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CARs race for supremacy against aggressive non-Hodgkin lymphoma
MADRID – Two chimeric antigen receptor T cell (CAR-T) constructs are showing promising activity against treatment-refractory, aggressive forms of non-Hodgkin lymphoma in multicenter clinical trials.
In the ZUMA-1 trial, axicabtagene ciloleucel (axi-cel), an autologous anti-CD19 CAR-T product, was associated with an 82% objective response rate (ORR), including 54% complete responses, in patients with refractory diffuse large B cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), or transformed follicular lymphoma (TFL), reported Yi Lin, MD, PhD, from the Mayo Clinic in Rochester Minnesota.
In an interim analysis from the JULIET study, a different anti-CD19 CAR-T construct labeled CTL019 was associated with a 59% ORR, consisting of 43% complete responses and 16% partial responses (PR) in patients with relapsed or refractory DLBCL, reported Gilles Salles, MD, PhD, from the University of Lyon, France.
The analysis “confirms the high response rates and durable responses observed in the previous single-center trial,” Dr. Salles said.
Although the CAR-T cell constructs in the study have different costimulatory molecules, each is created in a centralized facility, which allows for consistent manufacturing of cells sufficient for harvesting, transfecting, expanding, and reinfusing into heavily pretreated patients.
The construct used in ZUMA-1, also called KTE-C19 (Kite Pharma), has CD28 and CD3-zeta signaling domains. CTL019 (Novarits, U. Pennsylvania, and Oxford Biomedica) has CD3-zeta and 4-1BB costimulatory domains.
ZUMA-1
Dr. Lin reported phase II results from ZUMA-1, investigating axi-cel at a target dose of 2 x 106 cells per kilogram in 72 patients with refractory DLBCL (cohort 1), and 20 patients with refractory PMBCL or TFL (cohort 2).
The median patient age was 58 years. Patients had stage III or IV disease, 47% had International Prognostic Index (IPI) scores of 3-4, 77% had disease that was refractory to second-line therapies or beyond, and 21% had disease that relapsed within 12 months of an autologous bone marrow transplant
The axi-cel construct was successfully manufactured in 99% of patients, with an average turnaround time from apheresis to the clinical site of 17 days.
As noted before, the trial met its primary endpoint with an 82% ORR, consisting of 54% complete responses and 28% partial responses.
The median duration of response was 8.2 months, and for patients with complete responses the median duration has not been reached.
Median overall survival has also not been reached.
The treatment was generally safe, with only 13% of patients experiencing grade 3 or greater cytokine release syndrome (CRS), and 28% having grade 3 or greater neurologic events. The events were generally reversible, and the rates of each declined over time. The use of tociluzumab or steroids to control adverse events did not have a negative effect on responses, Dr. Lin said.
JULIET
In the ongoing JULIET study, patients with relapsed/refractory DLBCL after at least two prior lines of therapy and who are not candidates for stem cell transplants are enrolled.
In a safety analysis including 85 patients, the CRS was seen in 57% of all patients, including grade 3 in 17% and grade 4 in 9%.
Other common adverse events occurring within 8 weeks of CTL019 infusion were infections in 26% of patients, cytopenias lasting longer than 28 days in 26%, neurologic events in 21%, febrile neutropenia in 14%, and tumor lysis syndrome in 1%.
There were no cases of cerebral edema, and no deaths attributable to the CAR-T cell construct, Dr. Salles said.
Peter Borchmann, MD, from the University of Cologne, Germany, who attended the briefing but was not involved with either study, commented that investigators in ZUMA-1 need to monitor patients carefully, because previous clinical trials using other CAR-T cells with CD28 costimuatory domains have been associated with several cases of fatal cerebral edema.
“I think you can use CD28 in lymphoma, and it’s highly active as we have seen, but my personal impression is that you have to be aware that this might happen,” he said in an interview.
The ZUMA-1 study is funded by Kite Pharma. Dr. Lin disclosed research funding from Janssen. The JULIET study is supported by Novartis. Dr. Salles disclosed serving on an advisory board for the company. Dr. Borchmann had no disclosures.
