MAUI, HAWAII – The investigational bone-building agent romosozumab provided the therapeutic highlight in the field of osteoporosis during the past year, Dr. Martin J. Bergman said at the 2016 Rheumatology Winter Clinical Symposium.

Romosozumab is a monoclonal antibody directed against sclerostin, a glycoprotein that prevents mesenchymal cells from becoming osteoblasts. By inhibiting sclerostin, romosozumab promotes osteoblast production. The result is increased bone mineral density and bone formation coupled with decreased bone resorption, providing physicians with a promising new avenue for rapidly building strong bone, explained Dr. Bergman of Drexel University in Philadelphia and chief of the section of rheumatology at Taylor Hospital in Ridley Park, Pa.

Bruce Jancin/Frontline Medical News

Romosozumab caught his eye in a 12-month randomized trial presented last fall at the annual meeting of the American College of Rheumatology. The 430 postmenopausal participants were assigned to blinded romosozumab at 210 mg delivered by subcutaneous injection once per month, blinded placebo, or open-label teriparatide (Forteo). The primary endpoint in this secondary analysis was change in bone strength as measured using the Food and Drug Administration–approved method of finite element analysis based upon quantitative CT imaging.

Romosozumab boosted bone strength at the spine by 27.3% at 12 months, compared with a 3.9% reduction from baseline with placebo and an 18.5% increase with teriparatide. At the hip, romosozumab delivered a 3.6% increase in bone strength versus no significant change from baseline in the other two study arms. Thus, romosozumab increased bone strength both in the cortical and trabecular compartments even more than did teriparatide, the most potent drug currently available for building bone mass.

“The numbers are very impressive,” Dr. Bergman observed. “Trabecular bone, cortical bone, whole bone – across the board, we haven’t seen similar numbers before. I think this is going to be a very exciting new approach to the treatment of osteoporosis. We need to keep an eye on this.”

Romosozumab, which is being codeveloped by Amgen and UCB, is now in phase III testing.

The other big news in osteoporosis is that later this year the ACR will undertake a revision of its 2010 guidelines for the prevention and treatment of glucocorticoid-induced osteoporosis (Arthritis Care Res [Hoboken]. 2010 Nov;62[11]:1515-26).

Among the actions that need to be taken are the incorporation of denosumab (Prolia) and ibandronate (Boniva) into the treatment recommendations, as well as clarification of the recommendation for supplemental calcium in light of recent evidence of an association between high serum calcium and increased cardiovascular risk. Most of the lifestyle modification recommendations in the current guidelines are supported by a weak level of evidence C, meaning “expert opinion,” and the hope is that the evidence has become stronger since 2010, he said.

Dr. Bergman reported having no financial conflicts regarding his presentation.

[email protected]

MAUI, HAWAII – The investigational bone-building agent romosozumab provided the therapeutic highlight in the field of osteoporosis during the past year, Dr. Martin J. Bergman said at the 2016 Rheumatology Winter Clinical Symposium.

Romosozumab is a monoclonal antibody directed against sclerostin, a glycoprotein that prevents mesenchymal cells from becoming osteoblasts. By inhibiting sclerostin, romosozumab promotes osteoblast production. The result is increased bone mineral density and bone formation coupled with decreased bone resorption, providing physicians with a promising new avenue for rapidly building strong bone, explained Dr. Bergman of Drexel University in Philadelphia and chief of the section of rheumatology at Taylor Hospital in Ridley Park, Pa.

Bruce Jancin/Frontline Medical News

Romosozumab caught his eye in a 12-month randomized trial presented last fall at the annual meeting of the American College of Rheumatology. The 430 postmenopausal participants were assigned to blinded romosozumab at 210 mg delivered by subcutaneous injection once per month, blinded placebo, or open-label teriparatide (Forteo). The primary endpoint in this secondary analysis was change in bone strength as measured using the Food and Drug Administration–approved method of finite element analysis based upon quantitative CT imaging.

Romosozumab boosted bone strength at the spine by 27.3% at 12 months, compared with a 3.9% reduction from baseline with placebo and an 18.5% increase with teriparatide. At the hip, romosozumab delivered a 3.6% increase in bone strength versus no significant change from baseline in the other two study arms. Thus, romosozumab increased bone strength both in the cortical and trabecular compartments even more than did teriparatide, the most potent drug currently available for building bone mass.

“The numbers are very impressive,” Dr. Bergman observed. “Trabecular bone, cortical bone, whole bone – across the board, we haven’t seen similar numbers before. I think this is going to be a very exciting new approach to the treatment of osteoporosis. We need to keep an eye on this.”

Romosozumab, which is being codeveloped by Amgen and UCB, is now in phase III testing.

The other big news in osteoporosis is that later this year the ACR will undertake a revision of its 2010 guidelines for the prevention and treatment of glucocorticoid-induced osteoporosis (Arthritis Care Res [Hoboken]. 2010 Nov;62[11]:1515-26).

Among the actions that need to be taken are the incorporation of denosumab (Prolia) and ibandronate (Boniva) into the treatment recommendations, as well as clarification of the recommendation for supplemental calcium in light of recent evidence of an association between high serum calcium and increased cardiovascular risk. Most of the lifestyle modification recommendations in the current guidelines are supported by a weak level of evidence C, meaning “expert opinion,” and the hope is that the evidence has become stronger since 2010, he said.

Dr. Bergman reported having no financial conflicts regarding his presentation.

[email protected]

MAUI, HAWAII – The investigational bone-building agent romosozumab provided the therapeutic highlight in the field of osteoporosis during the past year, Dr. Martin J. Bergman said at the 2016 Rheumatology Winter Clinical Symposium.

Romosozumab is a monoclonal antibody directed against sclerostin, a glycoprotein that prevents mesenchymal cells from becoming osteoblasts. By inhibiting sclerostin, romosozumab promotes osteoblast production. The result is increased bone mineral density and bone formation coupled with decreased bone resorption, providing physicians with a promising new avenue for rapidly building strong bone, explained Dr. Bergman of Drexel University in Philadelphia and chief of the section of rheumatology at Taylor Hospital in Ridley Park, Pa.

Bruce Jancin/Frontline Medical News

Romosozumab caught his eye in a 12-month randomized trial presented last fall at the annual meeting of the American College of Rheumatology. The 430 postmenopausal participants were assigned to blinded romosozumab at 210 mg delivered by subcutaneous injection once per month, blinded placebo, or open-label teriparatide (Forteo). The primary endpoint in this secondary analysis was change in bone strength as measured using the Food and Drug Administration–approved method of finite element analysis based upon quantitative CT imaging.

Romosozumab boosted bone strength at the spine by 27.3% at 12 months, compared with a 3.9% reduction from baseline with placebo and an 18.5% increase with teriparatide. At the hip, romosozumab delivered a 3.6% increase in bone strength versus no significant change from baseline in the other two study arms. Thus, romosozumab increased bone strength both in the cortical and trabecular compartments even more than did teriparatide, the most potent drug currently available for building bone mass.

“The numbers are very impressive,” Dr. Bergman observed. “Trabecular bone, cortical bone, whole bone – across the board, we haven’t seen similar numbers before. I think this is going to be a very exciting new approach to the treatment of osteoporosis. We need to keep an eye on this.”

Romosozumab, which is being codeveloped by Amgen and UCB, is now in phase III testing.

The other big news in osteoporosis is that later this year the ACR will undertake a revision of its 2010 guidelines for the prevention and treatment of glucocorticoid-induced osteoporosis (Arthritis Care Res [Hoboken]. 2010 Nov;62[11]:1515-26).

Among the actions that need to be taken are the incorporation of denosumab (Prolia) and ibandronate (Boniva) into the treatment recommendations, as well as clarification of the recommendation for supplemental calcium in light of recent evidence of an association between high serum calcium and increased cardiovascular risk. Most of the lifestyle modification recommendations in the current guidelines are supported by a weak level of evidence C, meaning “expert opinion,” and the hope is that the evidence has become stronger since 2010, he said.

Dr. Bergman reported having no financial conflicts regarding his presentation.

[email protected]

It has been clear for a long time that a child who grows up in an environment dominated by adversity is more likely to enter adulthood scarred psychologically, and as a result is less likely to succeed. This well-described association has in the last few years become a hot button topic. A 2012 American Academy of Pediatrics policy statement alerted pediatricians to their potential role in identifying and managing what is now referred to as “toxic stress” (“Early Childhood Adversity, Toxic Stress, and the Role of the Pediatrician: Translating Developmental Science Into Lifelong Health”).

