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AVP stimulates red blood cell production
Researchers say they have uncovered a new function of arginine vasopressin (AVP).
It seems this hormone does more than maintain fluid balance for the kidneys.
AVP also stimulates the proliferation and differentiation of red blood cell precursors and improves recovery from anemia, according to the researchers.
The group speculates that drugs targeting an AVP receptor could be used to replenish red blood cells lost due to bleeding or treatment toxicity.
Eva Mezey, MD, PhD, of the National Institutes of Health in Bethesda, Maryland, and her colleagues conducted this research and reported the results in Science Translational Medicine.
The team uncovered the unexpected role for AVP by examining clinical data from 92 patients with central diabetes insipidus, a condition that causes AVP deficiency.
Of those individuals, 87% of males and 51% of females had anemia. In comparison, anemia rates in the US general population range from 1.5% to 6% for men and 4.4% to 12% for women.
The researchers also found that all 3 AVP receptors are present on human and murine hematopoietic stem and progenitor cells.
One of these receptors, AVPR1B, plays a predominant role in red blood cell production.
Further experiments revealed that AVP-deficient rats had delayed recovery from anemia, but treatment with AVP or the AVPR1B agonist d(Leu4Lys8)VP was able to speed up anemia recovery in mice.
The researchers tested AVP and the AVPR1B agonist in mouse models of hemorrhage. Compared to vehicle-treated mice, AVP-treated mice had an increase in hematocrit and reticulocyte numbers by day 2. Mice that received d(Leu4Lys8)VP only had an increase in reticulocytes.
The team also tested mice exposed to sublethal irradiation. When the mice received AVP for 2 days, they saw increases in hematocrit and corrected reticulocyte numbers.
The researchers then tested splenectomized mice subjected to hemorrhage. AVP-treated mice had an increase in hematocrit that was similar to that observed in non-splenectomized mice.
Finally, the researchers found that AVP’s effect on hematocrit is independent of erythropoietin. The team said AVP “appears to jump-start peripheral blood cell replenishment,” but later, erythropoietin seems to take over. 
Researchers say they have uncovered a new function of arginine vasopressin (AVP).
It seems this hormone does more than maintain fluid balance for the kidneys.
AVP also stimulates the proliferation and differentiation of red blood cell precursors and improves recovery from anemia, according to the researchers.
The group speculates that drugs targeting an AVP receptor could be used to replenish red blood cells lost due to bleeding or treatment toxicity.
Eva Mezey, MD, PhD, of the National Institutes of Health in Bethesda, Maryland, and her colleagues conducted this research and reported the results in Science Translational Medicine.
The team uncovered the unexpected role for AVP by examining clinical data from 92 patients with central diabetes insipidus, a condition that causes AVP deficiency.
Of those individuals, 87% of males and 51% of females had anemia. In comparison, anemia rates in the US general population range from 1.5% to 6% for men and 4.4% to 12% for women.
The researchers also found that all 3 AVP receptors are present on human and murine hematopoietic stem and progenitor cells.
One of these receptors, AVPR1B, plays a predominant role in red blood cell production.
Further experiments revealed that AVP-deficient rats had delayed recovery from anemia, but treatment with AVP or the AVPR1B agonist d(Leu4Lys8)VP was able to speed up anemia recovery in mice.
The researchers tested AVP and the AVPR1B agonist in mouse models of hemorrhage. Compared to vehicle-treated mice, AVP-treated mice had an increase in hematocrit and reticulocyte numbers by day 2. Mice that received d(Leu4Lys8)VP only had an increase in reticulocytes.
The team also tested mice exposed to sublethal irradiation. When the mice received AVP for 2 days, they saw increases in hematocrit and corrected reticulocyte numbers.
The researchers then tested splenectomized mice subjected to hemorrhage. AVP-treated mice had an increase in hematocrit that was similar to that observed in non-splenectomized mice.
Finally, the researchers found that AVP’s effect on hematocrit is independent of erythropoietin. The team said AVP “appears to jump-start peripheral blood cell replenishment,” but later, erythropoietin seems to take over.
Researchers say they have uncovered a new function of arginine vasopressin (AVP).
It seems this hormone does more than maintain fluid balance for the kidneys.
AVP also stimulates the proliferation and differentiation of red blood cell precursors and improves recovery from anemia, according to the researchers.
The group speculates that drugs targeting an AVP receptor could be used to replenish red blood cells lost due to bleeding or treatment toxicity.
Eva Mezey, MD, PhD, of the National Institutes of Health in Bethesda, Maryland, and her colleagues conducted this research and reported the results in Science Translational Medicine.
The team uncovered the unexpected role for AVP by examining clinical data from 92 patients with central diabetes insipidus, a condition that causes AVP deficiency.
Of those individuals, 87% of males and 51% of females had anemia. In comparison, anemia rates in the US general population range from 1.5% to 6% for men and 4.4% to 12% for women.
The researchers also found that all 3 AVP receptors are present on human and murine hematopoietic stem and progenitor cells.
One of these receptors, AVPR1B, plays a predominant role in red blood cell production.
Further experiments revealed that AVP-deficient rats had delayed recovery from anemia, but treatment with AVP or the AVPR1B agonist d(Leu4Lys8)VP was able to speed up anemia recovery in mice.
The researchers tested AVP and the AVPR1B agonist in mouse models of hemorrhage. Compared to vehicle-treated mice, AVP-treated mice had an increase in hematocrit and reticulocyte numbers by day 2. Mice that received d(Leu4Lys8)VP only had an increase in reticulocytes.
The team also tested mice exposed to sublethal irradiation. When the mice received AVP for 2 days, they saw increases in hematocrit and corrected reticulocyte numbers.
The researchers then tested splenectomized mice subjected to hemorrhage. AVP-treated mice had an increase in hematocrit that was similar to that observed in non-splenectomized mice.
Finally, the researchers found that AVP’s effect on hematocrit is independent of erythropoietin. The team said AVP “appears to jump-start peripheral blood cell replenishment,” but later, erythropoietin seems to take over.
FDA grants drug orphan designation for AML, MDS
The US Food and Drug Administration (FDA) has granted orphan drug designation to AMV564, a CD33/CD3 bispecific antibody, for the treatment of acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS).
AMV564 is a T-cell engager, derived from human protein sequences, that binds both CD33 and CD3 to mediate T-cell directed lysis of CD33-positive cancer cells.
Amphivena Therapeutics Inc., is currently conducting a phase 1 trial of AMV564 in relapsed or refractory AML. The company plans to launch a phase 1 trial in patients with MDS in early 2018.
According to Amphivena, AMV564 has demonstrated “potent activity” in AML patient samples, and that activity was independent of CD33 expression level, disease stage, and cytogenetic risk.
AMV564 also eliminated nearly all blasts from the bone marrow and spleen in a stringent AML patient-derived xenograft murine model.
In addition, Amphivena established a therapeutic window for AMV564 in cynomolgus monkeys, with rapid and sustained elimination of CD33-expressing cells during AMV564 dosing and rapid hematopoietic recovery following dosing.
About orphan designation
The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.
The US Food and Drug Administration (FDA) has granted orphan drug designation to AMV564, a CD33/CD3 bispecific antibody, for the treatment of acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS).
AMV564 is a T-cell engager, derived from human protein sequences, that binds both CD33 and CD3 to mediate T-cell directed lysis of CD33-positive cancer cells.
Amphivena Therapeutics Inc., is currently conducting a phase 1 trial of AMV564 in relapsed or refractory AML. The company plans to launch a phase 1 trial in patients with MDS in early 2018.
According to Amphivena, AMV564 has demonstrated “potent activity” in AML patient samples, and that activity was independent of CD33 expression level, disease stage, and cytogenetic risk.
AMV564 also eliminated nearly all blasts from the bone marrow and spleen in a stringent AML patient-derived xenograft murine model.
In addition, Amphivena established a therapeutic window for AMV564 in cynomolgus monkeys, with rapid and sustained elimination of CD33-expressing cells during AMV564 dosing and rapid hematopoietic recovery following dosing.
About orphan designation
The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.
The US Food and Drug Administration (FDA) has granted orphan drug designation to AMV564, a CD33/CD3 bispecific antibody, for the treatment of acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS).
AMV564 is a T-cell engager, derived from human protein sequences, that binds both CD33 and CD3 to mediate T-cell directed lysis of CD33-positive cancer cells.
Amphivena Therapeutics Inc., is currently conducting a phase 1 trial of AMV564 in relapsed or refractory AML. The company plans to launch a phase 1 trial in patients with MDS in early 2018.
According to Amphivena, AMV564 has demonstrated “potent activity” in AML patient samples, and that activity was independent of CD33 expression level, disease stage, and cytogenetic risk.
AMV564 also eliminated nearly all blasts from the bone marrow and spleen in a stringent AML patient-derived xenograft murine model.
In addition, Amphivena established a therapeutic window for AMV564 in cynomolgus monkeys, with rapid and sustained elimination of CD33-expressing cells during AMV564 dosing and rapid hematopoietic recovery following dosing.
About orphan designation
The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.
Vasopressin stimulates red blood cell production
The hormone vasopressin, well known for its antidiuretic effects, also appears to stimulate proliferation and differentiation of red blood cell (RBC) precursors, results of a series of preclinical investigations suggest.
Treating anemic mice with an arginine vasopressin (AVP) receptor agonist increased hematocrit and reticulocyte counts significantly, compared with controls, according to the results published in Science Translational Medicine (2017 Nov 29;9:eaao1632).
That finding could have implications for the development of new treatments designed to stimulate RBC production after bleeding, chemotherapy, or drug toxicity, according to the investigators.
“Currently, EPO is the only agent that is used clinically to stimulate erythropoiesis, but there are patients who do not respond to EPO or who cannot take the drug because it stimulates tumor growth,” the investigators wrote. “AVP appears to be an EPO-independent, fast-acting agent that increases RBC numbers after anemia.”
Dr. Mayer and his colleagues initially asked whether AVP might play a role in RBC production after observing that patients with central diabetes insipidus (CDI), who lack the antidiuretic hormone, are frequently anemic. A review of patient records from an NIH database revealed that 60% of CDI patients were anemic despite treatment with desmopressin.
They subsequently found that all three AVP receptor subtypes are expressed in human and mouse hematopoietic stem and progenitor cells. In particular, the AVPR1B subtype appeared to play the most important role in regulating erythropoiesis.
Accordingly, they tested the ability of both AVP and a AVPR1B-specific agonist to stimulate production of RBCs in mice that had anemia induced by bleeding or irradiation. They found significant improvements in both hematocrit and reticulocyte numbers as early as 2 days after treatment started.
