-risk patients with NRAS mutations and high hyperdiploidy had an increased risk of progression (HR=3.17, P=0.026) and death (HR=3.41, P=0.032).
The researchers concluded that the outcomes of clinical standard-risk patients with high-risk cytogenetics were equivalent to outcomes of clinical high-risk patients.
The team therefore believes that screening BCP-ALL patients for the aforementioned genetic abnormalities at relapse will improve patient stratification and outcomes.
Apparent Zika transmission via platelet transfusion
Photo from Flickr
Researchers have reported 2 cases in which the Zika virus seems to have been transmitted via platelet transfusion.
Brazilian health officials previously announced 2 cases of Zika virus—in a liver transplant recipient and a gunshot victim—that likely resulted from blood transfusions performed in 2015.
Now, researchers have reported possible transmission via transfusion in 2 more Brazilians—a patient with primary myelofibrosis (PMF) and one with acute myeloid leukemia (AML).
The researchers described these cases in a letter to NEJM.
An individual who donated platelets via apheresis on January 16, 2016, later tested positive for the Zika virus.
On January 19, platelets from that donor were transfused into a 54-year-old woman with PMF and a 14-year-old girl with AML who had also received a haploidentical bone marrow transplant on January 6.
The platelet donor called the blood bank on January 21 to report worrying symptoms—a cutaneous rash, retro-orbital pain, and pain in both knees—that had developed on January 18.
Subsequent testing revealed that the donor was negative for chikungunya and dengue virus. However, both plasma and urine samples tested positive for Zika virus.
Pre-transfusion samples collected from both of the recipients were negative for chikungunya, dengue, and Zika. However, samples collected after the transfusions—6 days after for the woman with PMF and 23 to 51 days after for the girl with AML—tested positive for Zika.
Researchers performed molecular sequencing and phylogenetic analysis of Zika virus RNA isolated from the donor and the recipients. Isolates from all 3 parties had nucleotide changes in the envelope gene (codons 11 and 186) that were not observed among other available isolates from Brazil.
The researchers said these results suggest the platelet transfusions were the source of Zika virus infection in the PMF patient and the AML patient.
Although both patients could have been exposed to Zika-carrying mosquitoes, both the RNA results and the timing of Zika infection suggest the transfusions were the cause.
Photo from Flickr
Researchers have reported 2 cases in which the Zika virus seems to have been transmitted via platelet transfusion.
Brazilian health officials previously announced 2 cases of Zika virus—in a liver transplant recipient and a gunshot victim—that likely resulted from blood transfusions performed in 2015.
Now, researchers have reported possible transmission via transfusion in 2 more Brazilians—a patient with primary myelofibrosis (PMF) and one with acute myeloid leukemia (AML).
The researchers described these cases in a letter to NEJM.
An individual who donated platelets via apheresis on January 16, 2016, later tested positive for the Zika virus.
On January 19, platelets from that donor were transfused into a 54-year-old woman with PMF and a 14-year-old girl with AML who had also received a haploidentical bone marrow transplant on January 6.
The platelet donor called the blood bank on January 21 to report worrying symptoms—a cutaneous rash, retro-orbital pain, and pain in both knees—that had developed on January 18.
Subsequent testing revealed that the donor was negative for chikungunya and dengue virus. However, both plasma and urine samples tested positive for Zika virus.
Pre-transfusion samples collected from both of the recipients were negative for chikungunya, dengue, and Zika. However, samples collected after the transfusions—6 days after for the woman with PMF and 23 to 51 days after for the girl with AML—tested positive for Zika.
Researchers performed molecular sequencing and phylogenetic analysis of Zika virus RNA isolated from the donor and the recipients. Isolates from all 3 parties had nucleotide changes in the envelope gene (codons 11 and 186) that were not observed among other available isolates from Brazil.
The researchers said these results suggest the platelet transfusions were the source of Zika virus infection in the PMF patient and the AML patient.
Although both patients could have been exposed to Zika-carrying mosquitoes, both the RNA results and the timing of Zika infection suggest the transfusions were the cause.
Photo from Flickr
Researchers have reported 2 cases in which the Zika virus seems to have been transmitted via platelet transfusion.
Brazilian health officials previously announced 2 cases of Zika virus—in a liver transplant recipient and a gunshot victim—that likely resulted from blood transfusions performed in 2015.
Now, researchers have reported possible transmission via transfusion in 2 more Brazilians—a patient with primary myelofibrosis (PMF) and one with acute myeloid leukemia (AML).
The researchers described these cases in a letter to NEJM.
An individual who donated platelets via apheresis on January 16, 2016, later tested positive for the Zika virus.
On January 19, platelets from that donor were transfused into a 54-year-old woman with PMF and a 14-year-old girl with AML who had also received a haploidentical bone marrow transplant on January 6.
The platelet donor called the blood bank on January 21 to report worrying symptoms—a cutaneous rash, retro-orbital pain, and pain in both knees—that had developed on January 18.
Subsequent testing revealed that the donor was negative for chikungunya and dengue virus. However, both plasma and urine samples tested positive for Zika virus.
Pre-transfusion samples collected from both of the recipients were negative for chikungunya, dengue, and Zika. However, samples collected after the transfusions—6 days after for the woman with PMF and 23 to 51 days after for the girl with AML—tested positive for Zika.
Researchers performed molecular sequencing and phylogenetic analysis of Zika virus RNA isolated from the donor and the recipients. Isolates from all 3 parties had nucleotide changes in the envelope gene (codons 11 and 186) that were not observed among other available isolates from Brazil.
The researchers said these results suggest the platelet transfusions were the source of Zika virus infection in the PMF patient and the AML patient.
Although both patients could have been exposed to Zika-carrying mosquitoes, both the RNA results and the timing of Zika infection suggest the transfusions were the cause.
Study supports expanded prenatal genetic testing
Photo by Nina Matthews
New research suggests expanded prenatal genetic testing may increase the detection of carrier status for potentially serious genetic conditions, including hemoglobinopathies.
Researchers analyzed nearly 350,000 adults of diverse racial and ethnic backgrounds and found evidence to suggest that expanded screening for up to 94 conditions can increase the detection of carrier status when compared with current genetic testing recommendations from professional societies.
Imran S. Haque, PhD, of Counsyl in San Francisco, California, and his colleagues reported these findings in JAMA. The study was funded by Counsyl, a laboratory providing expanded carrier screening.
Genetic testing of prospective parents to detect carriers of specific inherited recessive diseases is part of routine obstetrical practice. The current recommendations are to test for a limited number of individual diseases, in part based on self-reported racial/ethnic background.
Dr Haque and his colleagues wanted to determine if recent advances in genetic testing could facilitate screening for an expanded number of conditions independent of racial/ethnic background.
The researchers analyzed results from expanded carrier screening in 346,790 reproductive-aged individuals, primarily from the US, without known indication for specific genetic testing.
The individuals were tested for carrier status for up to 94 conditions. Tests were offered by clinicians providing reproductive care.
Risk was defined as the probability that a hypothetical fetus created from a random pairing of individuals (within or across 15 self-reported racial/ethnic categories) would be homozygous or compound heterozygous for 2 mutations presumed to cause severe or profound disease.
Severe conditions were defined as those that, if left untreated, cause intellectual disability or a substantially shortened lifespan. Profound conditions were those causing both intellectual disability and a shortened lifespan.
The researchers found that, in most racial/ethnic categories, expanded carrier screening modeled more hypothetical fetuses at risk for severe or profound conditions than did screening based on current professional guidelines.
Overall, relative to expanded carrier screening, guideline-based screening ranged from identifying 6% of hypothetical fetuses affected for East Asian couples to 87% for African or African American couples.
Though this study suggests expanded screening could be beneficial, the researchers said their findings should be confirmed with prospective studies comparing current carrier screening with expanded screening in at-risk populations.
Photo by Nina Matthews
New research suggests expanded prenatal genetic testing may increase the detection of carrier status for potentially serious genetic conditions, including hemoglobinopathies.
Researchers analyzed nearly 350,000 adults of diverse racial and ethnic backgrounds and found evidence to suggest that expanded screening for up to 94 conditions can increase the detection of carrier status when compared with current genetic testing recommendations from professional societies.
Imran S. Haque, PhD, of Counsyl in San Francisco, California, and his colleagues reported these findings in JAMA. The study was funded by Counsyl, a laboratory providing expanded carrier screening.
Genetic testing of prospective parents to detect carriers of specific inherited recessive diseases is part of routine obstetrical practice. The current recommendations are to test for a limited number of individual diseases, in part based on self-reported racial/ethnic background.
Dr Haque and his colleagues wanted to determine if recent advances in genetic testing could facilitate screening for an expanded number of conditions independent of racial/ethnic background.
The researchers analyzed results from expanded carrier screening in 346,790 reproductive-aged individuals, primarily from the US, without known indication for specific genetic testing.
