Hematology Times

Dottie Thomas with her

husband, E. Donnall Thomas,

at a 2005 reunion of transplant

patients in Seattle

Photo by Jim Linna

Dorothy “Dottie” Thomas, the wife and research partner of 1990 Nobel laureate E. Donnall “Don” Thomas, MD, passed away on January 9 at the age of 92.

Don, pioneer of the bone marrow transplant (BMT), preceded Dottie in passing away himself on October 20, 2012, also at the age of 92.

The Thomases formed the core of a team that proved BMT could cure leukemias and other hematologic malignancies, work that spanned several decades.

Dottie may have gotten the name “the mother of bone marrow transplantation,” from the late George Santos, MD, a BMT expert at Johns Hopkins University School of Medicine in Baltimore, Maryland, and a colleague.

“If Dr Thomas is the father of bone marrow transplantation, then Dottie Thomas is the mother,” he once said.

“Dottie’s life had a profound impact, not just on those who knew her personally, but also countless patients,” said Gary Gilliland, MD, PhD, president and director of the Fred Hutchinson Cancer Research Center in Seattle, Washington, who became friends with the Thomases when he and Don served on the advisory board of the José Carreras Leukemia Foundation.

“She and Don were amazing together in both what they accomplished and the way they cared for each other. They were so sweet together. Now, their legacy continues through the many whose lives have been saved by bone marrow transplant and those who will be saved in the future. Dottie truly helped change the future of medicine. All of us at Fred Hutch are part of her legacy.”

A romantic partnership becomes a professional one

A snowball to the face during a rare Texas snowfall in 1940 precipitated a partnership in love and work between Don and Dottie that spanned 70 years.

“I was a senior at the University of Texas when she was a freshman,” Don told The Seattle Times in a 1999 interview. “I was waiting tables at the girls dormitory, which is how I got my food.”

“It snowed in Texas, which is very unusual. And I came out of the dormitory after we’d finished serving breakfast, and there was about 6 inches of snow. This girl whacked me in the face with a snowball. She still claims she was throwing it at another fellow and hit me by mistake. One thing led to another, and we seemed to hit it off.”

The couple married in December 1942. Dottie was a journalism major in college when, in March 1943, Don was admitted to Harvard University Medical School under a US Army program. Dottie got a job as a secretary with the Navy while Don attended medical school.

“Dottie and I talked it over, and we decided that if we were going to spend time together, which it turned out we liked to do, that she probably ought to change her profession,” Don told The Seattle Times. “She’d taken a lot of science in her time in school, much more than most journalists. She liked science.”

So Dottie left her Navy job and enrolled in the medical technology training program at New England Deaconess Hospital.

“Because Dottie was a hematology technician, we used to look at smears and bone marrow together when we were students,” Don said.

She worked as a medical technician for some doctors in Boston until Don had his own laboratory. Then, she began to work with him. She worked part-time when their children were small, but, otherwise, she was in the lab full-time with her husband.

“Dottie was there at Don’s side through every part of developing marrow transplantation as a science,” said Fred Appelbaum, MD, executive vice president and deputy director of the Fred Hutchinson Cancer Research Center.

“Besides raising 3 children together, Dottie was Don’s partner in every aspect of his professional life, from working in the laboratory to editing manuscripts and administering his research program.”

Dottie’s journalism training was a big asset to the team, according to Don.

“In the laboratory days, my friends pointed out that Dottie, who had the library experience, would go to the library and look up all the background information for a study that we were going to do, and then she would go into the laboratory and do the work and get the data, and then, with her writing skills, she’d write the paper and complete the bibliography,” Don recalled. “All I would do is sign the letter to the editor.”

The couple moved to Seattle in 1963. Don joined the Fred Hutchinson Cancer Research Center in 1975, the year its doors opened in Seattle’s First Hill neighborhood. For the next 15 years, Dottie served as the chief administrator for the Clinical Research Division. Don stepped down from the clinical leadership position in 1990 and retired from the center in 2002.

The Thomases are survived by 2 sons and a daughter, 8 grandchildren, and 2 great-grandchildren.

The family requests that people who wish to honor Dottie do so by contributing to Dottie’s Bridge, an endowment to assist young researchers.

Dottie Thomas with her

husband, E. Donnall Thomas,

at a 2005 reunion of transplant

patients in Seattle

Photo by Jim Linna

Dorothy “Dottie” Thomas, the wife and research partner of 1990 Nobel laureate E. Donnall “Don” Thomas, MD, passed away on January 9 at the age of 92.

Don, pioneer of the bone marrow transplant (BMT), preceded Dottie in passing away himself on October 20, 2012, also at the age of 92.

The Thomases formed the core of a team that proved BMT could cure leukemias and other hematologic malignancies, work that spanned several decades.

Dottie may have gotten the name “the mother of bone marrow transplantation,” from the late George Santos, MD, a BMT expert at Johns Hopkins University School of Medicine in Baltimore, Maryland, and a colleague.

“If Dr Thomas is the father of bone marrow transplantation, then Dottie Thomas is the mother,” he once said.

“Dottie’s life had a profound impact, not just on those who knew her personally, but also countless patients,” said Gary Gilliland, MD, PhD, president and director of the Fred Hutchinson Cancer Research Center in Seattle, Washington, who became friends with the Thomases when he and Don served on the advisory board of the José Carreras Leukemia Foundation.

“She and Don were amazing together in both what they accomplished and the way they cared for each other. They were so sweet together. Now, their legacy continues through the many whose lives have been saved by bone marrow transplant and those who will be saved in the future. Dottie truly helped change the future of medicine. All of us at Fred Hutch are part of her legacy.”

A romantic partnership becomes a professional one

A snowball to the face during a rare Texas snowfall in 1940 precipitated a partnership in love and work between Don and Dottie that spanned 70 years.

“I was a senior at the University of Texas when she was a freshman,” Don told The Seattle Times in a 1999 interview. “I was waiting tables at the girls dormitory, which is how I got my food.”

“It snowed in Texas, which is very unusual. And I came out of the dormitory after we’d finished serving breakfast, and there was about 6 inches of snow. This girl whacked me in the face with a snowball. She still claims she was throwing it at another fellow and hit me by mistake. One thing led to another, and we seemed to hit it off.”

The couple married in December 1942. Dottie was a journalism major in college when, in March 1943, Don was admitted to Harvard University Medical School under a US Army program. Dottie got a job as a secretary with the Navy while Don attended medical school.

“Dottie and I talked it over, and we decided that if we were going to spend time together, which it turned out we liked to do, that she probably ought to change her profession,” Don told The Seattle Times. “She’d taken a lot of science in her time in school, much more than most journalists. She liked science.”

So Dottie left her Navy job and enrolled in the medical technology training program at New England Deaconess Hospital.

“Because Dottie was a hematology technician, we used to look at smears and bone marrow together when we were students,” Don said.

She worked as a medical technician for some doctors in Boston until Don had his own laboratory. Then, she began to work with him. She worked part-time when their children were small, but, otherwise, she was in the lab full-time with her husband.

“Dottie was there at Don’s side through every part of developing marrow transplantation as a science,” said Fred Appelbaum, MD, executive vice president and deputy director of the Fred Hutchinson Cancer Research Center.

“Besides raising 3 children together, Dottie was Don’s partner in every aspect of his professional life, from working in the laboratory to editing manuscripts and administering his research program.”

Dottie’s journalism training was a big asset to the team, according to Don.

“In the laboratory days, my friends pointed out that Dottie, who had the library experience, would go to the library and look up all the background information for a study that we were going to do, and then she would go into the laboratory and do the work and get the data, and then, with her writing skills, she’d write the paper and complete the bibliography,” Don recalled. “All I would do is sign the letter to the editor.”

The couple moved to Seattle in 1963. Don joined the Fred Hutchinson Cancer Research Center in 1975, the year its doors opened in Seattle’s First Hill neighborhood. For the next 15 years, Dottie served as the chief administrator for the Clinical Research Division. Don stepped down from the clinical leadership position in 1990 and retired from the center in 2002.

The Thomases are survived by 2 sons and a daughter, 8 grandchildren, and 2 great-grandchildren.

The family requests that people who wish to honor Dottie do so by contributing to Dottie’s Bridge, an endowment to assist young researchers.

Dottie Thomas with her

husband, E. Donnall Thomas,

at a 2005 reunion of transplant

patients in Seattle

Photo by Jim Linna

Dorothy “Dottie” Thomas, the wife and research partner of 1990 Nobel laureate E. Donnall “Don” Thomas, MD, passed away on January 9 at the age of 92.

Don, pioneer of the bone marrow transplant (BMT), preceded Dottie in passing away himself on October 20, 2012, also at the age of 92.

The Thomases formed the core of a team that proved BMT could cure leukemias and other hematologic malignancies, work that spanned several decades.

Dottie may have gotten the name “the mother of bone marrow transplantation,” from the late George Santos, MD, a BMT expert at Johns Hopkins University School of Medicine in Baltimore, Maryland, and a colleague.

“If Dr Thomas is the father of bone marrow transplantation, then Dottie Thomas is the mother,” he once said.

“Dottie’s life had a profound impact, not just on those who knew her personally, but also countless patients,” said Gary Gilliland, MD, PhD, president and director of the Fred Hutchinson Cancer Research Center in Seattle, Washington, who became friends with the Thomases when he and Don served on the advisory board of the José Carreras Leukemia Foundation.

“She and Don were amazing together in both what they accomplished and the way they cared for each other. They were so sweet together. Now, their legacy continues through the many whose lives have been saved by bone marrow transplant and those who will be saved in the future. Dottie truly helped change the future of medicine. All of us at Fred Hutch are part of her legacy.”

A romantic partnership becomes a professional one

A snowball to the face during a rare Texas snowfall in 1940 precipitated a partnership in love and work between Don and Dottie that spanned 70 years.

“I was a senior at the University of Texas when she was a freshman,” Don told The Seattle Times in a 1999 interview. “I was waiting tables at the girls dormitory, which is how I got my food.”

“It snowed in Texas, which is very unusual. And I came out of the dormitory after we’d finished serving breakfast, and there was about 6 inches of snow. This girl whacked me in the face with a snowball. She still claims she was throwing it at another fellow and hit me by mistake. One thing led to another, and we seemed to hit it off.”

