Four of nine acute myeloid leukemia patients went into complete remission – and a fifth responded – after being transfused with donor natural killer cells in a phase I study from Washington University in St. Louis.

The natural killer (NK) cells had been differentiated into “memorylike” NK cells by brief exposure to interleukin (IL) 12, 15, and 18 prior to transfusion. Although NK cells have traditionally been considered part of the innate immune system, it’s become clear recently that they have some adaptive abilities. The cytokine exposure in the St. Louis study seemed, in a sense, to train NK cells to remember and attack acute myeloid leukemia (AML).

The treated cells had enhanced interferon gamma production and cytotoxicity against AML cells in vitro. Once in the patients, they “proliferated extensively” and demonstrated robust responses against leukemia targets. Preactivation of NK cells with IL-12, IL-15, and IL-18 promotes “potent antileukemia functionality in vitro and in vivo and thus represent[s] a promising immunotherapy strategy for AML,” said investigators led by Rizwan Romee, MD, of the oncology division and clinical director of the haploidentical transplant program at Washington University (Sci Transl Med. 2016 Sep. 21. doi: 10.1126/scitranslmed.aaf2341).

NK cell therapy is an emerging treatment for AML, but it’s been unclear, at least until now, how best to maximize the cells’ anti-AML effect before transfer.

Prior studies have tried IL-2 or IL-15 overnight, which does increase NK cell functional capacity, but the effect is rapidly lost after transfer into patients.

That didn’t seem to be much of a problem when NK cells were differentiated into memorylike cells. “The longer-lasting increase in functional capacity ... combined with improved AML recognition, [enhanced] in vivo expansion and antileukemia responses, result[ed] in a several week ‘window of opportunity’ to attack AML blasts.” the authors said.

For safety, the initial cell dose was a tenth or twentieth of the typical adoptive NK cell dose. Even so, the memorylike cells consistently expanded to become greater than 90% of blood and most of bone marrow NK cells, which was “remarkable,” they said.

The National Cancer Institute and others funded the work. The authors had no disclosures.

aotto@frontlinemedcom.com

Four of nine acute myeloid leukemia patients went into complete remission – and a fifth responded – after being transfused with donor natural killer cells in a phase I study from Washington University in St. Louis.

The natural killer (NK) cells had been differentiated into “memorylike” NK cells by brief exposure to interleukin (IL) 12, 15, and 18 prior to transfusion. Although NK cells have traditionally been considered part of the innate immune system, it’s become clear recently that they have some adaptive abilities. The cytokine exposure in the St. Louis study seemed, in a sense, to train NK cells to remember and attack acute myeloid leukemia (AML).

The treated cells had enhanced interferon gamma production and cytotoxicity against AML cells in vitro. Once in the patients, they “proliferated extensively” and demonstrated robust responses against leukemia targets. Preactivation of NK cells with IL-12, IL-15, and IL-18 promotes “potent antileukemia functionality in vitro and in vivo and thus represent[s] a promising immunotherapy strategy for AML,” said investigators led by Rizwan Romee, MD, of the oncology division and clinical director of the haploidentical transplant program at Washington University (Sci Transl Med. 2016 Sep. 21. doi: 10.1126/scitranslmed.aaf2341).

NK cell therapy is an emerging treatment for AML, but it’s been unclear, at least until now, how best to maximize the cells’ anti-AML effect before transfer.

Prior studies have tried IL-2 or IL-15 overnight, which does increase NK cell functional capacity, but the effect is rapidly lost after transfer into patients.

That didn’t seem to be much of a problem when NK cells were differentiated into memorylike cells. “The longer-lasting increase in functional capacity ... combined with improved AML recognition, [enhanced] in vivo expansion and antileukemia responses, result[ed] in a several week ‘window of opportunity’ to attack AML blasts.” the authors said.

For safety, the initial cell dose was a tenth or twentieth of the typical adoptive NK cell dose. Even so, the memorylike cells consistently expanded to become greater than 90% of blood and most of bone marrow NK cells, which was “remarkable,” they said.

The National Cancer Institute and others funded the work. The authors had no disclosures.

aotto@frontlinemedcom.com

Four of nine acute myeloid leukemia patients went into complete remission – and a fifth responded – after being transfused with donor natural killer cells in a phase I study from Washington University in St. Louis.

The natural killer (NK) cells had been differentiated into “memorylike” NK cells by brief exposure to interleukin (IL) 12, 15, and 18 prior to transfusion. Although NK cells have traditionally been considered part of the innate immune system, it’s become clear recently that they have some adaptive abilities. The cytokine exposure in the St. Louis study seemed, in a sense, to train NK cells to remember and attack acute myeloid leukemia (AML).

The treated cells had enhanced interferon gamma production and cytotoxicity against AML cells in vitro. Once in the patients, they “proliferated extensively” and demonstrated robust responses against leukemia targets. Preactivation of NK cells with IL-12, IL-15, and IL-18 promotes “potent antileukemia functionality in vitro and in vivo and thus represent[s] a promising immunotherapy strategy for AML,” said investigators led by Rizwan Romee, MD, of the oncology division and clinical director of the haploidentical transplant program at Washington University (Sci Transl Med. 2016 Sep. 21. doi: 10.1126/scitranslmed.aaf2341).

NK cell therapy is an emerging treatment for AML, but it’s been unclear, at least until now, how best to maximize the cells’ anti-AML effect before transfer.

Prior studies have tried IL-2 or IL-15 overnight, which does increase NK cell functional capacity, but the effect is rapidly lost after transfer into patients.

That didn’t seem to be much of a problem when NK cells were differentiated into memorylike cells. “The longer-lasting increase in functional capacity ... combined with improved AML recognition, [enhanced] in vivo expansion and antileukemia responses, result[ed] in a several week ‘window of opportunity’ to attack AML blasts.” the authors said.

For safety, the initial cell dose was a tenth or twentieth of the typical adoptive NK cell dose. Even so, the memorylike cells consistently expanded to become greater than 90% of blood and most of bone marrow NK cells, which was “remarkable,” they said.

The National Cancer Institute and others funded the work. The authors had no disclosures.

aotto@frontlinemedcom.com

Hossein Khiabanian, PhD

Photo by Debbie Vogel

New research has revealed relapse-specific mutations in pediatric acute lymphoblastic leukemia (ALL) and suggests that mutations in the RAS family may drive both resistance and sensitivity to treatment.

Specifically, the study showed that KRAS-mutant ALL cells were resistant to methotrexate but exhibited increased sensitivity to vincristine.

Hossein Khiabanian, PhD, of Rutgers Cancer Institute of New Jersey, and his colleagues reported these findings in PNAS.

The researchers performed whole-exome and whole-genome sequencing on samples from 55 pediatric patients with relapsed ALL, identified specific genomic changes, and validated these findings in 279 additional samples.

“We found that ALL relapse emerges from small, often clinically undetectable populations of cancer cells that are only partially genetically similar to the dominant leukemic population at diagnosis,” Dr Khiabanian said. “We also identified numerous new mutations in genes involved in drug resistance that are specific to relapsed ALL.”

In the first 55 patients (33 T-cell ALLs and 22 B-cell precursor ALLs), the researchers identified 27 recurrently mutated genes whose mutations were preferentially selected or retained at the time of relapse.

The team said 23 (85%) of these mutated genes were not previously implicated in ALL relapse—HTR3A, MED12, USP9X, CACNA1H, TENM3, AACS, SAMD4A, ANO5, PAPPA, NAALADL2, HIST3H2A, FZD7, TBX15, NEB, GREB1L, PLXNA4, SGK223, TSC1, PTPRG, FGF10, SYCP2, TRPM3, and EYS.

The researchers found mutations in the same genes when they analyzed 49 paired diagnosis and relapse B-cell precursor ALL samples as well as an additional 230 relapsed B-cell precursor ALL samples. In addition, the analyses revealed mutations in NT5C2, NR3C1, CREBBP, KMT2D, JAK2, JAK3, and TP53.

The team also noted that some patient samples showed retention or emergence of RAS mutant clones at relapse. In other patients, RAS mutant clones that were present at diagnosis were replaced by RAS wild-type populations at relapse.

The researchers said this suggests a role for both positive and negative selection evolutionary pressures in clonal evolution of RAS-mutant leukemia.

To investigate this further, they analyzed mouse and human wild-type and mutant RAS isogenic leukemia cells. In these experiments, KRAS-mutant cells showed increased sensitivity to vincristine and increased resistance to methotrexate.

“These results highlight how drug therapy can impact the evolution of leukemia and show a previously unrecognized role of RAS mutations as causes of both sensitivity and resistance to chemotherapy,” Dr Khiabanian said.

“Early identification of these mutations, as well as other genetic alterations that have been shown to induce therapeutic resistance in leukemia patients, is pertinent in guiding precision medicine treatment strategies and prevention of relapsed disease—a goal that is now being pursued in my lab at Rutgers.”

