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Fostamatinib elicits responses in AIHA
The oral SYK inhibitor fostamatinib can produce responses in patients with warm antibody autoimmune hemolytic anemia (AIHA), according to Rigel Pharmaceuticals, Inc.
The company reported topline results from the first stage of the phase 2 SOAR study, which showed that fostamatinib produced a 35% response rate.
A response was defined as achieving a hemoglobin level of greater than 10 g/dL and at least a 2 g/dL increase from baseline.
“Many patients with AIHA suffer from severe, debilitating disease that negatively affects their quality of life,” said David J. Kuter, MD, the director for the Center of Hematology at Massachusetts General Hospital in Boston and the lead investigator of the SOAR study.
“There are no FDA-approved medications for the treatment of AIHA, which means that those living with the condition are in need of new and effective therapeutic options.”
In the SOAR study, Dr Kuter and his colleagues are evaluating fostamatinib in patients with warm antibody AIHA who previously received at least 1 treatment but did not have a meaningful benefit and are still anemic.
The study utilizes an open-label, Simon 2-stage design to evaluate fostamatinib given at 150 mg twice daily.
Stage 1 has enrolled 17 patients who have had at least 1 post-baseline hemoglobin measure.
Four of these patients responded to fostamatinib during the 12-week evaluation period, and an additional 2 patients met response criteria in the extension study after 12 weeks of dosing.
So the overall response rate was 35% (6/17), although Rigel Pharmaceuticals said these data are preliminary and require further verification.
Two patients withdrew from the study early due to non-safety-related reasons and will be replaced per the study protocol.
According to Rigel Pharmaceuticals, the treatment-emergent adverse events (AEs) in this trial were consistent with the prior clinical experience with fostamatinib.
Treatment-emergent AEs—which included diarrhea, elevated liver function tests, and hypertension—were manageable and mostly mild or moderate in nature.
There were 2 deaths reported during the trial. Both were due to non-treatment-related serious AEs, according to investigators. One patient had skin necrosis and infection. The other was an elderly patient who had pneumonia and was immunosuppressed due to prior chronic lymphocytic leukemia and steroid use.
A third patient experienced a non-treatment-related serious AE but recovered and continued on treatment.
Rigel Pharmaceuticals said a comprehensive analysis of the data will continue and will be presented at a future scientific conference.
The company also intends to begin enrollment for stage 2 of this study, in which 20 patients will be enrolled under the same protocol. 
The oral SYK inhibitor fostamatinib can produce responses in patients with warm antibody autoimmune hemolytic anemia (AIHA), according to Rigel Pharmaceuticals, Inc.
The company reported topline results from the first stage of the phase 2 SOAR study, which showed that fostamatinib produced a 35% response rate.
A response was defined as achieving a hemoglobin level of greater than 10 g/dL and at least a 2 g/dL increase from baseline.
“Many patients with AIHA suffer from severe, debilitating disease that negatively affects their quality of life,” said David J. Kuter, MD, the director for the Center of Hematology at Massachusetts General Hospital in Boston and the lead investigator of the SOAR study.
“There are no FDA-approved medications for the treatment of AIHA, which means that those living with the condition are in need of new and effective therapeutic options.”
In the SOAR study, Dr Kuter and his colleagues are evaluating fostamatinib in patients with warm antibody AIHA who previously received at least 1 treatment but did not have a meaningful benefit and are still anemic.
The study utilizes an open-label, Simon 2-stage design to evaluate fostamatinib given at 150 mg twice daily.
Stage 1 has enrolled 17 patients who have had at least 1 post-baseline hemoglobin measure.
Four of these patients responded to fostamatinib during the 12-week evaluation period, and an additional 2 patients met response criteria in the extension study after 12 weeks of dosing.
So the overall response rate was 35% (6/17), although Rigel Pharmaceuticals said these data are preliminary and require further verification.
Two patients withdrew from the study early due to non-safety-related reasons and will be replaced per the study protocol.
According to Rigel Pharmaceuticals, the treatment-emergent adverse events (AEs) in this trial were consistent with the prior clinical experience with fostamatinib.
Treatment-emergent AEs—which included diarrhea, elevated liver function tests, and hypertension—were manageable and mostly mild or moderate in nature.
There were 2 deaths reported during the trial. Both were due to non-treatment-related serious AEs, according to investigators. One patient had skin necrosis and infection. The other was an elderly patient who had pneumonia and was immunosuppressed due to prior chronic lymphocytic leukemia and steroid use.
A third patient experienced a non-treatment-related serious AE but recovered and continued on treatment.
Rigel Pharmaceuticals said a comprehensive analysis of the data will continue and will be presented at a future scientific conference.
The company also intends to begin enrollment for stage 2 of this study, in which 20 patients will be enrolled under the same protocol.
The oral SYK inhibitor fostamatinib can produce responses in patients with warm antibody autoimmune hemolytic anemia (AIHA), according to Rigel Pharmaceuticals, Inc.
The company reported topline results from the first stage of the phase 2 SOAR study, which showed that fostamatinib produced a 35% response rate.
A response was defined as achieving a hemoglobin level of greater than 10 g/dL and at least a 2 g/dL increase from baseline.
“Many patients with AIHA suffer from severe, debilitating disease that negatively affects their quality of life,” said David J. Kuter, MD, the director for the Center of Hematology at Massachusetts General Hospital in Boston and the lead investigator of the SOAR study.
“There are no FDA-approved medications for the treatment of AIHA, which means that those living with the condition are in need of new and effective therapeutic options.”
In the SOAR study, Dr Kuter and his colleagues are evaluating fostamatinib in patients with warm antibody AIHA who previously received at least 1 treatment but did not have a meaningful benefit and are still anemic.
The study utilizes an open-label, Simon 2-stage design to evaluate fostamatinib given at 150 mg twice daily.
Stage 1 has enrolled 17 patients who have had at least 1 post-baseline hemoglobin measure.
Four of these patients responded to fostamatinib during the 12-week evaluation period, and an additional 2 patients met response criteria in the extension study after 12 weeks of dosing.
So the overall response rate was 35% (6/17), although Rigel Pharmaceuticals said these data are preliminary and require further verification.
Two patients withdrew from the study early due to non-safety-related reasons and will be replaced per the study protocol.
According to Rigel Pharmaceuticals, the treatment-emergent adverse events (AEs) in this trial were consistent with the prior clinical experience with fostamatinib.
Treatment-emergent AEs—which included diarrhea, elevated liver function tests, and hypertension—were manageable and mostly mild or moderate in nature.
There were 2 deaths reported during the trial. Both were due to non-treatment-related serious AEs, according to investigators. One patient had skin necrosis and infection. The other was an elderly patient who had pneumonia and was immunosuppressed due to prior chronic lymphocytic leukemia and steroid use.
A third patient experienced a non-treatment-related serious AE but recovered and continued on treatment.
Rigel Pharmaceuticals said a comprehensive analysis of the data will continue and will be presented at a future scientific conference.
The company also intends to begin enrollment for stage 2 of this study, in which 20 patients will be enrolled under the same protocol.
Caplacizumab may enhance treatment of aTTP
Caplacizumab can improve upon standard care for patients with acquired thrombotic thrombocytopenic purpura (aTTP), according to results reported by Ablynx, the company developing caplacizumab.
In the phase 3 HERCULES trial, researchers compared caplacizumab, an anti-von Willebrand factor nanobody, plus standard care to placebo plus standard care in patients with aTTP.
Patients who received caplacizumab had a significant reduction in time to platelet count response.
In addition, they were significantly less likely than patients who received placebo to achieve the combined endpoint of aTTP-related death, aTTP recurrence, and experiencing at least 1 major thromboembolic event during the treatment period.
The safety profile of caplacizumab in this trial was said to be consistent with results from the phase 2 TITAN trial.
“The results of this landmark trial constitute a complete game-changer for patients with aTTP,” said HERCULES investigator Marie Scully, MBBS, of the University College Hospital in London, UK.
“They will revolutionize how we manage the acute phase of the disease, which is when patients are at highest risk for organ damage, recurrence, and death.”
Treatment
The HERCULES trial included 145 patients with an acute episode of aTTP. They were randomized 1:1 to receive either caplacizumab or placebo in addition to daily plasma exchange and immunosuppression (standard of care).
Patients received a single intravenous bolus of 10 mg of caplacizumab or placebo followed by a daily subcutaneous dose of 10 mg of caplacizumab or placebo until 30 days after the last daily plasma exchange.
If, at the end of this treatment period, there was evidence of persistent underlying disease activity indicative of an imminent risk for recurrence, the treatment could be extended for additional 7-day periods up to a maximum of 28 days. Patients were followed for a further 28 days after discontinuation of treatment.
In all, 71 patients received caplacizumab, and 58 (80.6%) of them completed the treatment. Seventy-three patients received placebo, and 50 of these patients (68.5%) completed treatment.
Baseline characteristics
At baseline, the mean age was 44.9 in the caplacizumab arm and 47.3 in the placebo arm. A majority of patients in both arms were female—68.1% and 69.9%, respectively.
The proportion of patients with an initial aTTP episode was 66.7% in the caplacizumab arm and 46.6% in the placebo arm. The proportion with a recurrent episode was 33.3% and 53.4%, respectively.
Most patients in both arms had ADAMTS13 activity below 10% at baseline—81.7% in the caplacizumab arm and 90.3% in the placebo arm.
The mean platelet count at baseline was 32.0 x 109/L in the caplacizumab arm and 39.1 x 109/L in the placebo arm.
Efficacy
The study’s primary endpoint was the time to confirmed normalization of platelet count response. There was a significant reduction in time to platelet count response in the caplacizumab arm compared to the placebo arm. The platelet normalization rate ratio was 1.55 (P<0.01).
A key secondary endpoint was the combination of aTTP-related death, aTTP recurrence, and at least 1 major thromboembolic event during study treatment. The incidence of this combined endpoint was 12.7% (n=9) in the caplacizumab arm and 49.3% (n=36) in the placebo arm (P<0.0001).
The incidence of aTTP-related death was 0% (n=0) in the caplacizumab arm and 4.1% (n=3) in the placebo arm. The incidence of aTTP recurrence was 4.2% (n=3) and 38.4% (n=28), respectively. And the incidence of at least 1 major thromboembolic event was 8.5% (n=6) and 8.2% (n=6), respectively.
Another key secondary endpoint was the incidence of aTTP recurrence during the overall study period, which was 12.7% (n=9) in the caplacizumab arm and 38.4% (n=28) in the placebo arm (P<0.001).
The incidence of aTTP recurrence during the follow-up period alone was 9.1% (n=6) in the caplacizumab arm and 0% (n=0) in the placebo arm.
A third key secondary endpoint was the percentage of patients with refractory aTTP, which was 0% (n=0) in the caplacizumab arm and 4.2% (n=3) in the placebo arm (P=0.0572).
Safety
The number and nature of treatment-emergent adverse events (AEs) were similar between the treatment arms, according to Ablynx. The proportion of patients with at least 1 treatment-emergent AE was 97.2% in the caplacizumab arm and 97.3% in the placebo arm.
The proportion of patients with at least 1 study-drug-related AE was 57.7% in the caplacizumab arm and 43.8% in the placebo arm. The rate of discontinuation due to at least 1 AE was 7.0% and 12.3%, respectively.
The incidence of bleeding-related AEs was higher in the caplacizumab arm than the placebo arm—66.2% and 49.3%, respectively. However, most bleeding-related events were mild or moderate in severity.
The proportion of patients with at least 1 serious AE was 39.4% (n=28) in the caplacizumab arm and 53.4% (n=39) in the placebo arm. The proportion of patients with at least 1 study-drug-related serious AE was 14.1% (n=10) and 5.5% (n=4), respectively.
During the treatment period, there were no deaths in the caplacizumab arm and 3 deaths in the placebo arm. There was 1 death in the caplacizumab arm during the follow-up period, but it was considered unrelated to caplacizumab.
Caplacizumab can improve upon standard care for patients with acquired thrombotic thrombocytopenic purpura (aTTP), according to results reported by Ablynx, the company developing caplacizumab.
In the phase 3 HERCULES trial, researchers compared caplacizumab, an anti-von Willebrand factor nanobody, plus standard care to placebo plus standard care in patients with aTTP.
Patients who received caplacizumab had a significant reduction in time to platelet count response.
In addition, they were significantly less likely than patients who received placebo to achieve the combined endpoint of aTTP-related death, aTTP recurrence, and experiencing at least 1 major thromboembolic event during the treatment period.