The individuals were tested for carrier status for up to 94 conditions. Tests were offered by clinicians providing reproductive care.
Risk was defined as the probability that a hypothetical fetus created from a random pairing of individuals (within or across 15 self-reported racial/ethnic categories) would be homozygous or compound heterozygous for 2 mutations presumed to cause severe or profound disease.
Severe conditions were defined as those that, if left untreated, cause intellectual disability or a substantially shortened lifespan. Profound conditions were those causing both intellectual disability and a shortened lifespan.
The researchers found that, in most racial/ethnic categories, expanded carrier screening modeled more hypothetical fetuses at risk for severe or profound conditions than did screening based on current professional guidelines.
Overall, relative to expanded carrier screening, guideline-based screening ranged from identifying 6% of hypothetical fetuses affected for East Asian couples to 87% for African or African American couples.
Though this study suggests expanded screening could be beneficial, the researchers said their findings should be confirmed with prospective studies comparing current carrier screening with expanded screening in at-risk populations.
Photo by Nina Matthews
New research suggests expanded prenatal genetic testing may increase the detection of carrier status for potentially serious genetic conditions, including hemoglobinopathies.
Researchers analyzed nearly 350,000 adults of diverse racial and ethnic backgrounds and found evidence to suggest that expanded screening for up to 94 conditions can increase the detection of carrier status when compared with current genetic testing recommendations from professional societies.
Imran S. Haque, PhD, of Counsyl in San Francisco, California, and his colleagues reported these findings in JAMA. The study was funded by Counsyl, a laboratory providing expanded carrier screening.
Genetic testing of prospective parents to detect carriers of specific inherited recessive diseases is part of routine obstetrical practice. The current recommendations are to test for a limited number of individual diseases, in part based on self-reported racial/ethnic background.
Dr Haque and his colleagues wanted to determine if recent advances in genetic testing could facilitate screening for an expanded number of conditions independent of racial/ethnic background.
The researchers analyzed results from expanded carrier screening in 346,790 reproductive-aged individuals, primarily from the US, without known indication for specific genetic testing.
The individuals were tested for carrier status for up to 94 conditions. Tests were offered by clinicians providing reproductive care.
Risk was defined as the probability that a hypothetical fetus created from a random pairing of individuals (within or across 15 self-reported racial/ethnic categories) would be homozygous or compound heterozygous for 2 mutations presumed to cause severe or profound disease.
Severe conditions were defined as those that, if left untreated, cause intellectual disability or a substantially shortened lifespan. Profound conditions were those causing both intellectual disability and a shortened lifespan.
The researchers found that, in most racial/ethnic categories, expanded carrier screening modeled more hypothetical fetuses at risk for severe or profound conditions than did screening based on current professional guidelines.
Overall, relative to expanded carrier screening, guideline-based screening ranged from identifying 6% of hypothetical fetuses affected for East Asian couples to 87% for African or African American couples.
Though this study suggests expanded screening could be beneficial, the researchers said their findings should be confirmed with prospective studies comparing current carrier screening with expanded screening in at-risk populations.
Immunogene therapy granted conditional authorization
Image by NIAID
The European Commission (EC) has granted conditional marketing authorization for an immunogene therapy known as Zalmoxis.
This means Zalmoxis can be marketed in the European Economic Area as an adjunctive therapy to aid immune reconstitution and help treat graft-versus-host disease (GVHD) in adults with high-risk hematologic malignancies who are receiving a haploidentical hematopoietic stem cell transplant (haplo-HSCT).
Zalmoxis consists of allogeneic T cells genetically modified to express both a truncated form of the human low-affinity nerve growth factor receptor (ΔLNGFR), as a cell-surface selectable marker, and the suicide gene herpes simplex I virus thymidine kinase (HSV-TK Mut2).
The modified T cells are given to haplo-HSCT recipients to help fight off infection, enhance the success of the transplant, and support long-lasting anticancer effects.
Because the T cells can also cause GVHD, they are equipped with the suicide gene, which makes them susceptible to treatment with ganciclovir or valganciclovir. So if a patient develops GVHD, he or she can receive ganciclovir/valganciclovir, which should kill the modified T cells and prevent further development of the disease.
Zalmoxis is being developed by MolMed S.p.A. The company said the treatment should become available in the first European market during the first half of 2017.
About conditional marketing authorization
Conditional marketing authorization represents an expedited path for approval. The EC grants this type of authorization before pivotal registration studies are completed.
Conditional marketing authorization is granted to products whose benefits are thought to outweigh their risks, products that address unmet needs, and products that are expected to provide a significant public health benefit.
Under the provisions of the conditional marketing authorization for Zalmoxis, MolMed will be required to complete a post-marketing study aimed at confirming the clinical benefit of the treatment.
The European Medicines Agency’s Committee for Medicinal Products for Human Use has accepted the ongoing phase 3 TK008 trial as a post-marketing confirmatory study.
Trials of Zalmoxis
The EC’s decision to grant Zalmoxis conditional marketing authorization was based on cumulative efficacy and safety data collected from patients enrolled in a phase 1/2 trial (TK007) and an ongoing phase 3 trial (TK008).
The Zalmoxis group comprised 30 patients from the TK007 trial and 15 patients from the experimental arm of the TK008 trial. The TK007 trial included haplo-HSCT recipients with various high-risk hematologic malignancies, and the TK008 trial is enrolling haplo-HSCT recipients with high-risk acute leukemia.
The data thus far have indicated that Zalmoxis can provide rapid immune reconstitution, an anti-leukemia effect, and complete control of GVHD, in the absence of any post-transplant immunosuppression.
Overall, these effects led to a clinically meaningful increase in survival rates in Zalmoxis-treated patients, when compared to historical controls from the European Society for Blood and Marrow Transplantation (EBMT) database.
The only adverse event related to Zalmoxis treatment was GVHD, which was fully resolved by the activation of the suicide gene system with ganciclovir treatment, without any GVHD-related death.
Detailed results of this analysis are set to be presented during the MolMed-sponsored symposium “A new era of haplo-transplantation” at the EBMT International Transplant Course, which is scheduled to take place September 9-11 in Barcelona, Spain.
Image by NIAID
The European Commission (EC) has granted conditional marketing authorization for an immunogene therapy known as Zalmoxis.
This means Zalmoxis can be marketed in the European Economic Area as an adjunctive therapy to aid immune reconstitution and help treat graft-versus-host disease (GVHD) in adults with high-risk hematologic malignancies who are receiving a haploidentical hematopoietic stem cell transplant (haplo-HSCT).
Zalmoxis consists of allogeneic T cells genetically modified to express both a truncated form of the human low-affinity nerve growth factor receptor (ΔLNGFR), as a cell-surface selectable marker, and the suicide gene herpes simplex I virus thymidine kinase (HSV-TK Mut2).
The modified T cells are given to haplo-HSCT recipients to help fight off infection, enhance the success of the transplant, and support long-lasting anticancer effects.
Because the T cells can also cause GVHD, they are equipped with the suicide gene, which makes them susceptible to treatment with ganciclovir or valganciclovir. So if a patient develops GVHD, he or she can receive ganciclovir/valganciclovir, which should kill the modified T cells and prevent further development of the disease.
Zalmoxis is being developed by MolMed S.p.A. The company said the treatment should become available in the first European market during the first half of 2017.
About conditional marketing authorization
Conditional marketing authorization represents an expedited path for approval. The EC grants this type of authorization before pivotal registration studies are completed.
Conditional marketing authorization is granted to products whose benefits are thought to outweigh their risks, products that address unmet needs, and products that are expected to provide a significant public health benefit.
Under the provisions of the conditional marketing authorization for Zalmoxis, MolMed will be required to complete a post-marketing study aimed at confirming the clinical benefit of the treatment.
The European Medicines Agency’s Committee for Medicinal Products for Human Use has accepted the ongoing phase 3 TK008 trial as a post-marketing confirmatory study.
Trials of Zalmoxis
The EC’s decision to grant Zalmoxis conditional marketing authorization was based on cumulative efficacy and safety data collected from patients enrolled in a phase 1/2 trial (TK007) and an ongoing phase 3 trial (TK008).
The Zalmoxis group comprised 30 patients from the TK007 trial and 15 patients from the experimental arm of the TK008 trial. The TK007 trial included haplo-HSCT recipients with various high-risk hematologic malignancies, and the TK008 trial is enrolling haplo-HSCT recipients with high-risk acute leukemia.
The data thus far have indicated that Zalmoxis can provide rapid immune reconstitution, an anti-leukemia effect, and complete control of GVHD, in the absence of any post-transplant immunosuppression.
Overall, these effects led to a clinically meaningful increase in survival rates in Zalmoxis-treated patients, when compared to historical controls from the European Society for Blood and Marrow Transplantation (EBMT) database.