Hossein Khiabanian, PhD

Photo by Debbie Vogel

New research has revealed relapse-specific mutations in pediatric acute lymphoblastic leukemia (ALL) and suggests that mutations in the RAS family may drive both resistance and sensitivity to treatment.

Specifically, the study showed that KRAS-mutant ALL cells were resistant to methotrexate but exhibited increased sensitivity to vincristine.

Hossein Khiabanian, PhD, of Rutgers Cancer Institute of New Jersey, and his colleagues reported these findings in PNAS.

The researchers performed whole-exome and whole-genome sequencing on samples from 55 pediatric patients with relapsed ALL, identified specific genomic changes, and validated these findings in 279 additional samples.

“We found that ALL relapse emerges from small, often clinically undetectable populations of cancer cells that are only partially genetically similar to the dominant leukemic population at diagnosis,” Dr Khiabanian said. “We also identified numerous new mutations in genes involved in drug resistance that are specific to relapsed ALL.”

In the first 55 patients (33 T-cell ALLs and 22 B-cell precursor ALLs), the researchers identified 27 recurrently mutated genes whose mutations were preferentially selected or retained at the time of relapse.

The team said 23 (85%) of these mutated genes were not previously implicated in ALL relapse—HTR3A, MED12, USP9X, CACNA1H, TENM3, AACS, SAMD4A, ANO5, PAPPA, NAALADL2, HIST3H2A, FZD7, TBX15, NEB, GREB1L, PLXNA4, SGK223, TSC1, PTPRG, FGF10, SYCP2, TRPM3, and EYS.

The researchers found mutations in the same genes when they analyzed 49 paired diagnosis and relapse B-cell precursor ALL samples as well as an additional 230 relapsed B-cell precursor ALL samples. In addition, the analyses revealed mutations in NT5C2, NR3C1, CREBBP, KMT2D, JAK2, JAK3, and TP53.

The team also noted that some patient samples showed retention or emergence of RAS mutant clones at relapse. In other patients, RAS mutant clones that were present at diagnosis were replaced by RAS wild-type populations at relapse.

The researchers said this suggests a role for both positive and negative selection evolutionary pressures in clonal evolution of RAS-mutant leukemia.

To investigate this further, they analyzed mouse and human wild-type and mutant RAS isogenic leukemia cells. In these experiments, KRAS-mutant cells showed increased sensitivity to vincristine and increased resistance to methotrexate.

“These results highlight how drug therapy can impact the evolution of leukemia and show a previously unrecognized role of RAS mutations as causes of both sensitivity and resistance to chemotherapy,” Dr Khiabanian said.

“Early identification of these mutations, as well as other genetic alterations that have been shown to induce therapeutic resistance in leukemia patients, is pertinent in guiding precision medicine treatment strategies and prevention of relapsed disease—a goal that is now being pursued in my lab at Rutgers.”

Hossein Khiabanian, PhD

Photo by Debbie Vogel

New research has revealed relapse-specific mutations in pediatric acute lymphoblastic leukemia (ALL) and suggests that mutations in the RAS family may drive both resistance and sensitivity to treatment.

Specifically, the study showed that KRAS-mutant ALL cells were resistant to methotrexate but exhibited increased sensitivity to vincristine.

Hossein Khiabanian, PhD, of Rutgers Cancer Institute of New Jersey, and his colleagues reported these findings in PNAS.

The researchers performed whole-exome and whole-genome sequencing on samples from 55 pediatric patients with relapsed ALL, identified specific genomic changes, and validated these findings in 279 additional samples.

“We found that ALL relapse emerges from small, often clinically undetectable populations of cancer cells that are only partially genetically similar to the dominant leukemic population at diagnosis,” Dr Khiabanian said. “We also identified numerous new mutations in genes involved in drug resistance that are specific to relapsed ALL.”

In the first 55 patients (33 T-cell ALLs and 22 B-cell precursor ALLs), the researchers identified 27 recurrently mutated genes whose mutations were preferentially selected or retained at the time of relapse.

The team said 23 (85%) of these mutated genes were not previously implicated in ALL relapse—HTR3A, MED12, USP9X, CACNA1H, TENM3, AACS, SAMD4A, ANO5, PAPPA, NAALADL2, HIST3H2A, FZD7, TBX15, NEB, GREB1L, PLXNA4, SGK223, TSC1, PTPRG, FGF10, SYCP2, TRPM3, and EYS.

The researchers found mutations in the same genes when they analyzed 49 paired diagnosis and relapse B-cell precursor ALL samples as well as an additional 230 relapsed B-cell precursor ALL samples. In addition, the analyses revealed mutations in NT5C2, NR3C1, CREBBP, KMT2D, JAK2, JAK3, and TP53.

The team also noted that some patient samples showed retention or emergence of RAS mutant clones at relapse. In other patients, RAS mutant clones that were present at diagnosis were replaced by RAS wild-type populations at relapse.

The researchers said this suggests a role for both positive and negative selection evolutionary pressures in clonal evolution of RAS-mutant leukemia.

To investigate this further, they analyzed mouse and human wild-type and mutant RAS isogenic leukemia cells. In these experiments, KRAS-mutant cells showed increased sensitivity to vincristine and increased resistance to methotrexate.

“These results highlight how drug therapy can impact the evolution of leukemia and show a previously unrecognized role of RAS mutations as causes of both sensitivity and resistance to chemotherapy,” Dr Khiabanian said.

“Early identification of these mutations, as well as other genetic alterations that have been shown to induce therapeutic resistance in leukemia patients, is pertinent in guiding precision medicine treatment strategies and prevention of relapsed disease—a goal that is now being pursued in my lab at Rutgers.”

AML cells

Researchers say they have determined the 3-dimensional, atomic structure of GPR56, an adhesion G protein-coupled receptor (aGPCR) linked to the development of several diseases, including acute myeloid leukemia (AML).

The team also engineered a molecule that can turn off GPR56, laying the groundwork for the development of treatments that target diseases mediated by GPR56 and other aGPCRs.

“Given the complicated biology mediated by aGPCRs, particularly in neurodevelopment, we believe our work will pave the way for future studies investigating the molecular details of these important processes, bringing us closer to the ultimate goal of combatting diseases influenced by aGPCRs,” said study author Gabriel Salzman, an MD/PhD student at the University of Chicago in Illinois.

Salzman and his colleagues detailed their work in the journal Neuron.

Over the past several years, researchers have discovered that aGPCRs play a range of biological roles, many of which are closely linked to human diseases.

aGPCRs are characterized by the presence of a large segment that sticks out into the extracellular space. However, a structural foundation for understanding the function of these extracellular regions has been lacking. And researchers didn’t know if these regions could be targeted for therapeutic intervention.

The focus of the current study is GPR56 (also known as ADGRG1), an aGPCR that has established biological roles in muscle cell development, neurodevelopment, and several cancers, including AML.

The researchers engineered a monobody molecule that binds to the extracellular region of GPR56 and causes intracellular signaling to decrease. They said this establishes that it’s possible to change the function of aGPCRs by targeting their extracellular regions with pharmaceuticals.

The team also determined the structure of the entire extracellular region of GPR56 at an atomic level, the first such structural description of any aGPCR. In doing so, they identified a unique protein domain called PLL, which, if deleted, corresponds to a naturally occurring variant of GPR56.

The researchers went on to show that deleting the PLL domain led to increased signaling, further supporting the concept that extracellular regions govern cell signaling.

Bioinformatics analysis also revealed a particular position in the PLL domain that is highly conserved across species, often a telltale sign of biological importance.

The researchers believe that understanding the biological roles played by aGPCR extracellular regions will give scientists more tools to develop treatments for diseases influenced by these protein receptors.

For example, recent studies have shown that AML therapy may benefit from GPR56 inhibition. And this study suggests a monobody like the one created by Salzman’s team might be useful in that respect.

“Our discovery that aGPCR extracellular regions regulate function in a multifaceted and complex manner provides important guidelines for developing therapeutics for diverse diseases in which aGPCRs play important roles,” Salzman said.

AML cells

Researchers say they have determined the 3-dimensional, atomic structure of GPR56, an adhesion G protein-coupled receptor (aGPCR) linked to the development of several diseases, including acute myeloid leukemia (AML).

The team also engineered a molecule that can turn off GPR56, laying the groundwork for the development of treatments that target diseases mediated by GPR56 and other aGPCRs.

“Given the complicated biology mediated by aGPCRs, particularly in neurodevelopment, we believe our work will pave the way for future studies investigating the molecular details of these important processes, bringing us closer to the ultimate goal of combatting diseases influenced by aGPCRs,” said study author Gabriel Salzman, an MD/PhD student at the University of Chicago in Illinois.

Salzman and his colleagues detailed their work in the journal Neuron.

Over the past several years, researchers have discovered that aGPCRs play a range of biological roles, many of which are closely linked to human diseases.

aGPCRs are characterized by the presence of a large segment that sticks out into the extracellular space. However, a structural foundation for understanding the function of these extracellular regions has been lacking. And researchers didn’t know if these regions could be targeted for therapeutic intervention.