The safety profile of caplacizumab in this trial was said to be consistent with results from the phase 2 TITAN trial.
“The results of this landmark trial constitute a complete game-changer for patients with aTTP,” said HERCULES investigator Marie Scully, MBBS, of the University College Hospital in London, UK.
“They will revolutionize how we manage the acute phase of the disease, which is when patients are at highest risk for organ damage, recurrence, and death.”
Treatment
The HERCULES trial included 145 patients with an acute episode of aTTP. They were randomized 1:1 to receive either caplacizumab or placebo in addition to daily plasma exchange and immunosuppression (standard of care).
Patients received a single intravenous bolus of 10 mg of caplacizumab or placebo followed by a daily subcutaneous dose of 10 mg of caplacizumab or placebo until 30 days after the last daily plasma exchange.
If, at the end of this treatment period, there was evidence of persistent underlying disease activity indicative of an imminent risk for recurrence, the treatment could be extended for additional 7-day periods up to a maximum of 28 days. Patients were followed for a further 28 days after discontinuation of treatment.
In all, 71 patients received caplacizumab, and 58 (80.6%) of them completed the treatment. Seventy-three patients received placebo, and 50 of these patients (68.5%) completed treatment.
Baseline characteristics
At baseline, the mean age was 44.9 in the caplacizumab arm and 47.3 in the placebo arm. A majority of patients in both arms were female—68.1% and 69.9%, respectively.
The proportion of patients with an initial aTTP episode was 66.7% in the caplacizumab arm and 46.6% in the placebo arm. The proportion with a recurrent episode was 33.3% and 53.4%, respectively.
Most patients in both arms had ADAMTS13 activity below 10% at baseline—81.7% in the caplacizumab arm and 90.3% in the placebo arm.
The mean platelet count at baseline was 32.0 x 109/L in the caplacizumab arm and 39.1 x 109/L in the placebo arm.
Efficacy
The study’s primary endpoint was the time to confirmed normalization of platelet count response. There was a significant reduction in time to platelet count response in the caplacizumab arm compared to the placebo arm. The platelet normalization rate ratio was 1.55 (P<0.01).
A key secondary endpoint was the combination of aTTP-related death, aTTP recurrence, and at least 1 major thromboembolic event during study treatment. The incidence of this combined endpoint was 12.7% (n=9) in the caplacizumab arm and 49.3% (n=36) in the placebo arm (P<0.0001).
The incidence of aTTP-related death was 0% (n=0) in the caplacizumab arm and 4.1% (n=3) in the placebo arm. The incidence of aTTP recurrence was 4.2% (n=3) and 38.4% (n=28), respectively. And the incidence of at least 1 major thromboembolic event was 8.5% (n=6) and 8.2% (n=6), respectively.
Another key secondary endpoint was the incidence of aTTP recurrence during the overall study period, which was 12.7% (n=9) in the caplacizumab arm and 38.4% (n=28) in the placebo arm (P<0.001).
The incidence of aTTP recurrence during the follow-up period alone was 9.1% (n=6) in the caplacizumab arm and 0% (n=0) in the placebo arm.
A third key secondary endpoint was the percentage of patients with refractory aTTP, which was 0% (n=0) in the caplacizumab arm and 4.2% (n=3) in the placebo arm (P=0.0572).
Safety
The number and nature of treatment-emergent adverse events (AEs) were similar between the treatment arms, according to Ablynx. The proportion of patients with at least 1 treatment-emergent AE was 97.2% in the caplacizumab arm and 97.3% in the placebo arm.
The proportion of patients with at least 1 study-drug-related AE was 57.7% in the caplacizumab arm and 43.8% in the placebo arm. The rate of discontinuation due to at least 1 AE was 7.0% and 12.3%, respectively.
The incidence of bleeding-related AEs was higher in the caplacizumab arm than the placebo arm—66.2% and 49.3%, respectively. However, most bleeding-related events were mild or moderate in severity.
The proportion of patients with at least 1 serious AE was 39.4% (n=28) in the caplacizumab arm and 53.4% (n=39) in the placebo arm. The proportion of patients with at least 1 study-drug-related serious AE was 14.1% (n=10) and 5.5% (n=4), respectively.
During the treatment period, there were no deaths in the caplacizumab arm and 3 deaths in the placebo arm. There was 1 death in the caplacizumab arm during the follow-up period, but it was considered unrelated to caplacizumab.
Caplacizumab can improve upon standard care for patients with acquired thrombotic thrombocytopenic purpura (aTTP), according to results reported by Ablynx, the company developing caplacizumab.
In the phase 3 HERCULES trial, researchers compared caplacizumab, an anti-von Willebrand factor nanobody, plus standard care to placebo plus standard care in patients with aTTP.
Patients who received caplacizumab had a significant reduction in time to platelet count response.
In addition, they were significantly less likely than patients who received placebo to achieve the combined endpoint of aTTP-related death, aTTP recurrence, and experiencing at least 1 major thromboembolic event during the treatment period.
The safety profile of caplacizumab in this trial was said to be consistent with results from the phase 2 TITAN trial.
“The results of this landmark trial constitute a complete game-changer for patients with aTTP,” said HERCULES investigator Marie Scully, MBBS, of the University College Hospital in London, UK.
“They will revolutionize how we manage the acute phase of the disease, which is when patients are at highest risk for organ damage, recurrence, and death.”
Treatment
The HERCULES trial included 145 patients with an acute episode of aTTP. They were randomized 1:1 to receive either caplacizumab or placebo in addition to daily plasma exchange and immunosuppression (standard of care).
Patients received a single intravenous bolus of 10 mg of caplacizumab or placebo followed by a daily subcutaneous dose of 10 mg of caplacizumab or placebo until 30 days after the last daily plasma exchange.
If, at the end of this treatment period, there was evidence of persistent underlying disease activity indicative of an imminent risk for recurrence, the treatment could be extended for additional 7-day periods up to a maximum of 28 days. Patients were followed for a further 28 days after discontinuation of treatment.
In all, 71 patients received caplacizumab, and 58 (80.6%) of them completed the treatment. Seventy-three patients received placebo, and 50 of these patients (68.5%) completed treatment.
Baseline characteristics
At baseline, the mean age was 44.9 in the caplacizumab arm and 47.3 in the placebo arm. A majority of patients in both arms were female—68.1% and 69.9%, respectively.
The proportion of patients with an initial aTTP episode was 66.7% in the caplacizumab arm and 46.6% in the placebo arm. The proportion with a recurrent episode was 33.3% and 53.4%, respectively.
Most patients in both arms had ADAMTS13 activity below 10% at baseline—81.7% in the caplacizumab arm and 90.3% in the placebo arm.
The mean platelet count at baseline was 32.0 x 109/L in the caplacizumab arm and 39.1 x 109/L in the placebo arm.
Efficacy
The study’s primary endpoint was the time to confirmed normalization of platelet count response. There was a significant reduction in time to platelet count response in the caplacizumab arm compared to the placebo arm. The platelet normalization rate ratio was 1.55 (P<0.01).
A key secondary endpoint was the combination of aTTP-related death, aTTP recurrence, and at least 1 major thromboembolic event during study treatment. The incidence of this combined endpoint was 12.7% (n=9) in the caplacizumab arm and 49.3% (n=36) in the placebo arm (P<0.0001).
The incidence of aTTP-related death was 0% (n=0) in the caplacizumab arm and 4.1% (n=3) in the placebo arm. The incidence of aTTP recurrence was 4.2% (n=3) and 38.4% (n=28), respectively. And the incidence of at least 1 major thromboembolic event was 8.5% (n=6) and 8.2% (n=6), respectively.
Another key secondary endpoint was the incidence of aTTP recurrence during the overall study period, which was 12.7% (n=9) in the caplacizumab arm and 38.4% (n=28) in the placebo arm (P<0.001).
The incidence of aTTP recurrence during the follow-up period alone was 9.1% (n=6) in the caplacizumab arm and 0% (n=0) in the placebo arm.
A third key secondary endpoint was the percentage of patients with refractory aTTP, which was 0% (n=0) in the caplacizumab arm and 4.2% (n=3) in the placebo arm (P=0.0572).
Safety
The number and nature of treatment-emergent adverse events (AEs) were similar between the treatment arms, according to Ablynx. The proportion of patients with at least 1 treatment-emergent AE was 97.2% in the caplacizumab arm and 97.3% in the placebo arm.
The proportion of patients with at least 1 study-drug-related AE was 57.7% in the caplacizumab arm and 43.8% in the placebo arm. The rate of discontinuation due to at least 1 AE was 7.0% and 12.3%, respectively.
The incidence of bleeding-related AEs was higher in the caplacizumab arm than the placebo arm—66.2% and 49.3%, respectively. However, most bleeding-related events were mild or moderate in severity.
The proportion of patients with at least 1 serious AE was 39.4% (n=28) in the caplacizumab arm and 53.4% (n=39) in the placebo arm. The proportion of patients with at least 1 study-drug-related serious AE was 14.1% (n=10) and 5.5% (n=4), respectively.
During the treatment period, there were no deaths in the caplacizumab arm and 3 deaths in the placebo arm. There was 1 death in the caplacizumab arm during the follow-up period, but it was considered unrelated to caplacizumab.
Many years on metformin linked to anemia risk
LISBON – People with type 2 diabetes who take metformin for many years are more likely to develop anemia than are those who do not, according to the results of a large analysis of data from an observational, population-based study with 20 years of follow-up.
“Metformin treatment was associated with a 6% higher risk of anemia for every cumulative year of metformin exposure,” Louise Donnelly, PhD, and her associates reported in a poster presentation at the annual meeting of the European Association for the Study of Diabetes.
In an interview, Dr. Donnelly, a postdoctoral research assistant at the University of Dundee (Scotland), explained why they looked at the use of metformin and anemia risk in people with type 2 diabetes.
“The Diabetes Prevention Program (DPP) study showed that long-term metformin use in individuals with impaired glucose tolerance was associated with an increased risk of anemia, and this was independent of vitamin B12 status,” she said (J Clin Endocrinol Metab. 2016;101:1754-61). “Anemia is a common finding in people with type 2 diabetes, but the impact of long-term metformin use on anemia hasn’t been studied.”
Dr. Donnelly and her associates obtained detailed information on metformin prescribing and hematology measures from electronic patient medical records from the Genetics of Diabetes Audit and Research in Tayside and Scotland (GoDARTS) cohort, based in Scotland. This database contains information on individuals with type 2 diabetes and matching controls and is available to researchers worldwide.
For the analysis, the team looked for people diagnosed from 1996 onward who had a baseline hemoglobin measurement. Of 6,440 individuals with type 2 diabetes in the GoDARTS cohort, just over half had a hemoglobin measurement.
“We used a definition of ‘moderate’ anemia and we excluded patients with mild anemia or worse at diabetes diagnosis,” Dr. Donnelly observed. Anemia was considered to be a hemoglobin level of less than 12 g/dL in women and less than 13 g/dL in men. In all, 280 individuals with anemia were excluded from further analysis as the aim was to follow people until they developed anemia, died, left the area, or until the end of the follow-up period, which was set at September 30, 2015. A discrete-time failure analysis was used to model the effect of cumulative metformin exposure on anemia risk.
After a median follow-up of 8 years and a median number of 11 hemoglobin measurements per patient, 2,487 study subjects (71%) had some exposure to metformin and 1,458 of the whole sample (41.8%) had become anemic. Of those who developed anemia, 745 (51%) were current metformin users, 194 (13%) were former users, and 519 (36%) had never taken metformin.
“Cumulative metformin use was independently associated with an increased risk of anemia,” Dr. Donnelly noted (odds ratio [OR], 1.06; 95% confidence interval [CI], 1.02-1.09; P = .0006). This association was not seen when they examined the data based on sulfonylurea use (OR 1.0; 95% CI 0.97-1.04, P = .8), she added.
“Anemia risk was higher with age at diagnosis, duration of diabetes, lower hemoglobin at baseline, and lower eGFR [estimated glomerular filtration rate],” she observed. ORs for first anemia event were 1.03 (95% CI, 1.02-1.04) for every year of increasing age, 1.05 (95% CI, 1.03-1.08) for every additional year since diabetes diagnosis, 0.70 (95% CI, 0.66-0.74) per 1 g/dL of hemoglobin at diagnosis, and eGFR 0.98 (95% CI, 0.98-1.01) per additional 1 mL/min per 1.732 (P less than .0001 for all).