The only adverse event related to Zalmoxis treatment was GVHD, which was fully resolved by the activation of the suicide gene system with ganciclovir treatment, without any GVHD-related death.
Detailed results of this analysis are set to be presented during the MolMed-sponsored symposium “A new era of haplo-transplantation” at the EBMT International Transplant Course, which is scheduled to take place September 9-11 in Barcelona, Spain.
Image by NIAID
The European Commission (EC) has granted conditional marketing authorization for an immunogene therapy known as Zalmoxis.
This means Zalmoxis can be marketed in the European Economic Area as an adjunctive therapy to aid immune reconstitution and help treat graft-versus-host disease (GVHD) in adults with high-risk hematologic malignancies who are receiving a haploidentical hematopoietic stem cell transplant (haplo-HSCT).
Zalmoxis consists of allogeneic T cells genetically modified to express both a truncated form of the human low-affinity nerve growth factor receptor (ΔLNGFR), as a cell-surface selectable marker, and the suicide gene herpes simplex I virus thymidine kinase (HSV-TK Mut2).
The modified T cells are given to haplo-HSCT recipients to help fight off infection, enhance the success of the transplant, and support long-lasting anticancer effects.
Because the T cells can also cause GVHD, they are equipped with the suicide gene, which makes them susceptible to treatment with ganciclovir or valganciclovir. So if a patient develops GVHD, he or she can receive ganciclovir/valganciclovir, which should kill the modified T cells and prevent further development of the disease.
Zalmoxis is being developed by MolMed S.p.A. The company said the treatment should become available in the first European market during the first half of 2017.
About conditional marketing authorization
Conditional marketing authorization represents an expedited path for approval. The EC grants this type of authorization before pivotal registration studies are completed.
Conditional marketing authorization is granted to products whose benefits are thought to outweigh their risks, products that address unmet needs, and products that are expected to provide a significant public health benefit.
Under the provisions of the conditional marketing authorization for Zalmoxis, MolMed will be required to complete a post-marketing study aimed at confirming the clinical benefit of the treatment.
The European Medicines Agency’s Committee for Medicinal Products for Human Use has accepted the ongoing phase 3 TK008 trial as a post-marketing confirmatory study.
Trials of Zalmoxis
The EC’s decision to grant Zalmoxis conditional marketing authorization was based on cumulative efficacy and safety data collected from patients enrolled in a phase 1/2 trial (TK007) and an ongoing phase 3 trial (TK008).
The Zalmoxis group comprised 30 patients from the TK007 trial and 15 patients from the experimental arm of the TK008 trial. The TK007 trial included haplo-HSCT recipients with various high-risk hematologic malignancies, and the TK008 trial is enrolling haplo-HSCT recipients with high-risk acute leukemia.
The data thus far have indicated that Zalmoxis can provide rapid immune reconstitution, an anti-leukemia effect, and complete control of GVHD, in the absence of any post-transplant immunosuppression.
Overall, these effects led to a clinically meaningful increase in survival rates in Zalmoxis-treated patients, when compared to historical controls from the European Society for Blood and Marrow Transplantation (EBMT) database.
The only adverse event related to Zalmoxis treatment was GVHD, which was fully resolved by the activation of the suicide gene system with ganciclovir treatment, without any GVHD-related death.
Detailed results of this analysis are set to be presented during the MolMed-sponsored symposium “A new era of haplo-transplantation” at the EBMT International Transplant Course, which is scheduled to take place September 9-11 in Barcelona, Spain.
Sociodemographic factors impact OS in MM
Photo courtesy of NCI
New research has revealed sociodemographic factors that appear to influence survival in younger patients with multiple myeloma (MM).
The study, which included more than 10,000 MM patients under the age of 65, suggested that marital status, insurance status, and county-level income all affect a patient’s chance of survival.
However, race/ethnicity and county-level educational achievement were not associated with overall survival (OS).
Luciano Costa, MD, PhD, of the University of Alabama at Birmingham, and his colleagues reported these findings in Cancer.
The researchers analyzed data on patients who were diagnosed with MM before the age of 65, between 2007 and 2012. There were 10,161 cases of MM, and the median follow-up was 27 months (range, 0-71 months).
The sociodemographic variables assessed were marital status, insurance status, median household income in the county of residence, and county-level educational achievement.
The researchers also looked at race/ethnicity, which was defined as a self-reported construct including Hispanic, non-Hispanic black, non-Hispanic white, and “other.”
The researchers found that patients had an increased risk of death if they were not married, did not have private insurance (were uninsured or on Medicaid), or lived in a low-income area (belonging to the lowest 2 income quartiles).
The 4-year estimated OS rate was 71.1% for patients who did not have any of these adverse sociodemographic factors, but it was 63.2% for patients with 1 factor, 53.4% for patients with 2 factors, and 46.5% for patients with all 3 factors (P<0.001).
The researchers did find that Hispanic and non-Hispanic black individuals had more adverse sociodemographic factors and worse OS than non-Hispanic whites and people belonging to the “other” category.
However, when the population was stratified by the cumulative number of sociodemographic factors and the researchers adjusted for confounders, there was no consistent association between race/ethnicity and OS.
The researchers said this suggests the apparent impact of race/ethnicity on OS may be due to the disparate distribution of sociodemographic factors observed among the different races/ethnicities rather than the race/ethnicity construct itself.
“This [study] strongly suggests that there is a huge disparity in outcomes that could potentially be overcome by improving access and affordability of treatments,” Dr Costa said.
“With the recent emphasis on comparative effectiveness in oncology, it also becomes crucial that all variables affecting outcomes—including sociodemographic factors—are accounted for when comparisons between different therapeutic approaches and healthcare systems are made.”
Photo courtesy of NCI
New research has revealed sociodemographic factors that appear to influence survival in younger patients with multiple myeloma (MM).
The study, which included more than 10,000 MM patients under the age of 65, suggested that marital status, insurance status, and county-level income all affect a patient’s chance of survival.
However, race/ethnicity and county-level educational achievement were not associated with overall survival (OS).
Luciano Costa, MD, PhD, of the University of Alabama at Birmingham, and his colleagues reported these findings in Cancer.
The researchers analyzed data on patients who were diagnosed with MM before the age of 65, between 2007 and 2012. There were 10,161 cases of MM, and the median follow-up was 27 months (range, 0-71 months).
The sociodemographic variables assessed were marital status, insurance status, median household income in the county of residence, and county-level educational achievement.
The researchers also looked at race/ethnicity, which was defined as a self-reported construct including Hispanic, non-Hispanic black, non-Hispanic white, and “other.”
The researchers found that patients had an increased risk of death if they were not married, did not have private insurance (were uninsured or on Medicaid), or lived in a low-income area (belonging to the lowest 2 income quartiles).
The 4-year estimated OS rate was 71.1% for patients who did not have any of these adverse sociodemographic factors, but it was 63.2% for patients with 1 factor, 53.4% for patients with 2 factors, and 46.5% for patients with all 3 factors (P<0.001).
The researchers did find that Hispanic and non-Hispanic black individuals had more adverse sociodemographic factors and worse OS than non-Hispanic whites and people belonging to the “other” category.
However, when the population was stratified by the cumulative number of sociodemographic factors and the researchers adjusted for confounders, there was no consistent association between race/ethnicity and OS.
The researchers said this suggests the apparent impact of race/ethnicity on OS may be due to the disparate distribution of sociodemographic factors observed among the different races/ethnicities rather than the race/ethnicity construct itself.
“This [study] strongly suggests that there is a huge disparity in outcomes that could potentially be overcome by improving access and affordability of treatments,” Dr Costa said.
“With the recent emphasis on comparative effectiveness in oncology, it also becomes crucial that all variables affecting outcomes—including sociodemographic factors—are accounted for when comparisons between different therapeutic approaches and healthcare systems are made.”
Photo courtesy of NCI
New research has revealed sociodemographic factors that appear to influence survival in younger patients with multiple myeloma (MM).
The study, which included more than 10,000 MM patients under the age of 65, suggested that marital status, insurance status, and county-level income all affect a patient’s chance of survival.
However, race/ethnicity and county-level educational achievement were not associated with overall survival (OS).
Luciano Costa, MD, PhD, of the University of Alabama at Birmingham, and his colleagues reported these findings in Cancer.
The researchers analyzed data on patients who were diagnosed with MM before the age of 65, between 2007 and 2012. There were 10,161 cases of MM, and the median follow-up was 27 months (range, 0-71 months).
The sociodemographic variables assessed were marital status, insurance status, median household income in the county of residence, and county-level educational achievement.
The researchers also looked at race/ethnicity, which was defined as a self-reported construct including Hispanic, non-Hispanic black, non-Hispanic white, and “other.”