Subsequent experiments were designed to determine whether the effect of AVP on RBC production was caused by EPO release. In fact, the effects of AVP occurred “long before an effect of EPO was observed,” investigators wrote.
The research was supported by the NIH. Some of the study authors are listed as inventors on a patent application held by the U.S. Department of Health and Human Services covering methods for modulating erythropoiesis with arginine vasopressin receptor 1b molecules.
The hormone vasopressin, well known for its antidiuretic effects, also appears to stimulate proliferation and differentiation of red blood cell (RBC) precursors, results of a series of preclinical investigations suggest.
Treating anemic mice with an arginine vasopressin (AVP) receptor agonist increased hematocrit and reticulocyte counts significantly, compared with controls, according to the results published in Science Translational Medicine (2017 Nov 29;9:eaao1632).
That finding could have implications for the development of new treatments designed to stimulate RBC production after bleeding, chemotherapy, or drug toxicity, according to the investigators.
“Currently, EPO is the only agent that is used clinically to stimulate erythropoiesis, but there are patients who do not respond to EPO or who cannot take the drug because it stimulates tumor growth,” the investigators wrote. “AVP appears to be an EPO-independent, fast-acting agent that increases RBC numbers after anemia.”
Dr. Mayer and his colleagues initially asked whether AVP might play a role in RBC production after observing that patients with central diabetes insipidus (CDI), who lack the antidiuretic hormone, are frequently anemic. A review of patient records from an NIH database revealed that 60% of CDI patients were anemic despite treatment with desmopressin.
They subsequently found that all three AVP receptor subtypes are expressed in human and mouse hematopoietic stem and progenitor cells. In particular, the AVPR1B subtype appeared to play the most important role in regulating erythropoiesis.
Accordingly, they tested the ability of both AVP and a AVPR1B-specific agonist to stimulate production of RBCs in mice that had anemia induced by bleeding or irradiation. They found significant improvements in both hematocrit and reticulocyte numbers as early as 2 days after treatment started.
Subsequent experiments were designed to determine whether the effect of AVP on RBC production was caused by EPO release. In fact, the effects of AVP occurred “long before an effect of EPO was observed,” investigators wrote.
The research was supported by the NIH. Some of the study authors are listed as inventors on a patent application held by the U.S. Department of Health and Human Services covering methods for modulating erythropoiesis with arginine vasopressin receptor 1b molecules.
The hormone vasopressin, well known for its antidiuretic effects, also appears to stimulate proliferation and differentiation of red blood cell (RBC) precursors, results of a series of preclinical investigations suggest.
Treating anemic mice with an arginine vasopressin (AVP) receptor agonist increased hematocrit and reticulocyte counts significantly, compared with controls, according to the results published in Science Translational Medicine (2017 Nov 29;9:eaao1632).
That finding could have implications for the development of new treatments designed to stimulate RBC production after bleeding, chemotherapy, or drug toxicity, according to the investigators.
“Currently, EPO is the only agent that is used clinically to stimulate erythropoiesis, but there are patients who do not respond to EPO or who cannot take the drug because it stimulates tumor growth,” the investigators wrote. “AVP appears to be an EPO-independent, fast-acting agent that increases RBC numbers after anemia.”
Dr. Mayer and his colleagues initially asked whether AVP might play a role in RBC production after observing that patients with central diabetes insipidus (CDI), who lack the antidiuretic hormone, are frequently anemic. A review of patient records from an NIH database revealed that 60% of CDI patients were anemic despite treatment with desmopressin.
They subsequently found that all three AVP receptor subtypes are expressed in human and mouse hematopoietic stem and progenitor cells. In particular, the AVPR1B subtype appeared to play the most important role in regulating erythropoiesis.
Accordingly, they tested the ability of both AVP and a AVPR1B-specific agonist to stimulate production of RBCs in mice that had anemia induced by bleeding or irradiation. They found significant improvements in both hematocrit and reticulocyte numbers as early as 2 days after treatment started.
Subsequent experiments were designed to determine whether the effect of AVP on RBC production was caused by EPO release. In fact, the effects of AVP occurred “long before an effect of EPO was observed,” investigators wrote.
The research was supported by the NIH. Some of the study authors are listed as inventors on a patent application held by the U.S. Department of Health and Human Services covering methods for modulating erythropoiesis with arginine vasopressin receptor 1b molecules.
FROM SCIENCE TRANSLATIONAL MEDICINE
Key clinical point:
Major finding: In anemic mice, treatment with a vasopressin or a vasopressin receptor agonist significantly increased hematocrit and reticulocyte number vs. controls.
Data source: A series of in vitro and in vivo experiments, plus a retrospective review of anemia incidence data in patients with central diabetes insipidus.
Disclosures: The research was supported by the National Institutes of Health. Some of the study authors are listed as inventors on a patent application held by the U.S. Department of Health and Human Services covering methods for modulating erythropoiesis with arginine vasopressin receptor 1b molecules.
FDA grants priority review to NDA for avatrombopag
The US Food and Drug Administration (FDA) has granted priority review to the new drug application (NDA) for avatrombopag.
Avatrombopag is a second-generation thrombopoietin receptor agonist that is intended to address the limitations of existing treatments for thrombocytopenia.
With this NDA, Dova Pharmaceuticals, Inc., is seeking approval of avatrombopag for the treatment of thrombocytopenia in patients with chronic liver disease who are scheduled to undergo a procedure.
The FDA expects to make a decision on the NDA by May 21, 2018.
The FDA’s goal is to take action on a priority review application within 6 months of receiving it, rather than the standard 10 months.
The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.
Phase 3 trials
The NDA submission for avatrombopag is supported by 2 identically designed phase 3 trials, ADAPT 1 and ADAPT 2. Results from these trials were presented at the 2017 American Association for the Study of Liver Disease (AASLD) Meeting last month (abstract 217).
The studies randomized 435 patients with thrombocytopenia and chronic liver disease who were scheduled to undergo a procedure.
Patients with low baseline platelet counts (<40x 109/L) were randomized to receive 60 mg of avatrombopag or placebo daily for 5 days.
Patients with higher baseline platelet counts (40 to <50 x 109/L) were randomized to receive 40 mg of avatrombopag or placebo daily for 5 days.
Patients underwent their procedures 5 to 8 days after their last dose of avatrombopag.
In ADAPT-1, 85 patients completed treatment with avatrombopag at 60 mg, 55 completed treatment with avatrombopag at 40 mg, and 78 controls completed the study.
In ADAPT-2, 68 patients completed treatment with avatrombopag at 60 mg, 55 completed treatment with avatrombopag at 40 mg, and 68 controls completed the study.
Efficacy
The primary efficacy endpoint of these trials was the proportion of patients who did not require any bleeding rescue up to 7 days post-procedure. Bleeding rescue included platelet transfusion, fresh frozen plasma, cryoprecipitate, vitamin K (phytonadione), desmopressin, recombinant activated factor VII, aminocaproicacid, tranexamic acid, whole blood transfusion, packed red cell transfusion, surgical intervention, or interventional radiology.
In ADAPT-1, the primary endpoint was achieved by 66% of patients who received avatrombopag at 60 mg and 23% of those who received placebo in the low-platelet-count cohort (P<0.0001). The endpoint was also achieved by 88% of patients who received avatrombopag at 40 mg and 38% of controls in the higher-platelet-count cohort (P<0.0001).
In ADAPT-2, the primary endpoint was achieved by 69% of patients who received avatrombopag at 60 mg and 35% of those who received placebo in the low-platelet-count cohort (P<0.0006). The endpoint was also achieved by 88% of patients who received avatrombopag at 40 mg and 33% of controls in the higher- platelet-count cohort (P<0.0001).
A secondary efficacy endpoint was the proportion of patients achieving the target platelet count (≥50 x 109/L).
In ADAPT-1, this endpoint was met by 69% of patients who received avatrombopag at 60 mg and 4% of controls in the low-platelet-count cohort (P<0.0001). It was also met by 88% of patients who received avatrombopag at 40 mg and 21% of controls in the higher-platelet-count cohort (P<0.0001)
In ADAPT-2, this endpoint was met by 67% of patients who received avatrombopag at 60 mg and 7% of controls in the low-platelet-count cohort (P<0.0001). It was also met by 93% of patients who received avatrombopag at 40 mg and 39% of controls in the higher-platelet-count cohort (P<0.0001).
Safety
The researchers pooled safety data from the 2 trials.
Treatment-emergent adverse events (AEs) occurred in 58.2% of controls and 56% of avatrombopag-treated patients in the low-platelet-count cohort (60 mg). Treatment-emergent AEs also occurred in 50.8% of controls and 51.3% of avatrombopag-treated patients in the higher-platelet-count cohort (40 mg).
The most frequently reported treatment-emergent AEs were pyrexia, abdominal pain, nausea, headache, diarrhea, and fatigue.
One patient experienced partial portal vein thrombosis that was considered non-serious and potentially related to avatrombopag.
Treatment-related AEs occurred in 17.6% of controls and 11.3% of avatrombopag-treated patients in the low-platelet-count cohort. Treatment-related AEs also occurred in 6.2% of controls and 7% of avatrombopag-treated patients in the higher-platelet-count cohort.
Serious AEs occurred in 13.2%, 6.9%, 3.1%, and 7.8%, respectively.
There were 3 deaths—2 in the 40 mg avatrombopag arm in ADAPT-1 and 1 in the control group in ADAPT-2. None of the deaths was considered treatment-related.
Future directions
Dova Pharmaceuticals, Inc., is planning to explore the potential use of avatrombopag in a broader population of patients with thrombocytopenia. This includes patients undergoing surgical procedures associated with a high risk of bleeding and patients who develop thrombocytopenia after receiving chemotherapy.
In addition, the company is exploring a potential regulatory approval pathway for avatrombopag for the treatment of adults with chronic immune thrombocytopenic purpura based on results from a completed phase 3 trial in this patient population.
The US Food and Drug Administration (FDA) has granted priority review to the new drug application (NDA) for avatrombopag.
Avatrombopag is a second-generation thrombopoietin receptor agonist that is intended to address the limitations of existing treatments for thrombocytopenia.
With this NDA, Dova Pharmaceuticals, Inc., is seeking approval of avatrombopag for the treatment of thrombocytopenia in patients with chronic liver disease who are scheduled to undergo a procedure.
The FDA expects to make a decision on the NDA by May 21, 2018.
The FDA’s goal is to take action on a priority review application within 6 months of receiving it, rather than the standard 10 months.
The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.
Phase 3 trials
The NDA submission for avatrombopag is supported by 2 identically designed phase 3 trials, ADAPT 1 and ADAPT 2. Results from these trials were presented at the 2017 American Association for the Study of Liver Disease (AASLD) Meeting last month (abstract 217).