Although a childhood in which challenges outnumber advantages is often followed by an adult life characterized by failure and dysfunction, there are a few individuals who not only survive a disadvantaged childhood unscathed but somehow manage to thrive in its wake. For example, Joe Rantz, the central figure in Daniel James Brown’s nonfiction best seller “The Boys in the Boat” (New York: Viking Press, 2013) was abandoned several times by his family but emerged to power the University of Washington crew team to victory in the 1936 Olympics. Intrigued by these outliers, a developmental psychologist and clinician from the University of Minnesota named Norman Garmezy began looking for features that may have allowed these exceptional people to succeed and even excel despite incredibly difficult circumstances (“How People Learn to Become Resilient,” Maria Konnikova, The New Yorker, Feb. 11, 2016). His search for the characteristics that might have protected these individuals as children from the acute and chronic environmental threats of their disadvantaged childhoods has spawned a breed of developmental psychologists who devote their research to a quality now referred to as “resilience.”

In 1989, Emmy E. Werner, Ph.D., published a study of 698 children on the island of Kauai in Hawaii and identified several elements that might predict resilience (“Children of the Garden Island,” Sci Am. 1989;260[4]:106-11). Not surprisingly, one factor was the good luck of having formed a strong bond with a supportive person such as a caregiver or mentor. However, Dr. Werner also discovered that resilient individuals possessed a set of psychological characteristics that included a positive social orientation prompting them to “meet the world on their own terms.” They were likely to be autonomous and independent and had the attitude that “they, and not their circumstances, affected their achievements.”

These findings lead to the obvious question of whether those attributes that can protect against adversity can be taught. George Bonanno, a clinical psychologist at Columbia University’s Teachers College, found that an individual’s perception of the situation is the key element in resilience. In the New Yorker article on resilience, he was quoted in an interview as saying, “Events are not traumatic until we experience them as traumatic.” In his studies he has found that individuals can be taught how to reframe an event in positive terms that was initially perceived as negative. Unfortunately, the reverse can occur, and as Dr. Bonanno also said in the interview, “We can create or exaggerate stressors very easily in our own minds.” Every event is potentially traumatic if we perceive it that way.

Could it be that in some situations our behavior as adults, parents, and professionals creates an environment that transforms an event into one that is more easily perceived by a child as traumatizing? While it is important to be on the lookout for children who have been emotionally traumatized by an unfortunate event such as a school shooting, we must be careful to keep our responses measured and positive. Children should be reminded that it is they who control their own behavior and achievements, not the circumstances in which they find themselves.

Parents should be reminded that hovering and overinvolvement in their children’s lives is preventing the development of independence and a sense of autonomy, two important characteristics of resilience. The trend in education that emphasizes group solutions may be helping some children learn to cooperate with others and function as a team. But, we must also remember to offer each individual child abundant opportunities to learn so that he or she can also rely on himself or herself to solve problems.

Few of us will ever have the capacity for resiliency demonstrated by Louis Zamperini in the nonfiction best seller Unbroken, but we can and should be doing a better job helping children learn that even in the most adverse conditions, they have some control – if not over the circumstance, then at least over their perception of it.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics including “How to Say No to Your Toddler.”

It has been clear for a long time that a child who grows up in an environment dominated by adversity is more likely to enter adulthood scarred psychologically, and as a result is less likely to succeed. This well-described association has in the last few years become a hot button topic. A 2012 American Academy of Pediatrics policy statement alerted pediatricians to their potential role in identifying and managing what is now referred to as “toxic stress” (“Early Childhood Adversity, Toxic Stress, and the Role of the Pediatrician: Translating Developmental Science Into Lifelong Health”).

Although a childhood in which challenges outnumber advantages is often followed by an adult life characterized by failure and dysfunction, there are a few individuals who not only survive a disadvantaged childhood unscathed but somehow manage to thrive in its wake. For example, Joe Rantz, the central figure in Daniel James Brown’s nonfiction best seller “The Boys in the Boat” (New York: Viking Press, 2013) was abandoned several times by his family but emerged to power the University of Washington crew team to victory in the 1936 Olympics. Intrigued by these outliers, a developmental psychologist and clinician from the University of Minnesota named Norman Garmezy began looking for features that may have allowed these exceptional people to succeed and even excel despite incredibly difficult circumstances (“How People Learn to Become Resilient,” Maria Konnikova, The New Yorker, Feb. 11, 2016). His search for the characteristics that might have protected these individuals as children from the acute and chronic environmental threats of their disadvantaged childhoods has spawned a breed of developmental psychologists who devote their research to a quality now referred to as “resilience.”

In 1989, Emmy E. Werner, Ph.D., published a study of 698 children on the island of Kauai in Hawaii and identified several elements that might predict resilience (“Children of the Garden Island,” Sci Am. 1989;260[4]:106-11). Not surprisingly, one factor was the good luck of having formed a strong bond with a supportive person such as a caregiver or mentor. However, Dr. Werner also discovered that resilient individuals possessed a set of psychological characteristics that included a positive social orientation prompting them to “meet the world on their own terms.” They were likely to be autonomous and independent and had the attitude that “they, and not their circumstances, affected their achievements.”

These findings lead to the obvious question of whether those attributes that can protect against adversity can be taught. George Bonanno, a clinical psychologist at Columbia University’s Teachers College, found that an individual’s perception of the situation is the key element in resilience. In the New Yorker article on resilience, he was quoted in an interview as saying, “Events are not traumatic until we experience them as traumatic.” In his studies he has found that individuals can be taught how to reframe an event in positive terms that was initially perceived as negative. Unfortunately, the reverse can occur, and as Dr. Bonanno also said in the interview, “We can create or exaggerate stressors very easily in our own minds.” Every event is potentially traumatic if we perceive it that way.

Could it be that in some situations our behavior as adults, parents, and professionals creates an environment that transforms an event into one that is more easily perceived by a child as traumatizing? While it is important to be on the lookout for children who have been emotionally traumatized by an unfortunate event such as a school shooting, we must be careful to keep our responses measured and positive. Children should be reminded that it is they who control their own behavior and achievements, not the circumstances in which they find themselves.

Parents should be reminded that hovering and overinvolvement in their children’s lives is preventing the development of independence and a sense of autonomy, two important characteristics of resilience. The trend in education that emphasizes group solutions may be helping some children learn to cooperate with others and function as a team. But, we must also remember to offer each individual child abundant opportunities to learn so that he or she can also rely on himself or herself to solve problems.

Few of us will ever have the capacity for resiliency demonstrated by Louis Zamperini in the nonfiction best seller Unbroken, but we can and should be doing a better job helping children learn that even in the most adverse conditions, they have some control – if not over the circumstance, then at least over their perception of it.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics including “How to Say No to Your Toddler.”

It has been clear for a long time that a child who grows up in an environment dominated by adversity is more likely to enter adulthood scarred psychologically, and as a result is less likely to succeed. This well-described association has in the last few years become a hot button topic. A 2012 American Academy of Pediatrics policy statement alerted pediatricians to their potential role in identifying and managing what is now referred to as “toxic stress” (“Early Childhood Adversity, Toxic Stress, and the Role of the Pediatrician: Translating Developmental Science Into Lifelong Health”).

Although a childhood in which challenges outnumber advantages is often followed by an adult life characterized by failure and dysfunction, there are a few individuals who not only survive a disadvantaged childhood unscathed but somehow manage to thrive in its wake. For example, Joe Rantz, the central figure in Daniel James Brown’s nonfiction best seller “The Boys in the Boat” (New York: Viking Press, 2013) was abandoned several times by his family but emerged to power the University of Washington crew team to victory in the 1936 Olympics. Intrigued by these outliers, a developmental psychologist and clinician from the University of Minnesota named Norman Garmezy began looking for features that may have allowed these exceptional people to succeed and even excel despite incredibly difficult circumstances (“How People Learn to Become Resilient,” Maria Konnikova, The New Yorker, Feb. 11, 2016). His search for the characteristics that might have protected these individuals as children from the acute and chronic environmental threats of their disadvantaged childhoods has spawned a breed of developmental psychologists who devote their research to a quality now referred to as “resilience.”

In 1989, Emmy E. Werner, Ph.D., published a study of 698 children on the island of Kauai in Hawaii and identified several elements that might predict resilience (“Children of the Garden Island,” Sci Am. 1989;260[4]:106-11). Not surprisingly, one factor was the good luck of having formed a strong bond with a supportive person such as a caregiver or mentor. However, Dr. Werner also discovered that resilient individuals possessed a set of psychological characteristics that included a positive social orientation prompting them to “meet the world on their own terms.” They were likely to be autonomous and independent and had the attitude that “they, and not their circumstances, affected their achievements.”