The couple married in December 1942. Dottie was a journalism major in college when, in March 1943, Don was admitted to Harvard University Medical School under a US Army program. Dottie got a job as a secretary with the Navy while Don attended medical school.

“Dottie and I talked it over, and we decided that if we were going to spend time together, which it turned out we liked to do, that she probably ought to change her profession,” Don told The Seattle Times. “She’d taken a lot of science in her time in school, much more than most journalists. She liked science.”

So Dottie left her Navy job and enrolled in the medical technology training program at New England Deaconess Hospital.

“Because Dottie was a hematology technician, we used to look at smears and bone marrow together when we were students,” Don said.

She worked as a medical technician for some doctors in Boston until Don had his own laboratory. Then, she began to work with him. She worked part-time when their children were small, but, otherwise, she was in the lab full-time with her husband.

“Dottie was there at Don’s side through every part of developing marrow transplantation as a science,” said Fred Appelbaum, MD, executive vice president and deputy director of the Fred Hutchinson Cancer Research Center.

“Besides raising 3 children together, Dottie was Don’s partner in every aspect of his professional life, from working in the laboratory to editing manuscripts and administering his research program.”

Dottie’s journalism training was a big asset to the team, according to Don.

“In the laboratory days, my friends pointed out that Dottie, who had the library experience, would go to the library and look up all the background information for a study that we were going to do, and then she would go into the laboratory and do the work and get the data, and then, with her writing skills, she’d write the paper and complete the bibliography,” Don recalled. “All I would do is sign the letter to the editor.”

The couple moved to Seattle in 1963. Don joined the Fred Hutchinson Cancer Research Center in 1975, the year its doors opened in Seattle’s First Hill neighborhood. For the next 15 years, Dottie served as the chief administrator for the Clinical Research Division. Don stepped down from the clinical leadership position in 1990 and retired from the center in 2002.

The Thomases are survived by 2 sons and a daughter, 8 grandchildren, and 2 great-grandchildren.

The family requests that people who wish to honor Dottie do so by contributing to Dottie’s Bridge, an endowment to assist young researchers.

Syringe

A study of more than 2000 patients refutes the idea that biopsies cause cancer to spread.

In a study published in Gut, researchers showed that patients who received a biopsy had better overall survival and similar cancer-free survival rates as patients who did not have a biopsy.

The team studied pancreatic cancer but said their findings likely apply to other cancers because the diagnostic technique used in this study—fine needle aspiration—is commonly used across tumor types.

“This study shows that physicians and patients should feel reassured that a biopsy is very safe,” said study author Michael Wallace, MD, of the Mayo Clinic in Jacksonville, Florida.

“We do millions of biopsies of cancer a year in the US, but one or two case studies have led to this common myth that biopsies spread cancer.”

This is the second study Dr Wallace and his team have conducted to examine the risk of biopsy.

In a 2013 study published in Endoscopy, the researchers examined outcomes in 256 pancreatic cancer patients treated at the Mayo Clinic in Jacksonville. The team found no difference in cancer recurrence between 208 patients who had ultrasound-guided fine needle aspiration (EUS-FNA) and the 48 patients who did not have a biopsy.

In the current study, the researchers examined 11 years (1998-2009) of Medicare data on patients with non-metastatic pancreatic cancer who underwent surgery. The team examined overall survival and pancreatic cancer-specific survival in 498 patients who had EUS-FNA and in 1536 patients who did not have a biopsy.

During a mean follow-up time of 21 months, 285 patients (57%) in the EUS-FNA group and 1167 patients (76%) in the non-EUS-FNA group died. Pancreatic cancer was identified as the cause of death for 251 patients (50%) in the EUS-FNA group and 980 patients (64%) in the non-EUS-FNA group.

The median overall survival in the EUS-FNA group was 22 months, compared to 15 months in the non-EUS-FNA group. Multivariate analysis showed that receipt of EUS-FNA had a borderline significant association with improved overall survival (hazard ratio=0.84, P=0.03).

The median cancer-specific survival was 24 months in the EUS-FNA group and 18 months in the non-EUS-FNA group. Multivariate analysis revealed no significant difference between the two groups (hazard ratio=0.87, P=0.12).

“[Biopsies provide] very valuable information that allow us to tailor treatment,” Dr Wallace noted. “In some cases, we can offer chemotherapy and radiation before surgery for a better outcome, and, in other cases, we can avoid surgery and other therapy altogether.”

Syringe

A study of more than 2000 patients refutes the idea that biopsies cause cancer to spread.

In a study published in Gut, researchers showed that patients who received a biopsy had better overall survival and similar cancer-free survival rates as patients who did not have a biopsy.

The team studied pancreatic cancer but said their findings likely apply to other cancers because the diagnostic technique used in this study—fine needle aspiration—is commonly used across tumor types.

“This study shows that physicians and patients should feel reassured that a biopsy is very safe,” said study author Michael Wallace, MD, of the Mayo Clinic in Jacksonville, Florida.

“We do millions of biopsies of cancer a year in the US, but one or two case studies have led to this common myth that biopsies spread cancer.”

This is the second study Dr Wallace and his team have conducted to examine the risk of biopsy.

In a 2013 study published in Endoscopy, the researchers examined outcomes in 256 pancreatic cancer patients treated at the Mayo Clinic in Jacksonville. The team found no difference in cancer recurrence between 208 patients who had ultrasound-guided fine needle aspiration (EUS-FNA) and the 48 patients who did not have a biopsy.

In the current study, the researchers examined 11 years (1998-2009) of Medicare data on patients with non-metastatic pancreatic cancer who underwent surgery. The team examined overall survival and pancreatic cancer-specific survival in 498 patients who had EUS-FNA and in 1536 patients who did not have a biopsy.

During a mean follow-up time of 21 months, 285 patients (57%) in the EUS-FNA group and 1167 patients (76%) in the non-EUS-FNA group died. Pancreatic cancer was identified as the cause of death for 251 patients (50%) in the EUS-FNA group and 980 patients (64%) in the non-EUS-FNA group.

The median overall survival in the EUS-FNA group was 22 months, compared to 15 months in the non-EUS-FNA group. Multivariate analysis showed that receipt of EUS-FNA had a borderline significant association with improved overall survival (hazard ratio=0.84, P=0.03).

The median cancer-specific survival was 24 months in the EUS-FNA group and 18 months in the non-EUS-FNA group. Multivariate analysis revealed no significant difference between the two groups (hazard ratio=0.87, P=0.12).

“[Biopsies provide] very valuable information that allow us to tailor treatment,” Dr Wallace noted. “In some cases, we can offer chemotherapy and radiation before surgery for a better outcome, and, in other cases, we can avoid surgery and other therapy altogether.”

Syringe

A study of more than 2000 patients refutes the idea that biopsies cause cancer to spread.

In a study published in Gut, researchers showed that patients who received a biopsy had better overall survival and similar cancer-free survival rates as patients who did not have a biopsy.

The team studied pancreatic cancer but said their findings likely apply to other cancers because the diagnostic technique used in this study—fine needle aspiration—is commonly used across tumor types.

“This study shows that physicians and patients should feel reassured that a biopsy is very safe,” said study author Michael Wallace, MD, of the Mayo Clinic in Jacksonville, Florida.

“We do millions of biopsies of cancer a year in the US, but one or two case studies have led to this common myth that biopsies spread cancer.”

This is the second study Dr Wallace and his team have conducted to examine the risk of biopsy.

In a 2013 study published in Endoscopy, the researchers examined outcomes in 256 pancreatic cancer patients treated at the Mayo Clinic in Jacksonville. The team found no difference in cancer recurrence between 208 patients who had ultrasound-guided fine needle aspiration (EUS-FNA) and the 48 patients who did not have a biopsy.

In the current study, the researchers examined 11 years (1998-2009) of Medicare data on patients with non-metastatic pancreatic cancer who underwent surgery. The team examined overall survival and pancreatic cancer-specific survival in 498 patients who had EUS-FNA and in 1536 patients who did not have a biopsy.

During a mean follow-up time of 21 months, 285 patients (57%) in the EUS-FNA group and 1167 patients (76%) in the non-EUS-FNA group died. Pancreatic cancer was identified as the cause of death for 251 patients (50%) in the EUS-FNA group and 980 patients (64%) in the non-EUS-FNA group.

The median overall survival in the EUS-FNA group was 22 months, compared to 15 months in the non-EUS-FNA group. Multivariate analysis showed that receipt of EUS-FNA had a borderline significant association with improved overall survival (hazard ratio=0.84, P=0.03).

The median cancer-specific survival was 24 months in the EUS-FNA group and 18 months in the non-EUS-FNA group. Multivariate analysis revealed no significant difference between the two groups (hazard ratio=0.87, P=0.12).

“[Biopsies provide] very valuable information that allow us to tailor treatment,” Dr Wallace noted. “In some cases, we can offer chemotherapy and radiation before surgery for a better outcome, and, in other cases, we can avoid surgery and other therapy altogether.”

Thrombus

Credit: Kevin MacKenzie

An intravenous (IV) bolus of the factor Xa inhibitor antidote andexanet alfa can significantly and immediately reverse the steady-state anticoagulation activity of rivaroxaban in healthy subjects, according to initial results of the phase 3 ANNEXA-R study.

Portola Pharmaceuticals, the company developing andexanet alfa, recently announced these results from the first part of the study.

The company expects to present the full data set on March 16 at the American College of Cardiology’s 64th Annual Scientific Session & Expo in San Diego.

The second part of the ANNEXA-R study, in which researchers are evaluating a bolus plus a continuous infusion of andexanet alfa to sustain reversal, is ongoing.

Portola is developing andexanet alfa as a universal antidote for patients treated with oral and injectable factor Xa inhibitors who are experiencing a major bleeding episode or who require emergency surgery.

Andexanet alfa acts as a factor Xa decoy that targets and sequesters 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 allowing for the restoration of normal hemostatic processes.

ANNEXA-R details

This randomized, double-blind, placebo-controlled study is an evaluation of andexanet alfa in reversing rivaroxaban-induced anticoagulation in healthy volunteers ages 50 to 75 years.