The studies randomized 435 patients with thrombocytopenia and chronic liver disease who were scheduled to undergo a procedure.
Patients with low baseline platelet counts (<40x 109/L) were randomized to receive 60 mg of avatrombopag or placebo daily for 5 days.
Patients with higher baseline platelet counts (40 to <50 x 109/L) were randomized to receive 40 mg of avatrombopag or placebo daily for 5 days.
Patients underwent their procedures 5 to 8 days after their last dose of avatrombopag.
In ADAPT-1, 85 patients completed treatment with avatrombopag at 60 mg, 55 completed treatment with avatrombopag at 40 mg, and 78 controls completed the study.
In ADAPT-2, 68 patients completed treatment with avatrombopag at 60 mg, 55 completed treatment with avatrombopag at 40 mg, and 68 controls completed the study.
Efficacy
The primary efficacy endpoint of these trials was the proportion of patients who did not require any bleeding rescue up to 7 days post-procedure. Bleeding rescue included platelet transfusion, fresh frozen plasma, cryoprecipitate, vitamin K (phytonadione), desmopressin, recombinant activated factor VII, aminocaproicacid, tranexamic acid, whole blood transfusion, packed red cell transfusion, surgical intervention, or interventional radiology.
In ADAPT-1, the primary endpoint was achieved by 66% of patients who received avatrombopag at 60 mg and 23% of those who received placebo in the low-platelet-count cohort (P<0.0001). The endpoint was also achieved by 88% of patients who received avatrombopag at 40 mg and 38% of controls in the higher-platelet-count cohort (P<0.0001).
In ADAPT-2, the primary endpoint was achieved by 69% of patients who received avatrombopag at 60 mg and 35% of those who received placebo in the low-platelet-count cohort (P<0.0006). The endpoint was also achieved by 88% of patients who received avatrombopag at 40 mg and 33% of controls in the higher- platelet-count cohort (P<0.0001).
A secondary efficacy endpoint was the proportion of patients achieving the target platelet count (≥50 x 109/L).
In ADAPT-1, this endpoint was met by 69% of patients who received avatrombopag at 60 mg and 4% of controls in the low-platelet-count cohort (P<0.0001). It was also met by 88% of patients who received avatrombopag at 40 mg and 21% of controls in the higher-platelet-count cohort (P<0.0001)
In ADAPT-2, this endpoint was met by 67% of patients who received avatrombopag at 60 mg and 7% of controls in the low-platelet-count cohort (P<0.0001). It was also met by 93% of patients who received avatrombopag at 40 mg and 39% of controls in the higher-platelet-count cohort (P<0.0001).
Safety
The researchers pooled safety data from the 2 trials.
Treatment-emergent adverse events (AEs) occurred in 58.2% of controls and 56% of avatrombopag-treated patients in the low-platelet-count cohort (60 mg). Treatment-emergent AEs also occurred in 50.8% of controls and 51.3% of avatrombopag-treated patients in the higher-platelet-count cohort (40 mg).
The most frequently reported treatment-emergent AEs were pyrexia, abdominal pain, nausea, headache, diarrhea, and fatigue.
One patient experienced partial portal vein thrombosis that was considered non-serious and potentially related to avatrombopag.
Treatment-related AEs occurred in 17.6% of controls and 11.3% of avatrombopag-treated patients in the low-platelet-count cohort. Treatment-related AEs also occurred in 6.2% of controls and 7% of avatrombopag-treated patients in the higher-platelet-count cohort.
Serious AEs occurred in 13.2%, 6.9%, 3.1%, and 7.8%, respectively.
There were 3 deaths—2 in the 40 mg avatrombopag arm in ADAPT-1 and 1 in the control group in ADAPT-2. None of the deaths was considered treatment-related.
Future directions
Dova Pharmaceuticals, Inc., is planning to explore the potential use of avatrombopag in a broader population of patients with thrombocytopenia. This includes patients undergoing surgical procedures associated with a high risk of bleeding and patients who develop thrombocytopenia after receiving chemotherapy.
In addition, the company is exploring a potential regulatory approval pathway for avatrombopag for the treatment of adults with chronic immune thrombocytopenic purpura based on results from a completed phase 3 trial in this patient population.
The US Food and Drug Administration (FDA) has granted priority review to the new drug application (NDA) for avatrombopag.
Avatrombopag is a second-generation thrombopoietin receptor agonist that is intended to address the limitations of existing treatments for thrombocytopenia.
With this NDA, Dova Pharmaceuticals, Inc., is seeking approval of avatrombopag for the treatment of thrombocytopenia in patients with chronic liver disease who are scheduled to undergo a procedure.
The FDA expects to make a decision on the NDA by May 21, 2018.
The FDA’s goal is to take action on a priority review application within 6 months of receiving it, rather than the standard 10 months.
The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.
Phase 3 trials
The NDA submission for avatrombopag is supported by 2 identically designed phase 3 trials, ADAPT 1 and ADAPT 2. Results from these trials were presented at the 2017 American Association for the Study of Liver Disease (AASLD) Meeting last month (abstract 217).
The studies randomized 435 patients with thrombocytopenia and chronic liver disease who were scheduled to undergo a procedure.
Patients with low baseline platelet counts (<40x 109/L) were randomized to receive 60 mg of avatrombopag or placebo daily for 5 days.
Patients with higher baseline platelet counts (40 to <50 x 109/L) were randomized to receive 40 mg of avatrombopag or placebo daily for 5 days.
Patients underwent their procedures 5 to 8 days after their last dose of avatrombopag.
In ADAPT-1, 85 patients completed treatment with avatrombopag at 60 mg, 55 completed treatment with avatrombopag at 40 mg, and 78 controls completed the study.
In ADAPT-2, 68 patients completed treatment with avatrombopag at 60 mg, 55 completed treatment with avatrombopag at 40 mg, and 68 controls completed the study.
Efficacy
The primary efficacy endpoint of these trials was the proportion of patients who did not require any bleeding rescue up to 7 days post-procedure. Bleeding rescue included platelet transfusion, fresh frozen plasma, cryoprecipitate, vitamin K (phytonadione), desmopressin, recombinant activated factor VII, aminocaproicacid, tranexamic acid, whole blood transfusion, packed red cell transfusion, surgical intervention, or interventional radiology.
In ADAPT-1, the primary endpoint was achieved by 66% of patients who received avatrombopag at 60 mg and 23% of those who received placebo in the low-platelet-count cohort (P<0.0001). The endpoint was also achieved by 88% of patients who received avatrombopag at 40 mg and 38% of controls in the higher-platelet-count cohort (P<0.0001).
In ADAPT-2, the primary endpoint was achieved by 69% of patients who received avatrombopag at 60 mg and 35% of those who received placebo in the low-platelet-count cohort (P<0.0006). The endpoint was also achieved by 88% of patients who received avatrombopag at 40 mg and 33% of controls in the higher- platelet-count cohort (P<0.0001).
A secondary efficacy endpoint was the proportion of patients achieving the target platelet count (≥50 x 109/L).
In ADAPT-1, this endpoint was met by 69% of patients who received avatrombopag at 60 mg and 4% of controls in the low-platelet-count cohort (P<0.0001). It was also met by 88% of patients who received avatrombopag at 40 mg and 21% of controls in the higher-platelet-count cohort (P<0.0001)
In ADAPT-2, this endpoint was met by 67% of patients who received avatrombopag at 60 mg and 7% of controls in the low-platelet-count cohort (P<0.0001). It was also met by 93% of patients who received avatrombopag at 40 mg and 39% of controls in the higher-platelet-count cohort (P<0.0001).
Safety
The researchers pooled safety data from the 2 trials.
Treatment-emergent adverse events (AEs) occurred in 58.2% of controls and 56% of avatrombopag-treated patients in the low-platelet-count cohort (60 mg). Treatment-emergent AEs also occurred in 50.8% of controls and 51.3% of avatrombopag-treated patients in the higher-platelet-count cohort (40 mg).
The most frequently reported treatment-emergent AEs were pyrexia, abdominal pain, nausea, headache, diarrhea, and fatigue.
One patient experienced partial portal vein thrombosis that was considered non-serious and potentially related to avatrombopag.
Treatment-related AEs occurred in 17.6% of controls and 11.3% of avatrombopag-treated patients in the low-platelet-count cohort. Treatment-related AEs also occurred in 6.2% of controls and 7% of avatrombopag-treated patients in the higher-platelet-count cohort.
Serious AEs occurred in 13.2%, 6.9%, 3.1%, and 7.8%, respectively.
There were 3 deaths—2 in the 40 mg avatrombopag arm in ADAPT-1 and 1 in the control group in ADAPT-2. None of the deaths was considered treatment-related.
Future directions
Dova Pharmaceuticals, Inc., is planning to explore the potential use of avatrombopag in a broader population of patients with thrombocytopenia. This includes patients undergoing surgical procedures associated with a high risk of bleeding and patients who develop thrombocytopenia after receiving chemotherapy.
In addition, the company is exploring a potential regulatory approval pathway for avatrombopag for the treatment of adults with chronic immune thrombocytopenic purpura based on results from a completed phase 3 trial in this patient population.
Thoughts, emotions linked to opioid use in SCD
Results of a small study suggest that negative thoughts and emotions may increase opioid use in patients with sickle cell disease (SCD).
Researchers analyzed data from daily electronic patient diaries and found that patients were more likely to use short-acting opioids both when they experienced increased pain and “catastrophic” thoughts about that pain.
In fact, pain catastrophizing led to an increased use of short-acting opioids even when patients reported low levels of pain.
In addition, patients were more likely to use long-acting opioids when they experienced negative emotions.
The researchers noted that this study wasn’t designed to show that negative emotions or thinking cause an increase in opioid use. It was only designed to determine if there was an association.
Patrick Finan, PhD, of Johns Hopkins University School of Medicine in Baltimore, Maryland, and his colleagues described this study in The Journal of Pain.
The researchers enrolled 85 adults with SCD in this study. Patients were asked to fill out electronic diaries on a handheld personal computer every evening for 90 days.
The final analysis included only 45 patients, as these were the subjects who filled out the diary more than 25% of the time and had taken opioid pills at least once during the study period.
The patients had an average age of 37, and 71% were female. Most (93%) were African American, and 7% were classified as “other” or did not report their race.
At the start of the study, the patients reported on the dosage and type of opioid pill they were prescribed for long-acting and short-acting use. The daily diary collected data on the number of long-acting and short-acting opioid pills taken per day.
Patients rated their daily pain level on a scale of 0 to 10, with 0 being no pain and 10 being the worst pain imaginable.