These findings lead to the obvious question of whether those attributes that can protect against adversity can be taught. George Bonanno, a clinical psychologist at Columbia University’s Teachers College, found that an individual’s perception of the situation is the key element in resilience. In the New Yorker article on resilience, he was quoted in an interview as saying, “Events are not traumatic until we experience them as traumatic.” In his studies he has found that individuals can be taught how to reframe an event in positive terms that was initially perceived as negative. Unfortunately, the reverse can occur, and as Dr. Bonanno also said in the interview, “We can create or exaggerate stressors very easily in our own minds.” Every event is potentially traumatic if we perceive it that way.

Could it be that in some situations our behavior as adults, parents, and professionals creates an environment that transforms an event into one that is more easily perceived by a child as traumatizing? While it is important to be on the lookout for children who have been emotionally traumatized by an unfortunate event such as a school shooting, we must be careful to keep our responses measured and positive. Children should be reminded that it is they who control their own behavior and achievements, not the circumstances in which they find themselves.

Parents should be reminded that hovering and overinvolvement in their children’s lives is preventing the development of independence and a sense of autonomy, two important characteristics of resilience. The trend in education that emphasizes group solutions may be helping some children learn to cooperate with others and function as a team. But, we must also remember to offer each individual child abundant opportunities to learn so that he or she can also rely on himself or herself to solve problems.

Few of us will ever have the capacity for resiliency demonstrated by Louis Zamperini in the nonfiction best seller Unbroken, but we can and should be doing a better job helping children learn that even in the most adverse conditions, they have some control – if not over the circumstance, then at least over their perception of it.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics including “How to Say No to Your Toddler.”

Lab mouse

Preclinical research has revealed a treatment approach that could prove effective against acute myeloid leukemia (AML).

Researchers tested the IAP inhibitor birinapant in combination with p38 inhibitors and observed antileukemic activity in mouse models of AML and samples from patients with the disease.

Combination treatment proved more effective than either agent alone, and the combination was less toxic than single-agent chemotherapy.

Najoua Lalaoui, PhD, of the Walter and Eliza Hall Institute of Medical Research in Parkville, Victoria, Australia, and her colleagues conducted this research and relayed the results in an article published in Cancer Cell.

The researchers generated several mouse models of AML—MLL-ENL ± NRas^G12D, MLL-AF9 ± Nras^G12D, AML1-ETO9a + Nras^G12D, CBFβ-MYH11 + Nras^G12D, NUP98-HoxA9, and HoxA9/Meis1.

In these models, the team tested birinapant with 1 of 2 p38 inhibitors—LY2228820 or SCIO-469—or with the MK2 inhibitor PF-3644022. They said each combination “dramatically” increased cell death, when compared to birinapant alone, in most models. The exceptions were AML1-ETO9a + Nras^G12D and CBFβ-MYH11 + Nras^G12D.

Next, the researchers tested LY2228820 plus birinapant in samples from 8 AML patients. The samples had FLT3-ITD mutations (patients 1, 2, 4, 6, and 7), a FLT3 D835 missense mutation (patient 4), nucleophosmin exon-12 mutations (patients 2 and 4), an MLL translocation (patient 3), inv(3) (patient 1), and inv(16) (patient 8).

All 8 samples were sensitive to birinapant alone. And although LY2228820 alone did not induce cell death in any of the samples, the drug had a synergistic effect with birinapant in 4 of the samples (patients 2, 3, 4, and 7).

The researchers also found that peripheral blood mononuclear cells from healthy donors proved more resistant to combination LY2228820 (at 10 µM) and birinapant (at 500 nM) than to cytarabine (10 µM), daunorubicin (at 0.4 µM), or idarubicin (at 0.4 µM).

In addition, 4 weeks of treatment with birinapant and LY2228820 was well-tolerated in mice without tumors.

Finally, the researchers tested birinapant and LY2228820, either alone or in combination, in mouse models of MLL-ENL, MLL-AF9, and NRas^G12D mutant/MLL-AF9/Luc AML.

Combination treatment prolonged survival in all 3 models, when compared with mice that received single agents or no treatment. However, unlike in the MLL-ENL and MLL-AF9 models, the combination was unable to cure NRas^G12D mutant/MLL-AF9/Luc mice of their leukemia.

“Our findings have made us hopeful that a combination of birinapant and a p38 inhibitor may be more effective in treating AML than current therapies and also have less toxicity for patients,” Dr Lalaoui said.

“We tested forms of AML that are highly resistant to chemotherapy and found that birinapant and p38 inhibitors could even kill these cancer cells, which is great news.”

Birinapant is being developed by TetraLogic Pharmaceuticals Corporation, and some of the researchers involved in this work reported relationships with the company.

Lab mouse

Preclinical research has revealed a treatment approach that could prove effective against acute myeloid leukemia (AML).

Researchers tested the IAP inhibitor birinapant in combination with p38 inhibitors and observed antileukemic activity in mouse models of AML and samples from patients with the disease.

Combination treatment proved more effective than either agent alone, and the combination was less toxic than single-agent chemotherapy.

Najoua Lalaoui, PhD, of the Walter and Eliza Hall Institute of Medical Research in Parkville, Victoria, Australia, and her colleagues conducted this research and relayed the results in an article published in Cancer Cell.

The researchers generated several mouse models of AML—MLL-ENL ± NRas^G12D, MLL-AF9 ± Nras^G12D, AML1-ETO9a + Nras^G12D, CBFβ-MYH11 + Nras^G12D, NUP98-HoxA9, and HoxA9/Meis1.

In these models, the team tested birinapant with 1 of 2 p38 inhibitors—LY2228820 or SCIO-469—or with the MK2 inhibitor PF-3644022. They said each combination “dramatically” increased cell death, when compared to birinapant alone, in most models. The exceptions were AML1-ETO9a + Nras^G12D and CBFβ-MYH11 + Nras^G12D.

Next, the researchers tested LY2228820 plus birinapant in samples from 8 AML patients. The samples had FLT3-ITD mutations (patients 1, 2, 4, 6, and 7), a FLT3 D835 missense mutation (patient 4), nucleophosmin exon-12 mutations (patients 2 and 4), an MLL translocation (patient 3), inv(3) (patient 1), and inv(16) (patient 8).

All 8 samples were sensitive to birinapant alone. And although LY2228820 alone did not induce cell death in any of the samples, the drug had a synergistic effect with birinapant in 4 of the samples (patients 2, 3, 4, and 7).

The researchers also found that peripheral blood mononuclear cells from healthy donors proved more resistant to combination LY2228820 (at 10 µM) and birinapant (at 500 nM) than to cytarabine (10 µM), daunorubicin (at 0.4 µM), or idarubicin (at 0.4 µM).

In addition, 4 weeks of treatment with birinapant and LY2228820 was well-tolerated in mice without tumors.

Finally, the researchers tested birinapant and LY2228820, either alone or in combination, in mouse models of MLL-ENL, MLL-AF9, and NRas^G12D mutant/MLL-AF9/Luc AML.

Combination treatment prolonged survival in all 3 models, when compared with mice that received single agents or no treatment. However, unlike in the MLL-ENL and MLL-AF9 models, the combination was unable to cure NRas^G12D mutant/MLL-AF9/Luc mice of their leukemia.

“Our findings have made us hopeful that a combination of birinapant and a p38 inhibitor may be more effective in treating AML than current therapies and also have less toxicity for patients,” Dr Lalaoui said.

“We tested forms of AML that are highly resistant to chemotherapy and found that birinapant and p38 inhibitors could even kill these cancer cells, which is great news.”

Birinapant is being developed by TetraLogic Pharmaceuticals Corporation, and some of the researchers involved in this work reported relationships with the company.

Lab mouse

Preclinical research has revealed a treatment approach that could prove effective against acute myeloid leukemia (AML).

Researchers tested the IAP inhibitor birinapant in combination with p38 inhibitors and observed antileukemic activity in mouse models of AML and samples from patients with the disease.

Combination treatment proved more effective than either agent alone, and the combination was less toxic than single-agent chemotherapy.

Najoua Lalaoui, PhD, of the Walter and Eliza Hall Institute of Medical Research in Parkville, Victoria, Australia, and her colleagues conducted this research and relayed the results in an article published in Cancer Cell.

The researchers generated several mouse models of AML—MLL-ENL ± NRas^G12D, MLL-AF9 ± Nras^G12D, AML1-ETO9a + Nras^G12D, CBFβ-MYH11 + Nras^G12D, NUP98-HoxA9, and HoxA9/Meis1.