Why cumulative metformin use is associated with an increased of anemia is unclear, however, and Dr. Donnelly noted that this needs further investigation. “We do have data from two other clinical trials now, showing similar results, and maybe through those data we might be able to untangle it.”
The team does not think the anemia is related to B12 deficiency, however, as people who developed anemia while taking metformin were more likely to develop microcytic (12% vs. 7.3%) than macrocytic (7.6% vs. 12.3%), anemia, compared with people with anemia who were not exposed to metformin (P less than .0001).
“In terms of mechanism, we can only conjecture,” Ewan Pearson, MB, senior author of the study and professor of medicine at the University of Dundee, said during a discussion at the poster presentation. “It is important to stress that metformin is a great drug and we shouldn’t stop it because of a potentially increased risk of anemia.”
The Medical Research Council supported the work. Dr. Donnelly reported having no financial disclosures.
LISBON – People with type 2 diabetes who take metformin for many years are more likely to develop anemia than are those who do not, according to the results of a large analysis of data from an observational, population-based study with 20 years of follow-up.
“Metformin treatment was associated with a 6% higher risk of anemia for every cumulative year of metformin exposure,” Louise Donnelly, PhD, and her associates reported in a poster presentation at the annual meeting of the European Association for the Study of Diabetes.
In an interview, Dr. Donnelly, a postdoctoral research assistant at the University of Dundee (Scotland), explained why they looked at the use of metformin and anemia risk in people with type 2 diabetes.
“The Diabetes Prevention Program (DPP) study showed that long-term metformin use in individuals with impaired glucose tolerance was associated with an increased risk of anemia, and this was independent of vitamin B12 status,” she said (J Clin Endocrinol Metab. 2016;101:1754-61). “Anemia is a common finding in people with type 2 diabetes, but the impact of long-term metformin use on anemia hasn’t been studied.”
Dr. Donnelly and her associates obtained detailed information on metformin prescribing and hematology measures from electronic patient medical records from the Genetics of Diabetes Audit and Research in Tayside and Scotland (GoDARTS) cohort, based in Scotland. This database contains information on individuals with type 2 diabetes and matching controls and is available to researchers worldwide.
For the analysis, the team looked for people diagnosed from 1996 onward who had a baseline hemoglobin measurement. Of 6,440 individuals with type 2 diabetes in the GoDARTS cohort, just over half had a hemoglobin measurement.
“We used a definition of ‘moderate’ anemia and we excluded patients with mild anemia or worse at diabetes diagnosis,” Dr. Donnelly observed. Anemia was considered to be a hemoglobin level of less than 12 g/dL in women and less than 13 g/dL in men. In all, 280 individuals with anemia were excluded from further analysis as the aim was to follow people until they developed anemia, died, left the area, or until the end of the follow-up period, which was set at September 30, 2015. A discrete-time failure analysis was used to model the effect of cumulative metformin exposure on anemia risk.
After a median follow-up of 8 years and a median number of 11 hemoglobin measurements per patient, 2,487 study subjects (71%) had some exposure to metformin and 1,458 of the whole sample (41.8%) had become anemic. Of those who developed anemia, 745 (51%) were current metformin users, 194 (13%) were former users, and 519 (36%) had never taken metformin.
“Cumulative metformin use was independently associated with an increased risk of anemia,” Dr. Donnelly noted (odds ratio [OR], 1.06; 95% confidence interval [CI], 1.02-1.09; P = .0006). This association was not seen when they examined the data based on sulfonylurea use (OR 1.0; 95% CI 0.97-1.04, P = .8), she added.
“Anemia risk was higher with age at diagnosis, duration of diabetes, lower hemoglobin at baseline, and lower eGFR [estimated glomerular filtration rate],” she observed. ORs for first anemia event were 1.03 (95% CI, 1.02-1.04) for every year of increasing age, 1.05 (95% CI, 1.03-1.08) for every additional year since diabetes diagnosis, 0.70 (95% CI, 0.66-0.74) per 1 g/dL of hemoglobin at diagnosis, and eGFR 0.98 (95% CI, 0.98-1.01) per additional 1 mL/min per 1.732 (P less than .0001 for all).
Why cumulative metformin use is associated with an increased of anemia is unclear, however, and Dr. Donnelly noted that this needs further investigation. “We do have data from two other clinical trials now, showing similar results, and maybe through those data we might be able to untangle it.”
The team does not think the anemia is related to B12 deficiency, however, as people who developed anemia while taking metformin were more likely to develop microcytic (12% vs. 7.3%) than macrocytic (7.6% vs. 12.3%), anemia, compared with people with anemia who were not exposed to metformin (P less than .0001).
“In terms of mechanism, we can only conjecture,” Ewan Pearson, MB, senior author of the study and professor of medicine at the University of Dundee, said during a discussion at the poster presentation. “It is important to stress that metformin is a great drug and we shouldn’t stop it because of a potentially increased risk of anemia.”
The Medical Research Council supported the work. Dr. Donnelly reported having no financial disclosures.
LISBON – People with type 2 diabetes who take metformin for many years are more likely to develop anemia than are those who do not, according to the results of a large analysis of data from an observational, population-based study with 20 years of follow-up.
“Metformin treatment was associated with a 6% higher risk of anemia for every cumulative year of metformin exposure,” Louise Donnelly, PhD, and her associates reported in a poster presentation at the annual meeting of the European Association for the Study of Diabetes.
In an interview, Dr. Donnelly, a postdoctoral research assistant at the University of Dundee (Scotland), explained why they looked at the use of metformin and anemia risk in people with type 2 diabetes.
“The Diabetes Prevention Program (DPP) study showed that long-term metformin use in individuals with impaired glucose tolerance was associated with an increased risk of anemia, and this was independent of vitamin B12 status,” she said (J Clin Endocrinol Metab. 2016;101:1754-61). “Anemia is a common finding in people with type 2 diabetes, but the impact of long-term metformin use on anemia hasn’t been studied.”
Dr. Donnelly and her associates obtained detailed information on metformin prescribing and hematology measures from electronic patient medical records from the Genetics of Diabetes Audit and Research in Tayside and Scotland (GoDARTS) cohort, based in Scotland. This database contains information on individuals with type 2 diabetes and matching controls and is available to researchers worldwide.
For the analysis, the team looked for people diagnosed from 1996 onward who had a baseline hemoglobin measurement. Of 6,440 individuals with type 2 diabetes in the GoDARTS cohort, just over half had a hemoglobin measurement.
“We used a definition of ‘moderate’ anemia and we excluded patients with mild anemia or worse at diabetes diagnosis,” Dr. Donnelly observed. Anemia was considered to be a hemoglobin level of less than 12 g/dL in women and less than 13 g/dL in men. In all, 280 individuals with anemia were excluded from further analysis as the aim was to follow people until they developed anemia, died, left the area, or until the end of the follow-up period, which was set at September 30, 2015. A discrete-time failure analysis was used to model the effect of cumulative metformin exposure on anemia risk.
After a median follow-up of 8 years and a median number of 11 hemoglobin measurements per patient, 2,487 study subjects (71%) had some exposure to metformin and 1,458 of the whole sample (41.8%) had become anemic. Of those who developed anemia, 745 (51%) were current metformin users, 194 (13%) were former users, and 519 (36%) had never taken metformin.
“Cumulative metformin use was independently associated with an increased risk of anemia,” Dr. Donnelly noted (odds ratio [OR], 1.06; 95% confidence interval [CI], 1.02-1.09; P = .0006). This association was not seen when they examined the data based on sulfonylurea use (OR 1.0; 95% CI 0.97-1.04, P = .8), she added.
“Anemia risk was higher with age at diagnosis, duration of diabetes, lower hemoglobin at baseline, and lower eGFR [estimated glomerular filtration rate],” she observed. ORs for first anemia event were 1.03 (95% CI, 1.02-1.04) for every year of increasing age, 1.05 (95% CI, 1.03-1.08) for every additional year since diabetes diagnosis, 0.70 (95% CI, 0.66-0.74) per 1 g/dL of hemoglobin at diagnosis, and eGFR 0.98 (95% CI, 0.98-1.01) per additional 1 mL/min per 1.732 (P less than .0001 for all).
Why cumulative metformin use is associated with an increased of anemia is unclear, however, and Dr. Donnelly noted that this needs further investigation. “We do have data from two other clinical trials now, showing similar results, and maybe through those data we might be able to untangle it.”
The team does not think the anemia is related to B12 deficiency, however, as people who developed anemia while taking metformin were more likely to develop microcytic (12% vs. 7.3%) than macrocytic (7.6% vs. 12.3%), anemia, compared with people with anemia who were not exposed to metformin (P less than .0001).
“In terms of mechanism, we can only conjecture,” Ewan Pearson, MB, senior author of the study and professor of medicine at the University of Dundee, said during a discussion at the poster presentation. “It is important to stress that metformin is a great drug and we shouldn’t stop it because of a potentially increased risk of anemia.”
The Medical Research Council supported the work. Dr. Donnelly reported having no financial disclosures.
AT EASD 2017
Key clinical point: Cumulative metformin use was associated with an increased risk for anemia in patients with type 2 diabetes.
Major finding: For every additional year of metformin use, there was a 6% increase in the risk for anemia.
Data source: Data analysis of 3,435 individuals with type 2 diabetes who participated in a large observational, population-based study with almost 20 years of follow-up.
Disclosures: The Medical Research Council supported the work. Dr. Donnelly reported having no financial disclosures.
Long-term specialist care reduces post-RYGB anemia risk
Patients who underwent Roux-en-Y gastric bypass surgery (RYGB) without long-term bariatric specialist follow-up experienced a significantly higher rate of anemia at 10 years than did patients who had such specialist follow-up, according to findings from a database review.
Among 74 patients available for analysis – 58 men and 16 women with a mean age of 51 years who underwent RYGB at a single Veterans Affairs medical center between 2002 and 2006 – the mean rate of preoperative anemia was 20% (15 patients). The rate increased to 28% (21 patients) at 1 year, 31% (23 patients) at 5 years, and 47% (35 patients) at 10 years, according to a research letter by Gao Linda Chen, MD, and her colleagues in the surgical service of the VA Palo Alto (Calif.) Health Care System (JAMA Surg. 2017. Sep 20. doi: 10.1001/jamasurg.2017.3158).
Among 58 patients with no bariatric specialist follow-up after 5 years, the anemia rate increased from 22% (13 patients) before surgery to 57% (33 patients) at 10 years, while the corresponding rates for those with specialty follow-up were 19% (3 patients) and 13% (2 patients). After adjustment for preoperative anemia, those without specialist follow-up had significantly higher odds of anemia at 10 years (odds ratio, 6.1).
“Long-term complications of RYGB, such as anemia, may go unrecognized by nonbariatric specialists,” the investigators wrote, noting that the high rates of anemia at 10 years “may reflect a mixed vitamin and mineral deficiency, because patients had normocytic anemia.
“Our study suggests that follow-up with bariatric specialists more than 5 years after surgery, rather than with specialists with no bariatric expertise, can decrease long-term anemia risk,” they continued. “This finding may demonstrate the bariatric specialist’s specific understanding of the long-term risk for nutritional deficiency after RYGB and the importance of vitamin and mineral supplementation.”
The findings suggest a bariatric team approach with planning for long-term follow-up. “We implemented a hub-and-spoke model for bariatric care, including health care specialist education, in which the bariatric team communicates regularly with the patient’s primary care clinician before and after surgery.”
Although the study is limited by small sample size, the findings nevertheless underscore that “long-term follow-up should be an integral part of bariatric programs, and additional studies are needed to identify potential barriers to successful follow-up,” they concluded.
The authors reported having no disclosures.
Patients who underwent Roux-en-Y gastric bypass surgery (RYGB) without long-term bariatric specialist follow-up experienced a significantly higher rate of anemia at 10 years than did patients who had such specialist follow-up, according to findings from a database review.
Among 74 patients available for analysis – 58 men and 16 women with a mean age of 51 years who underwent RYGB at a single Veterans Affairs medical center between 2002 and 2006 – the mean rate of preoperative anemia was 20% (15 patients). The rate increased to 28% (21 patients) at 1 year, 31% (23 patients) at 5 years, and 47% (35 patients) at 10 years, according to a research letter by Gao Linda Chen, MD, and her colleagues in the surgical service of the VA Palo Alto (Calif.) Health Care System (JAMA Surg. 2017. Sep 20. doi: 10.1001/jamasurg.2017.3158).