In the first part of the study, 41 subjects received rivaroxaban at 20 mg once daily for 4 days. Then, they were randomized in a 2:1 ratio to receive either andexanet alfa administered as an 800 mg IV bolus (n=27) or to placebo (n=14).

Results showed that andexanet alfa significantly and immediately reversed the anticoagulation activity of rivaroxaban. Furthermore, andexanet alfa appeared to be well tolerated.

For the second part of the ANNEXA-R study, researchers plan to enroll about 40 healthy volunteers and give them rivaroxaban at 20 mg once daily for 4 days.

Then, subjects will be randomized to receive either placebo or andexanet alfa administered as an 800 mg IV bolus, followed by a continuous infusion of 8 mg/min for 120 minutes. Data from this part of the study are expected in mid-2015.

Andexanet alfa development

Andexanet alfa is the only compound being studied as a reversal agent for factor Xa inhibitors that directly and specifically corrects anti-factor Xa activity.

Portola is evaluating andexanet alfa in randomized, placebo-controlled phase 3 ANNEXA registration studies using pharmacodynamic endpoints agreed to with the US Food and Drug Administration (FDA), such as anti-factor Xa inhibitor units, to demonstrate efficacy.

Researchers recently reported statistically significant results from the first part of the phase 3 ANNEXA-A study, in which researchers evaluated andexanet alfa administered as a single IV bolus dose with the direct factor Xa inhibitor apixaban.

The second part of the study is ongoing. It’s an evaluation of an IV bolus plus a continuous infusion of andexanet alfa to sustain the reversal of anticoagulation activity.

“The statistically significant phase 3 ANNEXA-R study data, together with results presented previously with apixaban, provide compelling evidence that this ground-breaking agent could serve as a universal antidote for factor Xa inhibitor anticoagulants,” said John T. Curnutte, MD, PhD, executive vice president, research and development for Portola.

“Andexanet alfa is unique among the other reversal agents in development in that it has been the only agent to immediately and significantly reverse all of the key pharmacodynamic measurements of coagulation that have been agreed to with the FDA for accelerated approval. These include anti-factor Xa levels, thrombin generation, and unbound anticoagulant (free-fraction). This has been demonstrated with all of the factor Xa inhibitors studied to date—apixaban, rivaroxaban, edoxaban, and enoxaparin.”

Thrombus

Credit: Kevin MacKenzie

An intravenous (IV) bolus of the factor Xa inhibitor antidote andexanet alfa can significantly and immediately reverse the steady-state anticoagulation activity of rivaroxaban in healthy subjects, according to initial results of the phase 3 ANNEXA-R study.

Portola Pharmaceuticals, the company developing andexanet alfa, recently announced these results from the first part of the study.

The company expects to present the full data set on March 16 at the American College of Cardiology’s 64th Annual Scientific Session & Expo in San Diego.

The second part of the ANNEXA-R study, in which researchers are evaluating a bolus plus a continuous infusion of andexanet alfa to sustain reversal, is ongoing.

Portola is developing andexanet alfa as a universal antidote for patients treated with oral and injectable factor Xa inhibitors who are experiencing a major bleeding episode or who require emergency surgery.

Andexanet alfa acts as a factor Xa decoy that targets and sequesters 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 allowing for the restoration of normal hemostatic processes.

ANNEXA-R details

This randomized, double-blind, placebo-controlled study is an evaluation of andexanet alfa in reversing rivaroxaban-induced anticoagulation in healthy volunteers ages 50 to 75 years.

In the first part of the study, 41 subjects received rivaroxaban at 20 mg once daily for 4 days. Then, they were randomized in a 2:1 ratio to receive either andexanet alfa administered as an 800 mg IV bolus (n=27) or to placebo (n=14).

Results showed that andexanet alfa significantly and immediately reversed the anticoagulation activity of rivaroxaban. Furthermore, andexanet alfa appeared to be well tolerated.

For the second part of the ANNEXA-R study, researchers plan to enroll about 40 healthy volunteers and give them rivaroxaban at 20 mg once daily for 4 days.

Then, subjects will be randomized to receive either placebo or andexanet alfa administered as an 800 mg IV bolus, followed by a continuous infusion of 8 mg/min for 120 minutes. Data from this part of the study are expected in mid-2015.

Andexanet alfa development

Andexanet alfa is the only compound being studied as a reversal agent for factor Xa inhibitors that directly and specifically corrects anti-factor Xa activity.

Portola is evaluating andexanet alfa in randomized, placebo-controlled phase 3 ANNEXA registration studies using pharmacodynamic endpoints agreed to with the US Food and Drug Administration (FDA), such as anti-factor Xa inhibitor units, to demonstrate efficacy.

Researchers recently reported statistically significant results from the first part of the phase 3 ANNEXA-A study, in which researchers evaluated andexanet alfa administered as a single IV bolus dose with the direct factor Xa inhibitor apixaban.

The second part of the study is ongoing. It’s an evaluation of an IV bolus plus a continuous infusion of andexanet alfa to sustain the reversal of anticoagulation activity.

“The statistically significant phase 3 ANNEXA-R study data, together with results presented previously with apixaban, provide compelling evidence that this ground-breaking agent could serve as a universal antidote for factor Xa inhibitor anticoagulants,” said John T. Curnutte, MD, PhD, executive vice president, research and development for Portola.

“Andexanet alfa is unique among the other reversal agents in development in that it has been the only agent to immediately and significantly reverse all of the key pharmacodynamic measurements of coagulation that have been agreed to with the FDA for accelerated approval. These include anti-factor Xa levels, thrombin generation, and unbound anticoagulant (free-fraction). This has been demonstrated with all of the factor Xa inhibitors studied to date—apixaban, rivaroxaban, edoxaban, and enoxaparin.”

Thrombus

Credit: Kevin MacKenzie

An intravenous (IV) bolus of the factor Xa inhibitor antidote andexanet alfa can significantly and immediately reverse the steady-state anticoagulation activity of rivaroxaban in healthy subjects, according to initial results of the phase 3 ANNEXA-R study.

Portola Pharmaceuticals, the company developing andexanet alfa, recently announced these results from the first part of the study.

The company expects to present the full data set on March 16 at the American College of Cardiology’s 64th Annual Scientific Session & Expo in San Diego.

The second part of the ANNEXA-R study, in which researchers are evaluating a bolus plus a continuous infusion of andexanet alfa to sustain reversal, is ongoing.

Portola is developing andexanet alfa as a universal antidote for patients treated with oral and injectable factor Xa inhibitors who are experiencing a major bleeding episode or who require emergency surgery.

Andexanet alfa acts as a factor Xa decoy that targets and sequesters 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 allowing for the restoration of normal hemostatic processes.

ANNEXA-R details

This randomized, double-blind, placebo-controlled study is an evaluation of andexanet alfa in reversing rivaroxaban-induced anticoagulation in healthy volunteers ages 50 to 75 years.

In the first part of the study, 41 subjects received rivaroxaban at 20 mg once daily for 4 days. Then, they were randomized in a 2:1 ratio to receive either andexanet alfa administered as an 800 mg IV bolus (n=27) or to placebo (n=14).

Results showed that andexanet alfa significantly and immediately reversed the anticoagulation activity of rivaroxaban. Furthermore, andexanet alfa appeared to be well tolerated.

For the second part of the ANNEXA-R study, researchers plan to enroll about 40 healthy volunteers and give them rivaroxaban at 20 mg once daily for 4 days.

Then, subjects will be randomized to receive either placebo or andexanet alfa administered as an 800 mg IV bolus, followed by a continuous infusion of 8 mg/min for 120 minutes. Data from this part of the study are expected in mid-2015.

Andexanet alfa development

Andexanet alfa is the only compound being studied as a reversal agent for factor Xa inhibitors that directly and specifically corrects anti-factor Xa activity.

Portola is evaluating andexanet alfa in randomized, placebo-controlled phase 3 ANNEXA registration studies using pharmacodynamic endpoints agreed to with the US Food and Drug Administration (FDA), such as anti-factor Xa inhibitor units, to demonstrate efficacy.

Researchers recently reported statistically significant results from the first part of the phase 3 ANNEXA-A study, in which researchers evaluated andexanet alfa administered as a single IV bolus dose with the direct factor Xa inhibitor apixaban.

The second part of the study is ongoing. It’s an evaluation of an IV bolus plus a continuous infusion of andexanet alfa to sustain the reversal of anticoagulation activity.

“The statistically significant phase 3 ANNEXA-R study data, together with results presented previously with apixaban, provide compelling evidence that this ground-breaking agent could serve as a universal antidote for factor Xa inhibitor anticoagulants,” said John T. Curnutte, MD, PhD, executive vice president, research and development for Portola.

“Andexanet alfa is unique among the other reversal agents in development in that it has been the only agent to immediately and significantly reverse all of the key pharmacodynamic measurements of coagulation that have been agreed to with the FDA for accelerated approval. These include anti-factor Xa levels, thrombin generation, and unbound anticoagulant (free-fraction). This has been demonstrated with all of the factor Xa inhibitors studied to date—apixaban, rivaroxaban, edoxaban, and enoxaparin.”

Drug production

Credit: FDA

The US Food and Drug Administration (FDA) has approved the oral, direct factor Xa inhibitor edoxaban (Savaysa) for use in two patient populations.

The anticoagulant is now approved to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF) and to treat venous thromboembolism (VTE) in patients who have already received parenteral anticoagulation for 5 to 10 days.

The drug has been approved with a Boxed Warning.

The warning states that edoxaban is less effective in NVAF patients with a creatinine clearance greater than 95 mL/min. Patients with creatinine clearance above this limit have an increased risk of stroke if they receive edoxaban (compared to the risk with warfarin), so these patients should not receive edoxaban.

The warning also states that premature discontinuation of edoxaban increases the risk of stroke. Furthermore, spinal or epidural hematomas may occur in patients on edoxaban who are receiving anesthesia injected around the spine or undergoing spinal puncture.