Patients also rated positive emotions—including happy, calm, and cheerful—and negative emotions—including lonely, sad, anxious, and tired—on a scale of 0 to 10, with 0 being no emotion and 10 being the most intense emotion. The scores were converted to a 0-to-100 scale for the data analysis.
Separately, the researchers measured negative thinking using a Pain Catastrophizing Scale to rate “rumination,” or focus on pain, helplessness, and magnification of a current pain situation.
Results
Negative emotions were significantly associated with increased levels of long-acting opioids (P=0.001). The opioid dosage increased by 3.4 morphine milligram equivalents for every 10-point increase in negative emotions.
On the other hand, patients’ daily pain level, positive emotions, and negative thinking through catastrophizing did not significantly affect the amount of long-acting opioids taken.
“When someone is prescribed a daily, long-acting opioid, it is typically supposed to be at a fixed dose, and their pain level or emotions shouldn’t dictate whether they take more of this prescription or not,” Dr Finan said.
“Although we can’t prove misuse of the medication in our study, these data suggest that physicians and patients should clearly communicate about how patients should be taking their daily, long-acting opioids in order to minimize the potential for misuse.”
The researchers also found a significant association with short-acting opioid use and daily pain levels (P=0.006) as well as negative thinking by catastrophizing (P<0.001).
For every 10-point increase on the pain scale, the amount of short-acting opioids increased by 1.8 morphine milligram equivalents, and for every 10-point increase on the catastrophizing scale, pain medicine dosage increased by 2.5 morphine milligram equivalents.
Positive and negative emotions had no significant effect on the use of short-acting opioids.
“When pain was reported as low, sickle cell disease patients reported higher opioid use if they catastrophized, or focused their thinking on their pain, than if they didn’t,” Dr Finan said. “When pain levels were higher, negative thinking played less of a role in influencing opioid use.”
Dr Finan cautioned that studies such as this have some weaknesses, including the fact that self-reports are always uncertain, and the study only included 1 time point per day, although a person’s mood may fluctuate throughout the day based on life events and experiences.
For future studies, Dr Finan wants to use smartphone technology that can assess moods randomly throughout the day.
“Once we have a more intensive study to track mood variations throughout the day,” Dr Finan said, “then we can determine when it will be appropriate to send messages through text to intervene and affect patient behavior.”
Results of a small study suggest that negative thoughts and emotions may increase opioid use in patients with sickle cell disease (SCD).
Researchers analyzed data from daily electronic patient diaries and found that patients were more likely to use short-acting opioids both when they experienced increased pain and “catastrophic” thoughts about that pain.
In fact, pain catastrophizing led to an increased use of short-acting opioids even when patients reported low levels of pain.
In addition, patients were more likely to use long-acting opioids when they experienced negative emotions.
The researchers noted that this study wasn’t designed to show that negative emotions or thinking cause an increase in opioid use. It was only designed to determine if there was an association.
Patrick Finan, PhD, of Johns Hopkins University School of Medicine in Baltimore, Maryland, and his colleagues described this study in The Journal of Pain.
The researchers enrolled 85 adults with SCD in this study. Patients were asked to fill out electronic diaries on a handheld personal computer every evening for 90 days.
The final analysis included only 45 patients, as these were the subjects who filled out the diary more than 25% of the time and had taken opioid pills at least once during the study period.
The patients had an average age of 37, and 71% were female. Most (93%) were African American, and 7% were classified as “other” or did not report their race.
At the start of the study, the patients reported on the dosage and type of opioid pill they were prescribed for long-acting and short-acting use. The daily diary collected data on the number of long-acting and short-acting opioid pills taken per day.
Patients rated their daily pain level on a scale of 0 to 10, with 0 being no pain and 10 being the worst pain imaginable.
Patients also rated positive emotions—including happy, calm, and cheerful—and negative emotions—including lonely, sad, anxious, and tired—on a scale of 0 to 10, with 0 being no emotion and 10 being the most intense emotion. The scores were converted to a 0-to-100 scale for the data analysis.
Separately, the researchers measured negative thinking using a Pain Catastrophizing Scale to rate “rumination,” or focus on pain, helplessness, and magnification of a current pain situation.
Results
Negative emotions were significantly associated with increased levels of long-acting opioids (P=0.001). The opioid dosage increased by 3.4 morphine milligram equivalents for every 10-point increase in negative emotions.
On the other hand, patients’ daily pain level, positive emotions, and negative thinking through catastrophizing did not significantly affect the amount of long-acting opioids taken.
“When someone is prescribed a daily, long-acting opioid, it is typically supposed to be at a fixed dose, and their pain level or emotions shouldn’t dictate whether they take more of this prescription or not,” Dr Finan said.
“Although we can’t prove misuse of the medication in our study, these data suggest that physicians and patients should clearly communicate about how patients should be taking their daily, long-acting opioids in order to minimize the potential for misuse.”
The researchers also found a significant association with short-acting opioid use and daily pain levels (P=0.006) as well as negative thinking by catastrophizing (P<0.001).
For every 10-point increase on the pain scale, the amount of short-acting opioids increased by 1.8 morphine milligram equivalents, and for every 10-point increase on the catastrophizing scale, pain medicine dosage increased by 2.5 morphine milligram equivalents.
Positive and negative emotions had no significant effect on the use of short-acting opioids.
“When pain was reported as low, sickle cell disease patients reported higher opioid use if they catastrophized, or focused their thinking on their pain, than if they didn’t,” Dr Finan said. “When pain levels were higher, negative thinking played less of a role in influencing opioid use.”
Dr Finan cautioned that studies such as this have some weaknesses, including the fact that self-reports are always uncertain, and the study only included 1 time point per day, although a person’s mood may fluctuate throughout the day based on life events and experiences.
For future studies, Dr Finan wants to use smartphone technology that can assess moods randomly throughout the day.
“Once we have a more intensive study to track mood variations throughout the day,” Dr Finan said, “then we can determine when it will be appropriate to send messages through text to intervene and affect patient behavior.”
Results of a small study suggest that negative thoughts and emotions may increase opioid use in patients with sickle cell disease (SCD).
Researchers analyzed data from daily electronic patient diaries and found that patients were more likely to use short-acting opioids both when they experienced increased pain and “catastrophic” thoughts about that pain.
In fact, pain catastrophizing led to an increased use of short-acting opioids even when patients reported low levels of pain.
In addition, patients were more likely to use long-acting opioids when they experienced negative emotions.
The researchers noted that this study wasn’t designed to show that negative emotions or thinking cause an increase in opioid use. It was only designed to determine if there was an association.
Patrick Finan, PhD, of Johns Hopkins University School of Medicine in Baltimore, Maryland, and his colleagues described this study in The Journal of Pain.
The researchers enrolled 85 adults with SCD in this study. Patients were asked to fill out electronic diaries on a handheld personal computer every evening for 90 days.
The final analysis included only 45 patients, as these were the subjects who filled out the diary more than 25% of the time and had taken opioid pills at least once during the study period.
The patients had an average age of 37, and 71% were female. Most (93%) were African American, and 7% were classified as “other” or did not report their race.
At the start of the study, the patients reported on the dosage and type of opioid pill they were prescribed for long-acting and short-acting use. The daily diary collected data on the number of long-acting and short-acting opioid pills taken per day.
Patients rated their daily pain level on a scale of 0 to 10, with 0 being no pain and 10 being the worst pain imaginable.
Patients also rated positive emotions—including happy, calm, and cheerful—and negative emotions—including lonely, sad, anxious, and tired—on a scale of 0 to 10, with 0 being no emotion and 10 being the most intense emotion. The scores were converted to a 0-to-100 scale for the data analysis.
Separately, the researchers measured negative thinking using a Pain Catastrophizing Scale to rate “rumination,” or focus on pain, helplessness, and magnification of a current pain situation.
Results
Negative emotions were significantly associated with increased levels of long-acting opioids (P=0.001). The opioid dosage increased by 3.4 morphine milligram equivalents for every 10-point increase in negative emotions.
On the other hand, patients’ daily pain level, positive emotions, and negative thinking through catastrophizing did not significantly affect the amount of long-acting opioids taken.
“When someone is prescribed a daily, long-acting opioid, it is typically supposed to be at a fixed dose, and their pain level or emotions shouldn’t dictate whether they take more of this prescription or not,” Dr Finan said.
“Although we can’t prove misuse of the medication in our study, these data suggest that physicians and patients should clearly communicate about how patients should be taking their daily, long-acting opioids in order to minimize the potential for misuse.”
The researchers also found a significant association with short-acting opioid use and daily pain levels (P=0.006) as well as negative thinking by catastrophizing (P<0.001).
For every 10-point increase on the pain scale, the amount of short-acting opioids increased by 1.8 morphine milligram equivalents, and for every 10-point increase on the catastrophizing scale, pain medicine dosage increased by 2.5 morphine milligram equivalents.
Positive and negative emotions had no significant effect on the use of short-acting opioids.
“When pain was reported as low, sickle cell disease patients reported higher opioid use if they catastrophized, or focused their thinking on their pain, than if they didn’t,” Dr Finan said. “When pain levels were higher, negative thinking played less of a role in influencing opioid use.”
Dr Finan cautioned that studies such as this have some weaknesses, including the fact that self-reports are always uncertain, and the study only included 1 time point per day, although a person’s mood may fluctuate throughout the day based on life events and experiences.
For future studies, Dr Finan wants to use smartphone technology that can assess moods randomly throughout the day.
“Once we have a more intensive study to track mood variations throughout the day,” Dr Finan said, “then we can determine when it will be appropriate to send messages through text to intervene and affect patient behavior.”
Emerging sickle cell agents target new pathways
CONCORD, N.C. – Approved treatments for sickle cell disease have been extremely limited, but there are several therapies in the research pipeline that use new pathways to target the disease.
“We do have much better understanding of the pathophysiology, which is getting us a few more targets to aim at,” Julie Kanter, MD, director of sickle cell research at the Medical University of South Carolina, Charleston, said at Sickle Cell Disease Symposium held by Carolinas Health Care System. These targets include influencing how cells interact with the vascular endothelium, inhibiting platelets, and preventing cell sickling and inflammation.
“I’m waiting to see who’s willing to take it just because it is a lot of powder that the patient has to mix and drink twice a day, but it does look promising to reduce inflammation,” Dr. Kanter said.
SCD pipeline
Deeper in the sickle cell pipeline is a class of antisickling agents known as hemoglobin modifiers. “We’re tying to change the way hemoglobin binds to oxygen, and if we can keep hemoglobin binding to oxygen longer, it actually decreases the risk of hemoglobin sickling and polymerizing in the cell,” Dr. Kanter explained.