Among 58 patients with no bariatric specialist follow-up after 5 years, the anemia rate increased from 22% (13 patients) before surgery to 57% (33 patients) at 10 years, while the corresponding rates for those with specialty follow-up were 19% (3 patients) and 13% (2 patients). After adjustment for preoperative anemia, those without specialist follow-up had significantly higher odds of anemia at 10 years (odds ratio, 6.1).
“Long-term complications of RYGB, such as anemia, may go unrecognized by nonbariatric specialists,” the investigators wrote, noting that the high rates of anemia at 10 years “may reflect a mixed vitamin and mineral deficiency, because patients had normocytic anemia.
“Our study suggests that follow-up with bariatric specialists more than 5 years after surgery, rather than with specialists with no bariatric expertise, can decrease long-term anemia risk,” they continued. “This finding may demonstrate the bariatric specialist’s specific understanding of the long-term risk for nutritional deficiency after RYGB and the importance of vitamin and mineral supplementation.”
The findings suggest a bariatric team approach with planning for long-term follow-up. “We implemented a hub-and-spoke model for bariatric care, including health care specialist education, in which the bariatric team communicates regularly with the patient’s primary care clinician before and after surgery.”
Although the study is limited by small sample size, the findings nevertheless underscore that “long-term follow-up should be an integral part of bariatric programs, and additional studies are needed to identify potential barriers to successful follow-up,” they concluded.
The authors reported having no disclosures.
Patients who underwent Roux-en-Y gastric bypass surgery (RYGB) without long-term bariatric specialist follow-up experienced a significantly higher rate of anemia at 10 years than did patients who had such specialist follow-up, according to findings from a database review.
Among 74 patients available for analysis – 58 men and 16 women with a mean age of 51 years who underwent RYGB at a single Veterans Affairs medical center between 2002 and 2006 – the mean rate of preoperative anemia was 20% (15 patients). The rate increased to 28% (21 patients) at 1 year, 31% (23 patients) at 5 years, and 47% (35 patients) at 10 years, according to a research letter by Gao Linda Chen, MD, and her colleagues in the surgical service of the VA Palo Alto (Calif.) Health Care System (JAMA Surg. 2017. Sep 20. doi: 10.1001/jamasurg.2017.3158).
Among 58 patients with no bariatric specialist follow-up after 5 years, the anemia rate increased from 22% (13 patients) before surgery to 57% (33 patients) at 10 years, while the corresponding rates for those with specialty follow-up were 19% (3 patients) and 13% (2 patients). After adjustment for preoperative anemia, those without specialist follow-up had significantly higher odds of anemia at 10 years (odds ratio, 6.1).
“Long-term complications of RYGB, such as anemia, may go unrecognized by nonbariatric specialists,” the investigators wrote, noting that the high rates of anemia at 10 years “may reflect a mixed vitamin and mineral deficiency, because patients had normocytic anemia.
“Our study suggests that follow-up with bariatric specialists more than 5 years after surgery, rather than with specialists with no bariatric expertise, can decrease long-term anemia risk,” they continued. “This finding may demonstrate the bariatric specialist’s specific understanding of the long-term risk for nutritional deficiency after RYGB and the importance of vitamin and mineral supplementation.”
The findings suggest a bariatric team approach with planning for long-term follow-up. “We implemented a hub-and-spoke model for bariatric care, including health care specialist education, in which the bariatric team communicates regularly with the patient’s primary care clinician before and after surgery.”
Although the study is limited by small sample size, the findings nevertheless underscore that “long-term follow-up should be an integral part of bariatric programs, and additional studies are needed to identify potential barriers to successful follow-up,” they concluded.
The authors reported having no disclosures.
FROM JAMA SURGERY
Key clinical point:
Major finding: RYGB patients without specialist follow-up had significantly higher odds of anemia at 10 years (adjusted odds ratio, 6.1).
Data source: A retrospective review of 74 patients from a prospective 10-year database.
Disclosures: The authors reported having no disclosures.
Mutations impact outcomes in AML, MDS
Researchers say they have identified genetic mutations that can significantly affect treatment outcomes in patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS).
The findings come from a clinical trial in which the team examined whether combining vorinostat with azacitidine could improve survival in patients with AML and MDS.
The results showed no additional benefit with the combination, when compared to azacitidine alone.
However, researchers did find that patients had significantly shorter survival times if they had mutations in CDKN2A, IDH1, or TP53.
“This important trial . . . has rapidly answered the important question of whether combining azacitidine with vorinostat improves outcomes for people with AML and MDS and emphasizes the need for further studies with new drug partners for azacitidine,” said Charles Craddock, DPhil, of the Queen Elizabeth Hospital in Birmingham, UK.
“Importantly, the linked molecular studies have shed new light on which people will benefit most from azacitidine. Furthermore, discovering that the CDKN2A gene mutation affects treatment response may be hugely valuable in helping doctors to design new treatment combinations in the future.”
Dr Craddock and his colleagues reported their discoveries in Clinical Cancer Research.
Previous, smaller trials had suggested that adding vorinostat to treatment with azacitidine could improve outcomes for patients with AML and MDS.
To test this idea, Dr Craddock and his colleagues enrolled 259 patients in the current trial. Most of these patients (n=217) had AML—111 were newly diagnosed, 73 had relapsed AML, and 33 had refractory disease.
The remaining 42 patients had MDS—36 were newly diagnosed, 5 had relapsed MDS, and 1 had refractory disease.
Half of patients (n=130) received azacitidine and vorinostat, and the other half received azacitidine alone (n=129).
In both arms, azacitidine was given at 75 mg/m2 on a 5-2-2 schedule, beginning on day 1 of a 28-day cycle for up to 6 cycles. In the combination arm, patients also received vorinostat at 300 mg twice daily for 7 consecutive days, beginning on day 3 of each cycle.
Results
The combination did not significantly improve response rates or survival times.
The overall response rate was 41% in the azacitidine arm and 42% in the combination arm (odds ratio [OR]=1.05, P=0.84).
The rate of compete response (CR)/CR with incomplete count recovery/marrow CR was 22% in the azacitidine arm and 26% in the combination arm (OR=0.82, P=0.49).
The median overall survival (OS) was 9.6 months in the azacitidine arm and 11.0 months in the combination arm (hazard ratio[HR]=1.15, P=0.32).
Impact of mutations
In a multivariable analysis adjusted for all clinical variables, mutations in NPM1 were associated with reduced overall response (OR=8.6, P=0.012).
In another multivariate analysis, mutations in CDKN2A, IDH1, and TP53 were associated with decreased OS. The HRs were 10.0 (P<0.001), 3.6 (P=0.001), and 4.7 (P<0.001), respectively.
The median OS was 4.5 months in patients with CDKN2A mutations and 11.0 months in patients without them.
The median OS was 7.6 months in patients with TP53 mutations and 11.3 months in patients without them.
And the median OS was 5.6 months in patients with IDH1 mutations and 11.1 months in patients without them.
The researchers believe that testing patients newly diagnosed with AML and MDS for CDKN2A, IDH1, and TP53 mutations could help doctors tailor treatment for patients who are less likely to do well.
The team also said the information gleaned from this trial will guide the choice of new drug partners with the potential to increase azacitidine’s clinical activity.
Researchers say they have identified genetic mutations that can significantly affect treatment outcomes in patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS).
The findings come from a clinical trial in which the team examined whether combining vorinostat with azacitidine could improve survival in patients with AML and MDS.
The results showed no additional benefit with the combination, when compared to azacitidine alone.
However, researchers did find that patients had significantly shorter survival times if they had mutations in CDKN2A, IDH1, or TP53.
“This important trial . . . has rapidly answered the important question of whether combining azacitidine with vorinostat improves outcomes for people with AML and MDS and emphasizes the need for further studies with new drug partners for azacitidine,” said Charles Craddock, DPhil, of the Queen Elizabeth Hospital in Birmingham, UK.
“Importantly, the linked molecular studies have shed new light on which people will benefit most from azacitidine. Furthermore, discovering that the CDKN2A gene mutation affects treatment response may be hugely valuable in helping doctors to design new treatment combinations in the future.”
Dr Craddock and his colleagues reported their discoveries in Clinical Cancer Research.
Previous, smaller trials had suggested that adding vorinostat to treatment with azacitidine could improve outcomes for patients with AML and MDS.
To test this idea, Dr Craddock and his colleagues enrolled 259 patients in the current trial. Most of these patients (n=217) had AML—111 were newly diagnosed, 73 had relapsed AML, and 33 had refractory disease.
The remaining 42 patients had MDS—36 were newly diagnosed, 5 had relapsed MDS, and 1 had refractory disease.
Half of patients (n=130) received azacitidine and vorinostat, and the other half received azacitidine alone (n=129).
In both arms, azacitidine was given at 75 mg/m2 on a 5-2-2 schedule, beginning on day 1 of a 28-day cycle for up to 6 cycles. In the combination arm, patients also received vorinostat at 300 mg twice daily for 7 consecutive days, beginning on day 3 of each cycle.
Results
The combination did not significantly improve response rates or survival times.
The overall response rate was 41% in the azacitidine arm and 42% in the combination arm (odds ratio [OR]=1.05, P=0.84).
The rate of compete response (CR)/CR with incomplete count recovery/marrow CR was 22% in the azacitidine arm and 26% in the combination arm (OR=0.82, P=0.49).
The median overall survival (OS) was 9.6 months in the azacitidine arm and 11.0 months in the combination arm (hazard ratio[HR]=1.15, P=0.32).
Impact of mutations
In a multivariable analysis adjusted for all clinical variables, mutations in NPM1 were associated with reduced overall response (OR=8.6, P=0.012).
In another multivariate analysis, mutations in CDKN2A, IDH1, and TP53 were associated with decreased OS. The HRs were 10.0 (P<0.001), 3.6 (P=0.001), and 4.7 (P<0.001), respectively.
The median OS was 4.5 months in patients with CDKN2A mutations and 11.0 months in patients without them.
The median OS was 7.6 months in patients with TP53 mutations and 11.3 months in patients without them.
And the median OS was 5.6 months in patients with IDH1 mutations and 11.1 months in patients without them.
The researchers believe that testing patients newly diagnosed with AML and MDS for CDKN2A, IDH1, and TP53 mutations could help doctors tailor treatment for patients who are less likely to do well.
The team also said the information gleaned from this trial will guide the choice of new drug partners with the potential to increase azacitidine’s clinical activity.
Researchers say they have identified genetic mutations that can significantly affect treatment outcomes in patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS).
The findings come from a clinical trial in which the team examined whether combining vorinostat with azacitidine could improve survival in patients with AML and MDS.
The results showed no additional benefit with the combination, when compared to azacitidine alone.
However, researchers did find that patients had significantly shorter survival times if they had mutations in CDKN2A, IDH1, or TP53.
“This important trial . . . has rapidly answered the important question of whether combining azacitidine with vorinostat improves outcomes for people with AML and MDS and emphasizes the need for further studies with new drug partners for azacitidine,” said Charles Craddock, DPhil, of the Queen Elizabeth Hospital in Birmingham, UK.
“Importantly, the linked molecular studies have shed new light on which people will benefit most from azacitidine. Furthermore, discovering that the CDKN2A gene mutation affects treatment response may be hugely valuable in helping doctors to design new treatment combinations in the future.”
Dr Craddock and his colleagues reported their discoveries in Clinical Cancer Research.
Previous, smaller trials had suggested that adding vorinostat to treatment with azacitidine could improve outcomes for patients with AML and MDS.
To test this idea, Dr Craddock and his colleagues enrolled 259 patients in the current trial. Most of these patients (n=217) had AML—111 were newly diagnosed, 73 had relapsed AML, and 33 had refractory disease.
The remaining 42 patients had MDS—36 were newly diagnosed, 5 had relapsed MDS, and 1 had refractory disease.
Half of patients (n=130) received azacitidine and vorinostat, and the other half received azacitidine alone (n=129).
In both arms, azacitidine was given at 75 mg/m2 on a 5-2-2 schedule, beginning on day 1 of a 28-day cycle for up to 6 cycles. In the combination arm, patients also received vorinostat at 300 mg twice daily for 7 consecutive days, beginning on day 3 of each cycle.
Results
The combination did not significantly improve response rates or survival times.
The overall response rate was 41% in the azacitidine arm and 42% in the combination arm (odds ratio [OR]=1.05, P=0.84).
The rate of compete response (CR)/CR with incomplete count recovery/marrow CR was 22% in the azacitidine arm and 26% in the combination arm (OR=0.82, P=0.49).