Edoxaban for VTE

In the Hokusai-VTE trial, researchers evaluated edoxaban in 4921 patients with deep vein thrombosis and 3319 with pulmonary embolism. Patients received initial treatment with low-molecular-weight heparin and were then randomized to receive edoxaban or warfarin daily for 3 to 12 months.

Overall, edoxaban proved as effective as warfarin. Recurrent, symptomatic VTE occurred in 3.2% and 3.5% of patients, respectively (P<0.001 for non-inferiority).

Edoxaban proved superior when it came to the primary safety outcome. Clinically relevant bleeding occurred in 8.5% of edoxaban-treated patients and 10.3% of warfarin-treated patients (P=0.004 for superiority).

In the edoxaban arm, there were 2 fatal bleeds and 13 non-fatal bleeds in a critical site. With warfarin, there were 10 fatal bleeds and 25 non-fatal bleeds in a critical site.

Edoxaban in NVAF

In the ENGAGE AF-TIMI 48 trial, researchers compared edoxaban and warfarin for the prevention of stroke or systemic embolic events (SEE) in patients with NVAF.

The trial included 21,105 patients who were randomized to receive warfarin (n=7036), edoxaban at 60 mg (n=7035), or edoxaban at 30 mg (n=7034).

Edoxaban was at least non-inferior to warfarin with regard to efficacy. The annual incidence of stroke or SEE was 1.50% with warfarin, 1.18% with edoxaban at 60 mg (P<0.001 for non-inferiority), and 1.61% with edoxaban at 30 mg (P=0.005 for non-inferiority).

Annualized rates for the secondary composite endpoint of stroke, SEE, and cardiovascular death were 4.43% with warfarin, 3.85% with edoxaban at 60 mg (P=0.005), and 4.23% with edoxaban at 30 mg (P=0.32).

In addition, edoxaban was associated with a significantly lower rate of major and fatal bleeding. The annual incidence of major bleeding was 3.43% with warfarin, 2.75% with edoxaban at 60 mg (P<0.001), and 1.61% with edoxaban at 30 mg (P<0.001).

Fatal bleeds occurred at an annual rate of 0.38% with warfarin, 0.21% with edoxaban at 60 mg (P=0.006), and 0.13% with edoxaban at 30 mg (P<0.001).

Edoxaban is under development by Daiichi Sankyo Co., Ltd.

Drug production

Credit: FDA

The US Food and Drug Administration (FDA) has approved the oral, direct factor Xa inhibitor edoxaban (Savaysa) for use in two patient populations.

The anticoagulant is now approved to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF) and to treat venous thromboembolism (VTE) in patients who have already received parenteral anticoagulation for 5 to 10 days.

The drug has been approved with a Boxed Warning.

The warning states that edoxaban is less effective in NVAF patients with a creatinine clearance greater than 95 mL/min. Patients with creatinine clearance above this limit have an increased risk of stroke if they receive edoxaban (compared to the risk with warfarin), so these patients should not receive edoxaban.

The warning also states that premature discontinuation of edoxaban increases the risk of stroke. Furthermore, spinal or epidural hematomas may occur in patients on edoxaban who are receiving anesthesia injected around the spine or undergoing spinal puncture.

Edoxaban for VTE

In the Hokusai-VTE trial, researchers evaluated edoxaban in 4921 patients with deep vein thrombosis and 3319 with pulmonary embolism. Patients received initial treatment with low-molecular-weight heparin and were then randomized to receive edoxaban or warfarin daily for 3 to 12 months.

Overall, edoxaban proved as effective as warfarin. Recurrent, symptomatic VTE occurred in 3.2% and 3.5% of patients, respectively (P<0.001 for non-inferiority).

Edoxaban proved superior when it came to the primary safety outcome. Clinically relevant bleeding occurred in 8.5% of edoxaban-treated patients and 10.3% of warfarin-treated patients (P=0.004 for superiority).

In the edoxaban arm, there were 2 fatal bleeds and 13 non-fatal bleeds in a critical site. With warfarin, there were 10 fatal bleeds and 25 non-fatal bleeds in a critical site.

Edoxaban in NVAF

In the ENGAGE AF-TIMI 48 trial, researchers compared edoxaban and warfarin for the prevention of stroke or systemic embolic events (SEE) in patients with NVAF.

The trial included 21,105 patients who were randomized to receive warfarin (n=7036), edoxaban at 60 mg (n=7035), or edoxaban at 30 mg (n=7034).

Edoxaban was at least non-inferior to warfarin with regard to efficacy. The annual incidence of stroke or SEE was 1.50% with warfarin, 1.18% with edoxaban at 60 mg (P<0.001 for non-inferiority), and 1.61% with edoxaban at 30 mg (P=0.005 for non-inferiority).

Annualized rates for the secondary composite endpoint of stroke, SEE, and cardiovascular death were 4.43% with warfarin, 3.85% with edoxaban at 60 mg (P=0.005), and 4.23% with edoxaban at 30 mg (P=0.32).

In addition, edoxaban was associated with a significantly lower rate of major and fatal bleeding. The annual incidence of major bleeding was 3.43% with warfarin, 2.75% with edoxaban at 60 mg (P<0.001), and 1.61% with edoxaban at 30 mg (P<0.001).

Fatal bleeds occurred at an annual rate of 0.38% with warfarin, 0.21% with edoxaban at 60 mg (P=0.006), and 0.13% with edoxaban at 30 mg (P<0.001).

Edoxaban is under development by Daiichi Sankyo Co., Ltd.

Drug production

Credit: FDA

The US Food and Drug Administration (FDA) has approved the oral, direct factor Xa inhibitor edoxaban (Savaysa) for use in two patient populations.

The anticoagulant is now approved to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF) and to treat venous thromboembolism (VTE) in patients who have already received parenteral anticoagulation for 5 to 10 days.

The drug has been approved with a Boxed Warning.

The warning states that edoxaban is less effective in NVAF patients with a creatinine clearance greater than 95 mL/min. Patients with creatinine clearance above this limit have an increased risk of stroke if they receive edoxaban (compared to the risk with warfarin), so these patients should not receive edoxaban.

The warning also states that premature discontinuation of edoxaban increases the risk of stroke. Furthermore, spinal or epidural hematomas may occur in patients on edoxaban who are receiving anesthesia injected around the spine or undergoing spinal puncture.

Edoxaban for VTE

In the Hokusai-VTE trial, researchers evaluated edoxaban in 4921 patients with deep vein thrombosis and 3319 with pulmonary embolism. Patients received initial treatment with low-molecular-weight heparin and were then randomized to receive edoxaban or warfarin daily for 3 to 12 months.

Overall, edoxaban proved as effective as warfarin. Recurrent, symptomatic VTE occurred in 3.2% and 3.5% of patients, respectively (P<0.001 for non-inferiority).

Edoxaban proved superior when it came to the primary safety outcome. Clinically relevant bleeding occurred in 8.5% of edoxaban-treated patients and 10.3% of warfarin-treated patients (P=0.004 for superiority).

In the edoxaban arm, there were 2 fatal bleeds and 13 non-fatal bleeds in a critical site. With warfarin, there were 10 fatal bleeds and 25 non-fatal bleeds in a critical site.

Edoxaban in NVAF

In the ENGAGE AF-TIMI 48 trial, researchers compared edoxaban and warfarin for the prevention of stroke or systemic embolic events (SEE) in patients with NVAF.

The trial included 21,105 patients who were randomized to receive warfarin (n=7036), edoxaban at 60 mg (n=7035), or edoxaban at 30 mg (n=7034).

Edoxaban was at least non-inferior to warfarin with regard to efficacy. The annual incidence of stroke or SEE was 1.50% with warfarin, 1.18% with edoxaban at 60 mg (P<0.001 for non-inferiority), and 1.61% with edoxaban at 30 mg (P=0.005 for non-inferiority).

Annualized rates for the secondary composite endpoint of stroke, SEE, and cardiovascular death were 4.43% with warfarin, 3.85% with edoxaban at 60 mg (P=0.005), and 4.23% with edoxaban at 30 mg (P=0.32).

In addition, edoxaban was associated with a significantly lower rate of major and fatal bleeding. The annual incidence of major bleeding was 3.43% with warfarin, 2.75% with edoxaban at 60 mg (P<0.001), and 1.61% with edoxaban at 30 mg (P<0.001).

Fatal bleeds occurred at an annual rate of 0.38% with warfarin, 0.21% with edoxaban at 60 mg (P=0.006), and 0.13% with edoxaban at 30 mg (P<0.001).

Edoxaban is under development by Daiichi Sankyo Co., Ltd.

Micrograph showing

mycosis fungoides

The US Food and Drug Administration (FDA) has granted fast track designation to SGX301 as a first-line treatment for cutaneous T-cell lymphoma (CTCL).

SGX301 is a photodynamic therapy utilizing safe, visible light for activation. The active ingredient in SGX301 is synthetic hypericin, a photosensitizer that is applied to skin lesions and then activated by fluorescent light 16 to 24 hours later.

Combined with photoactivation, hypericin has demonstrated significant antiproliferative effects on activated, normal human lymphoid cells and inhibited the growth of malignant T cells isolated from CTCL patients. Topical hypericin has also proven safe in a phase 1 study of healthy volunteers.

In a phase 2 trial of patients with CTCL (mycosis fungoides only) or psoriasis, topical hypericin conferred a significant improvement over placebo. Among CTCL patients, the treatment prompted a response rate of 58.3%, compared to an 8.3% response rate for placebo (P≤0.04).

Topical hypericin was also well tolerated in this trial. There were no deaths or serious adverse events related to the treatment. However, there were reports of mild to moderate burning, itching, erythema, and pruritus at the application site.

A phase 3 trial of SGX301 is set to begin in the first half of this year. In addition to its new fast track status, SGX301 also has orphan designation from the FDA.

About fast track designation

The FDA grants fast track designation to a drug that is intended to treat a serious or life-threatening condition and that demonstrates the potential to address an unmet medical need for the condition.

Fast track designation is designed to facilitate the development and expedite the review of new drugs. For instance, Soligenix, Inc., the company developing SGX301, is eligible to submit a new drug application (NDA) for SGX301 on a rolling basis, allowing the FDA to review sections of the NDA prior to receiving the complete submission.