One hemoglobin modifier is voxelotor (previously called GBT440), a once-daily oral agent that Global Blood Therapeutics has in development.
Another category of antisickling agents that researchers are looking at is anti-inflammatory moderators, Dr. Kanter said. These include nitric oxide donors like sildenafil, which did not “quite work” in SCD, and arginine and glutamine, which increase the amount of nitric oxide once in the body “and hopefully reduce the risk of sickling,” she said. “If we can improve inflammation, we might be able to improve the risk of crisis.”
Cell adhesion modifiers are a drug class that aims to prevent cells from binding to each other. These include platelet inhibitors and endothelial blockers. “There are several antiplatelet agents that are approved really for stroke prevention or heart attack prevention, and we’re trying to see if we can repurpose these in sickle cell disease in a specific pathway that allows the platelet to stick to the endothelium, but if we only inhibit one pathway it should not increase the risk of bleeding,” Dr. Kanter said.
One platelet inhibition pathway that researchers are focused on is the P2Y12 adenosine diphosphate blockade, which the platelet inhibitor prasugrel (Effient) acts on. A 2016 study of this pathway in SCD “wasn’t successful,” Dr. Kanter said, “but it had some interesting results” – namely that the drug may be most effective in adolescents (N Engl J Med. 2016 Feb 18;374[7]:625-35).
Selectin-blocking medications are a drug class that act on white blood cell adhesion to, and movement through, the endothelium, Dr. Kanter said. “Neutrophils can instigate a sickle cell crisis, so if we can interrupt some of this rolling or sticking, could we decrease the risk of a sickle cell crisis?” The drug GMI-1070 is currently being studied in a phase III trial and so far has shown “a significant decrease in the amount of opioids used by those individuals who received the study drug,” she said.
Crizanlizumab (also known as SelG1) is a humanized monoclonal antibody with an affinity to P-selectin and is the subject of the phase II SUSTAIN trial, which included a cohort that also was taking hydroxyurea. Treatment with high-dose crizanlizumab resulted in an annual rate of sickle cell–related pain crises that was more than 45% lower than with placebo (N Engl J Med. 2017 Feb 2;376[5]:429-39).
Stem cell transplants
Besides drugs, stem cell transplants to treat SCD have advanced in recent years to the point where cure rates are exceeding 90%, Dr. Kanter noted. “However, the real issue with stem cells is that patients still don’t have enough donors,” she said.
SCD is also potentially amenable to gene therapy, Dr. Kanter said, noting that SCD gene therapy trials in progress are looking at harvesting patients’ own bone marrow, using the lentivirus viral vector, inserting a gene to increase production of nonsickle hemoglobin, and using myeloablative chemotherapy to remove old marrow and replace it with new, manipulated bone marrow.
Several programs are investigating using a gene editing technique, known as CRISPR/Cas9, to alter the BCL11A gene to maintain fetal hemoglobin production.
“We all make fetal hemoglobin at birth, and then over 6 months to 1 year of life, our bodies convert fetal hemoglobin to adult hemoglobin,” she said. “In sickle cell disease, it converts to sickle hemoglobin. What if we could prevent that conversion and keep the fetal hemoglobin turned on?” That could potentially eradicate the complications of SCD starting at an early age, Dr. Kanter said.
Dr. Kanter, who has been involved in several of the SCD trials, reported relationships with Pfizer, AstraZeneca, Bluebird Bio, Global Blood Therapeutics, Novartis, Guidepoint, GLG, ApoPharma, and Purdue Pharma.
CONCORD, N.C. – Approved treatments for sickle cell disease have been extremely limited, but there are several therapies in the research pipeline that use new pathways to target the disease.
“We do have much better understanding of the pathophysiology, which is getting us a few more targets to aim at,” Julie Kanter, MD, director of sickle cell research at the Medical University of South Carolina, Charleston, said at Sickle Cell Disease Symposium held by Carolinas Health Care System. These targets include influencing how cells interact with the vascular endothelium, inhibiting platelets, and preventing cell sickling and inflammation.
“I’m waiting to see who’s willing to take it just because it is a lot of powder that the patient has to mix and drink twice a day, but it does look promising to reduce inflammation,” Dr. Kanter said.
SCD pipeline
Deeper in the sickle cell pipeline is a class of antisickling agents known as hemoglobin modifiers. “We’re tying to change the way hemoglobin binds to oxygen, and if we can keep hemoglobin binding to oxygen longer, it actually decreases the risk of hemoglobin sickling and polymerizing in the cell,” Dr. Kanter explained.
One hemoglobin modifier is voxelotor (previously called GBT440), a once-daily oral agent that Global Blood Therapeutics has in development.
Another category of antisickling agents that researchers are looking at is anti-inflammatory moderators, Dr. Kanter said. These include nitric oxide donors like sildenafil, which did not “quite work” in SCD, and arginine and glutamine, which increase the amount of nitric oxide once in the body “and hopefully reduce the risk of sickling,” she said. “If we can improve inflammation, we might be able to improve the risk of crisis.”
Cell adhesion modifiers are a drug class that aims to prevent cells from binding to each other. These include platelet inhibitors and endothelial blockers. “There are several antiplatelet agents that are approved really for stroke prevention or heart attack prevention, and we’re trying to see if we can repurpose these in sickle cell disease in a specific pathway that allows the platelet to stick to the endothelium, but if we only inhibit one pathway it should not increase the risk of bleeding,” Dr. Kanter said.
One platelet inhibition pathway that researchers are focused on is the P2Y12 adenosine diphosphate blockade, which the platelet inhibitor prasugrel (Effient) acts on. A 2016 study of this pathway in SCD “wasn’t successful,” Dr. Kanter said, “but it had some interesting results” – namely that the drug may be most effective in adolescents (N Engl J Med. 2016 Feb 18;374[7]:625-35).
Selectin-blocking medications are a drug class that act on white blood cell adhesion to, and movement through, the endothelium, Dr. Kanter said. “Neutrophils can instigate a sickle cell crisis, so if we can interrupt some of this rolling or sticking, could we decrease the risk of a sickle cell crisis?” The drug GMI-1070 is currently being studied in a phase III trial and so far has shown “a significant decrease in the amount of opioids used by those individuals who received the study drug,” she said.
Crizanlizumab (also known as SelG1) is a humanized monoclonal antibody with an affinity to P-selectin and is the subject of the phase II SUSTAIN trial, which included a cohort that also was taking hydroxyurea. Treatment with high-dose crizanlizumab resulted in an annual rate of sickle cell–related pain crises that was more than 45% lower than with placebo (N Engl J Med. 2017 Feb 2;376[5]:429-39).
Stem cell transplants
Besides drugs, stem cell transplants to treat SCD have advanced in recent years to the point where cure rates are exceeding 90%, Dr. Kanter noted. “However, the real issue with stem cells is that patients still don’t have enough donors,” she said.
SCD is also potentially amenable to gene therapy, Dr. Kanter said, noting that SCD gene therapy trials in progress are looking at harvesting patients’ own bone marrow, using the lentivirus viral vector, inserting a gene to increase production of nonsickle hemoglobin, and using myeloablative chemotherapy to remove old marrow and replace it with new, manipulated bone marrow.
Several programs are investigating using a gene editing technique, known as CRISPR/Cas9, to alter the BCL11A gene to maintain fetal hemoglobin production.
“We all make fetal hemoglobin at birth, and then over 6 months to 1 year of life, our bodies convert fetal hemoglobin to adult hemoglobin,” she said. “In sickle cell disease, it converts to sickle hemoglobin. What if we could prevent that conversion and keep the fetal hemoglobin turned on?” That could potentially eradicate the complications of SCD starting at an early age, Dr. Kanter said.
Dr. Kanter, who has been involved in several of the SCD trials, reported relationships with Pfizer, AstraZeneca, Bluebird Bio, Global Blood Therapeutics, Novartis, Guidepoint, GLG, ApoPharma, and Purdue Pharma.
CONCORD, N.C. – Approved treatments for sickle cell disease have been extremely limited, but there are several therapies in the research pipeline that use new pathways to target the disease.
“We do have much better understanding of the pathophysiology, which is getting us a few more targets to aim at,” Julie Kanter, MD, director of sickle cell research at the Medical University of South Carolina, Charleston, said at Sickle Cell Disease Symposium held by Carolinas Health Care System. These targets include influencing how cells interact with the vascular endothelium, inhibiting platelets, and preventing cell sickling and inflammation.
“I’m waiting to see who’s willing to take it just because it is a lot of powder that the patient has to mix and drink twice a day, but it does look promising to reduce inflammation,” Dr. Kanter said.
SCD pipeline
Deeper in the sickle cell pipeline is a class of antisickling agents known as hemoglobin modifiers. “We’re tying to change the way hemoglobin binds to oxygen, and if we can keep hemoglobin binding to oxygen longer, it actually decreases the risk of hemoglobin sickling and polymerizing in the cell,” Dr. Kanter explained.
One hemoglobin modifier is voxelotor (previously called GBT440), a once-daily oral agent that Global Blood Therapeutics has in development.
Another category of antisickling agents that researchers are looking at is anti-inflammatory moderators, Dr. Kanter said. These include nitric oxide donors like sildenafil, which did not “quite work” in SCD, and arginine and glutamine, which increase the amount of nitric oxide once in the body “and hopefully reduce the risk of sickling,” she said. “If we can improve inflammation, we might be able to improve the risk of crisis.”
Cell adhesion modifiers are a drug class that aims to prevent cells from binding to each other. These include platelet inhibitors and endothelial blockers. “There are several antiplatelet agents that are approved really for stroke prevention or heart attack prevention, and we’re trying to see if we can repurpose these in sickle cell disease in a specific pathway that allows the platelet to stick to the endothelium, but if we only inhibit one pathway it should not increase the risk of bleeding,” Dr. Kanter said.
One platelet inhibition pathway that researchers are focused on is the P2Y12 adenosine diphosphate blockade, which the platelet inhibitor prasugrel (Effient) acts on. A 2016 study of this pathway in SCD “wasn’t successful,” Dr. Kanter said, “but it had some interesting results” – namely that the drug may be most effective in adolescents (N Engl J Med. 2016 Feb 18;374[7]:625-35).
Selectin-blocking medications are a drug class that act on white blood cell adhesion to, and movement through, the endothelium, Dr. Kanter said. “Neutrophils can instigate a sickle cell crisis, so if we can interrupt some of this rolling or sticking, could we decrease the risk of a sickle cell crisis?” The drug GMI-1070 is currently being studied in a phase III trial and so far has shown “a significant decrease in the amount of opioids used by those individuals who received the study drug,” she said.