The researchers found that patients had an increased risk of death if they were not married, did not have private insurance (were uninsured or on Medicaid), or lived in a low-income area (belonging to the lowest 2 income quartiles).
The 4-year estimated OS rate was 71.1% for patients who did not have any of these adverse sociodemographic factors, but it was 63.2% for patients with 1 factor, 53.4% for patients with 2 factors, and 46.5% for patients with all 3 factors (P<0.001).
The researchers did find that Hispanic and non-Hispanic black individuals had more adverse sociodemographic factors and worse OS than non-Hispanic whites and people belonging to the “other” category.
However, when the population was stratified by the cumulative number of sociodemographic factors and the researchers adjusted for confounders, there was no consistent association between race/ethnicity and OS.
The researchers said this suggests the apparent impact of race/ethnicity on OS may be due to the disparate distribution of sociodemographic factors observed among the different races/ethnicities rather than the race/ethnicity construct itself.
“This [study] strongly suggests that there is a huge disparity in outcomes that could potentially be overcome by improving access and affordability of treatments,” Dr Costa said.
“With the recent emphasis on comparative effectiveness in oncology, it also becomes crucial that all variables affecting outcomes—including sociodemographic factors—are accounted for when comparisons between different therapeutic approaches and healthcare systems are made.”
Drug granted orphan designation for MAS
Image from Flickr
The US Food and Drug Administration (FDA) has granted orphan drug designation for dusquetide as a treatment for macrophage activation syndrome (MAS).
Dusquetide is an innate defense regulator, a new class of short, synthetic peptides that accelerate bacterial clearance and resolution of tissue damage while modulating inflammation following exposure to bacterial pathogens, radiation, chemotherapy, and other agents.
According to researchers, dusquetide has demonstrated preclinical efficacy and safety in several animal models.
In a mouse model of MAS, dusquetide was shown to reduce pancytopenia, inhibit IL-12 responses, and improve body weight maintenance.
SGX942, the drug product containing dusquetide, has demonstrated safety in a phase 1 study of 84 healthy volunteers.
In addition, SGX942 has demonstrated preliminary efficacy and safety in an exploratory phase 2 study of 111 patients with oral mucositis due to chemoradiation therapy for head and neck cancer.
SGX942 is being developed by Solgenix, Inc.
About orphan designation
The FDA grants orphan designation to drugs and biologics intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the drug is approved.
About MAS
MAS is a life-threatening complication of rheumatic disease that, for unknown reasons, frequently occurs in individuals with systemic juvenile idiopathic arthritis. MAS also occurs in patients with systemic lupus erythematosus, Kawasaki disease, adult-onset Still’s disease, and various vasculitic syndromes.
MAS is characterized by pancytopenia, liver insufficiency, coagulopathy, and neurologic symptoms.
MAS is thought to be caused by the activation and uncontrolled proliferation of T lymphocytes and well-differentiated macrophages, leading to widespread hemophagocytosis and cytokine overproduction.
Image from Flickr
The US Food and Drug Administration (FDA) has granted orphan drug designation for dusquetide as a treatment for macrophage activation syndrome (MAS).
Dusquetide is an innate defense regulator, a new class of short, synthetic peptides that accelerate bacterial clearance and resolution of tissue damage while modulating inflammation following exposure to bacterial pathogens, radiation, chemotherapy, and other agents.
According to researchers, dusquetide has demonstrated preclinical efficacy and safety in several animal models.
In a mouse model of MAS, dusquetide was shown to reduce pancytopenia, inhibit IL-12 responses, and improve body weight maintenance.
SGX942, the drug product containing dusquetide, has demonstrated safety in a phase 1 study of 84 healthy volunteers.
In addition, SGX942 has demonstrated preliminary efficacy and safety in an exploratory phase 2 study of 111 patients with oral mucositis due to chemoradiation therapy for head and neck cancer.
SGX942 is being developed by Solgenix, Inc.
About orphan designation
The FDA grants orphan designation to drugs and biologics intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the drug is approved.
About MAS
MAS is a life-threatening complication of rheumatic disease that, for unknown reasons, frequently occurs in individuals with systemic juvenile idiopathic arthritis. MAS also occurs in patients with systemic lupus erythematosus, Kawasaki disease, adult-onset Still’s disease, and various vasculitic syndromes.
MAS is characterized by pancytopenia, liver insufficiency, coagulopathy, and neurologic symptoms.
MAS is thought to be caused by the activation and uncontrolled proliferation of T lymphocytes and well-differentiated macrophages, leading to widespread hemophagocytosis and cytokine overproduction.
Image from Flickr
The US Food and Drug Administration (FDA) has granted orphan drug designation for dusquetide as a treatment for macrophage activation syndrome (MAS).
Dusquetide is an innate defense regulator, a new class of short, synthetic peptides that accelerate bacterial clearance and resolution of tissue damage while modulating inflammation following exposure to bacterial pathogens, radiation, chemotherapy, and other agents.
According to researchers, dusquetide has demonstrated preclinical efficacy and safety in several animal models.
In a mouse model of MAS, dusquetide was shown to reduce pancytopenia, inhibit IL-12 responses, and improve body weight maintenance.
SGX942, the drug product containing dusquetide, has demonstrated safety in a phase 1 study of 84 healthy volunteers.
In addition, SGX942 has demonstrated preliminary efficacy and safety in an exploratory phase 2 study of 111 patients with oral mucositis due to chemoradiation therapy for head and neck cancer.
SGX942 is being developed by Solgenix, Inc.
About orphan designation
The FDA grants orphan designation to drugs and biologics intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the drug is approved.
About MAS
MAS is a life-threatening complication of rheumatic disease that, for unknown reasons, frequently occurs in individuals with systemic juvenile idiopathic arthritis. MAS also occurs in patients with systemic lupus erythematosus, Kawasaki disease, adult-onset Still’s disease, and various vasculitic syndromes.
MAS is characterized by pancytopenia, liver insufficiency, coagulopathy, and neurologic symptoms.
MAS is thought to be caused by the activation and uncontrolled proliferation of T lymphocytes and well-differentiated macrophages, leading to widespread hemophagocytosis and cytokine overproduction.
VTE linked to permanent work-related disability
Image by Andre E.X. Brown
Unprovoked venous thromboembolism (VTE) may increase the risk of permanent work-related disability, according to research published in the Journal of Thrombosis and Haemostasis.
Researchers evaluated data from more than 60,000 people and found that individuals with unprovoked VTE had a 52% higher risk of work-related disability than those without VTE.
However, there was no association between provoked VTE and work-related disability.
In addition, only deep vein thrombosis (DVT)—not pulmonary embolism (PE)—was significantly associated with an increased risk of work-related disability.
For this study, the researchers analyzed data from the Tromsø Study and the Nord-Trøndelag Health Study, which enrolled 66,005 subjects from 1994 to 1997. The subjects’ mean age at inclusion was 41.3 (range, 20-65), and about half (51.2%, n=33,901) were women.
The subjects were followed through 2008. During the follow-up period, 384 individuals had a first VTE, and 9862 received a disability pension due to work-related disability.
Compared to individuals without VTE, those who had a VTE were slightly older and had a higher body mass index. VTE patients were more likely to have a history of cancer and cardiovascular disease, and they were more likely to have paying jobs.
In addition, subjects with VTE were more likely to have work-related disability. The crude incidence rate of disability was 37.5 per 1000 person-years among VTE patients and 13.5 per 1000 person-years among subjects without VTE.
VTE patients who received disability pension were slightly older than those who did not, and a higher proportion of the VTEs were DVTs rather than PEs. Half of the VTEs were unprovoked.
Multivariable analysis suggested that subjects with unprovoked VTE had a 52% higher risk of work-related disability than individuals without VTE (hazard ratio [HR]=1.52). However, there was no association between provoked VTE and work-related disability (HR=0.83).
When the researchers analyzed DVT and PE separately, they found that subjects with DVT had an 80% higher risk of work-related disability than those without DVT (HR=1.80). Subjects with PE had a moderately increased risk of work-related disability that was not statistically significant (HR=1.28).
When the researchers adjusted for baseline characteristics other than self-rated health, the association between work-related disability and DVT remained strong (HR=1.66), and there was no association between work-related disability and PE (HR=1.06).
The researchers said this study is the first of its kind to document a relationship between VTE and subsequent work-related disability. And the findings suggest the economic burden of VTE goes beyond costs to the healthcare system. The loss of economic output from people who are unable to work due to VTE-related complications is also a substantial economic cost of VTE.
Image by Andre E.X. Brown
Unprovoked venous thromboembolism (VTE) may increase the risk of permanent work-related disability, according to research published in the Journal of Thrombosis and Haemostasis.
Researchers evaluated data from more than 60,000 people and found that individuals with unprovoked VTE had a 52% higher risk of work-related disability than those without VTE.
However, there was no association between provoked VTE and work-related disability.