The median overall survival (OS) was 9.6 months in the azacitidine arm and 11.0 months in the combination arm (hazard ratio[HR]=1.15, P=0.32).
Impact of mutations
In a multivariable analysis adjusted for all clinical variables, mutations in NPM1 were associated with reduced overall response (OR=8.6, P=0.012).
In another multivariate analysis, mutations in CDKN2A, IDH1, and TP53 were associated with decreased OS. The HRs were 10.0 (P<0.001), 3.6 (P=0.001), and 4.7 (P<0.001), respectively.
The median OS was 4.5 months in patients with CDKN2A mutations and 11.0 months in patients without them.
The median OS was 7.6 months in patients with TP53 mutations and 11.3 months in patients without them.
And the median OS was 5.6 months in patients with IDH1 mutations and 11.1 months in patients without them.
The researchers believe that testing patients newly diagnosed with AML and MDS for CDKN2A, IDH1, and TP53 mutations could help doctors tailor treatment for patients who are less likely to do well.
The team also said the information gleaned from this trial will guide the choice of new drug partners with the potential to increase azacitidine’s clinical activity.
SCD drug receives rare pediatric disease designation
The US Food and Drug Administration (FDA) has granted rare pediatric disease designation to Altemia™ soft gelatin capsules for the treatment of children with sickle cell disease (SCD).
Altemia (formerly SC411) is being developed by Sancilio Pharmaceuticals Company, Inc. (SPCI) to treat SCD patients between the ages of 5 and 17 years.
Altemia consists of a mixture of fatty acids, primarily in the form of Ethyl Cervonate™ (a proprietary blend of docosahexaenoic acid and other omega-3 fatty acids), and surface active agents formulated using Advanced Lipid Technologies®.
According to SPCI, Advanced Lipid Technologies are proprietary formulation and manufacturing techniques used to create lipophilic drug products capable of increased bioavailability, avoidance of the first pass effect, and elimination of the food effects commonly associated with oral administration.
Altemia is designed to replenish the lipids destroyed by sickle hemoglobin. The product is intended to be taken once daily to reduce vaso-occlusive crises, anemia, organ damage, and other complications of SCD.
Altemia also has orphan drug designation from the FDA.
SPCI is currently conducting a phase 2 trial of Altemia. In this randomized, double-blind, placebo-controlled trial, researchers are evaluating the efficacy and safety of Altemia in pediatric patients with SCD.
The company plans to report top-line results from the study, known as the SCOT trial, early in the fourth quarter of this year.
About rare pediatric disease designation
Rare pediatric disease designation is granted to drugs that show promise to treat diseases affecting fewer than 200,000 patients in the US, primarily patients age 18 or younger.
The designation provides incentives to advance the development of drugs for rare disease, including access to the FDA’s expedited review and approval programs.
Under the FDA’s Rare Pediatric Disease Priority Review Voucher Program, if a drug with rare pediatric disease designation is approved, the drug’s developer may qualify for a voucher that can be redeemed to obtain priority review for any subsequent marketing application.
The US Food and Drug Administration (FDA) has granted rare pediatric disease designation to Altemia™ soft gelatin capsules for the treatment of children with sickle cell disease (SCD).
Altemia (formerly SC411) is being developed by Sancilio Pharmaceuticals Company, Inc. (SPCI) to treat SCD patients between the ages of 5 and 17 years.
Altemia consists of a mixture of fatty acids, primarily in the form of Ethyl Cervonate™ (a proprietary blend of docosahexaenoic acid and other omega-3 fatty acids), and surface active agents formulated using Advanced Lipid Technologies®.
According to SPCI, Advanced Lipid Technologies are proprietary formulation and manufacturing techniques used to create lipophilic drug products capable of increased bioavailability, avoidance of the first pass effect, and elimination of the food effects commonly associated with oral administration.
Altemia is designed to replenish the lipids destroyed by sickle hemoglobin. The product is intended to be taken once daily to reduce vaso-occlusive crises, anemia, organ damage, and other complications of SCD.
Altemia also has orphan drug designation from the FDA.
SPCI is currently conducting a phase 2 trial of Altemia. In this randomized, double-blind, placebo-controlled trial, researchers are evaluating the efficacy and safety of Altemia in pediatric patients with SCD.
The company plans to report top-line results from the study, known as the SCOT trial, early in the fourth quarter of this year.
About rare pediatric disease designation
Rare pediatric disease designation is granted to drugs that show promise to treat diseases affecting fewer than 200,000 patients in the US, primarily patients age 18 or younger.
The designation provides incentives to advance the development of drugs for rare disease, including access to the FDA’s expedited review and approval programs.
Under the FDA’s Rare Pediatric Disease Priority Review Voucher Program, if a drug with rare pediatric disease designation is approved, the drug’s developer may qualify for a voucher that can be redeemed to obtain priority review for any subsequent marketing application.
The US Food and Drug Administration (FDA) has granted rare pediatric disease designation to Altemia™ soft gelatin capsules for the treatment of children with sickle cell disease (SCD).
Altemia (formerly SC411) is being developed by Sancilio Pharmaceuticals Company, Inc. (SPCI) to treat SCD patients between the ages of 5 and 17 years.
Altemia consists of a mixture of fatty acids, primarily in the form of Ethyl Cervonate™ (a proprietary blend of docosahexaenoic acid and other omega-3 fatty acids), and surface active agents formulated using Advanced Lipid Technologies®.
According to SPCI, Advanced Lipid Technologies are proprietary formulation and manufacturing techniques used to create lipophilic drug products capable of increased bioavailability, avoidance of the first pass effect, and elimination of the food effects commonly associated with oral administration.
Altemia is designed to replenish the lipids destroyed by sickle hemoglobin. The product is intended to be taken once daily to reduce vaso-occlusive crises, anemia, organ damage, and other complications of SCD.
Altemia also has orphan drug designation from the FDA.
SPCI is currently conducting a phase 2 trial of Altemia. In this randomized, double-blind, placebo-controlled trial, researchers are evaluating the efficacy and safety of Altemia in pediatric patients with SCD.
The company plans to report top-line results from the study, known as the SCOT trial, early in the fourth quarter of this year.
About rare pediatric disease designation
Rare pediatric disease designation is granted to drugs that show promise to treat diseases affecting fewer than 200,000 patients in the US, primarily patients age 18 or younger.
The designation provides incentives to advance the development of drugs for rare disease, including access to the FDA’s expedited review and approval programs.
Under the FDA’s Rare Pediatric Disease Priority Review Voucher Program, if a drug with rare pediatric disease designation is approved, the drug’s developer may qualify for a voucher that can be redeemed to obtain priority review for any subsequent marketing application.
FDA grants RMAT designation to HSCT adjunct
The US Food and Drug Administration (FDA) has granted Regenerative Medicine Advanced Therapy (RMAT) designation to ATIR101™, which is intended to be used as an adjunct to haploidentical hematopoietic stem cell transplant (HSCT).
ATIR101 is a personalized T-cell immunotherapy—a donor lymphocyte preparation selectively depleted of host-alloreactive T cells through the use of photo-dynamic therapy.
Recipient-reactive T cells from the donor are activated in a unidirectional mixed-lymphocyte reaction. The cells are then treated with TH9402 (a rhodamide-like dye), which is selectively retained in activated T cells.
Subsequent light exposure eliminates the activated recipient-reactive T cells but preserves the other T cells.
The final product is infused after CD34-selected haploidentical HSCT with the goal of preventing infectious complications, graft-versus-host disease (GVHD), and relapse.
About RMAT designation
The RMAT pathway is analogous to the breakthrough therapy designation designed for traditional drug candidates and medical devices. RMAT designation was specifically created by the US Congress in 2016 in the hopes of getting new cell therapies and advanced medicinal products to patients earlier.
Just like breakthrough designation, RMAT designation allows companies developing regenerative medicine therapies to interact with the FDA more frequently in the clinical testing process. In addition, RMAT-designated products may be eligible for priority review and accelerated approval.
A regenerative medicine is eligible for RMAT designation if it is intended to treat, modify, reverse, or cure a serious or life-threatening disease or condition, and if preliminary clinical evidence indicates the treatment has the potential to address unmet medical needs for such a disease or condition.
“To receive the RMAT designation from the FDA is an important milestone for Kiadis Pharma and a recognition by the FDA of the significant potential for ATIR101 to help patients receive safer and more effective bone marrow transplantations,” said Arthur Lahr, CEO of Kiadis Pharma, the company developing ATIR101.
“We are now going to work even closer with the FDA to agree a path to make this cell therapy treatment available for patients in the US as soon as possible. In Europe, ATIR101 was filed for registration in April 2017, and we continue to prepare the company for the potential European launch in 2019.”
ATIR101 trials
Results of a phase 2 trial of ATIR101 were presented at the 42nd Annual Meeting of the European Society of Blood and Marrow Transplantation in 2016.
Patients who received ATIR101 after haploidentical HSCT had significant improvements in transplant-related mortality and overall survival when compared to historical controls who received a T-cell-depleted haploidentical HSCT without ATIR101.
None of the patients who received ATIR101 developed grade 3-4 GVHD, but a few patients did develop grade 2 GVHD.
A phase 3 trial of ATIR101 is now underway. The trial is expected to enroll 200 patients with acute myeloid leukemia, acute lymphoblastic leukemia, or myelodysplastic syndrome.
The patients will receive a haploidentical HSCT with either a T-cell-depleted graft and adjunctive treatment with ATIR101 or a T-cell-replete graft and post-transplant cyclophosphamide.
The US Food and Drug Administration (FDA) has granted Regenerative Medicine Advanced Therapy (RMAT) designation to ATIR101™, which is intended to be used as an adjunct to haploidentical hematopoietic stem cell transplant (HSCT).
ATIR101 is a personalized T-cell immunotherapy—a donor lymphocyte preparation selectively depleted of host-alloreactive T cells through the use of photo-dynamic therapy.
Recipient-reactive T cells from the donor are activated in a unidirectional mixed-lymphocyte reaction. The cells are then treated with TH9402 (a rhodamide-like dye), which is selectively retained in activated T cells.
Subsequent light exposure eliminates the activated recipient-reactive T cells but preserves the other T cells.
The final product is infused after CD34-selected haploidentical HSCT with the goal of preventing infectious complications, graft-versus-host disease (GVHD), and relapse.
About RMAT designation
The RMAT pathway is analogous to the breakthrough therapy designation designed for traditional drug candidates and medical devices. RMAT designation was specifically created by the US Congress in 2016 in the hopes of getting new cell therapies and advanced medicinal products to patients earlier.
Just like breakthrough designation, RMAT designation allows companies developing regenerative medicine therapies to interact with the FDA more frequently in the clinical testing process. In addition, RMAT-designated products may be eligible for priority review and accelerated approval.
A regenerative medicine is eligible for RMAT designation if it is intended to treat, modify, reverse, or cure a serious or life-threatening disease or condition, and if preliminary clinical evidence indicates the treatment has the potential to address unmet medical needs for such a disease or condition.
“To receive the RMAT designation from the FDA is an important milestone for Kiadis Pharma and a recognition by the FDA of the significant potential for ATIR101 to help patients receive safer and more effective bone marrow transplantations,” said Arthur Lahr, CEO of Kiadis Pharma, the company developing ATIR101.
“We are now going to work even closer with the FDA to agree a path to make this cell therapy treatment available for patients in the US as soon as possible. In Europe, ATIR101 was filed for registration in April 2017, and we continue to prepare the company for the potential European launch in 2019.”
ATIR101 trials
Results of a phase 2 trial of ATIR101 were presented at the 42nd Annual Meeting of the European Society of Blood and Marrow Transplantation in 2016.
Patients who received ATIR101 after haploidentical HSCT had significant improvements in transplant-related mortality and overall survival when compared to historical controls who received a T-cell-depleted haploidentical HSCT without ATIR101.
None of the patients who received ATIR101 developed grade 3-4 GVHD, but a few patients did develop grade 2 GVHD.
A phase 3 trial of ATIR101 is now underway. The trial is expected to enroll 200 patients with acute myeloid leukemia, acute lymphoblastic leukemia, or myelodysplastic syndrome.
The patients will receive a haploidentical HSCT with either a T-cell-depleted graft and adjunctive treatment with ATIR101 or a T-cell-replete graft and post-transplant cyclophosphamide.
The US Food and Drug Administration (FDA) has granted Regenerative Medicine Advanced Therapy (RMAT) designation to ATIR101™, which is intended to be used as an adjunct to haploidentical hematopoietic stem cell transplant (HSCT).