Crizanlizumab (also known as SelG1) is a humanized monoclonal antibody with an affinity to P-selectin and is the subject of the phase II SUSTAIN trial, which included a cohort that also was taking hydroxyurea. Treatment with high-dose crizanlizumab resulted in an annual rate of sickle cell–related pain crises that was more than 45% lower than with placebo (N Engl J Med. 2017 Feb 2;376[5]:429-39).
Stem cell transplants
Besides drugs, stem cell transplants to treat SCD have advanced in recent years to the point where cure rates are exceeding 90%, Dr. Kanter noted. “However, the real issue with stem cells is that patients still don’t have enough donors,” she said.
SCD is also potentially amenable to gene therapy, Dr. Kanter said, noting that SCD gene therapy trials in progress are looking at harvesting patients’ own bone marrow, using the lentivirus viral vector, inserting a gene to increase production of nonsickle hemoglobin, and using myeloablative chemotherapy to remove old marrow and replace it with new, manipulated bone marrow.
Several programs are investigating using a gene editing technique, known as CRISPR/Cas9, to alter the BCL11A gene to maintain fetal hemoglobin production.
“We all make fetal hemoglobin at birth, and then over 6 months to 1 year of life, our bodies convert fetal hemoglobin to adult hemoglobin,” she said. “In sickle cell disease, it converts to sickle hemoglobin. What if we could prevent that conversion and keep the fetal hemoglobin turned on?” That could potentially eradicate the complications of SCD starting at an early age, Dr. Kanter said.
Dr. Kanter, who has been involved in several of the SCD trials, reported relationships with Pfizer, AstraZeneca, Bluebird Bio, Global Blood Therapeutics, Novartis, Guidepoint, GLG, ApoPharma, and Purdue Pharma.
EXPERT ANALYSIS FROM A MEETING ON SICKLE CELL DISEASE
Dedicated sickle cell center offers roadmap for care
CONCORD, N.C. – A care center for acute sickle cell pain management, which includes a dedicated emergency room and a daytime management unit in the hospital, decreased health system costs and the frequency of acute care visits by sickle cell patients, James Eckman, MD, reported at Sickle Cell Disease Symposium held by Carolinas Health Care System.
“In the first 5 years of the center, acute care visits dropped from 16 per patient per year to 10, and admissions per active patient per year dropped from 2.1 to less than one,” said Dr. Eckman, former medical director of the Georgia Comprehensive Sickle Cell Center at Grady Health System in Atlanta.
By 2011, those numbers had dropped further, falling to less than four acute care visits per patient per year and less than 0.5 admissions per patient per year.
The results Dr. Eckman reported are based on 37 years of his experience at Grady Health System, which included setting up an emergency room dedicated to patients with sickle cell disease (SCD) and the launch of a tertiary care clinic in 1985. The Grady SCD database includes more than 4,500 patients, with about 1,000 adults active at any given time.
It’s , according to Emory University.
“We really developed a model that was very cost effective for the management of this disease,” said Dr. Eckman, professor emeritus in hematology and medical oncology at Emory University. “We actually consistently turned a profit in our budget.”
Previously, SCD patients went to the regular emergency department for their acute pain crises, and they would often wait for hours without treatment. “You need to initiate treatment rapidly in these patients,” Dr. Eckman said. “It’s really unacceptable now what’s happening in our emergency rooms, where they have to wait 3, 4, or more hours to get treated while they’re in intolerable pain.”
In 2014, an expert panel issued guidelines for pain management in SCD calling for the initiation of pain treatment for acute crisis within 30 minutes of the patient’s arrival in the emergency department (JAMA. 2014 Sep 10;312[10]:1033-48). “Our goal is 20 minutes to have a complete assessment, get a laboratory draw, and have them on therapy,” he said. “And we were relatively successful in being able to do that.”
Each patient at the center was enrolled in a care management program consisting of 35 assessment and intervention elements. Assessment includes a complete medical evaluation, along with social and psychological evaluations. Intervention entails developing a detailed problem list – including medical, social, and psychological issues – a detailed management plan, and a social support plan. The initial assessment can take 4-8 hours.
For the first decade, the program tracked acute care visits and admissions in 166 continuing patients and saw dramatic declines in both. “The data only go through 1995, but they actually look exactly the same after 1995 all the way up to 2015,” Dr. Eckman said. “This sustained a really marked decrease in health care utilization.”
The program also identified a small group of patients – fewer than 75 out of a base of 1,000 – who accounted for 90% of visits, he said.
Although the Georgia experience is based on a dedicated care center for SCD, the results can be replicated without that type of dedicated infrastructure, Dr. Eckman said. “It is not the 24-hour acute care center,” he said. “It’s the carefully thought out and implemented comprehensive care plan by a multidisciplinary care team dedicated to care of the individuals with sickle cell disease that makes the difference.”
Dr. Eckman reported having no financial disclosures.
CONCORD, N.C. – A care center for acute sickle cell pain management, which includes a dedicated emergency room and a daytime management unit in the hospital, decreased health system costs and the frequency of acute care visits by sickle cell patients, James Eckman, MD, reported at Sickle Cell Disease Symposium held by Carolinas Health Care System.
“In the first 5 years of the center, acute care visits dropped from 16 per patient per year to 10, and admissions per active patient per year dropped from 2.1 to less than one,” said Dr. Eckman, former medical director of the Georgia Comprehensive Sickle Cell Center at Grady Health System in Atlanta.
By 2011, those numbers had dropped further, falling to less than four acute care visits per patient per year and less than 0.5 admissions per patient per year.
The results Dr. Eckman reported are based on 37 years of his experience at Grady Health System, which included setting up an emergency room dedicated to patients with sickle cell disease (SCD) and the launch of a tertiary care clinic in 1985. The Grady SCD database includes more than 4,500 patients, with about 1,000 adults active at any given time.
It’s , according to Emory University.
“We really developed a model that was very cost effective for the management of this disease,” said Dr. Eckman, professor emeritus in hematology and medical oncology at Emory University. “We actually consistently turned a profit in our budget.”
Previously, SCD patients went to the regular emergency department for their acute pain crises, and they would often wait for hours without treatment. “You need to initiate treatment rapidly in these patients,” Dr. Eckman said. “It’s really unacceptable now what’s happening in our emergency rooms, where they have to wait 3, 4, or more hours to get treated while they’re in intolerable pain.”
In 2014, an expert panel issued guidelines for pain management in SCD calling for the initiation of pain treatment for acute crisis within 30 minutes of the patient’s arrival in the emergency department (JAMA. 2014 Sep 10;312[10]:1033-48). “Our goal is 20 minutes to have a complete assessment, get a laboratory draw, and have them on therapy,” he said. “And we were relatively successful in being able to do that.”
Each patient at the center was enrolled in a care management program consisting of 35 assessment and intervention elements. Assessment includes a complete medical evaluation, along with social and psychological evaluations. Intervention entails developing a detailed problem list – including medical, social, and psychological issues – a detailed management plan, and a social support plan. The initial assessment can take 4-8 hours.
For the first decade, the program tracked acute care visits and admissions in 166 continuing patients and saw dramatic declines in both. “The data only go through 1995, but they actually look exactly the same after 1995 all the way up to 2015,” Dr. Eckman said. “This sustained a really marked decrease in health care utilization.”
The program also identified a small group of patients – fewer than 75 out of a base of 1,000 – who accounted for 90% of visits, he said.
Although the Georgia experience is based on a dedicated care center for SCD, the results can be replicated without that type of dedicated infrastructure, Dr. Eckman said. “It is not the 24-hour acute care center,” he said. “It’s the carefully thought out and implemented comprehensive care plan by a multidisciplinary care team dedicated to care of the individuals with sickle cell disease that makes the difference.”
Dr. Eckman reported having no financial disclosures.
CONCORD, N.C. – A care center for acute sickle cell pain management, which includes a dedicated emergency room and a daytime management unit in the hospital, decreased health system costs and the frequency of acute care visits by sickle cell patients, James Eckman, MD, reported at Sickle Cell Disease Symposium held by Carolinas Health Care System.
“In the first 5 years of the center, acute care visits dropped from 16 per patient per year to 10, and admissions per active patient per year dropped from 2.1 to less than one,” said Dr. Eckman, former medical director of the Georgia Comprehensive Sickle Cell Center at Grady Health System in Atlanta.
By 2011, those numbers had dropped further, falling to less than four acute care visits per patient per year and less than 0.5 admissions per patient per year.
The results Dr. Eckman reported are based on 37 years of his experience at Grady Health System, which included setting up an emergency room dedicated to patients with sickle cell disease (SCD) and the launch of a tertiary care clinic in 1985. The Grady SCD database includes more than 4,500 patients, with about 1,000 adults active at any given time.
It’s , according to Emory University.
“We really developed a model that was very cost effective for the management of this disease,” said Dr. Eckman, professor emeritus in hematology and medical oncology at Emory University. “We actually consistently turned a profit in our budget.”
Previously, SCD patients went to the regular emergency department for their acute pain crises, and they would often wait for hours without treatment. “You need to initiate treatment rapidly in these patients,” Dr. Eckman said. “It’s really unacceptable now what’s happening in our emergency rooms, where they have to wait 3, 4, or more hours to get treated while they’re in intolerable pain.”
In 2014, an expert panel issued guidelines for pain management in SCD calling for the initiation of pain treatment for acute crisis within 30 minutes of the patient’s arrival in the emergency department (JAMA. 2014 Sep 10;312[10]:1033-48). “Our goal is 20 minutes to have a complete assessment, get a laboratory draw, and have them on therapy,” he said. “And we were relatively successful in being able to do that.”
Each patient at the center was enrolled in a care management program consisting of 35 assessment and intervention elements. Assessment includes a complete medical evaluation, along with social and psychological evaluations. Intervention entails developing a detailed problem list – including medical, social, and psychological issues – a detailed management plan, and a social support plan. The initial assessment can take 4-8 hours.
For the first decade, the program tracked acute care visits and admissions in 166 continuing patients and saw dramatic declines in both. “The data only go through 1995, but they actually look exactly the same after 1995 all the way up to 2015,” Dr. Eckman said. “This sustained a really marked decrease in health care utilization.”
The program also identified a small group of patients – fewer than 75 out of a base of 1,000 – who accounted for 90% of visits, he said.
Although the Georgia experience is based on a dedicated care center for SCD, the results can be replicated without that type of dedicated infrastructure, Dr. Eckman said. “It is not the 24-hour acute care center,” he said. “It’s the carefully thought out and implemented comprehensive care plan by a multidisciplinary care team dedicated to care of the individuals with sickle cell disease that makes the difference.”
Dr. Eckman reported having no financial disclosures.