Additionally, NDAs for fast track development programs ordinarily will be eligible for priority review, which imparts an abbreviated review time of approximately 6 months.

Micrograph showing

mycosis fungoides

The US Food and Drug Administration (FDA) has granted fast track designation to SGX301 as a first-line treatment for cutaneous T-cell lymphoma (CTCL).

SGX301 is a photodynamic therapy utilizing safe, visible light for activation. The active ingredient in SGX301 is synthetic hypericin, a photosensitizer that is applied to skin lesions and then activated by fluorescent light 16 to 24 hours later.

Combined with photoactivation, hypericin has demonstrated significant antiproliferative effects on activated, normal human lymphoid cells and inhibited the growth of malignant T cells isolated from CTCL patients. Topical hypericin has also proven safe in a phase 1 study of healthy volunteers.

In a phase 2 trial of patients with CTCL (mycosis fungoides only) or psoriasis, topical hypericin conferred a significant improvement over placebo. Among CTCL patients, the treatment prompted a response rate of 58.3%, compared to an 8.3% response rate for placebo (P≤0.04).

Topical hypericin was also well tolerated in this trial. There were no deaths or serious adverse events related to the treatment. However, there were reports of mild to moderate burning, itching, erythema, and pruritus at the application site.

A phase 3 trial of SGX301 is set to begin in the first half of this year. In addition to its new fast track status, SGX301 also has orphan designation from the FDA.

About fast track designation

The FDA grants fast track designation to a drug that is intended to treat a serious or life-threatening condition and that demonstrates the potential to address an unmet medical need for the condition.

Fast track designation is designed to facilitate the development and expedite the review of new drugs. For instance, Soligenix, Inc., the company developing SGX301, is eligible to submit a new drug application (NDA) for SGX301 on a rolling basis, allowing the FDA to review sections of the NDA prior to receiving the complete submission.

Additionally, NDAs for fast track development programs ordinarily will be eligible for priority review, which imparts an abbreviated review time of approximately 6 months.

Micrograph showing

mycosis fungoides

The US Food and Drug Administration (FDA) has granted fast track designation to SGX301 as a first-line treatment for cutaneous T-cell lymphoma (CTCL).

SGX301 is a photodynamic therapy utilizing safe, visible light for activation. The active ingredient in SGX301 is synthetic hypericin, a photosensitizer that is applied to skin lesions and then activated by fluorescent light 16 to 24 hours later.

Combined with photoactivation, hypericin has demonstrated significant antiproliferative effects on activated, normal human lymphoid cells and inhibited the growth of malignant T cells isolated from CTCL patients. Topical hypericin has also proven safe in a phase 1 study of healthy volunteers.

In a phase 2 trial of patients with CTCL (mycosis fungoides only) or psoriasis, topical hypericin conferred a significant improvement over placebo. Among CTCL patients, the treatment prompted a response rate of 58.3%, compared to an 8.3% response rate for placebo (P≤0.04).

Topical hypericin was also well tolerated in this trial. There were no deaths or serious adverse events related to the treatment. However, there were reports of mild to moderate burning, itching, erythema, and pruritus at the application site.

A phase 3 trial of SGX301 is set to begin in the first half of this year. In addition to its new fast track status, SGX301 also has orphan designation from the FDA.

About fast track designation

The FDA grants fast track designation to a drug that is intended to treat a serious or life-threatening condition and that demonstrates the potential to address an unmet medical need for the condition.

Fast track designation is designed to facilitate the development and expedite the review of new drugs. For instance, Soligenix, Inc., the company developing SGX301, is eligible to submit a new drug application (NDA) for SGX301 on a rolling basis, allowing the FDA to review sections of the NDA prior to receiving the complete submission.

Additionally, NDAs for fast track development programs ordinarily will be eligible for priority review, which imparts an abbreviated review time of approximately 6 months.

Micrograph showing MM

The US Food and Drug Administration (FDA) has granted selinexor (KPT-330) orphan drug designation to treat multiple myeloma (MM).

Selinexor already has orphan designation from the FDA to treat acute myeloid leukemia (AML) and diffuse large B-cell lymphoma (DLBCL).

The drug has also received orphan designation from the European Medicines Agency (EMA) to treat MM, AML, DLBCL, and chronic lymphocytic leukemia/small lymphocytic lymphoma, including Richter’s transformation.

“Orphan drug designation by the FDA for multiple myeloma is another significant milestone in the selinexor development program,” said Sharon Shacham, PhD, President and Chief Scientific Officer of Karyopharm Therapeutics, Inc., the company developing selinexor.

In the US, orphan designation qualifies a company for certain benefits, including an accelerated approval process, 7 years of market exclusivity following the drug’s approval, tax credits on US clinical trials, eligibility for orphan drug grants, and a waiver of certain administrative fees.

About selinexor

Selinexor (KPT-330) is a first-in-class, oral, selective inhibitor of nuclear export compound. The drug functions by inhibiting the nuclear export protein XPO1 (also called CRM1).

This leads to the accumulation of tumor suppressor proteins in the cell nucleus, which subsequently reinitiates and amplifies their tumor suppressor function. This is thought to prompt apoptosis in cancer cells while largely sparing normal cells.

Selinexor combos in MM

In a poster presented at the 2014 ASH Annual Meeting (4773), researchers reported results observed with selinexor plus dexamethasone in preclinical models and in patients with heavily pretreated, refractory MM.

The study included 9 evaluable patients who received selinexor at 45 mg/m² twice weekly and dexamethasone at 20 mg twice weekly. The combination prompted an overall response rate of 67%, with one stringent complete response (11%) and 5 partial responses (56%), as well as a clinical benefit rate of 89%.

The combination demonstrated a reduction in nausea grades and very little weight loss compared with selinexor alone. The most common grade 1/2 adverse events were nausea, fatigue, anorexia, and vomiting.

The combination was also associated with an increase in time on study relative to selinexor alone. Sixty-six percent of patients remained on study for at least 16 weeks, including one patient for 28 weeks and one for 43 weeks as of December 1, 2014.

During the dose-evaluation part of the study, the 60 mg/m² selinexor dose was deemed intolerable in this heavily pretreated patient population. So 45 mg/m² is the recommended future study dose.

In another poster presented at the 2014 ASH Annual Meeting (3443), researchers described the activity of selinexor in combination with carfilzomib. This preclinical study revealed a novel, intracellular, membrane-embedded mechanism of caspase activation.

The results suggested a model of synergy wherein the selinexor-carfilzomib combination promotes caspase activation, likely by induced proximity, cleavage of other caspases, and subsequent apoptosis as well as autophagy.

Micrograph showing MM

The US Food and Drug Administration (FDA) has granted selinexor (KPT-330) orphan drug designation to treat multiple myeloma (MM).

Selinexor already has orphan designation from the FDA to treat acute myeloid leukemia (AML) and diffuse large B-cell lymphoma (DLBCL).

The drug has also received orphan designation from the European Medicines Agency (EMA) to treat MM, AML, DLBCL, and chronic lymphocytic leukemia/small lymphocytic lymphoma, including Richter’s transformation.

“Orphan drug designation by the FDA for multiple myeloma is another significant milestone in the selinexor development program,” said Sharon Shacham, PhD, President and Chief Scientific Officer of Karyopharm Therapeutics, Inc., the company developing selinexor.

In the US, orphan designation qualifies a company for certain benefits, including an accelerated approval process, 7 years of market exclusivity following the drug’s approval, tax credits on US clinical trials, eligibility for orphan drug grants, and a waiver of certain administrative fees.

About selinexor

Selinexor (KPT-330) is a first-in-class, oral, selective inhibitor of nuclear export compound. The drug functions by inhibiting the nuclear export protein XPO1 (also called CRM1).

This leads to the accumulation of tumor suppressor proteins in the cell nucleus, which subsequently reinitiates and amplifies their tumor suppressor function. This is thought to prompt apoptosis in cancer cells while largely sparing normal cells.

Selinexor combos in MM

In a poster presented at the 2014 ASH Annual Meeting (4773), researchers reported results observed with selinexor plus dexamethasone in preclinical models and in patients with heavily pretreated, refractory MM.

The study included 9 evaluable patients who received selinexor at 45 mg/m² twice weekly and dexamethasone at 20 mg twice weekly. The combination prompted an overall response rate of 67%, with one stringent complete response (11%) and 5 partial responses (56%), as well as a clinical benefit rate of 89%.

The combination demonstrated a reduction in nausea grades and very little weight loss compared with selinexor alone. The most common grade 1/2 adverse events were nausea, fatigue, anorexia, and vomiting.

The combination was also associated with an increase in time on study relative to selinexor alone. Sixty-six percent of patients remained on study for at least 16 weeks, including one patient for 28 weeks and one for 43 weeks as of December 1, 2014.

During the dose-evaluation part of the study, the 60 mg/m² selinexor dose was deemed intolerable in this heavily pretreated patient population. So 45 mg/m² is the recommended future study dose.

In another poster presented at the 2014 ASH Annual Meeting (3443), researchers described the activity of selinexor in combination with carfilzomib. This preclinical study revealed a novel, intracellular, membrane-embedded mechanism of caspase activation.

The results suggested a model of synergy wherein the selinexor-carfilzomib combination promotes caspase activation, likely by induced proximity, cleavage of other caspases, and subsequent apoptosis as well as autophagy.

Micrograph showing MM

The US Food and Drug Administration (FDA) has granted selinexor (KPT-330) orphan drug designation to treat multiple myeloma (MM).

Selinexor already has orphan designation from the FDA to treat acute myeloid leukemia (AML) and diffuse large B-cell lymphoma (DLBCL).

The drug has also received orphan designation from the European Medicines Agency (EMA) to treat MM, AML, DLBCL, and chronic lymphocytic leukemia/small lymphocytic lymphoma, including Richter’s transformation.

“Orphan drug designation by the FDA for multiple myeloma is another significant milestone in the selinexor development program,” said Sharon Shacham, PhD, President and Chief Scientific Officer of Karyopharm Therapeutics, Inc., the company developing selinexor.

In the US, orphan designation qualifies a company for certain benefits, including an accelerated approval process, 7 years of market exclusivity following the drug’s approval, tax credits on US clinical trials, eligibility for orphan drug grants, and a waiver of certain administrative fees.