In these models, the team tested birinapant with 1 of 2 p38 inhibitors—LY2228820 or SCIO-469—or with the MK2 inhibitor PF-3644022. They said each combination “dramatically” increased cell death, when compared to birinapant alone, in most models. The exceptions were AML1-ETO9a + Nras^G12D and CBFβ-MYH11 + Nras^G12D.

Next, the researchers tested LY2228820 plus birinapant in samples from 8 AML patients. The samples had FLT3-ITD mutations (patients 1, 2, 4, 6, and 7), a FLT3 D835 missense mutation (patient 4), nucleophosmin exon-12 mutations (patients 2 and 4), an MLL translocation (patient 3), inv(3) (patient 1), and inv(16) (patient 8).

All 8 samples were sensitive to birinapant alone. And although LY2228820 alone did not induce cell death in any of the samples, the drug had a synergistic effect with birinapant in 4 of the samples (patients 2, 3, 4, and 7).

The researchers also found that peripheral blood mononuclear cells from healthy donors proved more resistant to combination LY2228820 (at 10 µM) and birinapant (at 500 nM) than to cytarabine (10 µM), daunorubicin (at 0.4 µM), or idarubicin (at 0.4 µM).

In addition, 4 weeks of treatment with birinapant and LY2228820 was well-tolerated in mice without tumors.

Finally, the researchers tested birinapant and LY2228820, either alone or in combination, in mouse models of MLL-ENL, MLL-AF9, and NRas^G12D mutant/MLL-AF9/Luc AML.

Combination treatment prolonged survival in all 3 models, when compared with mice that received single agents or no treatment. However, unlike in the MLL-ENL and MLL-AF9 models, the combination was unable to cure NRas^G12D mutant/MLL-AF9/Luc mice of their leukemia.

“Our findings have made us hopeful that a combination of birinapant and a p38 inhibitor may be more effective in treating AML than current therapies and also have less toxicity for patients,” Dr Lalaoui said.

“We tested forms of AML that are highly resistant to chemotherapy and found that birinapant and p38 inhibitors could even kill these cancer cells, which is great news.”

Birinapant is being developed by TetraLogic Pharmaceuticals Corporation, and some of the researchers involved in this work reported relationships with the company.

Red blood cells

The European Commission (EC) has granted orphan drug designation for TNT009 to treat autoimmune hemolytic anemia, including cold agglutinin disease.

TNT009 is a monoclonal antibody that selectively inhibits the classical complement pathway by targeting C1s, a serine protease within the C1-complex in the complement pathway.

The drug thereby prevents downstream disease processes involving phagocytosis, inflammation, and cell lysis.

TNT009 is being developed by True North Therapeutics.

The drug is currently in development for the treatment of autoimmune hemolytic anemia, which is characterized by the premature destruction of healthy red blood cells by autoantibodies.

In cold agglutinin disease, this destruction of red blood cells results in anemia, fatigue, and potentially fatal thrombosis.

TNT009 is also being evaluated in patients with bullous pemphigoid and end-stage renal disease.

Top-line results from a phase 1b trial of TNT009 are expected in mid-2016.

About orphan designation

The EC grants orphan designation to products intended to treat, prevent, or diagnose a life-threatening condition affecting up to 5 in 10,000 people in the European Union. The product must provide significant benefit to those affected by the condition.

Orphan drug designation from the EC provides companies with certain development incentives, including protocol assistance, a type of scientific advice specific for orphan drugs, and 10 years of market exclusivity once the drug is on the market.

Red blood cells

The European Commission (EC) has granted orphan drug designation for TNT009 to treat autoimmune hemolytic anemia, including cold agglutinin disease.

TNT009 is a monoclonal antibody that selectively inhibits the classical complement pathway by targeting C1s, a serine protease within the C1-complex in the complement pathway.

The drug thereby prevents downstream disease processes involving phagocytosis, inflammation, and cell lysis.

TNT009 is being developed by True North Therapeutics.

The drug is currently in development for the treatment of autoimmune hemolytic anemia, which is characterized by the premature destruction of healthy red blood cells by autoantibodies.

In cold agglutinin disease, this destruction of red blood cells results in anemia, fatigue, and potentially fatal thrombosis.

TNT009 is also being evaluated in patients with bullous pemphigoid and end-stage renal disease.

Top-line results from a phase 1b trial of TNT009 are expected in mid-2016.

About orphan designation

The EC grants orphan designation to products intended to treat, prevent, or diagnose a life-threatening condition affecting up to 5 in 10,000 people in the European Union. The product must provide significant benefit to those affected by the condition.

Orphan drug designation from the EC provides companies with certain development incentives, including protocol assistance, a type of scientific advice specific for orphan drugs, and 10 years of market exclusivity once the drug is on the market.

Red blood cells

The European Commission (EC) has granted orphan drug designation for TNT009 to treat autoimmune hemolytic anemia, including cold agglutinin disease.

TNT009 is a monoclonal antibody that selectively inhibits the classical complement pathway by targeting C1s, a serine protease within the C1-complex in the complement pathway.

The drug thereby prevents downstream disease processes involving phagocytosis, inflammation, and cell lysis.

TNT009 is being developed by True North Therapeutics.

The drug is currently in development for the treatment of autoimmune hemolytic anemia, which is characterized by the premature destruction of healthy red blood cells by autoantibodies.

In cold agglutinin disease, this destruction of red blood cells results in anemia, fatigue, and potentially fatal thrombosis.

TNT009 is also being evaluated in patients with bullous pemphigoid and end-stage renal disease.

Top-line results from a phase 1b trial of TNT009 are expected in mid-2016.

About orphan designation

The EC grants orphan designation to products intended to treat, prevent, or diagnose a life-threatening condition affecting up to 5 in 10,000 people in the European Union. The product must provide significant benefit to those affected by the condition.

Orphan drug designation from the EC provides companies with certain development incentives, including protocol assistance, a type of scientific advice specific for orphan drugs, and 10 years of market exclusivity once the drug is on the market.

This April, the Society of Hospital Medicine (SHM) will offer two free live webinars on how two of its signature mentored implementation programs are changing the way hospitals manage two key issues: readmissions and glycemic control.

Project BOOST is an evidence-based approach to reduce preventable admissions, decrease average length of stay, and improve patient satisfaction. It includes one year of individualized mentoring from a physician leader with expertise in clinical quality, on-site mentoring and training from leaders in the field, access to an online tool kit with clinical resources, and more. Find out how to get involved with Project BOOST and take the first steps toward reducing readmissions with our complimentary webinar in April.

Learn more at www.hospitalmedicine.org/BOOST.

Another signature program, SHM’s Glycemic Control Mentored Implementation Program, has supported the development and implementation of glycemic control in more than 100 hospitals nationwide. Added benefits include data collection and analysis tools, monthly coaching calls with mentors, SHM-facilitated calls and live webinars, and access to an online web-based glycemic control collaborative to share best practices.

Join more than 100 hospitals working with SHM to improve glycemic control at an upcoming free live webinar. More information is available at www.hospitalmedicine.org/gc.

A comprehensive suite of mentored implementation programs offered through SHM’s Center for Hospital Innovation and Improvement is designed to provide institutions with coaching by national physician experts to map current processes, identify root causes of deficiencies, and tailor interventions to the unique needs of the institution for sustainable results.

For more information, visit www.hospitalmedicine.org and click on Quality & Innovation.

This April, the Society of Hospital Medicine (SHM) will offer two free live webinars on how two of its signature mentored implementation programs are changing the way hospitals manage two key issues: readmissions and glycemic control.

Project BOOST is an evidence-based approach to reduce preventable admissions, decrease average length of stay, and improve patient satisfaction. It includes one year of individualized mentoring from a physician leader with expertise in clinical quality, on-site mentoring and training from leaders in the field, access to an online tool kit with clinical resources, and more. Find out how to get involved with Project BOOST and take the first steps toward reducing readmissions with our complimentary webinar in April.

Learn more at www.hospitalmedicine.org/BOOST.

Another signature program, SHM’s Glycemic Control Mentored Implementation Program, has supported the development and implementation of glycemic control in more than 100 hospitals nationwide. Added benefits include data collection and analysis tools, monthly coaching calls with mentors, SHM-facilitated calls and live webinars, and access to an online web-based glycemic control collaborative to share best practices.

Join more than 100 hospitals working with SHM to improve glycemic control at an upcoming free live webinar. More information is available at www.hospitalmedicine.org/gc.

A comprehensive suite of mentored implementation programs offered through SHM’s Center for Hospital Innovation and Improvement is designed to provide institutions with coaching by national physician experts to map current processes, identify root causes of deficiencies, and tailor interventions to the unique needs of the institution for sustainable results.

For more information, visit www.hospitalmedicine.org and click on Quality & Innovation.