MADRID – Two chimeric antigen receptor T cell (CAR-T) constructs are showing promising activity against treatment-refractory, aggressive forms of non-Hodgkin lymphoma in multicenter clinical trials.
In the ZUMA-1 trial, axicabtagene ciloleucel (axi-cel), an autologous anti-CD19 CAR-T product, was associated with an 82% objective response rate (ORR), including 54% complete responses, in patients with refractory diffuse large B cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), or transformed follicular lymphoma (TFL), reported Yi Lin, MD, PhD, from the Mayo Clinic in Rochester Minnesota.
In an interim analysis from the JULIET study, a different anti-CD19 CAR-T construct labeled CTL019 was associated with a 59% ORR, consisting of 43% complete responses and 16% partial responses (PR) in patients with relapsed or refractory DLBCL, reported Gilles Salles, MD, PhD, from the University of Lyon, France.
The analysis “confirms the high response rates and durable responses observed in the previous single-center trial,” Dr. Salles said.
Although the CAR-T cell constructs in the study have different costimulatory molecules, each is created in a centralized facility, which allows for consistent manufacturing of cells sufficient for harvesting, transfecting, expanding, and reinfusing into heavily pretreated patients.
The construct used in ZUMA-1, also called KTE-C19 (Kite Pharma), has CD28 and CD3-zeta signaling domains. CTL019 (Novarits, U. Pennsylvania, and Oxford Biomedica) has CD3-zeta and 4-1BB costimulatory domains.
ZUMA-1
Dr. Lin reported phase II results from ZUMA-1, investigating axi-cel at a target dose of 2 x 106 cells per kilogram in 72 patients with refractory DLBCL (cohort 1), and 20 patients with refractory PMBCL or TFL (cohort 2).
The median patient age was 58 years. Patients had stage III or IV disease, 47% had International Prognostic Index (IPI) scores of 3-4, 77% had disease that was refractory to second-line therapies or beyond, and 21% had disease that relapsed within 12 months of an autologous bone marrow transplant
The axi-cel construct was successfully manufactured in 99% of patients, with an average turnaround time from apheresis to the clinical site of 17 days.
As noted before, the trial met its primary endpoint with an 82% ORR, consisting of 54% complete responses and 28% partial responses.
The median duration of response was 8.2 months, and for patients with complete responses the median duration has not been reached.
Median overall survival has also not been reached.
The treatment was generally safe, with only 13% of patients experiencing grade 3 or greater cytokine release syndrome (CRS), and 28% having grade 3 or greater neurologic events. The events were generally reversible, and the rates of each declined over time. The use of tociluzumab or steroids to control adverse events did not have a negative effect on responses, Dr. Lin said.
JULIET
In the ongoing JULIET study, patients with relapsed/refractory DLBCL after at least two prior lines of therapy and who are not candidates for stem cell transplants are enrolled.
In a safety analysis including 85 patients, the CRS was seen in 57% of all patients, including grade 3 in 17% and grade 4 in 9%.
Other common adverse events occurring within 8 weeks of CTL019 infusion were infections in 26% of patients, cytopenias lasting longer than 28 days in 26%, neurologic events in 21%, febrile neutropenia in 14%, and tumor lysis syndrome in 1%.
There were no cases of cerebral edema, and no deaths attributable to the CAR-T cell construct, Dr. Salles said.
Peter Borchmann, MD, from the University of Cologne, Germany, who attended the briefing but was not involved with either study, commented that investigators in ZUMA-1 need to monitor patients carefully, because previous clinical trials using other CAR-T cells with CD28 costimuatory domains have been associated with several cases of fatal cerebral edema.
“I think you can use CD28 in lymphoma, and it’s highly active as we have seen, but my personal impression is that you have to be aware that this might happen,” he said in an interview.
The ZUMA-1 study is funded by Kite Pharma. Dr. Lin disclosed research funding from Janssen. The JULIET study is supported by Novartis. Dr. Salles disclosed serving on an advisory board for the company. Dr. Borchmann had no disclosures.