About selinexor

Selinexor (KPT-330) is a first-in-class, oral, selective inhibitor of nuclear export compound. The drug functions by inhibiting the nuclear export protein XPO1 (also called CRM1).

This leads to the accumulation of tumor suppressor proteins in the cell nucleus, which subsequently reinitiates and amplifies their tumor suppressor function. This is thought to prompt apoptosis in cancer cells while largely sparing normal cells.

Selinexor combos in MM

In a poster presented at the 2014 ASH Annual Meeting (4773), researchers reported results observed with selinexor plus dexamethasone in preclinical models and in patients with heavily pretreated, refractory MM.

The study included 9 evaluable patients who received selinexor at 45 mg/m² twice weekly and dexamethasone at 20 mg twice weekly. The combination prompted an overall response rate of 67%, with one stringent complete response (11%) and 5 partial responses (56%), as well as a clinical benefit rate of 89%.

The combination demonstrated a reduction in nausea grades and very little weight loss compared with selinexor alone. The most common grade 1/2 adverse events were nausea, fatigue, anorexia, and vomiting.

The combination was also associated with an increase in time on study relative to selinexor alone. Sixty-six percent of patients remained on study for at least 16 weeks, including one patient for 28 weeks and one for 43 weeks as of December 1, 2014.

During the dose-evaluation part of the study, the 60 mg/m² selinexor dose was deemed intolerable in this heavily pretreated patient population. So 45 mg/m² is the recommended future study dose.

In another poster presented at the 2014 ASH Annual Meeting (3443), researchers described the activity of selinexor in combination with carfilzomib. This preclinical study revealed a novel, intracellular, membrane-embedded mechanism of caspase activation.

The results suggested a model of synergy wherein the selinexor-carfilzomib combination promotes caspase activation, likely by induced proximity, cleavage of other caspases, and subsequent apoptosis as well as autophagy.

Sleeping newborn

Credit: Vera Kratochvil

Results of a new study indicate that current guidelines for exchange transfusions in infants can successfully prevent kernicterus, a rare and life-threatening type of cerebral palsy triggered by escalating bilirubin that injures the brain.

However, the research also showed that only infants whose levels of bilirubin were well above the level for exchange transfusion actually developed kernicterus. And those infants all had additional risk factors for brain damage.

This suggests perhaps the threshold for exchange transfusion could safely be raised for infants with high bilirubin levels who have no other risk factors for brain injury, according to Yvonne W. Wu, MD, of the University of California, San Francisco (UCSF).

Dr Wu and her colleagues evaluated the health records of two groups of infants selected from 525,409 births. The children had been born at 15 hospitals within the Kaiser Permanente Northern California region from 1995 through 2011.

One group comprised 1833 newborns with levels of bilirubin above the level at which the American Academy of Pediatrics (AAP) recommends exchange transfusions.

The second group was made up of 104,716 randomly sampled newborns, born at at least 35 weeks’ gestation with lower levels of bilirubin. The two groups were followed for an average of 7 and 6 years, respectively.

The researchers confirmed 3 cases of kernicterus based on the brain MRIs of children with cerebral palsy. All 3 cases had occurred in newborns with the highest levels of bilirubin. But further study revealed that each child had 2 or more risk factors for brain damage.

”We found that cerebral palsy consistent with kernicterus did not occur in a single infant with high bilirubin without the presence of additional risk factors for neurotoxicity, such as prematurity, sepsis, and the hereditary blood disorder G6PD deficiency,” said Michael W. Kuzniewicz, MD, of UCSF. “This was the case even in infants with very high bilirubin.”

In 2004, the AAP published a guideline for treating infants whose bilirubin remained high despite phototherapy. It recommended exchange transfusions based on the level of bilirubin, the age of the infant, and other risk factors for brain damage.

“Our study was the first to evaluate how well the exchange transfusion guidelines predicted risk of cerebral palsy and kernicterus in babies with jaundice,” said Thomas B. Newman, MD, of UCSF.

“It was reassuring that brain injury due to high bilirubin was rare and that only those infants whose levels were well above exchange transfusion guidelines developed kernicterus.”

“Based on our study, the current guidelines for when to perform exchange transfusions have been quite successful in preventing kernicterus,” Dr Wu added. “However, our study also raises the question whether the threshold for exchange transfusion could be higher for infants with high bilirubin levels who are otherwise healthy and who have no other risk factors for brain injury.”

This is especially important, she noted, because exchange transfusions pose risks such as blood clot formation, blood pressure instability, bleeding, and changes in blood chemistry.

Dr Wu and her colleagues described this research in JAMA Pediatrics.

Sleeping newborn

Credit: Vera Kratochvil

Results of a new study indicate that current guidelines for exchange transfusions in infants can successfully prevent kernicterus, a rare and life-threatening type of cerebral palsy triggered by escalating bilirubin that injures the brain.

However, the research also showed that only infants whose levels of bilirubin were well above the level for exchange transfusion actually developed kernicterus. And those infants all had additional risk factors for brain damage.

This suggests perhaps the threshold for exchange transfusion could safely be raised for infants with high bilirubin levels who have no other risk factors for brain injury, according to Yvonne W. Wu, MD, of the University of California, San Francisco (UCSF).

Dr Wu and her colleagues evaluated the health records of two groups of infants selected from 525,409 births. The children had been born at 15 hospitals within the Kaiser Permanente Northern California region from 1995 through 2011.

One group comprised 1833 newborns with levels of bilirubin above the level at which the American Academy of Pediatrics (AAP) recommends exchange transfusions.

The second group was made up of 104,716 randomly sampled newborns, born at at least 35 weeks’ gestation with lower levels of bilirubin. The two groups were followed for an average of 7 and 6 years, respectively.

The researchers confirmed 3 cases of kernicterus based on the brain MRIs of children with cerebral palsy. All 3 cases had occurred in newborns with the highest levels of bilirubin. But further study revealed that each child had 2 or more risk factors for brain damage.

”We found that cerebral palsy consistent with kernicterus did not occur in a single infant with high bilirubin without the presence of additional risk factors for neurotoxicity, such as prematurity, sepsis, and the hereditary blood disorder G6PD deficiency,” said Michael W. Kuzniewicz, MD, of UCSF. “This was the case even in infants with very high bilirubin.”

In 2004, the AAP published a guideline for treating infants whose bilirubin remained high despite phototherapy. It recommended exchange transfusions based on the level of bilirubin, the age of the infant, and other risk factors for brain damage.

“Our study was the first to evaluate how well the exchange transfusion guidelines predicted risk of cerebral palsy and kernicterus in babies with jaundice,” said Thomas B. Newman, MD, of UCSF.

“It was reassuring that brain injury due to high bilirubin was rare and that only those infants whose levels were well above exchange transfusion guidelines developed kernicterus.”

“Based on our study, the current guidelines for when to perform exchange transfusions have been quite successful in preventing kernicterus,” Dr Wu added. “However, our study also raises the question whether the threshold for exchange transfusion could be higher for infants with high bilirubin levels who are otherwise healthy and who have no other risk factors for brain injury.”

This is especially important, she noted, because exchange transfusions pose risks such as blood clot formation, blood pressure instability, bleeding, and changes in blood chemistry.

Dr Wu and her colleagues described this research in JAMA Pediatrics.

Sleeping newborn

Credit: Vera Kratochvil

Results of a new study indicate that current guidelines for exchange transfusions in infants can successfully prevent kernicterus, a rare and life-threatening type of cerebral palsy triggered by escalating bilirubin that injures the brain.

However, the research also showed that only infants whose levels of bilirubin were well above the level for exchange transfusion actually developed kernicterus. And those infants all had additional risk factors for brain damage.

This suggests perhaps the threshold for exchange transfusion could safely be raised for infants with high bilirubin levels who have no other risk factors for brain injury, according to Yvonne W. Wu, MD, of the University of California, San Francisco (UCSF).

Dr Wu and her colleagues evaluated the health records of two groups of infants selected from 525,409 births. The children had been born at 15 hospitals within the Kaiser Permanente Northern California region from 1995 through 2011.

One group comprised 1833 newborns with levels of bilirubin above the level at which the American Academy of Pediatrics (AAP) recommends exchange transfusions.

The second group was made up of 104,716 randomly sampled newborns, born at at least 35 weeks’ gestation with lower levels of bilirubin. The two groups were followed for an average of 7 and 6 years, respectively.

The researchers confirmed 3 cases of kernicterus based on the brain MRIs of children with cerebral palsy. All 3 cases had occurred in newborns with the highest levels of bilirubin. But further study revealed that each child had 2 or more risk factors for brain damage.

”We found that cerebral palsy consistent with kernicterus did not occur in a single infant with high bilirubin without the presence of additional risk factors for neurotoxicity, such as prematurity, sepsis, and the hereditary blood disorder G6PD deficiency,” said Michael W. Kuzniewicz, MD, of UCSF. “This was the case even in infants with very high bilirubin.”

In 2004, the AAP published a guideline for treating infants whose bilirubin remained high despite phototherapy. It recommended exchange transfusions based on the level of bilirubin, the age of the infant, and other risk factors for brain damage.

“Our study was the first to evaluate how well the exchange transfusion guidelines predicted risk of cerebral palsy and kernicterus in babies with jaundice,” said Thomas B. Newman, MD, of UCSF.

“It was reassuring that brain injury due to high bilirubin was rare and that only those infants whose levels were well above exchange transfusion guidelines developed kernicterus.”

“Based on our study, the current guidelines for when to perform exchange transfusions have been quite successful in preventing kernicterus,” Dr Wu added. “However, our study also raises the question whether the threshold for exchange transfusion could be higher for infants with high bilirubin levels who are otherwise healthy and who have no other risk factors for brain injury.”

This is especially important, she noted, because exchange transfusions pose risks such as blood clot formation, blood pressure instability, bleeding, and changes in blood chemistry.

Dr Wu and her colleagues described this research in JAMA Pediatrics.

Prescriptions

Credit: CDC

SAN FRANCISCO—An investigational, humanized antibody fragment known as idarucizumab can reverse the anticoagulation effects of dabigatran, new research suggests.