The focus of the current study is GPR56 (also known as ADGRG1), an aGPCR that has established biological roles in muscle cell development, neurodevelopment, and several cancers, including AML.

The researchers engineered a monobody molecule that binds to the extracellular region of GPR56 and causes intracellular signaling to decrease. They said this establishes that it’s possible to change the function of aGPCRs by targeting their extracellular regions with pharmaceuticals.

The team also determined the structure of the entire extracellular region of GPR56 at an atomic level, the first such structural description of any aGPCR. In doing so, they identified a unique protein domain called PLL, which, if deleted, corresponds to a naturally occurring variant of GPR56.

The researchers went on to show that deleting the PLL domain led to increased signaling, further supporting the concept that extracellular regions govern cell signaling.

Bioinformatics analysis also revealed a particular position in the PLL domain that is highly conserved across species, often a telltale sign of biological importance.

The researchers believe that understanding the biological roles played by aGPCR extracellular regions will give scientists more tools to develop treatments for diseases influenced by these protein receptors.

For example, recent studies have shown that AML therapy may benefit from GPR56 inhibition. And this study suggests a monobody like the one created by Salzman’s team might be useful in that respect.

“Our discovery that aGPCR extracellular regions regulate function in a multifaceted and complex manner provides important guidelines for developing therapeutics for diverse diseases in which aGPCRs play important roles,” Salzman said.

AML cells

Researchers say they have determined the 3-dimensional, atomic structure of GPR56, an adhesion G protein-coupled receptor (aGPCR) linked to the development of several diseases, including acute myeloid leukemia (AML).

The team also engineered a molecule that can turn off GPR56, laying the groundwork for the development of treatments that target diseases mediated by GPR56 and other aGPCRs.

“Given the complicated biology mediated by aGPCRs, particularly in neurodevelopment, we believe our work will pave the way for future studies investigating the molecular details of these important processes, bringing us closer to the ultimate goal of combatting diseases influenced by aGPCRs,” said study author Gabriel Salzman, an MD/PhD student at the University of Chicago in Illinois.

Salzman and his colleagues detailed their work in the journal Neuron.

Over the past several years, researchers have discovered that aGPCRs play a range of biological roles, many of which are closely linked to human diseases.

aGPCRs are characterized by the presence of a large segment that sticks out into the extracellular space. However, a structural foundation for understanding the function of these extracellular regions has been lacking. And researchers didn’t know if these regions could be targeted for therapeutic intervention.

The focus of the current study is GPR56 (also known as ADGRG1), an aGPCR that has established biological roles in muscle cell development, neurodevelopment, and several cancers, including AML.

The researchers engineered a monobody molecule that binds to the extracellular region of GPR56 and causes intracellular signaling to decrease. They said this establishes that it’s possible to change the function of aGPCRs by targeting their extracellular regions with pharmaceuticals.

The team also determined the structure of the entire extracellular region of GPR56 at an atomic level, the first such structural description of any aGPCR. In doing so, they identified a unique protein domain called PLL, which, if deleted, corresponds to a naturally occurring variant of GPR56.

The researchers went on to show that deleting the PLL domain led to increased signaling, further supporting the concept that extracellular regions govern cell signaling.

Bioinformatics analysis also revealed a particular position in the PLL domain that is highly conserved across species, often a telltale sign of biological importance.

The researchers believe that understanding the biological roles played by aGPCR extracellular regions will give scientists more tools to develop treatments for diseases influenced by these protein receptors.

For example, recent studies have shown that AML therapy may benefit from GPR56 inhibition. And this study suggests a monobody like the one created by Salzman’s team might be useful in that respect.

“Our discovery that aGPCR extracellular regions regulate function in a multifaceted and complex manner provides important guidelines for developing therapeutics for diverse diseases in which aGPCRs play important roles,” Salzman said.

Plasmodium sporozoite

Image by Ute Frevert

and Margaret Shear

The US Food and Drug Administration (FDA) has granted fast track designation to an investigational malaria vaccine.

Sanaria® PfSPZ Vaccine is composed of live but weakened Plasmodium falciparum sporozoites and is being developed by Sanaria, Inc.

The FDA’s fast track program is designed to facilitate the development and expedite the review of products intended to treat or prevent serious or life-threatening conditions and address unmet medical need.

Through the FDA’s fast track program, a product may be eligible for priority review. In addition, the company developing the product may be allowed to submit sections of the biologic license application or new drug application on a rolling basis as data become available.

Fast track designation also provides the company with opportunities for more frequent meetings and written communications with the FDA.

Trials of Sanaria® PfSPZ Vaccine

In a phase 1 study published in Science in 2013, 80% of patients who received higher doses of Sanaria® PfSPZ Vaccine were protected from malaria at 3 weeks after vaccination.

In another phase 1 study published in Nature Medicine in 2016, 4 doses of the vaccine protected 73% of subjects from malaria at 3 weeks and 55% of subjects at 21 weeks.

Five of the subjects without parasitemia at 21 weeks were exposed to malaria-carrying mosquitoes again at 59 weeks, and none developed parasitemia.

To date, 1165 volunteers have received Sanaria’s PfSPZ-based products in more than 2 dozen clinical trials in the US, Europe, and Africa.

Clinical trials are in progress in Tanzania, Kenya, Mali, Burkina Faso, Germany, and the US, and are intended to begin soon in Equatorial Guinea.

Plasmodium sporozoite

Image by Ute Frevert

and Margaret Shear

The US Food and Drug Administration (FDA) has granted fast track designation to an investigational malaria vaccine.

Sanaria® PfSPZ Vaccine is composed of live but weakened Plasmodium falciparum sporozoites and is being developed by Sanaria, Inc.

The FDA’s fast track program is designed to facilitate the development and expedite the review of products intended to treat or prevent serious or life-threatening conditions and address unmet medical need.

Through the FDA’s fast track program, a product may be eligible for priority review. In addition, the company developing the product may be allowed to submit sections of the biologic license application or new drug application on a rolling basis as data become available.

Fast track designation also provides the company with opportunities for more frequent meetings and written communications with the FDA.

Trials of Sanaria® PfSPZ Vaccine

In a phase 1 study published in Science in 2013, 80% of patients who received higher doses of Sanaria® PfSPZ Vaccine were protected from malaria at 3 weeks after vaccination.

In another phase 1 study published in Nature Medicine in 2016, 4 doses of the vaccine protected 73% of subjects from malaria at 3 weeks and 55% of subjects at 21 weeks.

Five of the subjects without parasitemia at 21 weeks were exposed to malaria-carrying mosquitoes again at 59 weeks, and none developed parasitemia.

To date, 1165 volunteers have received Sanaria’s PfSPZ-based products in more than 2 dozen clinical trials in the US, Europe, and Africa.

Clinical trials are in progress in Tanzania, Kenya, Mali, Burkina Faso, Germany, and the US, and are intended to begin soon in Equatorial Guinea.

Plasmodium sporozoite

Image by Ute Frevert

and Margaret Shear

The US Food and Drug Administration (FDA) has granted fast track designation to an investigational malaria vaccine.

Sanaria® PfSPZ Vaccine is composed of live but weakened Plasmodium falciparum sporozoites and is being developed by Sanaria, Inc.

The FDA’s fast track program is designed to facilitate the development and expedite the review of products intended to treat or prevent serious or life-threatening conditions and address unmet medical need.

Through the FDA’s fast track program, a product may be eligible for priority review. In addition, the company developing the product may be allowed to submit sections of the biologic license application or new drug application on a rolling basis as data become available.

Fast track designation also provides the company with opportunities for more frequent meetings and written communications with the FDA.

Trials of Sanaria® PfSPZ Vaccine

In a phase 1 study published in Science in 2013, 80% of patients who received higher doses of Sanaria® PfSPZ Vaccine were protected from malaria at 3 weeks after vaccination.

In another phase 1 study published in Nature Medicine in 2016, 4 doses of the vaccine protected 73% of subjects from malaria at 3 weeks and 55% of subjects at 21 weeks.

Five of the subjects without parasitemia at 21 weeks were exposed to malaria-carrying mosquitoes again at 59 weeks, and none developed parasitemia.

To date, 1165 volunteers have received Sanaria’s PfSPZ-based products in more than 2 dozen clinical trials in the US, Europe, and Africa.

Clinical trials are in progress in Tanzania, Kenya, Mali, Burkina Faso, Germany, and the US, and are intended to begin soon in Equatorial Guinea.

Layer of cells lining a blood

vessel with nuclei in blue,

protein skeletons in red,

and beta-catenin in green.

Image courtesy of

NYU Langone Medical Center

Drugs intended to treat high blood pressure might also be effective for treating cerebral malaria, according to preclinical research published in the Journal of Clinical Investigation.

Researchers tested these drugs—angiotensin II (Ang II) receptor modulators—in mice.

In an initial experiment, 2 of the drugs—losartan and CGP-42112A—reduced the incidence of cerebral malaria.

In another experiment, 2 other Ang II receptor modulators—irbesartan and compound 21 (C21)—were each combined with the antimalarial chloroquine.