EXPERT ANALYSIS FROM A MEETING ON SICKLE CELL DISEASE
Rigosertib produces better OS in MDS than tAML
Rigosertib has demonstrated activity and tolerability in patients with myelodysplastic syndromes (MDS) and acute myeloid leukemia transformed from MDS (tAML), according to researchers.
In a phase 1/2 study, rigosertib produced responses in a quarter of MDS/tAML patients and enabled stable disease in another quarter.
Overall survival (OS) was about a year longer for responders than for non-responders.
MDS patients were more likely to respond to rigosertib and therefore enjoyed longer OS than tAML patients.
Overall, rigosertib was considered well-tolerated. There were no treatment-related deaths, though 18% of patients experienced treatment-related serious adverse events (AEs).
Lewis Silverman, MD, of Icahn School of Medicine at Mount Sinai in New York, New York, and his colleagues described these results in Leukemia Research.
The study was sponsored by Onconova Therapeutics, Inc., the company developing rigosertib.
Rigosertib is an inhibitor of Ras-effector pathways that interacts with the Ras binding domains common to several signaling proteins, including Raf and PI3 kinase.
Dr Silverman and his colleagues tested intravenous rigosertib in a dose-escalation, phase 1/2 study of 22 patients. Patients had tAML (n=13), high-risk MDS (n=6), intermediate-2-risk MDS (n=2), or chronic myelomonocytic leukemia (n=1).
All patients had relapsed or were refractory to standard therapy and had no approved options for second-line therapies. The patients’ median age was 78 (range, 59-84), and 90% were male.
Patients received 3- to 7-day continuous infusions of rigosertib at doses ranging from 650 mg/m2/day to 1700 mg/m2/day in 14-day cycles.
The mean number of treatment cycles was 5.6 ± 5.8 (range, 1-23). The maximum tolerated dose of rigosertib was 1700 mg/m2/day, and the recommended phase 2 dose was 1375 mg/m2/day.
Safety
All patients had at least 1 AE. The most common AEs of any grade were fatigue (n=16, 73%), diarrhea (n=12, 55%), pyrexia (n=12, 55%), dyspnea (n=11, 50%), insomnia (n=11, 50%), anemia (n=10, 46%), constipation (n=9, 41%), nausea (n=9, 41%), cough (n=9, 41%), and decreased appetite (n=9, 41%).
The most common grade 3 or higher AEs were anemia (n=9, 41%), thrombocytopenia (n=5, 23%), pneumonia (n=5, 23%), hypoglycemia (n=4, 18%), hyponatremia (n=4, 18%), and hypophosphatemia (n=4, 18%).
Four patients (18%) had treatment-related serious AEs. This included hematuria and pollakiuria (n=1), dysuria and pollakiuria (n=1), asthenia (n=1), and dyspnea (n=1). Thirteen patients (59%) stopped treatment due to AEs.
Ten patients, who remained on study from 1 to 19 months, died within 30 days of stopping rigosertib. There were no treatment-related deaths.
Efficacy
Nineteen patients were evaluable for efficacy.
Five patients responded to treatment. Four patients with MDS had a marrow complete response, and 1 with tAML had a marrow partial response. Two of the patients with marrow complete response also had hematologic improvements.
Five patients had stable disease, 3 with MDS and 2 with tAML.
The median OS was 15.7 months for responders and 2.0 months for non-responders (P=0.0070). The median OS was 12.0 months for MDS patients and 2.0 months for tAML patients (P<0.0001).
“The publication of results from this historical study provides support of the relationship between bone marrow blast response and improvement in overall survival in this group of patients with MDS and acute myeloid leukemia for whom no FDA-approved treatments are currently available,” said Ramesh Kumar, president and chief executive officer of Onconova Therapeutics, Inc.
He added that these data are “fundamental to the rationale” of ongoing studies of rigosertib in high-risk MDS patients.
Rigosertib has demonstrated activity and tolerability in patients with myelodysplastic syndromes (MDS) and acute myeloid leukemia transformed from MDS (tAML), according to researchers.
In a phase 1/2 study, rigosertib produced responses in a quarter of MDS/tAML patients and enabled stable disease in another quarter.
Overall survival (OS) was about a year longer for responders than for non-responders.
MDS patients were more likely to respond to rigosertib and therefore enjoyed longer OS than tAML patients.
Overall, rigosertib was considered well-tolerated. There were no treatment-related deaths, though 18% of patients experienced treatment-related serious adverse events (AEs).
Lewis Silverman, MD, of Icahn School of Medicine at Mount Sinai in New York, New York, and his colleagues described these results in Leukemia Research.
The study was sponsored by Onconova Therapeutics, Inc., the company developing rigosertib.
Rigosertib is an inhibitor of Ras-effector pathways that interacts with the Ras binding domains common to several signaling proteins, including Raf and PI3 kinase.
Dr Silverman and his colleagues tested intravenous rigosertib in a dose-escalation, phase 1/2 study of 22 patients. Patients had tAML (n=13), high-risk MDS (n=6), intermediate-2-risk MDS (n=2), or chronic myelomonocytic leukemia (n=1).
All patients had relapsed or were refractory to standard therapy and had no approved options for second-line therapies. The patients’ median age was 78 (range, 59-84), and 90% were male.
Patients received 3- to 7-day continuous infusions of rigosertib at doses ranging from 650 mg/m2/day to 1700 mg/m2/day in 14-day cycles.
The mean number of treatment cycles was 5.6 ± 5.8 (range, 1-23). The maximum tolerated dose of rigosertib was 1700 mg/m2/day, and the recommended phase 2 dose was 1375 mg/m2/day.
Safety
All patients had at least 1 AE. The most common AEs of any grade were fatigue (n=16, 73%), diarrhea (n=12, 55%), pyrexia (n=12, 55%), dyspnea (n=11, 50%), insomnia (n=11, 50%), anemia (n=10, 46%), constipation (n=9, 41%), nausea (n=9, 41%), cough (n=9, 41%), and decreased appetite (n=9, 41%).
The most common grade 3 or higher AEs were anemia (n=9, 41%), thrombocytopenia (n=5, 23%), pneumonia (n=5, 23%), hypoglycemia (n=4, 18%), hyponatremia (n=4, 18%), and hypophosphatemia (n=4, 18%).
Four patients (18%) had treatment-related serious AEs. This included hematuria and pollakiuria (n=1), dysuria and pollakiuria (n=1), asthenia (n=1), and dyspnea (n=1). Thirteen patients (59%) stopped treatment due to AEs.
Ten patients, who remained on study from 1 to 19 months, died within 30 days of stopping rigosertib. There were no treatment-related deaths.
Efficacy
Nineteen patients were evaluable for efficacy.
Five patients responded to treatment. Four patients with MDS had a marrow complete response, and 1 with tAML had a marrow partial response. Two of the patients with marrow complete response also had hematologic improvements.
Five patients had stable disease, 3 with MDS and 2 with tAML.
The median OS was 15.7 months for responders and 2.0 months for non-responders (P=0.0070). The median OS was 12.0 months for MDS patients and 2.0 months for tAML patients (P<0.0001).
“The publication of results from this historical study provides support of the relationship between bone marrow blast response and improvement in overall survival in this group of patients with MDS and acute myeloid leukemia for whom no FDA-approved treatments are currently available,” said Ramesh Kumar, president and chief executive officer of Onconova Therapeutics, Inc.
He added that these data are “fundamental to the rationale” of ongoing studies of rigosertib in high-risk MDS patients.
Rigosertib has demonstrated activity and tolerability in patients with myelodysplastic syndromes (MDS) and acute myeloid leukemia transformed from MDS (tAML), according to researchers.
In a phase 1/2 study, rigosertib produced responses in a quarter of MDS/tAML patients and enabled stable disease in another quarter.
Overall survival (OS) was about a year longer for responders than for non-responders.
MDS patients were more likely to respond to rigosertib and therefore enjoyed longer OS than tAML patients.
Overall, rigosertib was considered well-tolerated. There were no treatment-related deaths, though 18% of patients experienced treatment-related serious adverse events (AEs).
Lewis Silverman, MD, of Icahn School of Medicine at Mount Sinai in New York, New York, and his colleagues described these results in Leukemia Research.
The study was sponsored by Onconova Therapeutics, Inc., the company developing rigosertib.
Rigosertib is an inhibitor of Ras-effector pathways that interacts with the Ras binding domains common to several signaling proteins, including Raf and PI3 kinase.
Dr Silverman and his colleagues tested intravenous rigosertib in a dose-escalation, phase 1/2 study of 22 patients. Patients had tAML (n=13), high-risk MDS (n=6), intermediate-2-risk MDS (n=2), or chronic myelomonocytic leukemia (n=1).
All patients had relapsed or were refractory to standard therapy and had no approved options for second-line therapies. The patients’ median age was 78 (range, 59-84), and 90% were male.
Patients received 3- to 7-day continuous infusions of rigosertib at doses ranging from 650 mg/m2/day to 1700 mg/m2/day in 14-day cycles.
The mean number of treatment cycles was 5.6 ± 5.8 (range, 1-23). The maximum tolerated dose of rigosertib was 1700 mg/m2/day, and the recommended phase 2 dose was 1375 mg/m2/day.
Safety
All patients had at least 1 AE. The most common AEs of any grade were fatigue (n=16, 73%), diarrhea (n=12, 55%), pyrexia (n=12, 55%), dyspnea (n=11, 50%), insomnia (n=11, 50%), anemia (n=10, 46%), constipation (n=9, 41%), nausea (n=9, 41%), cough (n=9, 41%), and decreased appetite (n=9, 41%).
The most common grade 3 or higher AEs were anemia (n=9, 41%), thrombocytopenia (n=5, 23%), pneumonia (n=5, 23%), hypoglycemia (n=4, 18%), hyponatremia (n=4, 18%), and hypophosphatemia (n=4, 18%).
Four patients (18%) had treatment-related serious AEs. This included hematuria and pollakiuria (n=1), dysuria and pollakiuria (n=1), asthenia (n=1), and dyspnea (n=1). Thirteen patients (59%) stopped treatment due to AEs.
Ten patients, who remained on study from 1 to 19 months, died within 30 days of stopping rigosertib. There were no treatment-related deaths.
Efficacy
Nineteen patients were evaluable for efficacy.
Five patients responded to treatment. Four patients with MDS had a marrow complete response, and 1 with tAML had a marrow partial response. Two of the patients with marrow complete response also had hematologic improvements.
Five patients had stable disease, 3 with MDS and 2 with tAML.
The median OS was 15.7 months for responders and 2.0 months for non-responders (P=0.0070). The median OS was 12.0 months for MDS patients and 2.0 months for tAML patients (P<0.0001).