In addition, only deep vein thrombosis (DVT)—not pulmonary embolism (PE)—was significantly associated with an increased risk of work-related disability.
For this study, the researchers analyzed data from the Tromsø Study and the Nord-Trøndelag Health Study, which enrolled 66,005 subjects from 1994 to 1997. The subjects’ mean age at inclusion was 41.3 (range, 20-65), and about half (51.2%, n=33,901) were women.
The subjects were followed through 2008. During the follow-up period, 384 individuals had a first VTE, and 9862 received a disability pension due to work-related disability.
Compared to individuals without VTE, those who had a VTE were slightly older and had a higher body mass index. VTE patients were more likely to have a history of cancer and cardiovascular disease, and they were more likely to have paying jobs.
In addition, subjects with VTE were more likely to have work-related disability. The crude incidence rate of disability was 37.5 per 1000 person-years among VTE patients and 13.5 per 1000 person-years among subjects without VTE.
VTE patients who received disability pension were slightly older than those who did not, and a higher proportion of the VTEs were DVTs rather than PEs. Half of the VTEs were unprovoked.
Multivariable analysis suggested that subjects with unprovoked VTE had a 52% higher risk of work-related disability than individuals without VTE (hazard ratio [HR]=1.52). However, there was no association between provoked VTE and work-related disability (HR=0.83).
When the researchers analyzed DVT and PE separately, they found that subjects with DVT had an 80% higher risk of work-related disability than those without DVT (HR=1.80). Subjects with PE had a moderately increased risk of work-related disability that was not statistically significant (HR=1.28).
When the researchers adjusted for baseline characteristics other than self-rated health, the association between work-related disability and DVT remained strong (HR=1.66), and there was no association between work-related disability and PE (HR=1.06).
The researchers said this study is the first of its kind to document a relationship between VTE and subsequent work-related disability. And the findings suggest the economic burden of VTE goes beyond costs to the healthcare system. The loss of economic output from people who are unable to work due to VTE-related complications is also a substantial economic cost of VTE.
Image by Andre E.X. Brown
Unprovoked venous thromboembolism (VTE) may increase the risk of permanent work-related disability, according to research published in the Journal of Thrombosis and Haemostasis.
Researchers evaluated data from more than 60,000 people and found that individuals with unprovoked VTE had a 52% higher risk of work-related disability than those without VTE.
However, there was no association between provoked VTE and work-related disability.
In addition, only deep vein thrombosis (DVT)—not pulmonary embolism (PE)—was significantly associated with an increased risk of work-related disability.
For this study, the researchers analyzed data from the Tromsø Study and the Nord-Trøndelag Health Study, which enrolled 66,005 subjects from 1994 to 1997. The subjects’ mean age at inclusion was 41.3 (range, 20-65), and about half (51.2%, n=33,901) were women.
The subjects were followed through 2008. During the follow-up period, 384 individuals had a first VTE, and 9862 received a disability pension due to work-related disability.
Compared to individuals without VTE, those who had a VTE were slightly older and had a higher body mass index. VTE patients were more likely to have a history of cancer and cardiovascular disease, and they were more likely to have paying jobs.
In addition, subjects with VTE were more likely to have work-related disability. The crude incidence rate of disability was 37.5 per 1000 person-years among VTE patients and 13.5 per 1000 person-years among subjects without VTE.
VTE patients who received disability pension were slightly older than those who did not, and a higher proportion of the VTEs were DVTs rather than PEs. Half of the VTEs were unprovoked.
Multivariable analysis suggested that subjects with unprovoked VTE had a 52% higher risk of work-related disability than individuals without VTE (hazard ratio [HR]=1.52). However, there was no association between provoked VTE and work-related disability (HR=0.83).
When the researchers analyzed DVT and PE separately, they found that subjects with DVT had an 80% higher risk of work-related disability than those without DVT (HR=1.80). Subjects with PE had a moderately increased risk of work-related disability that was not statistically significant (HR=1.28).
When the researchers adjusted for baseline characteristics other than self-rated health, the association between work-related disability and DVT remained strong (HR=1.66), and there was no association between work-related disability and PE (HR=1.06).
The researchers said this study is the first of its kind to document a relationship between VTE and subsequent work-related disability. And the findings suggest the economic burden of VTE goes beyond costs to the healthcare system. The loss of economic output from people who are unable to work due to VTE-related complications is also a substantial economic cost of VTE.
Potential treatment strategy for dyskeratosis congenita
Preclinical research has revealed a potential treatment strategy for dyskeratosis congenita (DC).
Researchers found that DC is characterized by reductions in telomerase, telomere length, and telomere capping, which reduces Wnt pathway activity, resulting in intestinal stem cell failure.
However, treatment with Wnt agonists restored the Wnt-telomere feedback loop and reversed gastrointestinal DC phenotypes in vitro and in vivo.
Christopher J. Lengner, PhD, of the University of Pennsylvania in Philadelphia, and his colleagues reported these discoveries in Cell Stem Cell.
“Right now, the main therapy for [DC] patients is a bone marrow transplant,” Dr Lengner said. “That can address the bone marrow failure but doesn’t fix other problems associated with the disease, and especially not the risk of cancer. This work suggests a way to address the underlying cause of the disease.”
Earlier research with mouse models of DC suggested there might be a connection between the Wnt pathway and telomerase. And a recent study in DC patients’ cells revealed a decrease in activity in the Wnt pathway.
So Dr Lengner and his colleagues wanted to explore whether activating Wnt could reverse the effects of the disease. To do so, the team used induced pluripotent stem cells (iPSCs), the CRISPR/Cas9 gene-editing system, and directed differentiation.
The researchers generated iPSCs from DKC1-mutant fibroblasts and from wild-type cells. The team also used CRISPR to introduce a DKC1 mutation into healthy human iPSCs and to correct the disease-causing mutation in iPSCs generated from DC patient samples.
The researchers then grew organoids through directed differentiation. iPSCs were coaxed to form a human intestinal organoid, which naturally forms a tube-like structure, recapitulating the tubes of the human gastrointestinal system.
When the researchers observed the development of intestinal organoids, they found that, initially, the DC cells seemed to form normally.
The original DKC1-mutant cells and the cells that had the DKC1 mutation introduced by CRISPR appeared to follow a normal course of development for several days. But by 2 weeks, they lacked the tube-like structure seen in the healthy samples and the disease-corrected samples.
The DKC1-mutant cells also had shorter telomeres, with the intestinal organoids from DC patients having the shortest of any cell type.
“We could see, at the molecular level, that this is accompanied by a failure to activate specific intestinal stem cell gene programs—specifically, genes in the Wnt pathway,” Dr Lengner said.
The next logical step was to activate Wnt to see if these defects could be reversed. The researchers treated organoids derived from DC patient iPSCs with a compound called CHIR that stimulates the Wnt pathway.
This restored the formation of the tube-like structure as well as intestinal stem cell gene expression. The treatment also increased telomerase activity and telomere length in the cells with mutant DKC1.
To assess this treatment approach in a more clinically relevant model, the researchers transplanted the human intestinal organoids into mice.
Mice that received a transplant containing the DKC1 mutation and received treatment with lithium, a stimulator of the Wnt pathway, maintained their intestinal tissue structure and had high expression of Wnt target genes.
In effect, these mice resembled the mice that received a transplant of an organoid derived from a healthy patient.
The researchers said this study offers proof of principle that activating the Wnt pathway can reverse at least the gastrointestinal phenotypes associated with DC. Looking ahead, the team would like to try accomplishing the same feat in other tissue types affected by the disease.
Preclinical research has revealed a potential treatment strategy for dyskeratosis congenita (DC).
Researchers found that DC is characterized by reductions in telomerase, telomere length, and telomere capping, which reduces Wnt pathway activity, resulting in intestinal stem cell failure.
However, treatment with Wnt agonists restored the Wnt-telomere feedback loop and reversed gastrointestinal DC phenotypes in vitro and in vivo.
Christopher J. Lengner, PhD, of the University of Pennsylvania in Philadelphia, and his colleagues reported these discoveries in Cell Stem Cell.
“Right now, the main therapy for [DC] patients is a bone marrow transplant,” Dr Lengner said. “That can address the bone marrow failure but doesn’t fix other problems associated with the disease, and especially not the risk of cancer. This work suggests a way to address the underlying cause of the disease.”
Earlier research with mouse models of DC suggested there might be a connection between the Wnt pathway and telomerase. And a recent study in DC patients’ cells revealed a decrease in activity in the Wnt pathway.
So Dr Lengner and his colleagues wanted to explore whether activating Wnt could reverse the effects of the disease. To do so, the team used induced pluripotent stem cells (iPSCs), the CRISPR/Cas9 gene-editing system, and directed differentiation.