Both combinations improved survival in mice with cerebral malaria when compared to chloroquine alone.

“About 1 in 5 patients with cerebral malaria die within 48 hours of being admitted to the hospital—the time it takes for the parasite-killing drug to take effect,” said study author Ana Rodriguez, PhD, of NYU Langone Medical Center in New York.

“If we could add a drug that stopped hemorrhages during that window, it would buy time and save lives.”

With this research, Dr Rodriguez and her colleagues showed that Ang II receptor modulators inhibit the activation of beta-catenin, a protein that plays a key role in cerebral malaria.

The team found that when Plasmodium falciparum–infected red blood cells rupture over human brain microvascular endothelial cells, this activates beta-catenin, which mediates the disruption of interendothelial junctions.

But inhibiting the activation of beta-catenin with Ang II receptor modulators protects endothelial cells from this disruption.

The researchers demonstrated this by infecting mice with P berghei ANKA, treating them with losartan or CGP-42112A, and monitoring them for neurological symptoms.

Seventy-five percent of control mice developed cerebral malaria, compared to 13.3% of mice treated with losartan and 28.5% treated with CGP-42112A.

In another experiment, the researchers treated malaria-infected mice with chloroquine, alone or in combination with irbesartan or C21, only after neurological signs were evident.

The team observed an increase in survival for mice treated with irbesartan or C21. The survival rate was 18% for the mice treated only with chloroquine, 65% for mice given irbesartan, and 73% percent for mice treated with C21.

The researchers also found that mice treated with irbesartan or C21 experienced fewer, smaller hemorrhages. And, in most cases, these mice fully recovered.

Dr Rodriguez and her colleagues said the next steps for this research will be to investigate the exact molecules coming from ruptured P falciparum–infected red blood cells that signal to beta-catenin in vessel walls, and to conduct trials that test the effects of Ang II receptor modulators in patients with cerebral malaria.

Layer of cells lining a blood

vessel with nuclei in blue,

protein skeletons in red,

and beta-catenin in green.

Image courtesy of

NYU Langone Medical Center

Drugs intended to treat high blood pressure might also be effective for treating cerebral malaria, according to preclinical research published in the Journal of Clinical Investigation.

Researchers tested these drugs—angiotensin II (Ang II) receptor modulators—in mice.

In an initial experiment, 2 of the drugs—losartan and CGP-42112A—reduced the incidence of cerebral malaria.

In another experiment, 2 other Ang II receptor modulators—irbesartan and compound 21 (C21)—were each combined with the antimalarial chloroquine.

Both combinations improved survival in mice with cerebral malaria when compared to chloroquine alone.

“About 1 in 5 patients with cerebral malaria die within 48 hours of being admitted to the hospital—the time it takes for the parasite-killing drug to take effect,” said study author Ana Rodriguez, PhD, of NYU Langone Medical Center in New York.

“If we could add a drug that stopped hemorrhages during that window, it would buy time and save lives.”

With this research, Dr Rodriguez and her colleagues showed that Ang II receptor modulators inhibit the activation of beta-catenin, a protein that plays a key role in cerebral malaria.

The team found that when Plasmodium falciparum–infected red blood cells rupture over human brain microvascular endothelial cells, this activates beta-catenin, which mediates the disruption of interendothelial junctions.

But inhibiting the activation of beta-catenin with Ang II receptor modulators protects endothelial cells from this disruption.

The researchers demonstrated this by infecting mice with P berghei ANKA, treating them with losartan or CGP-42112A, and monitoring them for neurological symptoms.

Seventy-five percent of control mice developed cerebral malaria, compared to 13.3% of mice treated with losartan and 28.5% treated with CGP-42112A.

In another experiment, the researchers treated malaria-infected mice with chloroquine, alone or in combination with irbesartan or C21, only after neurological signs were evident.

The team observed an increase in survival for mice treated with irbesartan or C21. The survival rate was 18% for the mice treated only with chloroquine, 65% for mice given irbesartan, and 73% percent for mice treated with C21.

The researchers also found that mice treated with irbesartan or C21 experienced fewer, smaller hemorrhages. And, in most cases, these mice fully recovered.

Dr Rodriguez and her colleagues said the next steps for this research will be to investigate the exact molecules coming from ruptured P falciparum–infected red blood cells that signal to beta-catenin in vessel walls, and to conduct trials that test the effects of Ang II receptor modulators in patients with cerebral malaria.

Layer of cells lining a blood

vessel with nuclei in blue,

protein skeletons in red,

and beta-catenin in green.

Image courtesy of

NYU Langone Medical Center

Drugs intended to treat high blood pressure might also be effective for treating cerebral malaria, according to preclinical research published in the Journal of Clinical Investigation.

Researchers tested these drugs—angiotensin II (Ang II) receptor modulators—in mice.

In an initial experiment, 2 of the drugs—losartan and CGP-42112A—reduced the incidence of cerebral malaria.

In another experiment, 2 other Ang II receptor modulators—irbesartan and compound 21 (C21)—were each combined with the antimalarial chloroquine.

Both combinations improved survival in mice with cerebral malaria when compared to chloroquine alone.

“About 1 in 5 patients with cerebral malaria die within 48 hours of being admitted to the hospital—the time it takes for the parasite-killing drug to take effect,” said study author Ana Rodriguez, PhD, of NYU Langone Medical Center in New York.

“If we could add a drug that stopped hemorrhages during that window, it would buy time and save lives.”

With this research, Dr Rodriguez and her colleagues showed that Ang II receptor modulators inhibit the activation of beta-catenin, a protein that plays a key role in cerebral malaria.

The team found that when Plasmodium falciparum–infected red blood cells rupture over human brain microvascular endothelial cells, this activates beta-catenin, which mediates the disruption of interendothelial junctions.

But inhibiting the activation of beta-catenin with Ang II receptor modulators protects endothelial cells from this disruption.

The researchers demonstrated this by infecting mice with P berghei ANKA, treating them with losartan or CGP-42112A, and monitoring them for neurological symptoms.

Seventy-five percent of control mice developed cerebral malaria, compared to 13.3% of mice treated with losartan and 28.5% treated with CGP-42112A.

In another experiment, the researchers treated malaria-infected mice with chloroquine, alone or in combination with irbesartan or C21, only after neurological signs were evident.

The team observed an increase in survival for mice treated with irbesartan or C21. The survival rate was 18% for the mice treated only with chloroquine, 65% for mice given irbesartan, and 73% percent for mice treated with C21.

The researchers also found that mice treated with irbesartan or C21 experienced fewer, smaller hemorrhages. And, in most cases, these mice fully recovered.

Dr Rodriguez and her colleagues said the next steps for this research will be to investigate the exact molecules coming from ruptured P falciparum–infected red blood cells that signal to beta-catenin in vessel walls, and to conduct trials that test the effects of Ang II receptor modulators in patients with cerebral malaria.

COLUMBUS, OHIO – The disparity in amputation rates between blacks and non-Hispanic whites in Chicago was higher than the national average and up to five times greater on the predominantly black South Side than on the predominantly white North Side of the city.

The reasons for this disparity are unclear, but a recent study of white and black Chicagoans has shown that the rates at which the races self-report claudication do not differ, suggesting that better utilization of public health resources in the black community could potentially reduce this disparity.

Reporting at the annual meeting of the Midwestern Vascular Surgery Society, lead investigator Samantha Minc, MD, of Rush University in Chicago, said the difference in amputation rates may be traced to later recognition of disease in nonwhites.

“Possible reasons for late recognition of disease include lack of access to care, communication issues with doctors, education issues, or the patient and/or caregiver and primary care provider having difficulty accessing specialists,” Dr. Minc said. “Another often-cited explanation for the late recognition is the possibility of differences in disease symptom manifestations in nonwhites, which is what we chose to study.”

Investigators from Rush University analyzed data from a combined cohort of Chicago residents age 65 years and older from two studies of aging: The Rush Memory and Aging Project and the Minority Aging Research Study.

Because of the segregated nature of Chicago – the North Side is mostly white, the South Side mostly black and the West Side mostly Hispanic – prior research has coupled census data with the Illinois Department of Public Health database to analyze care patterns. This data showed that the disparity in amputation rates among groups in Chicago was higher than the national average and up to five times greater on the South Side, compared with the North, Dr. Minc said.

The latest study matched blacks and whites from both studies 1:2 based on age, education, gender, and length of follow-up. In all, a cohort of 2,487 subjects was generated: 801 blacks and 1,686 non-Hispanic whites. Among blacks, 6.5% reported claudication at baseline, compared with 5.9% of whites, and at any point of the study 19.5% of blacks and 19.6% of non-Hispanic whites reported claudication, differences that were not statistically significant.

Blacks did have higher rates of diabetes, 27% vs. 12.6%, were more likely to have used tobacco, more likely to be female, and were slightly younger on average, but other demographic factors – such as income or rates of congestive heart failure and coronary artery disease – were not significantly different, Dr. Minc said.