“The publication of results from this historical study provides support of the relationship between bone marrow blast response and improvement in overall survival in this group of patients with MDS and acute myeloid leukemia for whom no FDA-approved treatments are currently available,” said Ramesh Kumar, president and chief executive officer of Onconova Therapeutics, Inc.
He added that these data are “fundamental to the rationale” of ongoing studies of rigosertib in high-risk MDS patients.
Drug can treat severely ill SCD patients, case suggests
ATLANTA—Results of a case study suggest voxelotor (previously GBT440) can be effective in severely ill patients with sickle cell disease (SCD).
Voxelotor is currently under investigation in the phase 3 HOPE study, which includes SCD patients age 12 and older.
A 67-year-old male SCD patient could not participate in the study due to severe, transfusion-refractory anemia, so he received voxelotor via compassionate access.
This patient’s results were presented at the Sickle Cell Disease Association of America (SCDAA) 45th Annual National Convention.
The patient had the HbSS genotype with severe anemia that was refractory to transfusion. The patient had developed red cell antibodies after receiving multiple transfusions, and these antibodies prevented further transfusions to correct his anemia.
The patient also had moderate chronic obstructive pulmonary disease requiring supplemental oxygen therapy, recurrent and frequent pain exacerbations, extreme fatigue, and clinical depression.
The patient received voxelotor at 900 mg orally once daily. He responded to the treatment within 1 to 2 weeks, experiencing improvements in pain, fatigue, and overall mental health (as measured by the Patient Health Quality-9 score).
The patient’s hemoglobin levels rose quickly, to approximately 1.5 g/dL above baseline, with a sustained increase over 66 weeks in the range of 1 to 1.5 g/dL.
There were reductions in reticulocyte count and bilirubin as well, both consistent with diminished hemolysis.
The patient’s blood oxygen saturation improved on the standard walk test, from 86 mmHg at baseline to 96 mmHg at 65 weeks, and he discontinued continuous oxygen supplementation.
The patient has not been hospitalized due to sickle cell pain since he started taking voxelotor.
He has experienced a treatment-related side effect—grade 2 diarrhea. This occurred 9 weeks after he started voxelotor treatment, when the dose was increased to 1500 mg daily, but it resolved upon return to 900 mg. The patient has experienced no other treatment-related side effects.
Clinical and laboratory improvements have continued for more than 17 months, and the patient remains on treatment today under compassionate use access.
“This severely ill SCD patient’s clinical response, assessed by both objective and subjective measures, illustrates why we are encouraged by the voxelotor program,” said Ted W. Love, MD, president and chief executive officer of Global Blood Therapeutics, the company developing voxelotor.
“We plan to present additional data from other severely ill sickle cell patients who have received voxelotor via single-patient compassionate access treatment at FSCDR [the Foundation for Sickle Cell Disease Research] at an upcoming medical meeting. Of course, controlled clinical trials are needed to assess the efficacy and safety of voxelotor in SCD patients, including those with severe anemia.”
ATLANTA—Results of a case study suggest voxelotor (previously GBT440) can be effective in severely ill patients with sickle cell disease (SCD).
Voxelotor is currently under investigation in the phase 3 HOPE study, which includes SCD patients age 12 and older.
A 67-year-old male SCD patient could not participate in the study due to severe, transfusion-refractory anemia, so he received voxelotor via compassionate access.
This patient’s results were presented at the Sickle Cell Disease Association of America (SCDAA) 45th Annual National Convention.
The patient had the HbSS genotype with severe anemia that was refractory to transfusion. The patient had developed red cell antibodies after receiving multiple transfusions, and these antibodies prevented further transfusions to correct his anemia.
The patient also had moderate chronic obstructive pulmonary disease requiring supplemental oxygen therapy, recurrent and frequent pain exacerbations, extreme fatigue, and clinical depression.
The patient received voxelotor at 900 mg orally once daily. He responded to the treatment within 1 to 2 weeks, experiencing improvements in pain, fatigue, and overall mental health (as measured by the Patient Health Quality-9 score).
The patient’s hemoglobin levels rose quickly, to approximately 1.5 g/dL above baseline, with a sustained increase over 66 weeks in the range of 1 to 1.5 g/dL.
There were reductions in reticulocyte count and bilirubin as well, both consistent with diminished hemolysis.
The patient’s blood oxygen saturation improved on the standard walk test, from 86 mmHg at baseline to 96 mmHg at 65 weeks, and he discontinued continuous oxygen supplementation.
The patient has not been hospitalized due to sickle cell pain since he started taking voxelotor.
He has experienced a treatment-related side effect—grade 2 diarrhea. This occurred 9 weeks after he started voxelotor treatment, when the dose was increased to 1500 mg daily, but it resolved upon return to 900 mg. The patient has experienced no other treatment-related side effects.
Clinical and laboratory improvements have continued for more than 17 months, and the patient remains on treatment today under compassionate use access.
“This severely ill SCD patient’s clinical response, assessed by both objective and subjective measures, illustrates why we are encouraged by the voxelotor program,” said Ted W. Love, MD, president and chief executive officer of Global Blood Therapeutics, the company developing voxelotor.
“We plan to present additional data from other severely ill sickle cell patients who have received voxelotor via single-patient compassionate access treatment at FSCDR [the Foundation for Sickle Cell Disease Research] at an upcoming medical meeting. Of course, controlled clinical trials are needed to assess the efficacy and safety of voxelotor in SCD patients, including those with severe anemia.”
ATLANTA—Results of a case study suggest voxelotor (previously GBT440) can be effective in severely ill patients with sickle cell disease (SCD).
Voxelotor is currently under investigation in the phase 3 HOPE study, which includes SCD patients age 12 and older.
A 67-year-old male SCD patient could not participate in the study due to severe, transfusion-refractory anemia, so he received voxelotor via compassionate access.
This patient’s results were presented at the Sickle Cell Disease Association of America (SCDAA) 45th Annual National Convention.
The patient had the HbSS genotype with severe anemia that was refractory to transfusion. The patient had developed red cell antibodies after receiving multiple transfusions, and these antibodies prevented further transfusions to correct his anemia.
The patient also had moderate chronic obstructive pulmonary disease requiring supplemental oxygen therapy, recurrent and frequent pain exacerbations, extreme fatigue, and clinical depression.
The patient received voxelotor at 900 mg orally once daily. He responded to the treatment within 1 to 2 weeks, experiencing improvements in pain, fatigue, and overall mental health (as measured by the Patient Health Quality-9 score).
The patient’s hemoglobin levels rose quickly, to approximately 1.5 g/dL above baseline, with a sustained increase over 66 weeks in the range of 1 to 1.5 g/dL.
There were reductions in reticulocyte count and bilirubin as well, both consistent with diminished hemolysis.
The patient’s blood oxygen saturation improved on the standard walk test, from 86 mmHg at baseline to 96 mmHg at 65 weeks, and he discontinued continuous oxygen supplementation.
The patient has not been hospitalized due to sickle cell pain since he started taking voxelotor.
He has experienced a treatment-related side effect—grade 2 diarrhea. This occurred 9 weeks after he started voxelotor treatment, when the dose was increased to 1500 mg daily, but it resolved upon return to 900 mg. The patient has experienced no other treatment-related side effects.
Clinical and laboratory improvements have continued for more than 17 months, and the patient remains on treatment today under compassionate use access.
“This severely ill SCD patient’s clinical response, assessed by both objective and subjective measures, illustrates why we are encouraged by the voxelotor program,” said Ted W. Love, MD, president and chief executive officer of Global Blood Therapeutics, the company developing voxelotor.
“We plan to present additional data from other severely ill sickle cell patients who have received voxelotor via single-patient compassionate access treatment at FSCDR [the Foundation for Sickle Cell Disease Research] at an upcoming medical meeting. Of course, controlled clinical trials are needed to assess the efficacy and safety of voxelotor in SCD patients, including those with severe anemia.”
Generic azacitidine approved in Canada
Health Canada has approved Dr. Reddy’s Laboratories Ltd.’s Azacitidine for Injection 100 mg/vial, a bioequivalent generic version of VIDAZA® (azacitidine for injection).
The generic drug is approved for the same indications as VIDAZA®.
This includes treating adults with intermediate-2 or high-risk myelodysplastic syndromes (according to the International Prognostic Scoring System) who are not eligible for hematopoietic stem cell transplant.
It also includes treating adults who have acute myeloid leukemia with 20% to 30% blasts and multi-lineage dysplasia (according to World Health Organization classification) who are not eligible for hematopoietic stem cell transplant.
“The approval and launch of Azacitidine for Injection is an important milestone for Dr. Reddy’s in Canada,” said Vinod Ramachandran, PhD, country manager, Dr. Reddy’s Canada.
“The launch of the first generic azacitidine for injection is another step in our long-term commitment to bring more cost-effective options to Canadian patients.”
Health Canada has approved Dr. Reddy’s Laboratories Ltd.’s Azacitidine for Injection 100 mg/vial, a bioequivalent generic version of VIDAZA® (azacitidine for injection).
The generic drug is approved for the same indications as VIDAZA®.
This includes treating adults with intermediate-2 or high-risk myelodysplastic syndromes (according to the International Prognostic Scoring System) who are not eligible for hematopoietic stem cell transplant.
It also includes treating adults who have acute myeloid leukemia with 20% to 30% blasts and multi-lineage dysplasia (according to World Health Organization classification) who are not eligible for hematopoietic stem cell transplant.
“The approval and launch of Azacitidine for Injection is an important milestone for Dr. Reddy’s in Canada,” said Vinod Ramachandran, PhD, country manager, Dr. Reddy’s Canada.
“The launch of the first generic azacitidine for injection is another step in our long-term commitment to bring more cost-effective options to Canadian patients.”
Health Canada has approved Dr. Reddy’s Laboratories Ltd.’s Azacitidine for Injection 100 mg/vial, a bioequivalent generic version of VIDAZA® (azacitidine for injection).
The generic drug is approved for the same indications as VIDAZA®.
This includes treating adults with intermediate-2 or high-risk myelodysplastic syndromes (according to the International Prognostic Scoring System) who are not eligible for hematopoietic stem cell transplant.
It also includes treating adults who have acute myeloid leukemia with 20% to 30% blasts and multi-lineage dysplasia (according to World Health Organization classification) who are not eligible for hematopoietic stem cell transplant.
“The approval and launch of Azacitidine for Injection is an important milestone for Dr. Reddy’s in Canada,” said Vinod Ramachandran, PhD, country manager, Dr. Reddy’s Canada.
“The launch of the first generic azacitidine for injection is another step in our long-term commitment to bring more cost-effective options to Canadian patients.”