The researchers generated iPSCs from DKC1-mutant fibroblasts and from wild-type cells. The team also used CRISPR to introduce a DKC1 mutation into healthy human iPSCs and to correct the disease-causing mutation in iPSCs generated from DC patient samples.
The researchers then grew organoids through directed differentiation. iPSCs were coaxed to form a human intestinal organoid, which naturally forms a tube-like structure, recapitulating the tubes of the human gastrointestinal system.
When the researchers observed the development of intestinal organoids, they found that, initially, the DC cells seemed to form normally.
The original DKC1-mutant cells and the cells that had the DKC1 mutation introduced by CRISPR appeared to follow a normal course of development for several days. But by 2 weeks, they lacked the tube-like structure seen in the healthy samples and the disease-corrected samples.
The DKC1-mutant cells also had shorter telomeres, with the intestinal organoids from DC patients having the shortest of any cell type.
“We could see, at the molecular level, that this is accompanied by a failure to activate specific intestinal stem cell gene programs—specifically, genes in the Wnt pathway,” Dr Lengner said.
The next logical step was to activate Wnt to see if these defects could be reversed. The researchers treated organoids derived from DC patient iPSCs with a compound called CHIR that stimulates the Wnt pathway.
This restored the formation of the tube-like structure as well as intestinal stem cell gene expression. The treatment also increased telomerase activity and telomere length in the cells with mutant DKC1.
To assess this treatment approach in a more clinically relevant model, the researchers transplanted the human intestinal organoids into mice.
Mice that received a transplant containing the DKC1 mutation and received treatment with lithium, a stimulator of the Wnt pathway, maintained their intestinal tissue structure and had high expression of Wnt target genes.
In effect, these mice resembled the mice that received a transplant of an organoid derived from a healthy patient.
The researchers said this study offers proof of principle that activating the Wnt pathway can reverse at least the gastrointestinal phenotypes associated with DC. Looking ahead, the team would like to try accomplishing the same feat in other tissue types affected by the disease.
Preclinical research has revealed a potential treatment strategy for dyskeratosis congenita (DC).
Researchers found that DC is characterized by reductions in telomerase, telomere length, and telomere capping, which reduces Wnt pathway activity, resulting in intestinal stem cell failure.
However, treatment with Wnt agonists restored the Wnt-telomere feedback loop and reversed gastrointestinal DC phenotypes in vitro and in vivo.
Christopher J. Lengner, PhD, of the University of Pennsylvania in Philadelphia, and his colleagues reported these discoveries in Cell Stem Cell.
“Right now, the main therapy for [DC] patients is a bone marrow transplant,” Dr Lengner said. “That can address the bone marrow failure but doesn’t fix other problems associated with the disease, and especially not the risk of cancer. This work suggests a way to address the underlying cause of the disease.”
Earlier research with mouse models of DC suggested there might be a connection between the Wnt pathway and telomerase. And a recent study in DC patients’ cells revealed a decrease in activity in the Wnt pathway.
So Dr Lengner and his colleagues wanted to explore whether activating Wnt could reverse the effects of the disease. To do so, the team used induced pluripotent stem cells (iPSCs), the CRISPR/Cas9 gene-editing system, and directed differentiation.
The researchers generated iPSCs from DKC1-mutant fibroblasts and from wild-type cells. The team also used CRISPR to introduce a DKC1 mutation into healthy human iPSCs and to correct the disease-causing mutation in iPSCs generated from DC patient samples.
The researchers then grew organoids through directed differentiation. iPSCs were coaxed to form a human intestinal organoid, which naturally forms a tube-like structure, recapitulating the tubes of the human gastrointestinal system.
When the researchers observed the development of intestinal organoids, they found that, initially, the DC cells seemed to form normally.
The original DKC1-mutant cells and the cells that had the DKC1 mutation introduced by CRISPR appeared to follow a normal course of development for several days. But by 2 weeks, they lacked the tube-like structure seen in the healthy samples and the disease-corrected samples.
The DKC1-mutant cells also had shorter telomeres, with the intestinal organoids from DC patients having the shortest of any cell type.
“We could see, at the molecular level, that this is accompanied by a failure to activate specific intestinal stem cell gene programs—specifically, genes in the Wnt pathway,” Dr Lengner said.
The next logical step was to activate Wnt to see if these defects could be reversed. The researchers treated organoids derived from DC patient iPSCs with a compound called CHIR that stimulates the Wnt pathway.
This restored the formation of the tube-like structure as well as intestinal stem cell gene expression. The treatment also increased telomerase activity and telomere length in the cells with mutant DKC1.
To assess this treatment approach in a more clinically relevant model, the researchers transplanted the human intestinal organoids into mice.
Mice that received a transplant containing the DKC1 mutation and received treatment with lithium, a stimulator of the Wnt pathway, maintained their intestinal tissue structure and had high expression of Wnt target genes.
In effect, these mice resembled the mice that received a transplant of an organoid derived from a healthy patient.
The researchers said this study offers proof of principle that activating the Wnt pathway can reverse at least the gastrointestinal phenotypes associated with DC. Looking ahead, the team would like to try accomplishing the same feat in other tissue types affected by the disease.
New treatment option for relapsed/refractory NHL
Results of the phase 3 GADOLIN trial have revealed a new treatment option for patients with relapsed/refractory non-Hodgkin lymphoma (NHL), according to researchers.
The trial showed that obinutuzumab plus bendamustine, followed by obinutuzumab maintenance, can ward off disease progression in NHL patients who have relapsed after rituximab-based
therapy or stopped responding to it.
The obinutuzumab regimen significantly improved progression-free survival (PFS) when compared to bendamustine alone (without maintenance).
However, there was no significant difference between the 2 treatment arms with regard to overall survival (OS).
Still, the trial was stopped before its protocol-specified final analysis because of the PFS benefit in the obinutuzumab arm.
Laurie Sehn, MD, of the BC Cancer Agency in Vancouver, British Columbia, Canada, and her colleagues reported the results of this trial in The Lancet. The research was funded by F. Hoffmann-La Roche Ltd.
Patients and treatment
GADOLIN enrolled patients with relapsed/refractory follicular lymphoma (FL), marginal zone lymphoma (MZL), small lymphocytic lymphoma (SLL), and Waldenstrom’s macroglobulinemia (WM).
The patients were randomized to receive one of the following treatments:
- bendamustine alone (120 mg/m2/day on days 1 and 2 for up to six 28-day cycles)
- bendamustine (90 mg/m2/day on days 1 and 2 for up to six 28-day cycles) plus obinutuzumab (1000 mg on days 1, 8, and 15 for cycle 1, followed by 1 dose for up to six 28-day cycles), followed by obinutuzumab maintenance (1000 mg every 2 months for 2 years or until progression).
The investigators said baseline characteristics were well-balanced between the treatment arms. Patients in both arms had received a median of 2 prior treatments, and the median time from last treatment was about 4 months.
Of the 194 patients randomized to the obinutuzumab arm, 155 had FL, 27 had MZL, and 12 had SLL. Of the 202 patients randomized to the bendamustine (control) arm, 166 had FL, 19 had MZL, 16 had SLL, and 1 had WM.
Ultimately, 156 patients completed induction in the obinutuzumab arm, as did 129 patients in the control arm. Thirty-six patients completed maintenance with obinutuzumab, and 46 were still receiving maintenance at the time of analysis.
The median follow-up was 21.9 months in the obinutuzumab arm and 20.3 months in the control arm.
Safety
Nearly all patients in both arms experienced at least 1 adverse event (AE).
Grade 3-5 AEs occurred in 68% of patients in the obinutuzumab arm and 62% in the control arm. The most frequent of these were neutropenia (33% vs 26%), thrombocytopenia (11% vs 16%), anemia (8% vs 10%), and infusion-related reactions (11% vs 6%).
Serious AEs occurred in 38% of patients in the obinutuzumab arm and 33% in the control arm. The most common were febrile neutropenia (4% vs 3%), infusion-related reactions (4% vs 2%), and pneumonia (3% vs 5%).
Response
According to an independent review committee, the overall response rate at the end of induction was 69% in the obinutuzumab arm and 63% in the control arm. The complete response rates were 11% and 12%, respectively.
The median duration of response was not reached in the obinutuzumab arm and was 13.2 months in the control arm.
Survival
The median PFS was not reached in the obinutuzumab arm and was 14.9 months in the control arm (P=0.0001), according to the independent review committee.
According to investigators, the median PFS was 29.2 months and 14 months, respectively (P<0.0001).
At last follow-up, the median OS had not been reached in either arm (P=0.40).
There were 34 deaths in the obinutuzumab arm and 41 in the control arm (18% and 20%, respectively). Most patients died of disease progression (65% and 71%, respectively).
Twelve patients in each arm (6%) died of AEs. Three of these deaths were treatment-related in the obinutuzumab arm (acute myeloid leukemia, vascular pseudoaneurysm, and pseudomonal sepsis).