MADRID – Two chimeric antigen receptor T cell (CAR-T) constructs are showing promising activity against treatment-refractory, aggressive forms of non-Hodgkin lymphoma in multicenter clinical trials.
In the ZUMA-1 trial, axicabtagene ciloleucel (axi-cel), an autologous anti-CD19 CAR-T product, was associated with an 82% objective response rate (ORR), including 54% complete responses, in patients with refractory diffuse large B cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), or transformed follicular lymphoma (TFL), reported Yi Lin, MD, PhD, from the Mayo Clinic in Rochester Minnesota.
In an interim analysis from the JULIET study, a different anti-CD19 CAR-T construct labeled CTL019 was associated with a 59% ORR, consisting of 43% complete responses and 16% partial responses (PR) in patients with relapsed or refractory DLBCL, reported Gilles Salles, MD, PhD, from the University of Lyon, France.
The analysis “confirms the high response rates and durable responses observed in the previous single-center trial,” Dr. Salles said.
Although the CAR-T cell constructs in the study have different costimulatory molecules, each is created in a centralized facility, which allows for consistent manufacturing of cells sufficient for harvesting, transfecting, expanding, and reinfusing into heavily pretreated patients.
The construct used in ZUMA-1, also called KTE-C19 (Kite Pharma), has CD28 and CD3-zeta signaling domains. CTL019 (Novarits, U. Pennsylvania, and Oxford Biomedica) has CD3-zeta and 4-1BB costimulatory domains.
ZUMA-1
Dr. Lin reported phase II results from ZUMA-1, investigating axi-cel at a target dose of 2 x 106 cells per kilogram in 72 patients with refractory DLBCL (cohort 1), and 20 patients with refractory PMBCL or TFL (cohort 2).
The median patient age was 58 years. Patients had stage III or IV disease, 47% had International Prognostic Index (IPI) scores of 3-4, 77% had disease that was refractory to second-line therapies or beyond, and 21% had disease that relapsed within 12 months of an autologous bone marrow transplant
The axi-cel construct was successfully manufactured in 99% of patients, with an average turnaround time from apheresis to the clinical site of 17 days.
As noted before, the trial met its primary endpoint with an 82% ORR, consisting of 54% complete responses and 28% partial responses.
The median duration of response was 8.2 months, and for patients with complete responses the median duration has not been reached.
Median overall survival has also not been reached.
The treatment was generally safe, with only 13% of patients experiencing grade 3 or greater cytokine release syndrome (CRS), and 28% having grade 3 or greater neurologic events. The events were generally reversible, and the rates of each declined over time. The use of tociluzumab or steroids to control adverse events did not have a negative effect on responses, Dr. Lin said.
JULIET
In the ongoing JULIET study, patients with relapsed/refractory DLBCL after at least two prior lines of therapy and who are not candidates for stem cell transplants are enrolled.
In a safety analysis including 85 patients, the CRS was seen in 57% of all patients, including grade 3 in 17% and grade 4 in 9%.
Other common adverse events occurring within 8 weeks of CTL019 infusion were infections in 26% of patients, cytopenias lasting longer than 28 days in 26%, neurologic events in 21%, febrile neutropenia in 14%, and tumor lysis syndrome in 1%.
There were no cases of cerebral edema, and no deaths attributable to the CAR-T cell construct, Dr. Salles said.
Peter Borchmann, MD, from the University of Cologne, Germany, who attended the briefing but was not involved with either study, commented that investigators in ZUMA-1 need to monitor patients carefully, because previous clinical trials using other CAR-T cells with CD28 costimuatory domains have been associated with several cases of fatal cerebral edema.
“I think you can use CD28 in lymphoma, and it’s highly active as we have seen, but my personal impression is that you have to be aware that this might happen,” he said in an interview.
The ZUMA-1 study is funded by Kite Pharma. Dr. Lin disclosed research funding from Janssen. The JULIET study is supported by Novartis. Dr. Salles disclosed serving on an advisory board for the company. Dr. Borchmann had no disclosures.
AT EHA 2017
Key clinical point: CAR-T cell therapies are showing good activity against relapsed/refractory non-Hodgkin lymphomas.