ATIR101 is a personalized T-cell immunotherapy—a donor lymphocyte preparation selectively depleted of host-alloreactive T cells through the use of photo-dynamic therapy.
Recipient-reactive T cells from the donor are activated in a unidirectional mixed-lymphocyte reaction. The cells are then treated with TH9402 (a rhodamide-like dye), which is selectively retained in activated T cells.
Subsequent light exposure eliminates the activated recipient-reactive T cells but preserves the other T cells.
The final product is infused after CD34-selected haploidentical HSCT with the goal of preventing infectious complications, graft-versus-host disease (GVHD), and relapse.
About RMAT designation
The RMAT pathway is analogous to the breakthrough therapy designation designed for traditional drug candidates and medical devices. RMAT designation was specifically created by the US Congress in 2016 in the hopes of getting new cell therapies and advanced medicinal products to patients earlier.
Just like breakthrough designation, RMAT designation allows companies developing regenerative medicine therapies to interact with the FDA more frequently in the clinical testing process. In addition, RMAT-designated products may be eligible for priority review and accelerated approval.
A regenerative medicine is eligible for RMAT designation if it is intended to treat, modify, reverse, or cure a serious or life-threatening disease or condition, and if preliminary clinical evidence indicates the treatment has the potential to address unmet medical needs for such a disease or condition.
“To receive the RMAT designation from the FDA is an important milestone for Kiadis Pharma and a recognition by the FDA of the significant potential for ATIR101 to help patients receive safer and more effective bone marrow transplantations,” said Arthur Lahr, CEO of Kiadis Pharma, the company developing ATIR101.
“We are now going to work even closer with the FDA to agree a path to make this cell therapy treatment available for patients in the US as soon as possible. In Europe, ATIR101 was filed for registration in April 2017, and we continue to prepare the company for the potential European launch in 2019.”
ATIR101 trials
Results of a phase 2 trial of ATIR101 were presented at the 42nd Annual Meeting of the European Society of Blood and Marrow Transplantation in 2016.
Patients who received ATIR101 after haploidentical HSCT had significant improvements in transplant-related mortality and overall survival when compared to historical controls who received a T-cell-depleted haploidentical HSCT without ATIR101.
None of the patients who received ATIR101 developed grade 3-4 GVHD, but a few patients did develop grade 2 GVHD.
A phase 3 trial of ATIR101 is now underway. The trial is expected to enroll 200 patients with acute myeloid leukemia, acute lymphoblastic leukemia, or myelodysplastic syndrome.
The patients will receive a haploidentical HSCT with either a T-cell-depleted graft and adjunctive treatment with ATIR101 or a T-cell-replete graft and post-transplant cyclophosphamide.
Antibody shows early promise in AML/MDS trial
MADRID—Interim results of a phase 1 study suggest flotetuzumab, a CD123 and CD3 bispecific antibody, may be a feasible treatment option for relapsed or refractory acute myeloid leukemia (AML) or intermediate/high-risk myelodysplastic syndromes (MDS).
Researchers said flotetuzumab demonstrated acceptable tolerability in the dose-escalation portion of the study, with infusion-related reactions (IRRs) and cytokine release syndrome (CRS) being the most common adverse events (AEs).
In addition, flotetuzumab exhibited anti-leukemic activity in 8 of 14 response-evaluable patients, with 6 patients achieving a response.
Norbert Vey, MD, of Institut Paoli-Calmettes in Marseille, France, presented these results at the ESMO 2017 Congress (abstract 995O*). The study is sponsored by MacroGenics, Inc., the company developing flotetuzumab.
Flotetuzumab (MGD006) recognizes CD123 and CD3. The primary mechanism of flotetuzumab is thought to be its ability to redirect T cells to kill CD123-expressing cells. To achieve this, the molecule combines a portion of an antibody recognizing CD3 (an activating molecule expressed by T cells) with an arm that recognizes CD123 on the target cancer cells.
In this ongoing phase 1 study of flotetuzumab, researchers have enrolled 47 patients with a median age of 64 (range, 29-84). About 89% of these patients had AML (n=42), and the rest (n=5) had MDS.
Twenty-four percent had relapsed AML (n=10), 55% had refractory AML (n=23), and 21% had failed treatment with hypomethylating agents (n=9). One patient had intermediate-1-risk MDS, 2 had intermediate-2-risk, and 2 had high-risk MDS.
Treatment
The study began with single patients receiving flotetuzumab at escalating doses—3 ng/kg/day, 10 ng/kg/day, 30 ng/kg/day, and 100 ng/kg/day.
Then, patients received a range of doses on 2 different schedules for cycle 1. One group received treatment 7 days a week. The other had a 4-days-on/3-days-off schedule.
All patients received a lead-in dose during the first week of cycle 1. They received 30 ng/kg/day for 3 days, then 100 ng/kg/day for 4 days.
For the rest of cycle 1, patients in the 4 days/3 days group received doses of 500 ng/kg, 700 ng/kg, 900 ng/kg, or 1000 ng/kg. Patients in the daily dosing group received doses of 300 ng/kg, 500 ng/kg, 700 ng/kg, 900 ng/kg, or 1000 ng/kg.
For cycle 2 and beyond, all patients were on the 4-days-on/3-days-off schedule.
Safety
The maximum tolerated dose and schedule was 500 ng/kg/day for 7 days.
Dose-limiting toxicities occurring at the 700 ng/kg/day dose included grade 2 IRRs/CRS in 2 patients and grade 3 myalgia in 1 patient. There was 1 drug-related central nervous system AE that led to treatment discontinuation.
IRRs/CRS occurred in 77% of patients, with 13% of patients having grade 3 events and 8.5% of patients discontinuing treatment due to IRRs/CRS.
The researchers said they found ways to decrease the incidence and severity of CRS. One is early intervention with tocilizumab. The other is a 2-step lead-in dose during week 1. So patients first receive 30 ng/kg, then 100 ng/kg, and then their target dose.
Other grade 3 AEs occurring in this trial include febrile neutropenia (11%), anemia (11%), and decreases in platelets (13%), white blood cells (11%), and lymphocytes (13%).
Efficacy
The researchers said they observed encouraging anti-leukemic activity in patients treated at 500 ng/kg/day or greater.
As of the data cut-off, 14 patients treated at this dose were evaluable for response. Eight (57%) patients had anti-leukemic activity, with 6 (43%) of these patients experiencing an objective response.
One patient achieved a complete response (CR), 2 had a CR with incomplete count recovery, and 1 had a molecular CR.
In most responders, anti-leukemic activity was observed after a single cycle of therapy.
MacroGenics is currently enrolling patients in dose-expansion cohorts. The company plans to present updated results from this trial at another scientific conference later this year.
*Slides from this presentation are available on the MacroGenics website at http://ir.macrogenics.com/events.cfm.
MADRID—Interim results of a phase 1 study suggest flotetuzumab, a CD123 and CD3 bispecific antibody, may be a feasible treatment option for relapsed or refractory acute myeloid leukemia (AML) or intermediate/high-risk myelodysplastic syndromes (MDS).
Researchers said flotetuzumab demonstrated acceptable tolerability in the dose-escalation portion of the study, with infusion-related reactions (IRRs) and cytokine release syndrome (CRS) being the most common adverse events (AEs).
In addition, flotetuzumab exhibited anti-leukemic activity in 8 of 14 response-evaluable patients, with 6 patients achieving a response.
Norbert Vey, MD, of Institut Paoli-Calmettes in Marseille, France, presented these results at the ESMO 2017 Congress (abstract 995O*). The study is sponsored by MacroGenics, Inc., the company developing flotetuzumab.
Flotetuzumab (MGD006) recognizes CD123 and CD3. The primary mechanism of flotetuzumab is thought to be its ability to redirect T cells to kill CD123-expressing cells. To achieve this, the molecule combines a portion of an antibody recognizing CD3 (an activating molecule expressed by T cells) with an arm that recognizes CD123 on the target cancer cells.
In this ongoing phase 1 study of flotetuzumab, researchers have enrolled 47 patients with a median age of 64 (range, 29-84). About 89% of these patients had AML (n=42), and the rest (n=5) had MDS.
Twenty-four percent had relapsed AML (n=10), 55% had refractory AML (n=23), and 21% had failed treatment with hypomethylating agents (n=9). One patient had intermediate-1-risk MDS, 2 had intermediate-2-risk, and 2 had high-risk MDS.
Treatment
The study began with single patients receiving flotetuzumab at escalating doses—3 ng/kg/day, 10 ng/kg/day, 30 ng/kg/day, and 100 ng/kg/day.
Then, patients received a range of doses on 2 different schedules for cycle 1. One group received treatment 7 days a week. The other had a 4-days-on/3-days-off schedule.
All patients received a lead-in dose during the first week of cycle 1. They received 30 ng/kg/day for 3 days, then 100 ng/kg/day for 4 days.
For the rest of cycle 1, patients in the 4 days/3 days group received doses of 500 ng/kg, 700 ng/kg, 900 ng/kg, or 1000 ng/kg. Patients in the daily dosing group received doses of 300 ng/kg, 500 ng/kg, 700 ng/kg, 900 ng/kg, or 1000 ng/kg.
For cycle 2 and beyond, all patients were on the 4-days-on/3-days-off schedule.
Safety
The maximum tolerated dose and schedule was 500 ng/kg/day for 7 days.
Dose-limiting toxicities occurring at the 700 ng/kg/day dose included grade 2 IRRs/CRS in 2 patients and grade 3 myalgia in 1 patient. There was 1 drug-related central nervous system AE that led to treatment discontinuation.
IRRs/CRS occurred in 77% of patients, with 13% of patients having grade 3 events and 8.5% of patients discontinuing treatment due to IRRs/CRS.
The researchers said they found ways to decrease the incidence and severity of CRS. One is early intervention with tocilizumab. The other is a 2-step lead-in dose during week 1. So patients first receive 30 ng/kg, then 100 ng/kg, and then their target dose.
Other grade 3 AEs occurring in this trial include febrile neutropenia (11%), anemia (11%), and decreases in platelets (13%), white blood cells (11%), and lymphocytes (13%).
Efficacy
The researchers said they observed encouraging anti-leukemic activity in patients treated at 500 ng/kg/day or greater.
As of the data cut-off, 14 patients treated at this dose were evaluable for response. Eight (57%) patients had anti-leukemic activity, with 6 (43%) of these patients experiencing an objective response.
One patient achieved a complete response (CR), 2 had a CR with incomplete count recovery, and 1 had a molecular CR.
In most responders, anti-leukemic activity was observed after a single cycle of therapy.
MacroGenics is currently enrolling patients in dose-expansion cohorts. The company plans to present updated results from this trial at another scientific conference later this year.
*Slides from this presentation are available on the MacroGenics website at http://ir.macrogenics.com/events.cfm.
MADRID—Interim results of a phase 1 study suggest flotetuzumab, a CD123 and CD3 bispecific antibody, may be a feasible treatment option for relapsed or refractory acute myeloid leukemia (AML) or intermediate/high-risk myelodysplastic syndromes (MDS).
Researchers said flotetuzumab demonstrated acceptable tolerability in the dose-escalation portion of the study, with infusion-related reactions (IRRs) and cytokine release syndrome (CRS) being the most common adverse events (AEs).
In addition, flotetuzumab exhibited anti-leukemic activity in 8 of 14 response-evaluable patients, with 6 patients achieving a response.
Norbert Vey, MD, of Institut Paoli-Calmettes in Marseille, France, presented these results at the ESMO 2017 Congress (abstract 995O*). The study is sponsored by MacroGenics, Inc., the company developing flotetuzumab.
Flotetuzumab (MGD006) recognizes CD123 and CD3. The primary mechanism of flotetuzumab is thought to be its ability to redirect T cells to kill CD123-expressing cells. To achieve this, the molecule combines a portion of an antibody recognizing CD3 (an activating molecule expressed by T cells) with an arm that recognizes CD123 on the target cancer cells.
In this ongoing phase 1 study of flotetuzumab, researchers have enrolled 47 patients with a median age of 64 (range, 29-84). About 89% of these patients had AML (n=42), and the rest (n=5) had MDS.
Twenty-four percent had relapsed AML (n=10), 55% had refractory AML (n=23), and 21% had failed treatment with hypomethylating agents (n=9). One patient had intermediate-1-risk MDS, 2 had intermediate-2-risk, and 2 had high-risk MDS.
Treatment
The study began with single patients receiving flotetuzumab at escalating doses—3 ng/kg/day, 10 ng/kg/day, 30 ng/kg/day, and 100 ng/kg/day.