The study findings will inform the Chicago Department of Public Health’s Healthy Chicago 2.0 initiative to reduce the disparity in amputation rates between whites and blacks by 10% by 2020.

Dr. Minc acknowledged limitations of the study, among them that participants were volunteers, aged 65 years and older, and 72% female, that Hispanics were excluded, and that the use of the Modified Rose/World Health Organization questionnaire to detect claudication is “specific, but not very sensitive.”

“Our findings suggest that the delay in recognition in disease in nonwhites is not due to a racial differences in disease manifestation or symptomatology and that addressing socioeconomic issues, such as access to care, communication, and education may reduce the racial disparity in amputation rates,” Dr. Minc said. “Public health resources should focus on early recognition of the disease in higher-risk groups to decrease this disparity.”

Dr. Minc and her coauthors had no relationships to disclose.

COLUMBUS, OHIO – The disparity in amputation rates between blacks and non-Hispanic whites in Chicago was higher than the national average and up to five times greater on the predominantly black South Side than on the predominantly white North Side of the city.

The reasons for this disparity are unclear, but a recent study of white and black Chicagoans has shown that the rates at which the races self-report claudication do not differ, suggesting that better utilization of public health resources in the black community could potentially reduce this disparity.

Reporting at the annual meeting of the Midwestern Vascular Surgery Society, lead investigator Samantha Minc, MD, of Rush University in Chicago, said the difference in amputation rates may be traced to later recognition of disease in nonwhites.

“Possible reasons for late recognition of disease include lack of access to care, communication issues with doctors, education issues, or the patient and/or caregiver and primary care provider having difficulty accessing specialists,” Dr. Minc said. “Another often-cited explanation for the late recognition is the possibility of differences in disease symptom manifestations in nonwhites, which is what we chose to study.”

Investigators from Rush University analyzed data from a combined cohort of Chicago residents age 65 years and older from two studies of aging: The Rush Memory and Aging Project and the Minority Aging Research Study.

Because of the segregated nature of Chicago – the North Side is mostly white, the South Side mostly black and the West Side mostly Hispanic – prior research has coupled census data with the Illinois Department of Public Health database to analyze care patterns. This data showed that the disparity in amputation rates among groups in Chicago was higher than the national average and up to five times greater on the South Side, compared with the North, Dr. Minc said.

The latest study matched blacks and whites from both studies 1:2 based on age, education, gender, and length of follow-up. In all, a cohort of 2,487 subjects was generated: 801 blacks and 1,686 non-Hispanic whites. Among blacks, 6.5% reported claudication at baseline, compared with 5.9% of whites, and at any point of the study 19.5% of blacks and 19.6% of non-Hispanic whites reported claudication, differences that were not statistically significant.

Blacks did have higher rates of diabetes, 27% vs. 12.6%, were more likely to have used tobacco, more likely to be female, and were slightly younger on average, but other demographic factors – such as income or rates of congestive heart failure and coronary artery disease – were not significantly different, Dr. Minc said.

The study findings will inform the Chicago Department of Public Health’s Healthy Chicago 2.0 initiative to reduce the disparity in amputation rates between whites and blacks by 10% by 2020.

Dr. Minc acknowledged limitations of the study, among them that participants were volunteers, aged 65 years and older, and 72% female, that Hispanics were excluded, and that the use of the Modified Rose/World Health Organization questionnaire to detect claudication is “specific, but not very sensitive.”

“Our findings suggest that the delay in recognition in disease in nonwhites is not due to a racial differences in disease manifestation or symptomatology and that addressing socioeconomic issues, such as access to care, communication, and education may reduce the racial disparity in amputation rates,” Dr. Minc said. “Public health resources should focus on early recognition of the disease in higher-risk groups to decrease this disparity.”

Dr. Minc and her coauthors had no relationships to disclose.

COLUMBUS, OHIO – The disparity in amputation rates between blacks and non-Hispanic whites in Chicago was higher than the national average and up to five times greater on the predominantly black South Side than on the predominantly white North Side of the city.

The reasons for this disparity are unclear, but a recent study of white and black Chicagoans has shown that the rates at which the races self-report claudication do not differ, suggesting that better utilization of public health resources in the black community could potentially reduce this disparity.

Reporting at the annual meeting of the Midwestern Vascular Surgery Society, lead investigator Samantha Minc, MD, of Rush University in Chicago, said the difference in amputation rates may be traced to later recognition of disease in nonwhites.

“Possible reasons for late recognition of disease include lack of access to care, communication issues with doctors, education issues, or the patient and/or caregiver and primary care provider having difficulty accessing specialists,” Dr. Minc said. “Another often-cited explanation for the late recognition is the possibility of differences in disease symptom manifestations in nonwhites, which is what we chose to study.”

Investigators from Rush University analyzed data from a combined cohort of Chicago residents age 65 years and older from two studies of aging: The Rush Memory and Aging Project and the Minority Aging Research Study.

Because of the segregated nature of Chicago – the North Side is mostly white, the South Side mostly black and the West Side mostly Hispanic – prior research has coupled census data with the Illinois Department of Public Health database to analyze care patterns. This data showed that the disparity in amputation rates among groups in Chicago was higher than the national average and up to five times greater on the South Side, compared with the North, Dr. Minc said.

The latest study matched blacks and whites from both studies 1:2 based on age, education, gender, and length of follow-up. In all, a cohort of 2,487 subjects was generated: 801 blacks and 1,686 non-Hispanic whites. Among blacks, 6.5% reported claudication at baseline, compared with 5.9% of whites, and at any point of the study 19.5% of blacks and 19.6% of non-Hispanic whites reported claudication, differences that were not statistically significant.

Blacks did have higher rates of diabetes, 27% vs. 12.6%, were more likely to have used tobacco, more likely to be female, and were slightly younger on average, but other demographic factors – such as income or rates of congestive heart failure and coronary artery disease – were not significantly different, Dr. Minc said.

The study findings will inform the Chicago Department of Public Health’s Healthy Chicago 2.0 initiative to reduce the disparity in amputation rates between whites and blacks by 10% by 2020.

Dr. Minc acknowledged limitations of the study, among them that participants were volunteers, aged 65 years and older, and 72% female, that Hispanics were excluded, and that the use of the Modified Rose/World Health Organization questionnaire to detect claudication is “specific, but not very sensitive.”

“Our findings suggest that the delay in recognition in disease in nonwhites is not due to a racial differences in disease manifestation or symptomatology and that addressing socioeconomic issues, such as access to care, communication, and education may reduce the racial disparity in amputation rates,” Dr. Minc said. “Public health resources should focus on early recognition of the disease in higher-risk groups to decrease this disparity.”

Dr. Minc and her coauthors had no relationships to disclose.

The Food and Drug Administration approved an extended-release combination of canagliflozin and metformin for first-line use as an adjunct to diet and exercise to improve blood glucose control in adults with type 2 diabetes, according to Janssen Pharmaceuticals.

Once-daily Invokamet XR combines canagliflozin (Invokana) and an extended-release formulation of metformin. Studies in healthy adults have shown that Invokamet XR results in the same levels of canagliflozin and metformin in the body as when corresponding dosages of the two medicines are administered as separate tablets.

Courtesy Wikimedia Commons/FitzColinGerald/Creative Commons License

Phase III studies showed that using canagliflozin and metformin lowered blood sugar and, in prespecified secondary endpoints, was linked to greater reductions in body weight and systolic blood pressure.

Invokamet XR is available with 50 mg or 150 mg of canagliflozin, and 500 mg or 1,000 mg of extended-release metformin. Invokamet XR contains a boxed warning regarding the risk of lactic acidosis.

Read the full company statement here.

llaubach@frontlinemedcom.com

The Food and Drug Administration approved an extended-release combination of canagliflozin and metformin for first-line use as an adjunct to diet and exercise to improve blood glucose control in adults with type 2 diabetes, according to Janssen Pharmaceuticals.

Once-daily Invokamet XR combines canagliflozin (Invokana) and an extended-release formulation of metformin. Studies in healthy adults have shown that Invokamet XR results in the same levels of canagliflozin and metformin in the body as when corresponding dosages of the two medicines are administered as separate tablets.

Courtesy Wikimedia Commons/FitzColinGerald/Creative Commons License

Phase III studies showed that using canagliflozin and metformin lowered blood sugar and, in prespecified secondary endpoints, was linked to greater reductions in body weight and systolic blood pressure.

Invokamet XR is available with 50 mg or 150 mg of canagliflozin, and 500 mg or 1,000 mg of extended-release metformin. Invokamet XR contains a boxed warning regarding the risk of lactic acidosis.

Read the full company statement here.

llaubach@frontlinemedcom.com

The Food and Drug Administration approved an extended-release combination of canagliflozin and metformin for first-line use as an adjunct to diet and exercise to improve blood glucose control in adults with type 2 diabetes, according to Janssen Pharmaceuticals.

Once-daily Invokamet XR combines canagliflozin (Invokana) and an extended-release formulation of metformin. Studies in healthy adults have shown that Invokamet XR results in the same levels of canagliflozin and metformin in the body as when corresponding dosages of the two medicines are administered as separate tablets.