In a small study, idarucizumab led to sustained reversal of dabigatran’s effects in healthy subjects, elderly volunteers, and participants with mild to moderate renal impairment.

Furthermore, dabigatran anticoagulation could be re-established 24 hours after the subjects had received idarucizumab.

Joachim Stangier, PhD, of Boehringer Ingelheim Pharma GmbH & Co KG in Biberach, Germany, presented these results at the 2014 ASH Annual Meeting as abstract 344*. Boehringer Ingelheim is the company developing idarucizumab.

Dr Stangier said idarucizumab binds dabigatran with high affinity, off-target binding is not expected, and no procoagulant effects have been observed with the drug.

In a previous study of healthy volunteers, idarucizumab provided immediate, complete, and sustained reversal of dabigatran’s anticoagulant effect. The effect was sustained when idarucizumab was given at 2 g and 4 g doses.

For the current study, Dr Stangier and his colleagues wanted to evaluate whether and to what extent doses of up to 5 g of idarucizumab would reverse the anticoagulant effects of dabigatran in healthy subjects, elderly participants, and renally impaired volunteers. The team also wanted to determine the effects of dabigatran given after subjects had received idarucizumab.

The study included 46 male and female subjects who were 45 to 80 years of age. Healthy subjects received dabigatran etexilate at 220 mg twice daily, and subjects with mild to moderate renal impairment received 150 mg twice daily, both over 4 days.

Subjects then received idarucizumab at 1 g, 2.5 g, 5 g, or 5 g given as 2 x 2.5 g 1 hour apart. They received these doses as 5-minute intravenous infusions 2 hours after their last dose of dabigatran.

The researchers found that dabigatran-prolonged clotting times—thrombin time, diluted thrombin time, ecarin clotting time, and activated partial thromboplastin time—were reversed to baseline immediately after the end of idarucizumab infusion.

And the team observed sustained reversal of dabigatran’s anticoagulant effects in all subjects.

The researchers then readministered dabigatran to healthy subjects 24 hours after idarucizumab treatment and to subjects who received placebo instead of idarucizumab.

Dabigatran-mediated anticoagulation was similar in subjects who received idarucizumab and those who received placebo. And anticoagulation was restored to levels comparable to initial levels.

Dr Stangier said there were no clinically relevant adverse events (AEs) related to idarucizumab, and there were no relevant changes in any of the investigated safety parameters. There were no AEs indicative of immunogenic reactions.

AEs and local tolerability reactions were similar for placebo and idarucizumab. And there was no relationship between the frequency of AEs and drug dose, gender, or renal function.

The researchers did observe a dose-dependent, transient increase in urine protein and low-weight proteins, but values returned to the normal range within 4 hours to 24 hours.

Based on these results, Dr Stangier said idarucizumab fulfills the requirements for a fast-acting and specific antidote to dabigatran with a favorable safety profile. Additional clinical testing of the antidote is ongoing.

*Information in the abstract differs from that presented.

Prescriptions

Credit: CDC

SAN FRANCISCO—An investigational, humanized antibody fragment known as idarucizumab can reverse the anticoagulation effects of dabigatran, new research suggests.

In a small study, idarucizumab led to sustained reversal of dabigatran’s effects in healthy subjects, elderly volunteers, and participants with mild to moderate renal impairment.

Furthermore, dabigatran anticoagulation could be re-established 24 hours after the subjects had received idarucizumab.

Joachim Stangier, PhD, of Boehringer Ingelheim Pharma GmbH & Co KG in Biberach, Germany, presented these results at the 2014 ASH Annual Meeting as abstract 344*. Boehringer Ingelheim is the company developing idarucizumab.

Dr Stangier said idarucizumab binds dabigatran with high affinity, off-target binding is not expected, and no procoagulant effects have been observed with the drug.

In a previous study of healthy volunteers, idarucizumab provided immediate, complete, and sustained reversal of dabigatran’s anticoagulant effect. The effect was sustained when idarucizumab was given at 2 g and 4 g doses.

For the current study, Dr Stangier and his colleagues wanted to evaluate whether and to what extent doses of up to 5 g of idarucizumab would reverse the anticoagulant effects of dabigatran in healthy subjects, elderly participants, and renally impaired volunteers. The team also wanted to determine the effects of dabigatran given after subjects had received idarucizumab.

The study included 46 male and female subjects who were 45 to 80 years of age. Healthy subjects received dabigatran etexilate at 220 mg twice daily, and subjects with mild to moderate renal impairment received 150 mg twice daily, both over 4 days.

Subjects then received idarucizumab at 1 g, 2.5 g, 5 g, or 5 g given as 2 x 2.5 g 1 hour apart. They received these doses as 5-minute intravenous infusions 2 hours after their last dose of dabigatran.

The researchers found that dabigatran-prolonged clotting times—thrombin time, diluted thrombin time, ecarin clotting time, and activated partial thromboplastin time—were reversed to baseline immediately after the end of idarucizumab infusion.

And the team observed sustained reversal of dabigatran’s anticoagulant effects in all subjects.

The researchers then readministered dabigatran to healthy subjects 24 hours after idarucizumab treatment and to subjects who received placebo instead of idarucizumab.

Dabigatran-mediated anticoagulation was similar in subjects who received idarucizumab and those who received placebo. And anticoagulation was restored to levels comparable to initial levels.

Dr Stangier said there were no clinically relevant adverse events (AEs) related to idarucizumab, and there were no relevant changes in any of the investigated safety parameters. There were no AEs indicative of immunogenic reactions.

AEs and local tolerability reactions were similar for placebo and idarucizumab. And there was no relationship between the frequency of AEs and drug dose, gender, or renal function.

The researchers did observe a dose-dependent, transient increase in urine protein and low-weight proteins, but values returned to the normal range within 4 hours to 24 hours.

Based on these results, Dr Stangier said idarucizumab fulfills the requirements for a fast-acting and specific antidote to dabigatran with a favorable safety profile. Additional clinical testing of the antidote is ongoing.

*Information in the abstract differs from that presented.

Prescriptions

Credit: CDC

SAN FRANCISCO—An investigational, humanized antibody fragment known as idarucizumab can reverse the anticoagulation effects of dabigatran, new research suggests.

In a small study, idarucizumab led to sustained reversal of dabigatran’s effects in healthy subjects, elderly volunteers, and participants with mild to moderate renal impairment.

Furthermore, dabigatran anticoagulation could be re-established 24 hours after the subjects had received idarucizumab.

Joachim Stangier, PhD, of Boehringer Ingelheim Pharma GmbH & Co KG in Biberach, Germany, presented these results at the 2014 ASH Annual Meeting as abstract 344*. Boehringer Ingelheim is the company developing idarucizumab.

Dr Stangier said idarucizumab binds dabigatran with high affinity, off-target binding is not expected, and no procoagulant effects have been observed with the drug.

In a previous study of healthy volunteers, idarucizumab provided immediate, complete, and sustained reversal of dabigatran’s anticoagulant effect. The effect was sustained when idarucizumab was given at 2 g and 4 g doses.

For the current study, Dr Stangier and his colleagues wanted to evaluate whether and to what extent doses of up to 5 g of idarucizumab would reverse the anticoagulant effects of dabigatran in healthy subjects, elderly participants, and renally impaired volunteers. The team also wanted to determine the effects of dabigatran given after subjects had received idarucizumab.

The study included 46 male and female subjects who were 45 to 80 years of age. Healthy subjects received dabigatran etexilate at 220 mg twice daily, and subjects with mild to moderate renal impairment received 150 mg twice daily, both over 4 days.

Subjects then received idarucizumab at 1 g, 2.5 g, 5 g, or 5 g given as 2 x 2.5 g 1 hour apart. They received these doses as 5-minute intravenous infusions 2 hours after their last dose of dabigatran.

The researchers found that dabigatran-prolonged clotting times—thrombin time, diluted thrombin time, ecarin clotting time, and activated partial thromboplastin time—were reversed to baseline immediately after the end of idarucizumab infusion.

And the team observed sustained reversal of dabigatran’s anticoagulant effects in all subjects.

The researchers then readministered dabigatran to healthy subjects 24 hours after idarucizumab treatment and to subjects who received placebo instead of idarucizumab.

Dabigatran-mediated anticoagulation was similar in subjects who received idarucizumab and those who received placebo. And anticoagulation was restored to levels comparable to initial levels.

Dr Stangier said there were no clinically relevant adverse events (AEs) related to idarucizumab, and there were no relevant changes in any of the investigated safety parameters. There were no AEs indicative of immunogenic reactions.

AEs and local tolerability reactions were similar for placebo and idarucizumab. And there was no relationship between the frequency of AEs and drug dose, gender, or renal function.

The researchers did observe a dose-dependent, transient increase in urine protein and low-weight proteins, but values returned to the normal range within 4 hours to 24 hours.

Based on these results, Dr Stangier said idarucizumab fulfills the requirements for a fast-acting and specific antidote to dabigatran with a favorable safety profile. Additional clinical testing of the antidote is ongoing.

*Information in the abstract differs from that presented.

Cord blood donation

Credit: NHS

The US Food and Drug Administration (FDA) has granted orphan designation to a cord blood product called NiCord for the treatment of acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), Hodgkin lymphoma (HL), and myelodysplastic syndromes (MDS).

NiCord consists of cells from a single cord blood unit cultured in nicotinamide—a vitamin B derivative—and cytokines that are typically used for expansion—thrombopoietin, interleukin 6, FLT3 ligand, and stem cell factor.

The FDA’s orphan drug designation for NiCord coincides with the positive opinion of the European Medicines Agency’s (EMA’s) Committee for Orphan Medicinal Products regarding NiCord as a treatment for AML. Gamida Cell, the company developing NiCord, intends to file for orphan drug status with the EMA for other indications as well.

“Receipt of orphan drug status for NiCord in the US and Europe advances Gamida Cell’s commercialization plans a major step further, as both afford significant advantages,” said Yael Margolin, President and CEO of Gamida Cell.

Orphan drug designation provides various regulatory and economic benefits, including 7 years of market exclusivity upon product approval in the US and 10 years in the European Union.