Five of the 12 AE deaths in the control arm were treatment-related (sepsis, 2 cases of leukemia, and 2 cases of Pneumocystis jirovecii pneumonia).
Taking these results together, the investigators said the obinutuzumab regimen had a manageable toxicity profile, and it produced a “clinically meaningful and significant” improvement in PFS when compared to bendamustine alone.
Results of the phase 3 GADOLIN trial have revealed a new treatment option for patients with relapsed/refractory non-Hodgkin lymphoma (NHL), according to researchers.
The trial showed that obinutuzumab plus bendamustine, followed by obinutuzumab maintenance, can ward off disease progression in NHL patients who have relapsed after rituximab-based
therapy or stopped responding to it.
The obinutuzumab regimen significantly improved progression-free survival (PFS) when compared to bendamustine alone (without maintenance).
However, there was no significant difference between the 2 treatment arms with regard to overall survival (OS).
Still, the trial was stopped before its protocol-specified final analysis because of the PFS benefit in the obinutuzumab arm.
Laurie Sehn, MD, of the BC Cancer Agency in Vancouver, British Columbia, Canada, and her colleagues reported the results of this trial in The Lancet. The research was funded by F. Hoffmann-La Roche Ltd.
Patients and treatment
GADOLIN enrolled patients with relapsed/refractory follicular lymphoma (FL), marginal zone lymphoma (MZL), small lymphocytic lymphoma (SLL), and Waldenstrom’s macroglobulinemia (WM).
The patients were randomized to receive one of the following treatments:
- bendamustine alone (120 mg/m2/day on days 1 and 2 for up to six 28-day cycles)
- bendamustine (90 mg/m2/day on days 1 and 2 for up to six 28-day cycles) plus obinutuzumab (1000 mg on days 1, 8, and 15 for cycle 1, followed by 1 dose for up to six 28-day cycles), followed by obinutuzumab maintenance (1000 mg every 2 months for 2 years or until progression).
The investigators said baseline characteristics were well-balanced between the treatment arms. Patients in both arms had received a median of 2 prior treatments, and the median time from last treatment was about 4 months.
Of the 194 patients randomized to the obinutuzumab arm, 155 had FL, 27 had MZL, and 12 had SLL. Of the 202 patients randomized to the bendamustine (control) arm, 166 had FL, 19 had MZL, 16 had SLL, and 1 had WM.
Ultimately, 156 patients completed induction in the obinutuzumab arm, as did 129 patients in the control arm. Thirty-six patients completed maintenance with obinutuzumab, and 46 were still receiving maintenance at the time of analysis.
The median follow-up was 21.9 months in the obinutuzumab arm and 20.3 months in the control arm.
Safety
Nearly all patients in both arms experienced at least 1 adverse event (AE).
Grade 3-5 AEs occurred in 68% of patients in the obinutuzumab arm and 62% in the control arm. The most frequent of these were neutropenia (33% vs 26%), thrombocytopenia (11% vs 16%), anemia (8% vs 10%), and infusion-related reactions (11% vs 6%).
Serious AEs occurred in 38% of patients in the obinutuzumab arm and 33% in the control arm. The most common were febrile neutropenia (4% vs 3%), infusion-related reactions (4% vs 2%), and pneumonia (3% vs 5%).
Response
According to an independent review committee, the overall response rate at the end of induction was 69% in the obinutuzumab arm and 63% in the control arm. The complete response rates were 11% and 12%, respectively.
The median duration of response was not reached in the obinutuzumab arm and was 13.2 months in the control arm.
Survival
The median PFS was not reached in the obinutuzumab arm and was 14.9 months in the control arm (P=0.0001), according to the independent review committee.
According to investigators, the median PFS was 29.2 months and 14 months, respectively (P<0.0001).
At last follow-up, the median OS had not been reached in either arm (P=0.40).
There were 34 deaths in the obinutuzumab arm and 41 in the control arm (18% and 20%, respectively). Most patients died of disease progression (65% and 71%, respectively).
Twelve patients in each arm (6%) died of AEs. Three of these deaths were treatment-related in the obinutuzumab arm (acute myeloid leukemia, vascular pseudoaneurysm, and pseudomonal sepsis).
Five of the 12 AE deaths in the control arm were treatment-related (sepsis, 2 cases of leukemia, and 2 cases of Pneumocystis jirovecii pneumonia).
Taking these results together, the investigators said the obinutuzumab regimen had a manageable toxicity profile, and it produced a “clinically meaningful and significant” improvement in PFS when compared to bendamustine alone.
Results of the phase 3 GADOLIN trial have revealed a new treatment option for patients with relapsed/refractory non-Hodgkin lymphoma (NHL), according to researchers.
The trial showed that obinutuzumab plus bendamustine, followed by obinutuzumab maintenance, can ward off disease progression in NHL patients who have relapsed after rituximab-based
therapy or stopped responding to it.
The obinutuzumab regimen significantly improved progression-free survival (PFS) when compared to bendamustine alone (without maintenance).
However, there was no significant difference between the 2 treatment arms with regard to overall survival (OS).
Still, the trial was stopped before its protocol-specified final analysis because of the PFS benefit in the obinutuzumab arm.
Laurie Sehn, MD, of the BC Cancer Agency in Vancouver, British Columbia, Canada, and her colleagues reported the results of this trial in The Lancet. The research was funded by F. Hoffmann-La Roche Ltd.
Patients and treatment
GADOLIN enrolled patients with relapsed/refractory follicular lymphoma (FL), marginal zone lymphoma (MZL), small lymphocytic lymphoma (SLL), and Waldenstrom’s macroglobulinemia (WM).
The patients were randomized to receive one of the following treatments:
- bendamustine alone (120 mg/m2/day on days 1 and 2 for up to six 28-day cycles)
- bendamustine (90 mg/m2/day on days 1 and 2 for up to six 28-day cycles) plus obinutuzumab (1000 mg on days 1, 8, and 15 for cycle 1, followed by 1 dose for up to six 28-day cycles), followed by obinutuzumab maintenance (1000 mg every 2 months for 2 years or until progression).
The investigators said baseline characteristics were well-balanced between the treatment arms. Patients in both arms had received a median of 2 prior treatments, and the median time from last treatment was about 4 months.
Of the 194 patients randomized to the obinutuzumab arm, 155 had FL, 27 had MZL, and 12 had SLL. Of the 202 patients randomized to the bendamustine (control) arm, 166 had FL, 19 had MZL, 16 had SLL, and 1 had WM.
Ultimately, 156 patients completed induction in the obinutuzumab arm, as did 129 patients in the control arm. Thirty-six patients completed maintenance with obinutuzumab, and 46 were still receiving maintenance at the time of analysis.
The median follow-up was 21.9 months in the obinutuzumab arm and 20.3 months in the control arm.
Safety
Nearly all patients in both arms experienced at least 1 adverse event (AE).
Grade 3-5 AEs occurred in 68% of patients in the obinutuzumab arm and 62% in the control arm. The most frequent of these were neutropenia (33% vs 26%), thrombocytopenia (11% vs 16%), anemia (8% vs 10%), and infusion-related reactions (11% vs 6%).
Serious AEs occurred in 38% of patients in the obinutuzumab arm and 33% in the control arm. The most common were febrile neutropenia (4% vs 3%), infusion-related reactions (4% vs 2%), and pneumonia (3% vs 5%).
Response
According to an independent review committee, the overall response rate at the end of induction was 69% in the obinutuzumab arm and 63% in the control arm. The complete response rates were 11% and 12%, respectively.
The median duration of response was not reached in the obinutuzumab arm and was 13.2 months in the control arm.
Survival
The median PFS was not reached in the obinutuzumab arm and was 14.9 months in the control arm (P=0.0001), according to the independent review committee.
According to investigators, the median PFS was 29.2 months and 14 months, respectively (P<0.0001).
At last follow-up, the median OS had not been reached in either arm (P=0.40).
There were 34 deaths in the obinutuzumab arm and 41 in the control arm (18% and 20%, respectively). Most patients died of disease progression (65% and 71%, respectively).
Twelve patients in each arm (6%) died of AEs. Three of these deaths were treatment-related in the obinutuzumab arm (acute myeloid leukemia, vascular pseudoaneurysm, and pseudomonal sepsis).
Five of the 12 AE deaths in the control arm were treatment-related (sepsis, 2 cases of leukemia, and 2 cases of Pneumocystis jirovecii pneumonia).
Taking these results together, the investigators said the obinutuzumab regimen had a manageable toxicity profile, and it produced a “clinically meaningful and significant” improvement in PFS when compared to bendamustine alone.
FDA rejects antidote to factor Xa inhibitors
Photo courtesy of Pfizer
and Bristol-Myers Squibb
The US Food and Drug Administration (FDA) has issued a complete response letter regarding the biologics license application for andexanet alfa (AndexXa™).