Then, patients received a range of doses on 2 different schedules for cycle 1. One group received treatment 7 days a week. The other had a 4-days-on/3-days-off schedule.
All patients received a lead-in dose during the first week of cycle 1. They received 30 ng/kg/day for 3 days, then 100 ng/kg/day for 4 days.
For the rest of cycle 1, patients in the 4 days/3 days group received doses of 500 ng/kg, 700 ng/kg, 900 ng/kg, or 1000 ng/kg. Patients in the daily dosing group received doses of 300 ng/kg, 500 ng/kg, 700 ng/kg, 900 ng/kg, or 1000 ng/kg.
For cycle 2 and beyond, all patients were on the 4-days-on/3-days-off schedule.
Safety
The maximum tolerated dose and schedule was 500 ng/kg/day for 7 days.
Dose-limiting toxicities occurring at the 700 ng/kg/day dose included grade 2 IRRs/CRS in 2 patients and grade 3 myalgia in 1 patient. There was 1 drug-related central nervous system AE that led to treatment discontinuation.
IRRs/CRS occurred in 77% of patients, with 13% of patients having grade 3 events and 8.5% of patients discontinuing treatment due to IRRs/CRS.
The researchers said they found ways to decrease the incidence and severity of CRS. One is early intervention with tocilizumab. The other is a 2-step lead-in dose during week 1. So patients first receive 30 ng/kg, then 100 ng/kg, and then their target dose.
Other grade 3 AEs occurring in this trial include febrile neutropenia (11%), anemia (11%), and decreases in platelets (13%), white blood cells (11%), and lymphocytes (13%).
Efficacy
The researchers said they observed encouraging anti-leukemic activity in patients treated at 500 ng/kg/day or greater.
As of the data cut-off, 14 patients treated at this dose were evaluable for response. Eight (57%) patients had anti-leukemic activity, with 6 (43%) of these patients experiencing an objective response.
One patient achieved a complete response (CR), 2 had a CR with incomplete count recovery, and 1 had a molecular CR.
In most responders, anti-leukemic activity was observed after a single cycle of therapy.
MacroGenics is currently enrolling patients in dose-expansion cohorts. The company plans to present updated results from this trial at another scientific conference later this year.
*Slides from this presentation are available on the MacroGenics website at http://ir.macrogenics.com/events.cfm.
CHMP recommends approval of generic imatinib
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended granting marketing authorization for Imatinib Teva B.V., a generic of Glivec.
The recommendation is that Imatinib Teva B.V. be approved to treat chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), hypereosinophilic syndrome (HES), chronic eosinophilic leukemia (CEL), myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPNs), gastrointestinal stromal tumors (GIST), and dermatofibrosarcoma protuberans (DFSP).
The European Commission typically adheres to the CHMP’s recommendations and delivers its final decision within 67 days of the CHMP’s recommendation.
The European Commission’s decision will be applicable to the entire European Economic Area—all member states of the European Union plus Iceland, Liechtenstein, and Norway.
If approved, Imatinib Teva B.V. will be available as capsules and film-coated tablets (100 mg and 400 mg). And it will be authorized:
- As monotherapy for pediatric patients with newly diagnosed, Philadelphia-chromosome-positive (Ph+) CML for whom bone marrow transplant is not considered the first line of treatment.
- As monotherapy for pediatric patients with Ph+ CML in chronic phase after failure of interferon-alpha therapy or in accelerated phase or blast crisis.
- As monotherapy for adults with Ph+ CML in blast crisis.
- Integrated with chemotherapy to treat adult and pediatric patients with newly diagnosed, Ph+ ALL.
- As monotherapy for adults with relapsed or refractory Ph+ ALL.
- As monotherapy for adults with MDS/MPNs associated with platelet-derived growth factor receptor gene re-arrangements.
- As monotherapy for adults with advanced HES and/or CEL with FIP1L1-PDGFRα rearrangement.
- As monotherapy for adults with Kit- (CD117-) positive, unresectable and/or metastatic malignant GISTs.
- For the adjuvant treatment of adults who are at significant risk of relapse following resection of Kit-positive GIST. Patients who have a low or very low risk of recurrence should not receive adjuvant treatment.
- As monotherapy for adults with unresectable DFSP and adults with recurrent and/or metastatic DFSP who are not eligible for surgery.
The CHMP said studies have demonstrated the satisfactory quality of Imatinib Teva B.V. and its bioequivalence to the reference product, Glivec.
In adult and pediatric patients, the effectiveness of imatinib is based on:
- Overall hematologic and cytogenetic response rates and progression-free survival in CML
- Hematologic and cytogenetic response rates in Ph+ ALL and MDS/MPNs
- Hematologic response rates in HES/CEL
- Objective response rates in adults with unresectable and/or metastatic GIST and DFSP
- Recurrence-free survival in adjuvant GIST.
The experience with imatinib in patients with MDS/MPNs associated with PDGFR gene re-arrangements is very limited. There are no controlled trials demonstrating a clinical benefit or increased survival for these diseases.
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended granting marketing authorization for Imatinib Teva B.V., a generic of Glivec.
The recommendation is that Imatinib Teva B.V. be approved to treat chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), hypereosinophilic syndrome (HES), chronic eosinophilic leukemia (CEL), myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPNs), gastrointestinal stromal tumors (GIST), and dermatofibrosarcoma protuberans (DFSP).
The European Commission typically adheres to the CHMP’s recommendations and delivers its final decision within 67 days of the CHMP’s recommendation.
The European Commission’s decision will be applicable to the entire European Economic Area—all member states of the European Union plus Iceland, Liechtenstein, and Norway.
If approved, Imatinib Teva B.V. will be available as capsules and film-coated tablets (100 mg and 400 mg). And it will be authorized:
- As monotherapy for pediatric patients with newly diagnosed, Philadelphia-chromosome-positive (Ph+) CML for whom bone marrow transplant is not considered the first line of treatment.
- As monotherapy for pediatric patients with Ph+ CML in chronic phase after failure of interferon-alpha therapy or in accelerated phase or blast crisis.
- As monotherapy for adults with Ph+ CML in blast crisis.
- Integrated with chemotherapy to treat adult and pediatric patients with newly diagnosed, Ph+ ALL.
- As monotherapy for adults with relapsed or refractory Ph+ ALL.
- As monotherapy for adults with MDS/MPNs associated with platelet-derived growth factor receptor gene re-arrangements.
- As monotherapy for adults with advanced HES and/or CEL with FIP1L1-PDGFRα rearrangement.
- As monotherapy for adults with Kit- (CD117-) positive, unresectable and/or metastatic malignant GISTs.
- For the adjuvant treatment of adults who are at significant risk of relapse following resection of Kit-positive GIST. Patients who have a low or very low risk of recurrence should not receive adjuvant treatment.
- As monotherapy for adults with unresectable DFSP and adults with recurrent and/or metastatic DFSP who are not eligible for surgery.
The CHMP said studies have demonstrated the satisfactory quality of Imatinib Teva B.V. and its bioequivalence to the reference product, Glivec.
In adult and pediatric patients, the effectiveness of imatinib is based on:
- Overall hematologic and cytogenetic response rates and progression-free survival in CML
- Hematologic and cytogenetic response rates in Ph+ ALL and MDS/MPNs
- Hematologic response rates in HES/CEL
- Objective response rates in adults with unresectable and/or metastatic GIST and DFSP
- Recurrence-free survival in adjuvant GIST.
The experience with imatinib in patients with MDS/MPNs associated with PDGFR gene re-arrangements is very limited. There are no controlled trials demonstrating a clinical benefit or increased survival for these diseases.
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended granting marketing authorization for Imatinib Teva B.V., a generic of Glivec.
The recommendation is that Imatinib Teva B.V. be approved to treat chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), hypereosinophilic syndrome (HES), chronic eosinophilic leukemia (CEL), myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPNs), gastrointestinal stromal tumors (GIST), and dermatofibrosarcoma protuberans (DFSP).
The European Commission typically adheres to the CHMP’s recommendations and delivers its final decision within 67 days of the CHMP’s recommendation.
The European Commission’s decision will be applicable to the entire European Economic Area—all member states of the European Union plus Iceland, Liechtenstein, and Norway.
If approved, Imatinib Teva B.V. will be available as capsules and film-coated tablets (100 mg and 400 mg). And it will be authorized:
- As monotherapy for pediatric patients with newly diagnosed, Philadelphia-chromosome-positive (Ph+) CML for whom bone marrow transplant is not considered the first line of treatment.
- As monotherapy for pediatric patients with Ph+ CML in chronic phase after failure of interferon-alpha therapy or in accelerated phase or blast crisis.
- As monotherapy for adults with Ph+ CML in blast crisis.
- Integrated with chemotherapy to treat adult and pediatric patients with newly diagnosed, Ph+ ALL.
- As monotherapy for adults with relapsed or refractory Ph+ ALL.
- As monotherapy for adults with MDS/MPNs associated with platelet-derived growth factor receptor gene re-arrangements.
- As monotherapy for adults with advanced HES and/or CEL with FIP1L1-PDGFRα rearrangement.
- As monotherapy for adults with Kit- (CD117-) positive, unresectable and/or metastatic malignant GISTs.
- For the adjuvant treatment of adults who are at significant risk of relapse following resection of Kit-positive GIST. Patients who have a low or very low risk of recurrence should not receive adjuvant treatment.
- As monotherapy for adults with unresectable DFSP and adults with recurrent and/or metastatic DFSP who are not eligible for surgery.
The CHMP said studies have demonstrated the satisfactory quality of Imatinib Teva B.V. and its bioequivalence to the reference product, Glivec.
In adult and pediatric patients, the effectiveness of imatinib is based on:
- Overall hematologic and cytogenetic response rates and progression-free survival in CML
- Hematologic and cytogenetic response rates in Ph+ ALL and MDS/MPNs
- Hematologic response rates in HES/CEL
- Objective response rates in adults with unresectable and/or metastatic GIST and DFSP
- Recurrence-free survival in adjuvant GIST.
The experience with imatinib in patients with MDS/MPNs associated with PDGFR gene re-arrangements is very limited. There are no controlled trials demonstrating a clinical benefit or increased survival for these diseases.
Study raises questions about anemia in astronauts
Previous research has suggested that astronauts develop anemia during space flight, but a new study indicates this is not the case for astronauts on long space missions.
“There is an idea of ‘space anemia’ that is associated with space flight,” said Richard Simpson, PhD, of the University of Houston in Texas.
“However, this is based on blood samples from astronauts collected after flight, which may be influenced by various factors—for example, the stress of landing and re-adaptation to conditions on Earth.”
“For this study . . ., living, whole blood samples were collected during space flight and returned to Earth for analysis. This unique sample allowed us to track hematological parameters—such as concentrations of red blood cells, hemoglobin, or hematocrit—in astronauts on board the International Space Station during flight.”
Dr Simpson and his colleagues reported their findings in BMC Hematology.
The researchers found that, during space flight, concentrations of red blood cells (RBCs), platelets, and hemoglobin were higher compared to pre-flight levels. Hematocrit also increased significantly during space flight.
While previous studies had shown this to be the case during the first few days of flight, this is the first study to show that RBC concentrations and hematocrit remain at higher levels even after astronauts’ bodies have adapted to microgravity.
To find out how the blood of astronauts may change if they spend a long time in space, the researchers collected blood samples from 31 astronauts who spent up to 6 months on the International Space Station (ISS). There were 6 female and 25 male subjects, and their mean age was 52 (range, 38–61).
Samples were collected at 180 days and 45 days before the astronauts flew to the ISS. Blood was also collected while they were in space—during the first 2 weeks (early time point), between 2 and 4 months (mid time point), and about 6 months into the mission (late time point).
Samples were returned to Earth for analysis either in Houston or at Star City, Russia, within 48 hours of collection. Post-flight samples were collected 3 to 8 hours after landing and 30 days after the mission had ended.
Results
The researchers said some of the changes observed in the in-flight blood samples were to be expected due to the 48-hour processing delay between sample collection and analysis.
However, the team found that RBC concentration was significantly elevated at all 3 in-flight time points, when compared to the 180-day pre-mission time point (baseline). And RBC counts returned to baseline levels upon Earth landing.