Trials of NiCord

NiCord is currently being tested in a phase 1/2 study as an investigational therapeutic treatment for hematologic malignancies. In this study, NiCord is being used as the sole stem cell source.

In a previous study, presented at the 11th Annual International Cord Blood Symposium, researchers transplanted a NiCord unit and an unmanipulated cord blood unit in patients with ALL, AML, MDS, HL, or non-Hodgkin lymphoma.

A majority of patients in this small, phase 1/2 study achieved early platelet and neutrophil engraftment. And, in some patients, that engraftment persisted for 2 years.

Eight of the 11 patients enrolled achieved engraftment with the NiCord unit, and 2 engrafted with the unmanipulated cord blood unit. One patient had primary graft failure.

There were no adverse events attributable to the NiCord unit, but 4 patients developed grade 1-2 acute GVHD, and 1 patient developed limited chronic GVHD.

For more information on NiCord, visit the Gamida Cell website.

Cord blood donation

Credit: NHS

The US Food and Drug Administration (FDA) has granted orphan designation to a cord blood product called NiCord for the treatment of acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), Hodgkin lymphoma (HL), and myelodysplastic syndromes (MDS).

NiCord consists of cells from a single cord blood unit cultured in nicotinamide—a vitamin B derivative—and cytokines that are typically used for expansion—thrombopoietin, interleukin 6, FLT3 ligand, and stem cell factor.

The FDA’s orphan drug designation for NiCord coincides with the positive opinion of the European Medicines Agency’s (EMA’s) Committee for Orphan Medicinal Products regarding NiCord as a treatment for AML. Gamida Cell, the company developing NiCord, intends to file for orphan drug status with the EMA for other indications as well.

“Receipt of orphan drug status for NiCord in the US and Europe advances Gamida Cell’s commercialization plans a major step further, as both afford significant advantages,” said Yael Margolin, President and CEO of Gamida Cell.

Orphan drug designation provides various regulatory and economic benefits, including 7 years of market exclusivity upon product approval in the US and 10 years in the European Union.

Trials of NiCord

NiCord is currently being tested in a phase 1/2 study as an investigational therapeutic treatment for hematologic malignancies. In this study, NiCord is being used as the sole stem cell source.

In a previous study, presented at the 11th Annual International Cord Blood Symposium, researchers transplanted a NiCord unit and an unmanipulated cord blood unit in patients with ALL, AML, MDS, HL, or non-Hodgkin lymphoma.

A majority of patients in this small, phase 1/2 study achieved early platelet and neutrophil engraftment. And, in some patients, that engraftment persisted for 2 years.

Eight of the 11 patients enrolled achieved engraftment with the NiCord unit, and 2 engrafted with the unmanipulated cord blood unit. One patient had primary graft failure.

There were no adverse events attributable to the NiCord unit, but 4 patients developed grade 1-2 acute GVHD, and 1 patient developed limited chronic GVHD.

For more information on NiCord, visit the Gamida Cell website.

Cord blood donation

Credit: NHS

The US Food and Drug Administration (FDA) has granted orphan designation to a cord blood product called NiCord for the treatment of acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), Hodgkin lymphoma (HL), and myelodysplastic syndromes (MDS).

NiCord consists of cells from a single cord blood unit cultured in nicotinamide—a vitamin B derivative—and cytokines that are typically used for expansion—thrombopoietin, interleukin 6, FLT3 ligand, and stem cell factor.

The FDA’s orphan drug designation for NiCord coincides with the positive opinion of the European Medicines Agency’s (EMA’s) Committee for Orphan Medicinal Products regarding NiCord as a treatment for AML. Gamida Cell, the company developing NiCord, intends to file for orphan drug status with the EMA for other indications as well.

“Receipt of orphan drug status for NiCord in the US and Europe advances Gamida Cell’s commercialization plans a major step further, as both afford significant advantages,” said Yael Margolin, President and CEO of Gamida Cell.

Orphan drug designation provides various regulatory and economic benefits, including 7 years of market exclusivity upon product approval in the US and 10 years in the European Union.

Trials of NiCord

NiCord is currently being tested in a phase 1/2 study as an investigational therapeutic treatment for hematologic malignancies. In this study, NiCord is being used as the sole stem cell source.

In a previous study, presented at the 11th Annual International Cord Blood Symposium, researchers transplanted a NiCord unit and an unmanipulated cord blood unit in patients with ALL, AML, MDS, HL, or non-Hodgkin lymphoma.

A majority of patients in this small, phase 1/2 study achieved early platelet and neutrophil engraftment. And, in some patients, that engraftment persisted for 2 years.

Eight of the 11 patients enrolled achieved engraftment with the NiCord unit, and 2 engrafted with the unmanipulated cord blood unit. One patient had primary graft failure.

There were no adverse events attributable to the NiCord unit, but 4 patients developed grade 1-2 acute GVHD, and 1 patient developed limited chronic GVHD.

For more information on NiCord, visit the Gamida Cell website.

Neutrophil engulfing bacteria

Credit: Volker Brinkmann

Enzymes linked to diabetes and obesity appear to play key roles in arthritis and leukemia, according to research published in Cell Metabolism.

Working with mice, researchers discovered that the same enzymes involved in turning carbohydrates into the building blocks of fats also influence the health of neutrophils.

“The link between these enzymes and neutrophils was a big surprise,” said study author Irfan J. Lodhi, PhD, of the Washington University School of Medicine in St. Louis.

“We had never thought about treating rheumatoid arthritis or leukemia by targeting enzymes that produce fatty acids, but this work supports that line of thinking.”

In the study, mice that couldn’t make enzymes needed to produce a certain type of fat abruptly lost weight and developed extremely low white blood cell counts, with very few neutrophils. Without this fat, called an ether lipid, neutrophils died.

That discovery could lead to the targeting of ether lipids as a way to reduce the number of neutrophils in inflammatory diseases and leukemias. The researchers believe limiting, rather than eliminating, ether lipids may be the best approach because neutrophils are important infection fighters.

“This may be a pathway to limit inflammation,” said study author Clay F. Semenkovich, MD, also of the Washington University School of Medicine.

“If we could reduce the activity of these enzymes without eliminating them entirely, it could lower the levels of ether lipids and potentially help patients with leukemia and inflammatory diseases such as arthritis.”

Dr Semenkovich said the enzymes specifically target neutrophils without affecting other immune cells, “so ether lipids appear to be a very precise target.”

The researchers also learned that inactivating the enzymes didn’t harm the precursors of neutrophils; only mature neutrophils were killed.

That could mean strategies to limit the production of ether lipids might lower neutrophil levels only temporarily so that when treatment stops, a patient’s neutrophil count would gradually rise, allowing the immune system to return to normal.

Neutrophil engulfing bacteria

Credit: Volker Brinkmann

Enzymes linked to diabetes and obesity appear to play key roles in arthritis and leukemia, according to research published in Cell Metabolism.

Working with mice, researchers discovered that the same enzymes involved in turning carbohydrates into the building blocks of fats also influence the health of neutrophils.

“The link between these enzymes and neutrophils was a big surprise,” said study author Irfan J. Lodhi, PhD, of the Washington University School of Medicine in St. Louis.

“We had never thought about treating rheumatoid arthritis or leukemia by targeting enzymes that produce fatty acids, but this work supports that line of thinking.”

In the study, mice that couldn’t make enzymes needed to produce a certain type of fat abruptly lost weight and developed extremely low white blood cell counts, with very few neutrophils. Without this fat, called an ether lipid, neutrophils died.

That discovery could lead to the targeting of ether lipids as a way to reduce the number of neutrophils in inflammatory diseases and leukemias. The researchers believe limiting, rather than eliminating, ether lipids may be the best approach because neutrophils are important infection fighters.

“This may be a pathway to limit inflammation,” said study author Clay F. Semenkovich, MD, also of the Washington University School of Medicine.

“If we could reduce the activity of these enzymes without eliminating them entirely, it could lower the levels of ether lipids and potentially help patients with leukemia and inflammatory diseases such as arthritis.”

Dr Semenkovich said the enzymes specifically target neutrophils without affecting other immune cells, “so ether lipids appear to be a very precise target.”

The researchers also learned that inactivating the enzymes didn’t harm the precursors of neutrophils; only mature neutrophils were killed.

That could mean strategies to limit the production of ether lipids might lower neutrophil levels only temporarily so that when treatment stops, a patient’s neutrophil count would gradually rise, allowing the immune system to return to normal.

Neutrophil engulfing bacteria

Credit: Volker Brinkmann

Enzymes linked to diabetes and obesity appear to play key roles in arthritis and leukemia, according to research published in Cell Metabolism.

Working with mice, researchers discovered that the same enzymes involved in turning carbohydrates into the building blocks of fats also influence the health of neutrophils.

“The link between these enzymes and neutrophils was a big surprise,” said study author Irfan J. Lodhi, PhD, of the Washington University School of Medicine in St. Louis.

“We had never thought about treating rheumatoid arthritis or leukemia by targeting enzymes that produce fatty acids, but this work supports that line of thinking.”

In the study, mice that couldn’t make enzymes needed to produce a certain type of fat abruptly lost weight and developed extremely low white blood cell counts, with very few neutrophils. Without this fat, called an ether lipid, neutrophils died.

That discovery could lead to the targeting of ether lipids as a way to reduce the number of neutrophils in inflammatory diseases and leukemias. The researchers believe limiting, rather than eliminating, ether lipids may be the best approach because neutrophils are important infection fighters.

“This may be a pathway to limit inflammation,” said study author Clay F. Semenkovich, MD, also of the Washington University School of Medicine.

“If we could reduce the activity of these enzymes without eliminating them entirely, it could lower the levels of ether lipids and potentially help patients with leukemia and inflammatory diseases such as arthritis.”

Dr Semenkovich said the enzymes specifically target neutrophils without affecting other immune cells, “so ether lipids appear to be a very precise target.”

The researchers also learned that inactivating the enzymes didn’t harm the precursors of neutrophils; only mature neutrophils were killed.

That could mean strategies to limit the production of ether lipids might lower neutrophil levels only temporarily so that when treatment stops, a patient’s neutrophil count would gradually rise, allowing the immune system to return to normal.