This April, the Society of Hospital Medicine (SHM) will offer two free live webinars on how two of its signature mentored implementation programs are changing the way hospitals manage two key issues: readmissions and glycemic control.

Project BOOST is an evidence-based approach to reduce preventable admissions, decrease average length of stay, and improve patient satisfaction. It includes one year of individualized mentoring from a physician leader with expertise in clinical quality, on-site mentoring and training from leaders in the field, access to an online tool kit with clinical resources, and more. Find out how to get involved with Project BOOST and take the first steps toward reducing readmissions with our complimentary webinar in April.

Learn more at www.hospitalmedicine.org/BOOST.

Another signature program, SHM’s Glycemic Control Mentored Implementation Program, has supported the development and implementation of glycemic control in more than 100 hospitals nationwide. Added benefits include data collection and analysis tools, monthly coaching calls with mentors, SHM-facilitated calls and live webinars, and access to an online web-based glycemic control collaborative to share best practices.

Join more than 100 hospitals working with SHM to improve glycemic control at an upcoming free live webinar. More information is available at www.hospitalmedicine.org/gc.

A comprehensive suite of mentored implementation programs offered through SHM’s Center for Hospital Innovation and Improvement is designed to provide institutions with coaching by national physician experts to map current processes, identify root causes of deficiencies, and tailor interventions to the unique needs of the institution for sustainable results.

For more information, visit www.hospitalmedicine.org and click on Quality & Innovation.

NEW YORK (Reuters Health) - The diabetes drug pioglitazone, given to non-diabetics with a recent history of stroke or transient ischemic attack (TIA), prevented subsequent strokes and reduced their odds of developing type 2 diabetes, a long-term multicenter study has concluded.

But the drug also increased the risk of fracture, weight gain, and edema.

After nearly five years of follow-up, the rate of stroke or heart attack was 11.8% with placebo and 9.0% with the drug (p=0.007). The target dose was 45 mg daily.

"That 25% relative reduction is a huge effect for a stroke trial," coauthor Dr. Wayne Clark, director of the Oregon Stroke Center at Oregon Health and Science University, told Reuters Health by phone. "That's on the same realm as aspirin and a big effect for stroke.

"We're always expecting negative results these days," because so many stroke drugs have failed in previous tests, he said. "This was a positive surprise."

Dr. Clark said he was particularly taken aback by the rate that diabetes developed in pioglitazone recipients. It manifested in 3.8% of drug recipients versus 7.7% of placebo

recipients (p<0.001).

"I didn't expect that at all," he said. "That has much wider implications and might take confirmatory studies."

The 3,876 volunteers studied at 179 sites worldwide were not diabetic but they had developed insulin resistance at the time of enrollment.

Drug therapy did not reduce mortality.The results of the study, known as IRIS, were presented February 17 at the American Heart Association and the American

Stroke Association's International Stroke Conference in Los Angeles, and online in the New England Journal of Medicine.

"The findings suggest that the administration of pioglitazone in 100 patients similar to those in our trial for about five years could prevent three patients from having a

stroke or myocardial infarction," the researchers wrote in the Journal. "However, during the same period, the treatment would be expected to result in bone fractures requiring surgery or hospitalization in two patients.

"It seems reasonable to consider individual treatment preference and risk of drug-related adverse events in addition to potential benefits when making patient-specific decisions regarding therapy," they concluded.

Serious fractures occurred in 5.1% of drug recipients versus 3.2% among placebo patients (p=0.003). A weight gain of more than 4.5 kg was seen in 52.2% of pioglitazone recipientscompared with 33.7% for placebo, and rates of edema were 35.6% with the drug versus 24.9% with placebo (both p<0.001).

The drug has been plagued by suspicions that it might increase the risk of heart failure and bladder cancer. In this study, 74 pioglitazone recipients developed heart failure versus 71 in the placebo group (p=0.80). A dozen drug recipients were diagnosed with bladder cancer compared with eight cases in the placebo group (p=0.37).

Dr. Clark said, "All of the stuff we're doing for risk-factor reduction -- blood pressure reduction, stop smoking and giving aspirin -- they're all on the same level of relative improvement, and all of those are widely used. Aspirin has a list of side effects that will fill up three pages."

At the start of the study, all of the volunteers were insulin resistant, at least 40 years old, and had experienced an ischemic stroke or TIA in the previous six months. Diabetics were excluded as were patients with heart failure, active liver disease, and an increased risk of bladder cancer.

By the end of the study, 60% of the pioglitazone patients were still taking their medicine compared with 67% of placebo recipients. The most common reason for discontinuing was edema or weight gain.

The National Institute of Neurological Disorders and Stroke funded this study. Eleven coauthors reported disclosures.

NEW YORK (Reuters Health) - The diabetes drug pioglitazone, given to non-diabetics with a recent history of stroke or transient ischemic attack (TIA), prevented subsequent strokes and reduced their odds of developing type 2 diabetes, a long-term multicenter study has concluded.

But the drug also increased the risk of fracture, weight gain, and edema.

After nearly five years of follow-up, the rate of stroke or heart attack was 11.8% with placebo and 9.0% with the drug (p=0.007). The target dose was 45 mg daily.

"That 25% relative reduction is a huge effect for a stroke trial," coauthor Dr. Wayne Clark, director of the Oregon Stroke Center at Oregon Health and Science University, told Reuters Health by phone. "That's on the same realm as aspirin and a big effect for stroke.

"We're always expecting negative results these days," because so many stroke drugs have failed in previous tests, he said. "This was a positive surprise."

Dr. Clark said he was particularly taken aback by the rate that diabetes developed in pioglitazone recipients. It manifested in 3.8% of drug recipients versus 7.7% of placebo

recipients (p<0.001).

"I didn't expect that at all," he said. "That has much wider implications and might take confirmatory studies."

The 3,876 volunteers studied at 179 sites worldwide were not diabetic but they had developed insulin resistance at the time of enrollment.

Drug therapy did not reduce mortality.The results of the study, known as IRIS, were presented February 17 at the American Heart Association and the American

Stroke Association's International Stroke Conference in Los Angeles, and online in the New England Journal of Medicine.

"The findings suggest that the administration of pioglitazone in 100 patients similar to those in our trial for about five years could prevent three patients from having a

stroke or myocardial infarction," the researchers wrote in the Journal. "However, during the same period, the treatment would be expected to result in bone fractures requiring surgery or hospitalization in two patients.

"It seems reasonable to consider individual treatment preference and risk of drug-related adverse events in addition to potential benefits when making patient-specific decisions regarding therapy," they concluded.

Serious fractures occurred in 5.1% of drug recipients versus 3.2% among placebo patients (p=0.003). A weight gain of more than 4.5 kg was seen in 52.2% of pioglitazone recipientscompared with 33.7% for placebo, and rates of edema were 35.6% with the drug versus 24.9% with placebo (both p<0.001).

The drug has been plagued by suspicions that it might increase the risk of heart failure and bladder cancer. In this study, 74 pioglitazone recipients developed heart failure versus 71 in the placebo group (p=0.80). A dozen drug recipients were diagnosed with bladder cancer compared with eight cases in the placebo group (p=0.37).

Dr. Clark said, "All of the stuff we're doing for risk-factor reduction -- blood pressure reduction, stop smoking and giving aspirin -- they're all on the same level of relative improvement, and all of those are widely used. Aspirin has a list of side effects that will fill up three pages."

At the start of the study, all of the volunteers were insulin resistant, at least 40 years old, and had experienced an ischemic stroke or TIA in the previous six months. Diabetics were excluded as were patients with heart failure, active liver disease, and an increased risk of bladder cancer.

By the end of the study, 60% of the pioglitazone patients were still taking their medicine compared with 67% of placebo recipients. The most common reason for discontinuing was edema or weight gain.

The National Institute of Neurological Disorders and Stroke funded this study. Eleven coauthors reported disclosures.

NEW YORK (Reuters Health) - The diabetes drug pioglitazone, given to non-diabetics with a recent history of stroke or transient ischemic attack (TIA), prevented subsequent strokes and reduced their odds of developing type 2 diabetes, a long-term multicenter study has concluded.

But the drug also increased the risk of fracture, weight gain, and edema.

After nearly five years of follow-up, the rate of stroke or heart attack was 11.8% with placebo and 9.0% with the drug (p=0.007). The target dose was 45 mg daily.

"That 25% relative reduction is a huge effect for a stroke trial," coauthor Dr. Wayne Clark, director of the Oregon Stroke Center at Oregon Health and Science University, told Reuters Health by phone. "That's on the same realm as aspirin and a big effect for stroke.