The mean RBC concentrations (x 106 cells/μL) were:
- 4.4 ± 0.4 (range, 3.5–5.1) at baseline
- 4.8 ± 0.5 (range, 3.9–5.7) at the early time point (P<0.05)
- 4.7 ± 0.4 (range, 3.9–5.4) at the mid time point (P<0.05)
- 4.7 ± 0.4 (range, 4.1–5.6) at the late time point (P<0.05).
Hemoglobin was elevated early in flight but returned to pre-flight levels during the mission and fell below baseline levels on landing day. The mean hemoglobin (g/dL) levels were:
- 14.1 ± 1.4 (range, 11.0–17.8) at baseline
- 15.0 ± 1.9 (range, 10.7–17.5) at the early time point (P<0.05)
- 13.5 ± 1.4 (range, 10.1–15.9) on landing day (P<0.05).
Mean corpuscular hemoglobin (MCH) decreased during the mission and was significantly lower than baseline at the late time point. However, MCH returned to pre-flight values upon landing. The mean MCH (pg) was:
- 31.7 ± 1.6 (range, 28.8–36.4) at baseline
- 31.3 ± 1.9 (range 26.3–34.0) at the late time point (P<0.05).
The researchers said they observed significant increases in mean corpuscular volume (MCV) during space flight. However, these reflect the changes observed following the 48-hour processing delay. So there were no variations in MCV attributable to space flight.
The changes observed in hematocrit during space flight were “striking,” according to the researchers. The mean hematocrit levels were:
- 40.9 ± 3.9 (range, 33.1–48.0) at baseline
- 45.9 ± 4.7 (range 38.2–52.1) at the early time point (P<0.05)
- 45.9 ± 5.5 (range 38.9–58.3) at the mid time point (P<0.05)
- 45.0 ± 2.5 (range 38.9–49.9) at the late time point (P<0.05).
Compared to pre-flight levels, hematocrit increased by 12.2% at early, 12.2% at mid, and 10.0% at late time points. In comparison, there was a 4.7% increase in hematocrit in reference samples from non-astronauts after the 48-hour processing delay.
Finally, the researchers found that platelet concentrations were elevated in flight, at the early and mid time points. However, platelets were not significantly elevated at the late time point, and they were stable upon landing.
For all of the astronauts, all blood parameters returned to pre-flight levels within 30 days of landing on Earth.
The researchers said these results are susceptible to the possible influence of dehydration or plasma volume alterations. However, the findings do suggest the increases observed in the ISS samples are partly due to a true in-flight increase in RBC count.
“Although the data does not indicate that significant anemia is present, it must be interpreted in the context of crew plasma volume during flight,” Dr Simpson said. “Overall plasma volume has been shown to be reduced during space flight, but this has not been assessed during long-duration missions.”
“In order to fully interpret the changes to RBC, hematocrit, and other parameters observed in this study, further research into plasma volume during long space missions is needed. This will be addressed in a separate, ongoing NASA investigation.”
Previous research has suggested that astronauts develop anemia during space flight, but a new study indicates this is not the case for astronauts on long space missions.
“There is an idea of ‘space anemia’ that is associated with space flight,” said Richard Simpson, PhD, of the University of Houston in Texas.
“However, this is based on blood samples from astronauts collected after flight, which may be influenced by various factors—for example, the stress of landing and re-adaptation to conditions on Earth.”
“For this study . . ., living, whole blood samples were collected during space flight and returned to Earth for analysis. This unique sample allowed us to track hematological parameters—such as concentrations of red blood cells, hemoglobin, or hematocrit—in astronauts on board the International Space Station during flight.”
Dr Simpson and his colleagues reported their findings in BMC Hematology.
The researchers found that, during space flight, concentrations of red blood cells (RBCs), platelets, and hemoglobin were higher compared to pre-flight levels. Hematocrit also increased significantly during space flight.
While previous studies had shown this to be the case during the first few days of flight, this is the first study to show that RBC concentrations and hematocrit remain at higher levels even after astronauts’ bodies have adapted to microgravity.
To find out how the blood of astronauts may change if they spend a long time in space, the researchers collected blood samples from 31 astronauts who spent up to 6 months on the International Space Station (ISS). There were 6 female and 25 male subjects, and their mean age was 52 (range, 38–61).
Samples were collected at 180 days and 45 days before the astronauts flew to the ISS. Blood was also collected while they were in space—during the first 2 weeks (early time point), between 2 and 4 months (mid time point), and about 6 months into the mission (late time point).
Samples were returned to Earth for analysis either in Houston or at Star City, Russia, within 48 hours of collection. Post-flight samples were collected 3 to 8 hours after landing and 30 days after the mission had ended.
Results
The researchers said some of the changes observed in the in-flight blood samples were to be expected due to the 48-hour processing delay between sample collection and analysis.
However, the team found that RBC concentration was significantly elevated at all 3 in-flight time points, when compared to the 180-day pre-mission time point (baseline). And RBC counts returned to baseline levels upon Earth landing.
The mean RBC concentrations (x 106 cells/μL) were:
- 4.4 ± 0.4 (range, 3.5–5.1) at baseline
- 4.8 ± 0.5 (range, 3.9–5.7) at the early time point (P<0.05)
- 4.7 ± 0.4 (range, 3.9–5.4) at the mid time point (P<0.05)
- 4.7 ± 0.4 (range, 4.1–5.6) at the late time point (P<0.05).
Hemoglobin was elevated early in flight but returned to pre-flight levels during the mission and fell below baseline levels on landing day. The mean hemoglobin (g/dL) levels were:
- 14.1 ± 1.4 (range, 11.0–17.8) at baseline
- 15.0 ± 1.9 (range, 10.7–17.5) at the early time point (P<0.05)
- 13.5 ± 1.4 (range, 10.1–15.9) on landing day (P<0.05).
Mean corpuscular hemoglobin (MCH) decreased during the mission and was significantly lower than baseline at the late time point. However, MCH returned to pre-flight values upon landing. The mean MCH (pg) was:
- 31.7 ± 1.6 (range, 28.8–36.4) at baseline
- 31.3 ± 1.9 (range 26.3–34.0) at the late time point (P<0.05).
The researchers said they observed significant increases in mean corpuscular volume (MCV) during space flight. However, these reflect the changes observed following the 48-hour processing delay. So there were no variations in MCV attributable to space flight.
The changes observed in hematocrit during space flight were “striking,” according to the researchers. The mean hematocrit levels were:
- 40.9 ± 3.9 (range, 33.1–48.0) at baseline
- 45.9 ± 4.7 (range 38.2–52.1) at the early time point (P<0.05)
- 45.9 ± 5.5 (range 38.9–58.3) at the mid time point (P<0.05)
- 45.0 ± 2.5 (range 38.9–49.9) at the late time point (P<0.05).
Compared to pre-flight levels, hematocrit increased by 12.2% at early, 12.2% at mid, and 10.0% at late time points. In comparison, there was a 4.7% increase in hematocrit in reference samples from non-astronauts after the 48-hour processing delay.
Finally, the researchers found that platelet concentrations were elevated in flight, at the early and mid time points. However, platelets were not significantly elevated at the late time point, and they were stable upon landing.
For all of the astronauts, all blood parameters returned to pre-flight levels within 30 days of landing on Earth.
The researchers said these results are susceptible to the possible influence of dehydration or plasma volume alterations. However, the findings do suggest the increases observed in the ISS samples are partly due to a true in-flight increase in RBC count.
“Although the data does not indicate that significant anemia is present, it must be interpreted in the context of crew plasma volume during flight,” Dr Simpson said. “Overall plasma volume has been shown to be reduced during space flight, but this has not been assessed during long-duration missions.”
“In order to fully interpret the changes to RBC, hematocrit, and other parameters observed in this study, further research into plasma volume during long space missions is needed. This will be addressed in a separate, ongoing NASA investigation.”
Previous research has suggested that astronauts develop anemia during space flight, but a new study indicates this is not the case for astronauts on long space missions.
“There is an idea of ‘space anemia’ that is associated with space flight,” said Richard Simpson, PhD, of the University of Houston in Texas.
“However, this is based on blood samples from astronauts collected after flight, which may be influenced by various factors—for example, the stress of landing and re-adaptation to conditions on Earth.”
“For this study . . ., living, whole blood samples were collected during space flight and returned to Earth for analysis. This unique sample allowed us to track hematological parameters—such as concentrations of red blood cells, hemoglobin, or hematocrit—in astronauts on board the International Space Station during flight.”
Dr Simpson and his colleagues reported their findings in BMC Hematology.
The researchers found that, during space flight, concentrations of red blood cells (RBCs), platelets, and hemoglobin were higher compared to pre-flight levels. Hematocrit also increased significantly during space flight.
While previous studies had shown this to be the case during the first few days of flight, this is the first study to show that RBC concentrations and hematocrit remain at higher levels even after astronauts’ bodies have adapted to microgravity.
To find out how the blood of astronauts may change if they spend a long time in space, the researchers collected blood samples from 31 astronauts who spent up to 6 months on the International Space Station (ISS). There were 6 female and 25 male subjects, and their mean age was 52 (range, 38–61).
Samples were collected at 180 days and 45 days before the astronauts flew to the ISS. Blood was also collected while they were in space—during the first 2 weeks (early time point), between 2 and 4 months (mid time point), and about 6 months into the mission (late time point).
Samples were returned to Earth for analysis either in Houston or at Star City, Russia, within 48 hours of collection. Post-flight samples were collected 3 to 8 hours after landing and 30 days after the mission had ended.
Results
The researchers said some of the changes observed in the in-flight blood samples were to be expected due to the 48-hour processing delay between sample collection and analysis.
However, the team found that RBC concentration was significantly elevated at all 3 in-flight time points, when compared to the 180-day pre-mission time point (baseline). And RBC counts returned to baseline levels upon Earth landing.
The mean RBC concentrations (x 106 cells/μL) were:
- 4.4 ± 0.4 (range, 3.5–5.1) at baseline
- 4.8 ± 0.5 (range, 3.9–5.7) at the early time point (P<0.05)
- 4.7 ± 0.4 (range, 3.9–5.4) at the mid time point (P<0.05)
- 4.7 ± 0.4 (range, 4.1–5.6) at the late time point (P<0.05).
Hemoglobin was elevated early in flight but returned to pre-flight levels during the mission and fell below baseline levels on landing day. The mean hemoglobin (g/dL) levels were:
- 14.1 ± 1.4 (range, 11.0–17.8) at baseline
- 15.0 ± 1.9 (range, 10.7–17.5) at the early time point (P<0.05)
- 13.5 ± 1.4 (range, 10.1–15.9) on landing day (P<0.05).
Mean corpuscular hemoglobin (MCH) decreased during the mission and was significantly lower than baseline at the late time point. However, MCH returned to pre-flight values upon landing. The mean MCH (pg) was:
- 31.7 ± 1.6 (range, 28.8–36.4) at baseline
- 31.3 ± 1.9 (range 26.3–34.0) at the late time point (P<0.05).
The researchers said they observed significant increases in mean corpuscular volume (MCV) during space flight. However, these reflect the changes observed following the 48-hour processing delay. So there were no variations in MCV attributable to space flight.
The changes observed in hematocrit during space flight were “striking,” according to the researchers. The mean hematocrit levels were:
- 40.9 ± 3.9 (range, 33.1–48.0) at baseline
- 45.9 ± 4.7 (range 38.2–52.1) at the early time point (P<0.05)
- 45.9 ± 5.5 (range 38.9–58.3) at the mid time point (P<0.05)
- 45.0 ± 2.5 (range 38.9–49.9) at the late time point (P<0.05).
Compared to pre-flight levels, hematocrit increased by 12.2% at early, 12.2% at mid, and 10.0% at late time points. In comparison, there was a 4.7% increase in hematocrit in reference samples from non-astronauts after the 48-hour processing delay.
Finally, the researchers found that platelet concentrations were elevated in flight, at the early and mid time points. However, platelets were not significantly elevated at the late time point, and they were stable upon landing.
For all of the astronauts, all blood parameters returned to pre-flight levels within 30 days of landing on Earth.
The researchers said these results are susceptible to the possible influence of dehydration or plasma volume alterations. However, the findings do suggest the increases observed in the ISS samples are partly due to a true in-flight increase in RBC count.
“Although the data does not indicate that significant anemia is present, it must be interpreted in the context of crew plasma volume during flight,” Dr Simpson said. “Overall plasma volume has been shown to be reduced during space flight, but this has not been assessed during long-duration missions.”
“In order to fully interpret the changes to RBC, hematocrit, and other parameters observed in this study, further research into plasma volume during long space missions is needed. This will be addressed in a separate, ongoing NASA investigation.”