Andexanet alfa is being developed as a reversal agent for the factor Xa inhibitors apixaban, rivaroxaban, edoxaban, and enoxaparin.
The agent is intended to be used when reversal of anticoagulation is needed due to life-threatening or uncontrolled bleeding.
In the complete response letter, the FDA requested that Portola Pharmaceuticals Inc., the company developing andexanet alfa, provide additional information related to manufacturing.
Portola said it could not provide many details on this request but stressed that the FDA did not question the company’s ability to manufacture the drug.
The FDA also asked Portola for additional data to support the inclusion of edoxaban and enoxaparin on andexanet alfa’s label.
The completed phase 3 studies of andexanet alfa were designed to assess the drug’s ability to reverse the effects of apixaban and rivaroxaban—but not edoxaban or enoxaparin—in healthy volunteers. Andexanet alfa’s effects on edoxaban and enoxaparin have been investigated in phase 2 studies, however.
Portola had assumed these studies would be sufficient because, overall, the research suggests andexanet alfa has broad activity against factor Xa inhibitors, according to Bill Lis, chief executive officer of Portola.
Lis also noted that the primary use of andexanet alfa, once approved, would be in patients receiving rivaroxaban or apixaban because fewer patients take edoxaban and enoxaparin.
The final issue the FDA mentioned in the complete response letter was the need to finalize its review of the clinical amendments to Portola’s post-marketing commitments.
“Because AndexXa addresses an urgent unmet medical need, we and the FDA are committed to resolving the outstanding questions and determining appropriate next steps,” Lis said.
“Portola’s goal is to define the most expedient path to approval so we can meet the needs of these patients who have no alternative. We plan to meet with the FDA as soon as possible.”
About andexanet alfa
Andexanet alfa is a modified human factor Xa molecule that acts as a decoy to target and sequester both oral and injectable factor Xa inhibitors in the blood. Once bound, the factor Xa inhibitors are unable to bind to and inhibit native factor Xa, thus potentially allowing for the restoration of normal hemostatic processes.
The FDA granted andexanet alfa orphan drug designation last year and breakthrough therapy designation in 2013.
Portola’s biologics license application for andexanet alfa was based on data from a pair of phase 3 studies of healthy volunteers—ANNEXA-A and ANNEXA-R.
In the ANNEXA-R trial, andexanet alfa successfully reversed the anticoagulant activity of rivaroxaban. In the ANNEXA-A trial, andexanet alfa reversed the anticoagulant activity of apixaban.
Results from these studies were published in NEJM last year.
The biologics license application also included limited adjudicated efficacy and safety data from initial patients enrolled in the ongoing ANNEXA-4 study.
In this phase 3b/4 study, researchers are evaluating andexanet alfa in patients receiving apixaban, rivaroxaban, edoxaban, or enoxaparin who present with an acute major bleed.
Photo courtesy of Pfizer
and Bristol-Myers Squibb
The US Food and Drug Administration (FDA) has issued a complete response letter regarding the biologics license application for andexanet alfa (AndexXa™).
Andexanet alfa is being developed as a reversal agent for the factor Xa inhibitors apixaban, rivaroxaban, edoxaban, and enoxaparin.
The agent is intended to be used when reversal of anticoagulation is needed due to life-threatening or uncontrolled bleeding.
In the complete response letter, the FDA requested that Portola Pharmaceuticals Inc., the company developing andexanet alfa, provide additional information related to manufacturing.
Portola said it could not provide many details on this request but stressed that the FDA did not question the company’s ability to manufacture the drug.
The FDA also asked Portola for additional data to support the inclusion of edoxaban and enoxaparin on andexanet alfa’s label.
The completed phase 3 studies of andexanet alfa were designed to assess the drug’s ability to reverse the effects of apixaban and rivaroxaban—but not edoxaban or enoxaparin—in healthy volunteers. Andexanet alfa’s effects on edoxaban and enoxaparin have been investigated in phase 2 studies, however.
Portola had assumed these studies would be sufficient because, overall, the research suggests andexanet alfa has broad activity against factor Xa inhibitors, according to Bill Lis, chief executive officer of Portola.
Lis also noted that the primary use of andexanet alfa, once approved, would be in patients receiving rivaroxaban or apixaban because fewer patients take edoxaban and enoxaparin.
The final issue the FDA mentioned in the complete response letter was the need to finalize its review of the clinical amendments to Portola’s post-marketing commitments.
“Because AndexXa addresses an urgent unmet medical need, we and the FDA are committed to resolving the outstanding questions and determining appropriate next steps,” Lis said.
“Portola’s goal is to define the most expedient path to approval so we can meet the needs of these patients who have no alternative. We plan to meet with the FDA as soon as possible.”
About andexanet alfa
Andexanet alfa is a modified human factor Xa molecule that acts as a decoy to target and sequester both oral and injectable factor Xa inhibitors in the blood. Once bound, the factor Xa inhibitors are unable to bind to and inhibit native factor Xa, thus potentially allowing for the restoration of normal hemostatic processes.
The FDA granted andexanet alfa orphan drug designation last year and breakthrough therapy designation in 2013.
Portola’s biologics license application for andexanet alfa was based on data from a pair of phase 3 studies of healthy volunteers—ANNEXA-A and ANNEXA-R.
In the ANNEXA-R trial, andexanet alfa successfully reversed the anticoagulant activity of rivaroxaban. In the ANNEXA-A trial, andexanet alfa reversed the anticoagulant activity of apixaban.
Results from these studies were published in NEJM last year.
The biologics license application also included limited adjudicated efficacy and safety data from initial patients enrolled in the ongoing ANNEXA-4 study.
In this phase 3b/4 study, researchers are evaluating andexanet alfa in patients receiving apixaban, rivaroxaban, edoxaban, or enoxaparin who present with an acute major bleed.
Photo courtesy of Pfizer
and Bristol-Myers Squibb
The US Food and Drug Administration (FDA) has issued a complete response letter regarding the biologics license application for andexanet alfa (AndexXa™).
Andexanet alfa is being developed as a reversal agent for the factor Xa inhibitors apixaban, rivaroxaban, edoxaban, and enoxaparin.
The agent is intended to be used when reversal of anticoagulation is needed due to life-threatening or uncontrolled bleeding.
In the complete response letter, the FDA requested that Portola Pharmaceuticals Inc., the company developing andexanet alfa, provide additional information related to manufacturing.
Portola said it could not provide many details on this request but stressed that the FDA did not question the company’s ability to manufacture the drug.
The FDA also asked Portola for additional data to support the inclusion of edoxaban and enoxaparin on andexanet alfa’s label.
The completed phase 3 studies of andexanet alfa were designed to assess the drug’s ability to reverse the effects of apixaban and rivaroxaban—but not edoxaban or enoxaparin—in healthy volunteers. Andexanet alfa’s effects on edoxaban and enoxaparin have been investigated in phase 2 studies, however.
Portola had assumed these studies would be sufficient because, overall, the research suggests andexanet alfa has broad activity against factor Xa inhibitors, according to Bill Lis, chief executive officer of Portola.
Lis also noted that the primary use of andexanet alfa, once approved, would be in patients receiving rivaroxaban or apixaban because fewer patients take edoxaban and enoxaparin.
The final issue the FDA mentioned in the complete response letter was the need to finalize its review of the clinical amendments to Portola’s post-marketing commitments.
“Because AndexXa addresses an urgent unmet medical need, we and the FDA are committed to resolving the outstanding questions and determining appropriate next steps,” Lis said.
“Portola’s goal is to define the most expedient path to approval so we can meet the needs of these patients who have no alternative. We plan to meet with the FDA as soon as possible.”
About andexanet alfa
Andexanet alfa is a modified human factor Xa molecule that acts as a decoy to target and sequester both oral and injectable factor Xa inhibitors in the blood. Once bound, the factor Xa inhibitors are unable to bind to and inhibit native factor Xa, thus potentially allowing for the restoration of normal hemostatic processes.
The FDA granted andexanet alfa orphan drug designation last year and breakthrough therapy designation in 2013.
Portola’s biologics license application for andexanet alfa was based on data from a pair of phase 3 studies of healthy volunteers—ANNEXA-A and ANNEXA-R.
In the ANNEXA-R trial, andexanet alfa successfully reversed the anticoagulant activity of rivaroxaban. In the ANNEXA-A trial, andexanet alfa reversed the anticoagulant activity of apixaban.
Results from these studies were published in NEJM last year.
The biologics license application also included limited adjudicated efficacy and safety data from initial patients enrolled in the ongoing ANNEXA-4 study.
In this phase 3b/4 study, researchers are evaluating andexanet alfa in patients receiving apixaban, rivaroxaban, edoxaban, or enoxaparin who present with an acute major bleed.