"We're always expecting negative results these days," because so many stroke drugs have failed in previous tests, he said. "This was a positive surprise."

Dr. Clark said he was particularly taken aback by the rate that diabetes developed in pioglitazone recipients. It manifested in 3.8% of drug recipients versus 7.7% of placebo

recipients (p<0.001).

"I didn't expect that at all," he said. "That has much wider implications and might take confirmatory studies."

The 3,876 volunteers studied at 179 sites worldwide were not diabetic but they had developed insulin resistance at the time of enrollment.

Drug therapy did not reduce mortality.The results of the study, known as IRIS, were presented February 17 at the American Heart Association and the American

Stroke Association's International Stroke Conference in Los Angeles, and online in the New England Journal of Medicine.

"The findings suggest that the administration of pioglitazone in 100 patients similar to those in our trial for about five years could prevent three patients from having a

stroke or myocardial infarction," the researchers wrote in the Journal. "However, during the same period, the treatment would be expected to result in bone fractures requiring surgery or hospitalization in two patients.

"It seems reasonable to consider individual treatment preference and risk of drug-related adverse events in addition to potential benefits when making patient-specific decisions regarding therapy," they concluded.

Serious fractures occurred in 5.1% of drug recipients versus 3.2% among placebo patients (p=0.003). A weight gain of more than 4.5 kg was seen in 52.2% of pioglitazone recipientscompared with 33.7% for placebo, and rates of edema were 35.6% with the drug versus 24.9% with placebo (both p<0.001).

The drug has been plagued by suspicions that it might increase the risk of heart failure and bladder cancer. In this study, 74 pioglitazone recipients developed heart failure versus 71 in the placebo group (p=0.80). A dozen drug recipients were diagnosed with bladder cancer compared with eight cases in the placebo group (p=0.37).

Dr. Clark said, "All of the stuff we're doing for risk-factor reduction -- blood pressure reduction, stop smoking and giving aspirin -- they're all on the same level of relative improvement, and all of those are widely used. Aspirin has a list of side effects that will fill up three pages."

At the start of the study, all of the volunteers were insulin resistant, at least 40 years old, and had experienced an ischemic stroke or TIA in the previous six months. Diabetics were excluded as were patients with heart failure, active liver disease, and an increased risk of bladder cancer.

By the end of the study, 60% of the pioglitazone patients were still taking their medicine compared with 67% of placebo recipients. The most common reason for discontinuing was edema or weight gain.

The National Institute of Neurological Disorders and Stroke funded this study. Eleven coauthors reported disclosures.

Micrograph showing AML

The European Commission has granted orphan drug designation for the oral BCL-2 inhibitor venetoclax to treat acute myeloid leukemia (AML).

The EC grants orphan designation to products intended to treat, prevent, or diagnose a life-threatening condition affecting up to 5 in 10,000 people in the

European Union. The product must provide significant benefit to those affected by the condition.

Orphan drug designation from the EC provides companies with certain development incentives, including protocol assistance, a type of scientific advice specific for orphan drugs, and 10 years of market exclusivity once the drug is on the market.

Venetoclax is being developed by AbbVie in partnership with Genentech and Roche.

Phase 2 study

Results from a phase 2 study of venetoclax in AML were presented at ASH 2014. At that time, the trial had enrolled 32 patients, 30 of whom had relapsed or refractory disease. Patients had a median age of 71 (range, 19 to 84), and half were male.

The overall response rate was 15.5%, with 1 patient achieving a complete response (CR) and 4 achieving a CR with incomplete count recovery (CRi).

The researchers noted that 3 of the patients who had a CR/CRi had IDH mutations. Two of these patients  also achieved minimal residual disease negativity.

The median bone marrow blast count in evaluable patients decreased 36% after treatment, and 6 patients (19%) had at least a 50% reduction in bone marrow blasts.

Common adverse events following treatment (occurring in at least 25% of patients) included nausea, diarrhea, fatigue, neutropenia, and vomiting.

Grade 3/4 adverse events (occurring in 3 or more patients) included febrile neutropenia, anemia, and pneumonia. No patient died as a result of treatment-related adverse events.

Micrograph showing AML

The European Commission has granted orphan drug designation for the oral BCL-2 inhibitor venetoclax to treat acute myeloid leukemia (AML).

The EC grants orphan designation to products intended to treat, prevent, or diagnose a life-threatening condition affecting up to 5 in 10,000 people in the

European Union. The product must provide significant benefit to those affected by the condition.

Orphan drug designation from the EC provides companies with certain development incentives, including protocol assistance, a type of scientific advice specific for orphan drugs, and 10 years of market exclusivity once the drug is on the market.

Venetoclax is being developed by AbbVie in partnership with Genentech and Roche.

Phase 2 study

Results from a phase 2 study of venetoclax in AML were presented at ASH 2014. At that time, the trial had enrolled 32 patients, 30 of whom had relapsed or refractory disease. Patients had a median age of 71 (range, 19 to 84), and half were male.

The overall response rate was 15.5%, with 1 patient achieving a complete response (CR) and 4 achieving a CR with incomplete count recovery (CRi).

The researchers noted that 3 of the patients who had a CR/CRi had IDH mutations. Two of these patients  also achieved minimal residual disease negativity.

The median bone marrow blast count in evaluable patients decreased 36% after treatment, and 6 patients (19%) had at least a 50% reduction in bone marrow blasts.

Common adverse events following treatment (occurring in at least 25% of patients) included nausea, diarrhea, fatigue, neutropenia, and vomiting.

Grade 3/4 adverse events (occurring in 3 or more patients) included febrile neutropenia, anemia, and pneumonia. No patient died as a result of treatment-related adverse events.

Micrograph showing AML

The European Commission has granted orphan drug designation for the oral BCL-2 inhibitor venetoclax to treat acute myeloid leukemia (AML).

The EC grants orphan designation to products intended to treat, prevent, or diagnose a life-threatening condition affecting up to 5 in 10,000 people in the

European Union. The product must provide significant benefit to those affected by the condition.

Orphan drug designation from the EC provides companies with certain development incentives, including protocol assistance, a type of scientific advice specific for orphan drugs, and 10 years of market exclusivity once the drug is on the market.

Venetoclax is being developed by AbbVie in partnership with Genentech and Roche.

Phase 2 study

Results from a phase 2 study of venetoclax in AML were presented at ASH 2014. At that time, the trial had enrolled 32 patients, 30 of whom had relapsed or refractory disease. Patients had a median age of 71 (range, 19 to 84), and half were male.

The overall response rate was 15.5%, with 1 patient achieving a complete response (CR) and 4 achieving a CR with incomplete count recovery (CRi).

The researchers noted that 3 of the patients who had a CR/CRi had IDH mutations. Two of these patients  also achieved minimal residual disease negativity.

The median bone marrow blast count in evaluable patients decreased 36% after treatment, and 6 patients (19%) had at least a 50% reduction in bone marrow blasts.

Common adverse events following treatment (occurring in at least 25% of patients) included nausea, diarrhea, fatigue, neutropenia, and vomiting.

Grade 3/4 adverse events (occurring in 3 or more patients) included febrile neutropenia, anemia, and pneumonia. No patient died as a result of treatment-related adverse events.

Antihemophilic factor

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended that albutrepenonacog alfa (Idelvion) receive marketing authorization to treat patients with hemophilia B.

Albutrepenonacog alfa is a recombinant fusion protein linking coagulation factor IX with albumin.

The CHMP’s recommendation will be reviewed by the European Commission, which usually follows the CHMP’s advice.

In 2010, the European Commission granted albutrepenonacog alfa orphan designation as a treatment for hemophilia B.

Albutrepenonacog alfa is being developed by CSL Behring. The product is approved for use in Canada. Regulatory agencies in the US, Australia, Switzerland, and Japan are reviewing applications for the drug.

Phase 3 trial

The CHMP’s recommendation to approve albutrepenonacog alfa is based on the PROLONG-9FP clinical development program. PROLONG-9FP includes phase 1, 2, and 3 studies evaluating the safety and efficacy of albutrepenonacog alfa in adults and children (ages 1 to 61) with hemophilia B.

Data from the phase 3 study were recently published in Blood. This study included 63 previously treated male patients with severe hemophilia B. They had a mean age of 33 (range, 12 to 61).

The patients were divided into 2 groups. Group 1 (n=40) received routine prophylaxis with albutrepenonacog alfa once every 7 days for 26 weeks, followed by a 7-, 10- or 14-day prophylaxis regimen for a mean of 50, 38, or 51 weeks, respectively.

Group 2 received on-demand treatment with albutrepenonacog alfa for bleeding episodes for 26 weeks (n=23) and then switched to a 7-day prophylaxis regimen for a mean of 45 weeks (n=19).