Courtesy Wikimedia Commons/FitzColinGerald/Creative Commons License

Phase III studies showed that using canagliflozin and metformin lowered blood sugar and, in prespecified secondary endpoints, was linked to greater reductions in body weight and systolic blood pressure.

Invokamet XR is available with 50 mg or 150 mg of canagliflozin, and 500 mg or 1,000 mg of extended-release metformin. Invokamet XR contains a boxed warning regarding the risk of lactic acidosis.

Read the full company statement here.

llaubach@frontlinemedcom.com

LONDON – Real-world data show that the disease-modifying multiple sclerosis drug alemtuzumab is as effective as natalizumab for preventing relapse and disability progression in patients with relapsing-remitting multiple sclerosis.

Three separate analyses of data involving more than 4,000 patients included in the MSBase Registry and from seven European MS centers showed that alemtuzumab (Lemtrada) was also more effective than subcutaneous interferon beta-1a (IFN beta-1a; Rebif) and fingolimod (Gilenya) for relapse prevention.

“We have seen that alemtuzumab is superior to IFN beta-1a subcutaneous administration in suppressing relapse activity and, in patients with a perilously high level of relapse activity, also in suppressing the probability of reaching disability progression and increasing the probability of reaching disability regression,” Tomas Kalincik, MD, said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

Furthermore, “alemtuzumab was superior to fingolimod in suppressing annualized relapse rates, and comparable to natalizumab (Tysabri) in controlling relapse activity and limiting the probability of disability progression,” said Dr. Kalincik of the University of Melbourne.

Head-to-head trials of MS therapies are lacking, so the aim of the observational study was to compare the treatment effectiveness of alemtuzumab versus natalizumab, IFN beta-1a, and fingolimod. Specifically, the aim was to look at the annualized relapse rate (ARR), cumulative hazard of relapses, and 6-month Expanded Disability Scale Score (EDSS) progression and regression. Propensity score matching was used to make the comparisons between alemtuzumab and the other MS treatments.

Patient data were retrospectively taken from the MSbase database, which includes prospectively collected data from more than 41,000 patients with MS treated at 119 centers in 35 countries. For inclusion in the present analysis, patients had to have definite relapsing-remitting multiple sclerosis, a baseline EDSS of 0-5.5, age of 65 years or younger, and duration of MS of 10 years or less, as well as one or more relapses in the previous year. Patients also needed to have a minimum follow-up of 12 months before and 6 months after they started treatment, and a minimum of two post-baseline visits that were 6 months apart.

Of 15,763 patients with definite MS who commenced treatment with one of the four MS therapies being considered, 4,332 met all the inclusion criteria. Of these, 189 were treated with alemtuzumab, 1,160 with natalizumab, 2,155 with IFN beta-1a, and 828 with fingolimod. Dr. Kalincik noted that the alemtuzumab patient data were combined from seven European MS centers and not the MSBase database.

Versus interferon beta-1a

The first data analysis involved 124 alemtuzumab-treated patients and 219 IFN beta-1a-treated patients with 5 years’ follow-up. Compared with IFN beta-1a, alemtuzumab was associated with an overall lower 5-year ARR of 0.2 versus 0.5 (P less than .001). The annual relapse rates by each individual year were also all significantly lower with alemtuzumab, and the cumulative hazard ratio (HR) of relapses was 0.42 (P less than .001), indicating an almost 60% reduction in relapses over time.

In terms of disability progression, alemtuzumab did not show an advantage over IFN beta-1a, which is in contrast to the findings of its pivotal trials, Dr. Kalincik observed. However, alemtuzumab was found to have an advantage over IFN beta-1a therapy in a secondary analysis if patients had highly active disease, defined as either three or more relapses over a 2-year period or two or more relapses over a 1-year period. The HR for confirmed disability progression was 0.64 (P = .016). Patients with on-treatment relapses within the previous year also fared better if treated with alemtuzumab, with a HR of 3.9 (P = .028) for confirmed disability regression.

Versus fingolimod

The second data analysis involved 114 alemtuzumab-treated patients and 195 fingolimod-treated patients with 3 years’ follow-up. When compared with fingolimod, there was again a much lower ARR overall (0.15 vs. 0.3; P less than .001) at 3 years, and at years 1, 2, and 3 individually (P less than .05). There was a nonsignificant 40% reduction in the relapse rate over time.

“For the disability outcomes, we haven’t seen any statistically significant difference, neither between the 6-month confirmed disability progression nor the 6-month confirmed disability regression,” Dr. Kalincik reported.

Versus natalizumab

The third and final analysis involved 138 alemtuzumab-treated patients and 223 natalizumab-treated patients with 4 years’ follow-up. There were no significant differences found in either the ARR overall (0.2 for both treatments; P = .8) or by follow-up year, and the cumulative hazard of relapses was the same.

Although there was no significant difference in confirmed disability progression at 6 months between the two treatments, there was a significant difference observed for the confirmed 6-month disability regression that favored natalizumab during the first year of treatment, Dr. Kalincik said. After 1 year, this potential advantage disappeared, he observed.

A large number of sensitivity analyses were performed and “largely confirm” the outcomes of the primary analyses.

Limitations include the lack of MRI data, and it was not possible to evaluate the relative safety of treatments.

Dr. Kalincik disclosed ties with Roche, Genzyme, Novartis, Merck, Biogen, WebMD Global, Sanofi, Teva, and BioCSL.

LONDON – Real-world data show that the disease-modifying multiple sclerosis drug alemtuzumab is as effective as natalizumab for preventing relapse and disability progression in patients with relapsing-remitting multiple sclerosis.

Three separate analyses of data involving more than 4,000 patients included in the MSBase Registry and from seven European MS centers showed that alemtuzumab (Lemtrada) was also more effective than subcutaneous interferon beta-1a (IFN beta-1a; Rebif) and fingolimod (Gilenya) for relapse prevention.

“We have seen that alemtuzumab is superior to IFN beta-1a subcutaneous administration in suppressing relapse activity and, in patients with a perilously high level of relapse activity, also in suppressing the probability of reaching disability progression and increasing the probability of reaching disability regression,” Tomas Kalincik, MD, said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

Furthermore, “alemtuzumab was superior to fingolimod in suppressing annualized relapse rates, and comparable to natalizumab (Tysabri) in controlling relapse activity and limiting the probability of disability progression,” said Dr. Kalincik of the University of Melbourne.

Head-to-head trials of MS therapies are lacking, so the aim of the observational study was to compare the treatment effectiveness of alemtuzumab versus natalizumab, IFN beta-1a, and fingolimod. Specifically, the aim was to look at the annualized relapse rate (ARR), cumulative hazard of relapses, and 6-month Expanded Disability Scale Score (EDSS) progression and regression. Propensity score matching was used to make the comparisons between alemtuzumab and the other MS treatments.

Patient data were retrospectively taken from the MSbase database, which includes prospectively collected data from more than 41,000 patients with MS treated at 119 centers in 35 countries. For inclusion in the present analysis, patients had to have definite relapsing-remitting multiple sclerosis, a baseline EDSS of 0-5.5, age of 65 years or younger, and duration of MS of 10 years or less, as well as one or more relapses in the previous year. Patients also needed to have a minimum follow-up of 12 months before and 6 months after they started treatment, and a minimum of two post-baseline visits that were 6 months apart.

Of 15,763 patients with definite MS who commenced treatment with one of the four MS therapies being considered, 4,332 met all the inclusion criteria. Of these, 189 were treated with alemtuzumab, 1,160 with natalizumab, 2,155 with IFN beta-1a, and 828 with fingolimod. Dr. Kalincik noted that the alemtuzumab patient data were combined from seven European MS centers and not the MSBase database.

Versus interferon beta-1a

The first data analysis involved 124 alemtuzumab-treated patients and 219 IFN beta-1a-treated patients with 5 years’ follow-up. Compared with IFN beta-1a, alemtuzumab was associated with an overall lower 5-year ARR of 0.2 versus 0.5 (P less than .001). The annual relapse rates by each individual year were also all significantly lower with alemtuzumab, and the cumulative hazard ratio (HR) of relapses was 0.42 (P less than .001), indicating an almost 60% reduction in relapses over time.

In terms of disability progression, alemtuzumab did not show an advantage over IFN beta-1a, which is in contrast to the findings of its pivotal trials, Dr. Kalincik observed. However, alemtuzumab was found to have an advantage over IFN beta-1a therapy in a secondary analysis if patients had highly active disease, defined as either three or more relapses over a 2-year period or two or more relapses over a 1-year period. The HR for confirmed disability progression was 0.64 (P = .016). Patients with on-treatment relapses within the previous year also fared better if treated with alemtuzumab, with a HR of 3.9 (P = .028) for confirmed disability regression.