The median annualized bleeding rate (ABR) was 2.0 in the prophylaxis arm (group 1) and 23.5 in the on-demand treatment arm (group 2). The median spontaneous ABRs were 0.0 and 17.0, respectively.

For patients in group 2, there was a significant reduction in median ABRs when patients switched from on-demand treatment to prophylaxis—19.22 and 1.58, respectively (P<0.0001). And there was a significant reduction in median spontaneous ABRs—15.43 and 0.00, respectively (P<0.0001).

Overall, 98.6% of bleeding episodes were treated successfully, including 93.6% that were treated with a single injection of albutrepenonacog alfa.

None of the patients developed inhibitors or experienced thromboembolic events, anaphylaxis, or life-threatening adverse events (AEs).

There were 347 treatment-emergent AEs reported in 54 (85.7%) patients. The most common were nasopharyngitis (25.4%), headache (23.8%), arthralgia (4.3%), and influenza (11.1%).

Eleven mild/moderate AEs in 5 patients (7.9%) were considered possibly related to albutrepenonacog alfa. Two patients discontinued treatment due to AEs—1 with hypersensitivity and 1 with headache.

Antihemophilic factor

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended that albutrepenonacog alfa (Idelvion) receive marketing authorization to treat patients with hemophilia B.

Albutrepenonacog alfa is a recombinant fusion protein linking coagulation factor IX with albumin.

The CHMP’s recommendation will be reviewed by the European Commission, which usually follows the CHMP’s advice.

In 2010, the European Commission granted albutrepenonacog alfa orphan designation as a treatment for hemophilia B.

Albutrepenonacog alfa is being developed by CSL Behring. The product is approved for use in Canada. Regulatory agencies in the US, Australia, Switzerland, and Japan are reviewing applications for the drug.

Phase 3 trial

The CHMP’s recommendation to approve albutrepenonacog alfa is based on the PROLONG-9FP clinical development program. PROLONG-9FP includes phase 1, 2, and 3 studies evaluating the safety and efficacy of albutrepenonacog alfa in adults and children (ages 1 to 61) with hemophilia B.

Data from the phase 3 study were recently published in Blood. This study included 63 previously treated male patients with severe hemophilia B. They had a mean age of 33 (range, 12 to 61).

The patients were divided into 2 groups. Group 1 (n=40) received routine prophylaxis with albutrepenonacog alfa once every 7 days for 26 weeks, followed by a 7-, 10- or 14-day prophylaxis regimen for a mean of 50, 38, or 51 weeks, respectively.

Group 2 received on-demand treatment with albutrepenonacog alfa for bleeding episodes for 26 weeks (n=23) and then switched to a 7-day prophylaxis regimen for a mean of 45 weeks (n=19).

The median annualized bleeding rate (ABR) was 2.0 in the prophylaxis arm (group 1) and 23.5 in the on-demand treatment arm (group 2). The median spontaneous ABRs were 0.0 and 17.0, respectively.

For patients in group 2, there was a significant reduction in median ABRs when patients switched from on-demand treatment to prophylaxis—19.22 and 1.58, respectively (P<0.0001). And there was a significant reduction in median spontaneous ABRs—15.43 and 0.00, respectively (P<0.0001).

Overall, 98.6% of bleeding episodes were treated successfully, including 93.6% that were treated with a single injection of albutrepenonacog alfa.

None of the patients developed inhibitors or experienced thromboembolic events, anaphylaxis, or life-threatening adverse events (AEs).

There were 347 treatment-emergent AEs reported in 54 (85.7%) patients. The most common were nasopharyngitis (25.4%), headache (23.8%), arthralgia (4.3%), and influenza (11.1%).

Eleven mild/moderate AEs in 5 patients (7.9%) were considered possibly related to albutrepenonacog alfa. Two patients discontinued treatment due to AEs—1 with hypersensitivity and 1 with headache.

Antihemophilic factor

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended that albutrepenonacog alfa (Idelvion) receive marketing authorization to treat patients with hemophilia B.

Albutrepenonacog alfa is a recombinant fusion protein linking coagulation factor IX with albumin.

The CHMP’s recommendation will be reviewed by the European Commission, which usually follows the CHMP’s advice.

In 2010, the European Commission granted albutrepenonacog alfa orphan designation as a treatment for hemophilia B.

Albutrepenonacog alfa is being developed by CSL Behring. The product is approved for use in Canada. Regulatory agencies in the US, Australia, Switzerland, and Japan are reviewing applications for the drug.

Phase 3 trial

The CHMP’s recommendation to approve albutrepenonacog alfa is based on the PROLONG-9FP clinical development program. PROLONG-9FP includes phase 1, 2, and 3 studies evaluating the safety and efficacy of albutrepenonacog alfa in adults and children (ages 1 to 61) with hemophilia B.

Data from the phase 3 study were recently published in Blood. This study included 63 previously treated male patients with severe hemophilia B. They had a mean age of 33 (range, 12 to 61).

The patients were divided into 2 groups. Group 1 (n=40) received routine prophylaxis with albutrepenonacog alfa once every 7 days for 26 weeks, followed by a 7-, 10- or 14-day prophylaxis regimen for a mean of 50, 38, or 51 weeks, respectively.

Group 2 received on-demand treatment with albutrepenonacog alfa for bleeding episodes for 26 weeks (n=23) and then switched to a 7-day prophylaxis regimen for a mean of 45 weeks (n=19).

The median annualized bleeding rate (ABR) was 2.0 in the prophylaxis arm (group 1) and 23.5 in the on-demand treatment arm (group 2). The median spontaneous ABRs were 0.0 and 17.0, respectively.

For patients in group 2, there was a significant reduction in median ABRs when patients switched from on-demand treatment to prophylaxis—19.22 and 1.58, respectively (P<0.0001). And there was a significant reduction in median spontaneous ABRs—15.43 and 0.00, respectively (P<0.0001).

Overall, 98.6% of bleeding episodes were treated successfully, including 93.6% that were treated with a single injection of albutrepenonacog alfa.

None of the patients developed inhibitors or experienced thromboembolic events, anaphylaxis, or life-threatening adverse events (AEs).

There were 347 treatment-emergent AEs reported in 54 (85.7%) patients. The most common were nasopharyngitis (25.4%), headache (23.8%), arthralgia (4.3%), and influenza (11.1%).

Eleven mild/moderate AEs in 5 patients (7.9%) were considered possibly related to albutrepenonacog alfa. Two patients discontinued treatment due to AEs—1 with hypersensitivity and 1 with headache.

Table of Contents

• Our Sacred Trust
• How to Make Your Patient With Sleep Apnea a Super User of Positive Airway Pressure Therapy
• Complete Atrioventricular Nodal Block Due to Malignancy-Related Hypercalcemia
• Peer Technical Consultant: Veteran Technical Support for VA Home-Based Telehealth Programs
• Polypharmacy Review of Vulnerable Elders: Can We IMPROVE Outcomes?
• Predictors of VA and Non-VA Health Care Service Use by Homeless Veterans Residing in a Low-Demand Emergency Shelter

Table of Contents

• Our Sacred Trust
• How to Make Your Patient With Sleep Apnea a Super User of Positive Airway Pressure Therapy
• Complete Atrioventricular Nodal Block Due to Malignancy-Related Hypercalcemia
• Peer Technical Consultant: Veteran Technical Support for VA Home-Based Telehealth Programs
• Polypharmacy Review of Vulnerable Elders: Can We IMPROVE Outcomes?
• Predictors of VA and Non-VA Health Care Service Use by Homeless Veterans Residing in a Low-Demand Emergency Shelter

Table of Contents

• Our Sacred Trust
• How to Make Your Patient With Sleep Apnea a Super User of Positive Airway Pressure Therapy
• Complete Atrioventricular Nodal Block Due to Malignancy-Related Hypercalcemia
• Peer Technical Consultant: Veteran Technical Support for VA Home-Based Telehealth Programs
• Polypharmacy Review of Vulnerable Elders: Can We IMPROVE Outcomes?
• Predictors of VA and Non-VA Health Care Service Use by Homeless Veterans Residing in a Low-Demand Emergency Shelter

The antidepressant mirtazapine improved weight loss, early satiation, nausea, and other signs and symptoms in patients with functional dyspepsia, said the authors of a placebo-controlled pilot study published in the March issue of Clinical Gastroenterology and Hepatology.

The findings suggest that mirtazapine “has the potential to become the treatment of choice for functional dyspepsia in patients with weight loss, and evaluation in larger multicenter studies is warranted,” said Dr. Jan Tack and his associates at the University of Leuven, Belgium.