Versus fingolimod

The second data analysis involved 114 alemtuzumab-treated patients and 195 fingolimod-treated patients with 3 years’ follow-up. When compared with fingolimod, there was again a much lower ARR overall (0.15 vs. 0.3; P less than .001) at 3 years, and at years 1, 2, and 3 individually (P less than .05). There was a nonsignificant 40% reduction in the relapse rate over time.

“For the disability outcomes, we haven’t seen any statistically significant difference, neither between the 6-month confirmed disability progression nor the 6-month confirmed disability regression,” Dr. Kalincik reported.

Versus natalizumab

The third and final analysis involved 138 alemtuzumab-treated patients and 223 natalizumab-treated patients with 4 years’ follow-up. There were no significant differences found in either the ARR overall (0.2 for both treatments; P = .8) or by follow-up year, and the cumulative hazard of relapses was the same.

Although there was no significant difference in confirmed disability progression at 6 months between the two treatments, there was a significant difference observed for the confirmed 6-month disability regression that favored natalizumab during the first year of treatment, Dr. Kalincik said. After 1 year, this potential advantage disappeared, he observed.

A large number of sensitivity analyses were performed and “largely confirm” the outcomes of the primary analyses.

Limitations include the lack of MRI data, and it was not possible to evaluate the relative safety of treatments.

Dr. Kalincik disclosed ties with Roche, Genzyme, Novartis, Merck, Biogen, WebMD Global, Sanofi, Teva, and BioCSL.

LONDON – Real-world data show that the disease-modifying multiple sclerosis drug alemtuzumab is as effective as natalizumab for preventing relapse and disability progression in patients with relapsing-remitting multiple sclerosis.

Three separate analyses of data involving more than 4,000 patients included in the MSBase Registry and from seven European MS centers showed that alemtuzumab (Lemtrada) was also more effective than subcutaneous interferon beta-1a (IFN beta-1a; Rebif) and fingolimod (Gilenya) for relapse prevention.

“We have seen that alemtuzumab is superior to IFN beta-1a subcutaneous administration in suppressing relapse activity and, in patients with a perilously high level of relapse activity, also in suppressing the probability of reaching disability progression and increasing the probability of reaching disability regression,” Tomas Kalincik, MD, said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

Furthermore, “alemtuzumab was superior to fingolimod in suppressing annualized relapse rates, and comparable to natalizumab (Tysabri) in controlling relapse activity and limiting the probability of disability progression,” said Dr. Kalincik of the University of Melbourne.

Head-to-head trials of MS therapies are lacking, so the aim of the observational study was to compare the treatment effectiveness of alemtuzumab versus natalizumab, IFN beta-1a, and fingolimod. Specifically, the aim was to look at the annualized relapse rate (ARR), cumulative hazard of relapses, and 6-month Expanded Disability Scale Score (EDSS) progression and regression. Propensity score matching was used to make the comparisons between alemtuzumab and the other MS treatments.

Patient data were retrospectively taken from the MSbase database, which includes prospectively collected data from more than 41,000 patients with MS treated at 119 centers in 35 countries. For inclusion in the present analysis, patients had to have definite relapsing-remitting multiple sclerosis, a baseline EDSS of 0-5.5, age of 65 years or younger, and duration of MS of 10 years or less, as well as one or more relapses in the previous year. Patients also needed to have a minimum follow-up of 12 months before and 6 months after they started treatment, and a minimum of two post-baseline visits that were 6 months apart.

Of 15,763 patients with definite MS who commenced treatment with one of the four MS therapies being considered, 4,332 met all the inclusion criteria. Of these, 189 were treated with alemtuzumab, 1,160 with natalizumab, 2,155 with IFN beta-1a, and 828 with fingolimod. Dr. Kalincik noted that the alemtuzumab patient data were combined from seven European MS centers and not the MSBase database.

Versus interferon beta-1a

The first data analysis involved 124 alemtuzumab-treated patients and 219 IFN beta-1a-treated patients with 5 years’ follow-up. Compared with IFN beta-1a, alemtuzumab was associated with an overall lower 5-year ARR of 0.2 versus 0.5 (P less than .001). The annual relapse rates by each individual year were also all significantly lower with alemtuzumab, and the cumulative hazard ratio (HR) of relapses was 0.42 (P less than .001), indicating an almost 60% reduction in relapses over time.

In terms of disability progression, alemtuzumab did not show an advantage over IFN beta-1a, which is in contrast to the findings of its pivotal trials, Dr. Kalincik observed. However, alemtuzumab was found to have an advantage over IFN beta-1a therapy in a secondary analysis if patients had highly active disease, defined as either three or more relapses over a 2-year period or two or more relapses over a 1-year period. The HR for confirmed disability progression was 0.64 (P = .016). Patients with on-treatment relapses within the previous year also fared better if treated with alemtuzumab, with a HR of 3.9 (P = .028) for confirmed disability regression.

Versus fingolimod

The second data analysis involved 114 alemtuzumab-treated patients and 195 fingolimod-treated patients with 3 years’ follow-up. When compared with fingolimod, there was again a much lower ARR overall (0.15 vs. 0.3; P less than .001) at 3 years, and at years 1, 2, and 3 individually (P less than .05). There was a nonsignificant 40% reduction in the relapse rate over time.

“For the disability outcomes, we haven’t seen any statistically significant difference, neither between the 6-month confirmed disability progression nor the 6-month confirmed disability regression,” Dr. Kalincik reported.

Versus natalizumab

The third and final analysis involved 138 alemtuzumab-treated patients and 223 natalizumab-treated patients with 4 years’ follow-up. There were no significant differences found in either the ARR overall (0.2 for both treatments; P = .8) or by follow-up year, and the cumulative hazard of relapses was the same.

Although there was no significant difference in confirmed disability progression at 6 months between the two treatments, there was a significant difference observed for the confirmed 6-month disability regression that favored natalizumab during the first year of treatment, Dr. Kalincik said. After 1 year, this potential advantage disappeared, he observed.

A large number of sensitivity analyses were performed and “largely confirm” the outcomes of the primary analyses.

Limitations include the lack of MRI data, and it was not possible to evaluate the relative safety of treatments.

Dr. Kalincik disclosed ties with Roche, Genzyme, Novartis, Merck, Biogen, WebMD Global, Sanofi, Teva, and BioCSL.

PORTLAND, OR—Higher serum levels of polychlorinated biphenyls (PCBs) are associated with increased risk of Parkinson’s disease in two independent study populations, according to research presented at the Fourth World Parkinson Congress.

PCBs are persistent environmental pollutants that are detectable in most people despite a worldwide ban on their production that has been in place for more than 20 years. PCBs cause selective dopaminergic toxicity in animal models, but have been minimally studied in Parkinson’s disease, the researchers said.

The investigators recently reported a significantly increased risk of Parkinson’s disease associated with higher levels of serum PCBs in a case–control study of Alaska Native people. In the present study, they investigated this association in a demographically dissimilar study population.

They identified people with Parkinson’s disease within the Agricultural Health Study, a cohort of pesticide applicators and their spouses in Iowa and North Carolina. They also randomly selected controls matched for age, sex, and state. They confirmed Parkinson’s disease diagnoses by in-person neurologist evaluation and consensus review. PCB congeners 118, 138, 153, and 180 were measured as ng/g lipid in serum using gas chromatography-mass spectroscopy. To assess dose-response, the researchers constructed quartiles for each congener and for the sum of congeners. The used logistic regression, adjusting for age, gender, and state, to calculate odds ratios.

Ninety-seven people with Parkinson’s disease and 113 controls were included in the study. About 25% of the participants were women. Mean age was 69. Parkinson’s disease was associated with higher levels of PCBs. A significant dose-response was seen across quartiles. Participants in the second, third, and fourth quartiles of total PCB levels had a 1.7-, 2.4-, and 2.7-fold greater risk of Parkinson’s disease, respectively, compared with participants in the lowest quartile of total PCB levels. Odds ratios were similar in the Agricultural Heath Study and the Alaska study. In both studies, PCB levels correlated positively with age but not with disease duration, which argues against reverse causation, the researchers said.

—Jake Remaly

PORTLAND, OR—Higher serum levels of polychlorinated biphenyls (PCBs) are associated with increased risk of Parkinson’s disease in two independent study populations, according to research presented at the Fourth World Parkinson Congress.

PCBs are persistent environmental pollutants that are detectable in most people despite a worldwide ban on their production that has been in place for more than 20 years. PCBs cause selective dopaminergic toxicity in animal models, but have been minimally studied in Parkinson’s disease, the researchers said.

The investigators recently reported a significantly increased risk of Parkinson’s disease associated with higher levels of serum PCBs in a case–control study of Alaska Native people. In the present study, they investigated this association in a demographically dissimilar study population.

They identified people with Parkinson’s disease within the Agricultural Health Study, a cohort of pesticide applicators and their spouses in Iowa and North Carolina. They also randomly selected controls matched for age, sex, and state. They confirmed Parkinson’s disease diagnoses by in-person neurologist evaluation and consensus review. PCB congeners 118, 138, 153, and 180 were measured as ng/g lipid in serum using gas chromatography-mass spectroscopy. To assess dose-response, the researchers constructed quartiles for each congener and for the sum of congeners. The used logistic regression, adjusting for age, gender, and state, to calculate odds ratios.