Functional dyspepsia, one of the most prevalent gastrointestinal disorders, is characterized by early satiation, postprandial fullness, and epigastric pain and burning in the absence of underlying systemic or metabolic disease. Up to 40% of affected patients lose weight, an “alarm symptom” that until now has lacked effective treatment, the researchers said.

©Artem_Furman/Thinkstockphotos.com

Mirtazapine, an antagonist of the H₁, alpha₂, 5-hydroxytryptamine (5-HT)_2c, and 5-HT₃ receptors, often causes weight gain when used to treat depression. Therefore, the investigators designed a double-blind single-center pilot trial of 34 patients with functional dyspepsia who had lost more than 10% of their original body weight. After a 2-week run-in period, half the patients were randomized to 15 mg of mirtazapine every evening and the other half to placebo (Clin Gastroenterol Hepatol. 2016 Jan 9. doi: 10.1016/j.cgh.2015.09.043).

The average weight of placebo patients remained almost unchanged throughout the trial, while patients on mirtazapine gained an average of 2.5 + 0.6 kg by week 4 (P = .003 for between-group comparison) and 3.9 + 0.7 kg, or 6.4% of their original body weight, by week 8 (P less than .0001). Mean scores on a validated dyspepsia symptom severity (DSS) questionnaire improved significantly between baseline and weeks 4 (P = .003) and 8 (P = .017) for mirtazapine but not placebo. Directly comparing the two groups in terms of the DSS revealed a large effect size that trended toward significance (P = .06) at week 4 but not at week 8 (P = .55). However, mirtazapine significantly outperformed placebo in measures of early satiety, quality of life, gastrointestinal-specific anxiety, and nutrient tolerance, “mostly with large effect sizes,” the investigators said.

Mirtazapine did not affect epigastric pain or gastric emptying, and had little effect on postprandial fullness. Moreover, 2 of 17 patients in the mirtazapine group dropped out of the study because of unacceptable levels of drowsiness, which is a common side effect of the medication.

Many patients with functional dyspepsia respond inadequately to first-line treatment with acid-suppressive or prokinetic drugs, the investigators noted. While tegaserod, buspirone, and acotiamide can improve gastric accommodation, it is unknown if they promote weight gain. The results for mirtazapine are promising, but the pilot trial included only tertiary care patients, and the small sample size precluded separate analyses of patients with postprandial distress syndrome as opposed to epigastric pain syndrome, the researchers said.

The study was funded by Leuven University, the FWO, and the KU Leuven Special Research Fund. Mirtazapine and placebo were supplied by MSD Belgium. The investigators had no disclosures.

The antidepressant mirtazapine improved weight loss, early satiation, nausea, and other signs and symptoms in patients with functional dyspepsia, said the authors of a placebo-controlled pilot study published in the March issue of Clinical Gastroenterology and Hepatology.

The findings suggest that mirtazapine “has the potential to become the treatment of choice for functional dyspepsia in patients with weight loss, and evaluation in larger multicenter studies is warranted,” said Dr. Jan Tack and his associates at the University of Leuven, Belgium.

Functional dyspepsia, one of the most prevalent gastrointestinal disorders, is characterized by early satiation, postprandial fullness, and epigastric pain and burning in the absence of underlying systemic or metabolic disease. Up to 40% of affected patients lose weight, an “alarm symptom” that until now has lacked effective treatment, the researchers said.

©Artem_Furman/Thinkstockphotos.com

Mirtazapine, an antagonist of the H₁, alpha₂, 5-hydroxytryptamine (5-HT)_2c, and 5-HT₃ receptors, often causes weight gain when used to treat depression. Therefore, the investigators designed a double-blind single-center pilot trial of 34 patients with functional dyspepsia who had lost more than 10% of their original body weight. After a 2-week run-in period, half the patients were randomized to 15 mg of mirtazapine every evening and the other half to placebo (Clin Gastroenterol Hepatol. 2016 Jan 9. doi: 10.1016/j.cgh.2015.09.043).

The average weight of placebo patients remained almost unchanged throughout the trial, while patients on mirtazapine gained an average of 2.5 + 0.6 kg by week 4 (P = .003 for between-group comparison) and 3.9 + 0.7 kg, or 6.4% of their original body weight, by week 8 (P less than .0001). Mean scores on a validated dyspepsia symptom severity (DSS) questionnaire improved significantly between baseline and weeks 4 (P = .003) and 8 (P = .017) for mirtazapine but not placebo. Directly comparing the two groups in terms of the DSS revealed a large effect size that trended toward significance (P = .06) at week 4 but not at week 8 (P = .55). However, mirtazapine significantly outperformed placebo in measures of early satiety, quality of life, gastrointestinal-specific anxiety, and nutrient tolerance, “mostly with large effect sizes,” the investigators said.

Mirtazapine did not affect epigastric pain or gastric emptying, and had little effect on postprandial fullness. Moreover, 2 of 17 patients in the mirtazapine group dropped out of the study because of unacceptable levels of drowsiness, which is a common side effect of the medication.

Many patients with functional dyspepsia respond inadequately to first-line treatment with acid-suppressive or prokinetic drugs, the investigators noted. While tegaserod, buspirone, and acotiamide can improve gastric accommodation, it is unknown if they promote weight gain. The results for mirtazapine are promising, but the pilot trial included only tertiary care patients, and the small sample size precluded separate analyses of patients with postprandial distress syndrome as opposed to epigastric pain syndrome, the researchers said.

The study was funded by Leuven University, the FWO, and the KU Leuven Special Research Fund. Mirtazapine and placebo were supplied by MSD Belgium. The investigators had no disclosures.

The antidepressant mirtazapine improved weight loss, early satiation, nausea, and other signs and symptoms in patients with functional dyspepsia, said the authors of a placebo-controlled pilot study published in the March issue of Clinical Gastroenterology and Hepatology.

The findings suggest that mirtazapine “has the potential to become the treatment of choice for functional dyspepsia in patients with weight loss, and evaluation in larger multicenter studies is warranted,” said Dr. Jan Tack and his associates at the University of Leuven, Belgium.

Functional dyspepsia, one of the most prevalent gastrointestinal disorders, is characterized by early satiation, postprandial fullness, and epigastric pain and burning in the absence of underlying systemic or metabolic disease. Up to 40% of affected patients lose weight, an “alarm symptom” that until now has lacked effective treatment, the researchers said.

©Artem_Furman/Thinkstockphotos.com

Mirtazapine, an antagonist of the H₁, alpha₂, 5-hydroxytryptamine (5-HT)_2c, and 5-HT₃ receptors, often causes weight gain when used to treat depression. Therefore, the investigators designed a double-blind single-center pilot trial of 34 patients with functional dyspepsia who had lost more than 10% of their original body weight. After a 2-week run-in period, half the patients were randomized to 15 mg of mirtazapine every evening and the other half to placebo (Clin Gastroenterol Hepatol. 2016 Jan 9. doi: 10.1016/j.cgh.2015.09.043).

The average weight of placebo patients remained almost unchanged throughout the trial, while patients on mirtazapine gained an average of 2.5 + 0.6 kg by week 4 (P = .003 for between-group comparison) and 3.9 + 0.7 kg, or 6.4% of their original body weight, by week 8 (P less than .0001). Mean scores on a validated dyspepsia symptom severity (DSS) questionnaire improved significantly between baseline and weeks 4 (P = .003) and 8 (P = .017) for mirtazapine but not placebo. Directly comparing the two groups in terms of the DSS revealed a large effect size that trended toward significance (P = .06) at week 4 but not at week 8 (P = .55). However, mirtazapine significantly outperformed placebo in measures of early satiety, quality of life, gastrointestinal-specific anxiety, and nutrient tolerance, “mostly with large effect sizes,” the investigators said.

Mirtazapine did not affect epigastric pain or gastric emptying, and had little effect on postprandial fullness. Moreover, 2 of 17 patients in the mirtazapine group dropped out of the study because of unacceptable levels of drowsiness, which is a common side effect of the medication.

Many patients with functional dyspepsia respond inadequately to first-line treatment with acid-suppressive or prokinetic drugs, the investigators noted. While tegaserod, buspirone, and acotiamide can improve gastric accommodation, it is unknown if they promote weight gain. The results for mirtazapine are promising, but the pilot trial included only tertiary care patients, and the small sample size precluded separate analyses of patients with postprandial distress syndrome as opposed to epigastric pain syndrome, the researchers said.

The study was funded by Leuven University, the FWO, and the KU Leuven Special Research Fund. Mirtazapine and placebo were supplied by MSD Belgium. The investigators had no disclosures.