Ninety-seven people with Parkinson’s disease and 113 controls were included in the study. About 25% of the participants were women. Mean age was 69. Parkinson’s disease was associated with higher levels of PCBs. A significant dose-response was seen across quartiles. Participants in the second, third, and fourth quartiles of total PCB levels had a 1.7-, 2.4-, and 2.7-fold greater risk of Parkinson’s disease, respectively, compared with participants in the lowest quartile of total PCB levels. Odds ratios were similar in the Agricultural Heath Study and the Alaska study. In both studies, PCB levels correlated positively with age but not with disease duration, which argues against reverse causation, the researchers said.

—Jake Remaly

PORTLAND, OR—Higher serum levels of polychlorinated biphenyls (PCBs) are associated with increased risk of Parkinson’s disease in two independent study populations, according to research presented at the Fourth World Parkinson Congress.

PCBs are persistent environmental pollutants that are detectable in most people despite a worldwide ban on their production that has been in place for more than 20 years. PCBs cause selective dopaminergic toxicity in animal models, but have been minimally studied in Parkinson’s disease, the researchers said.

The investigators recently reported a significantly increased risk of Parkinson’s disease associated with higher levels of serum PCBs in a case–control study of Alaska Native people. In the present study, they investigated this association in a demographically dissimilar study population.

They identified people with Parkinson’s disease within the Agricultural Health Study, a cohort of pesticide applicators and their spouses in Iowa and North Carolina. They also randomly selected controls matched for age, sex, and state. They confirmed Parkinson’s disease diagnoses by in-person neurologist evaluation and consensus review. PCB congeners 118, 138, 153, and 180 were measured as ng/g lipid in serum using gas chromatography-mass spectroscopy. To assess dose-response, the researchers constructed quartiles for each congener and for the sum of congeners. The used logistic regression, adjusting for age, gender, and state, to calculate odds ratios.

Ninety-seven people with Parkinson’s disease and 113 controls were included in the study. About 25% of the participants were women. Mean age was 69. Parkinson’s disease was associated with higher levels of PCBs. A significant dose-response was seen across quartiles. Participants in the second, third, and fourth quartiles of total PCB levels had a 1.7-, 2.4-, and 2.7-fold greater risk of Parkinson’s disease, respectively, compared with participants in the lowest quartile of total PCB levels. Odds ratios were similar in the Agricultural Heath Study and the Alaska study. In both studies, PCB levels correlated positively with age but not with disease duration, which argues against reverse causation, the researchers said.

—Jake Remaly

PORTLAND, OR—High doses of transdermal nicotine failed to improve off motor symptoms in patients with Parkinson’s disease, according to trial results presented at the Fourth World Parkinson Congress. Nicotine may have provided benefit on secondary outcome measures, researchers said.

Gabriel Villafane, MD, a neurologist at Henri Mondor University Hospital in Créteil, France, and colleagues conducted the Nicopark2 Study, a single-blind, controlled, randomized trial to evaluate the effect of high doses of transdermal nicotine (approximately 90 mg per day) on motor symptoms in Parkinson’s disease.

Cigarette smoking is associated with a dose-dependent reduction in risk of Parkinson’s disease. Nicotine’s effect on motor symptoms in Parkinson’s disease is controversial. Seven of eight open-label studies suggested that nicotine improves motor symptoms, but four placebo-controlled studies were negative.

The investigators enrolled 40 patients with Parkinson’s disease in the study. Eligible patients were nonsmokers age 35 to 70 with a Hoehn and Yahr off stage of four or less and a Hoehn and Yahr on stage of three or less. Patients had received levodopa treatment for at least three years. Exclusion criteria included neurosurgery, psychiatric disease, and symptomatic orthostatic hypotension.

The primary outcome was mean difference between groups in change of Unified Parkinson’s Disease Rating Scale off motor score from baseline to week 39 on blinded video rating.

Twenty patients were randomized to receive transdermal nicotine, and 20 patients were randomized to a control group. The change in motor score between groups was not statistically significant. Change in quality of life assessed by the Parkinson’s Disease Questionnaire was not statistically significant. At 39 weeks, a reduction in levodopa doses, a reduction in dyskinesias, and an improvement in activities of daily living were observed in the nicotine group, the researchers said.

Adverse events occurred in more patients the nicotine group than in the control group. They included worsening of parkinsonism (30% vs 5%), cutaneous reactions (35% vs 5%), gastrointestinal complaints (65% vs 15%), hypotension (25% vs 5%), insomnia (25% vs 5%), and nervousness and anxiety (20% vs 0%). Ten patients in the nicotine group had a serious adverse event, compared with three patients in the control group.

—Jake Remaly

PORTLAND, OR—High doses of transdermal nicotine failed to improve off motor symptoms in patients with Parkinson’s disease, according to trial results presented at the Fourth World Parkinson Congress. Nicotine may have provided benefit on secondary outcome measures, researchers said.

Gabriel Villafane, MD, a neurologist at Henri Mondor University Hospital in Créteil, France, and colleagues conducted the Nicopark2 Study, a single-blind, controlled, randomized trial to evaluate the effect of high doses of transdermal nicotine (approximately 90 mg per day) on motor symptoms in Parkinson’s disease.

Cigarette smoking is associated with a dose-dependent reduction in risk of Parkinson’s disease. Nicotine’s effect on motor symptoms in Parkinson’s disease is controversial. Seven of eight open-label studies suggested that nicotine improves motor symptoms, but four placebo-controlled studies were negative.

The investigators enrolled 40 patients with Parkinson’s disease in the study. Eligible patients were nonsmokers age 35 to 70 with a Hoehn and Yahr off stage of four or less and a Hoehn and Yahr on stage of three or less. Patients had received levodopa treatment for at least three years. Exclusion criteria included neurosurgery, psychiatric disease, and symptomatic orthostatic hypotension.

The primary outcome was mean difference between groups in change of Unified Parkinson’s Disease Rating Scale off motor score from baseline to week 39 on blinded video rating.

Twenty patients were randomized to receive transdermal nicotine, and 20 patients were randomized to a control group. The change in motor score between groups was not statistically significant. Change in quality of life assessed by the Parkinson’s Disease Questionnaire was not statistically significant. At 39 weeks, a reduction in levodopa doses, a reduction in dyskinesias, and an improvement in activities of daily living were observed in the nicotine group, the researchers said.

Adverse events occurred in more patients the nicotine group than in the control group. They included worsening of parkinsonism (30% vs 5%), cutaneous reactions (35% vs 5%), gastrointestinal complaints (65% vs 15%), hypotension (25% vs 5%), insomnia (25% vs 5%), and nervousness and anxiety (20% vs 0%). Ten patients in the nicotine group had a serious adverse event, compared with three patients in the control group.

—Jake Remaly

PORTLAND, OR—High doses of transdermal nicotine failed to improve off motor symptoms in patients with Parkinson’s disease, according to trial results presented at the Fourth World Parkinson Congress. Nicotine may have provided benefit on secondary outcome measures, researchers said.

Gabriel Villafane, MD, a neurologist at Henri Mondor University Hospital in Créteil, France, and colleagues conducted the Nicopark2 Study, a single-blind, controlled, randomized trial to evaluate the effect of high doses of transdermal nicotine (approximately 90 mg per day) on motor symptoms in Parkinson’s disease.

Cigarette smoking is associated with a dose-dependent reduction in risk of Parkinson’s disease. Nicotine’s effect on motor symptoms in Parkinson’s disease is controversial. Seven of eight open-label studies suggested that nicotine improves motor symptoms, but four placebo-controlled studies were negative.

The investigators enrolled 40 patients with Parkinson’s disease in the study. Eligible patients were nonsmokers age 35 to 70 with a Hoehn and Yahr off stage of four or less and a Hoehn and Yahr on stage of three or less. Patients had received levodopa treatment for at least three years. Exclusion criteria included neurosurgery, psychiatric disease, and symptomatic orthostatic hypotension.

The primary outcome was mean difference between groups in change of Unified Parkinson’s Disease Rating Scale off motor score from baseline to week 39 on blinded video rating.

Twenty patients were randomized to receive transdermal nicotine, and 20 patients were randomized to a control group. The change in motor score between groups was not statistically significant. Change in quality of life assessed by the Parkinson’s Disease Questionnaire was not statistically significant. At 39 weeks, a reduction in levodopa doses, a reduction in dyskinesias, and an improvement in activities of daily living were observed in the nicotine group, the researchers said.

Adverse events occurred in more patients the nicotine group than in the control group. They included worsening of parkinsonism (30% vs 5%), cutaneous reactions (35% vs 5%), gastrointestinal complaints (65% vs 15%), hypotension (25% vs 5%), insomnia (25% vs 5%), and nervousness and anxiety (20% vs 0%). Ten patients in the nicotine group had a serious adverse event, compared with three patients in the control group.

—Jake Remaly