Major finding: In ZUMA-1, the objective response rate was 82%. In JULIET, it was 59%
Data source: Two multicenter trials of CAR-T cells in patients with relapsed/refractory DLBCL, PMBCL, and TFL.
Disclosures: The ZUMA-1 study is funded by Kite Pharma. Dr. Lin disclosed research funding from Janssen. The JULIET study is supported by Novartis. Dr. Salles disclosed serving on an advisory board for the company. Dr. Borchmann had no disclosures.
Biosimilar immunogenicity studies produce no surprises
AT EULAR 2017
MADRID – Two biosimilar tumor necrosis factor inhibitor (TNFi) products are no more immunogenic than their reference biologic counterparts in patients with rheumatoid arthritis, according to the results of two studies presented at the European Congress of Rheumatology.
Results of one study, which involved 544 RA patients, showed 33.1% treated with SB5, a biosimilar candidate for adalimumab (Humira), and 32% of those who were treated with reference adalimumab developed antidrug antibodies (ADAbs) after 24 weeks’ treatment.
In the second study, which involved 596 RA patients, significantly fewer treated with SB4, a biosimilar candidate for etanercept (Enbrel) developed ADAbs versus reference etanercept (0.7% vs. 13.1%, P less than .001).
In both studies the development of ADAbs with the biosimilar or reference products was found to attenuate the clinical responses seen, with trends towards lower American College of Rheumatology (ACR) scores with higher levels of ADAbs.
Dr. Kay observed that for both SB5 and adalimumab, efficacy at week 24 was higher among patients who achieved drug trough levels of 1.274 microg/mL or more than this threshold set for achieving a good EULAR response. At week 24, 32.9% and 43.2% of patients treated with the biosimilar adalimumab and reference adalimumab, respectively, had drug trough levels greater than or equal to the threshold, and achieved a good EULAR response, with 61.7% and 51.8% achieving a moderate EULAR response, and 5.4% and 5% no EULAR response. Dr. Kay also reported that similar percentages of patients treated with the biosimilar and reference adalimumab achieved a low disease activity (LDA) score or were in remission at 24 weeks if the drug trough levels were 1.274 microg/mL or above, at 32.9% and 43.2% for LDA and 20.8% and 25.9% for remission.
“Efficacy tended to be lower in patients with ADAbs,” Dr. Vencovský, who is vice-director of the Institute of Rheumatology, Charles University in Prague, Czech Republic, said. For both the ACR50 and ACR70 responses at week 24, no differences were seen between the patients who received biosimilar or reference etanercept. The impact on the ACR20 response could not be evaluated in the biosimilar group due to the low incidence of ADAbs, Dr. Vencovský said. The effect of injection site reactions on efficacy was also studied, and while no correlation was found between injection site reactions and the development of ADAbs, efficacy did tend to be slightly lower in some parameters measured in the patients who experienced injection site reactions. Dr. Vencovský reported that fewer patients treated with the biosimilar candidate experienced injection site reactions than those with the reference etanercept (3% vs. 16%).
The study presented by Dr. Kay is currently under consideration for publication and has previously been presented at the American College of Rheumatology.
Samsung Biopics sponsored the studies. The company has several biosimilar products in the pipeline, including SB2, which is a biosimilar for infliximab (Remicade) that was approved for use in the United States in April 2017. Although not yet available in the U.S., the company’s biosimilar adalimumab (SB5) is undergoing regulatory review by the European Medicines Agency (EMA) and it’s biosimilar etanercept is available in Europe as Benpali and Canada as Brenzys.
Dr. Kay has received research support paid to his institution from AbbVie, Genentech, Pfizer, Roche Laboratories, and UCB. He has also acted as a consultant to several companies that develop or market biosimilars including Samsung Bioepis who make the two biosimilar products mentioned in this report. Dr. Vencovský disclosed acting as a consultant to Samsung Bioepis and to Biogen, and acting as a speaker for UCB, Pfizer, AbbVie, MSD, Novartis, and Eli Lilly.
AT EULAR 2017
MADRID – Two biosimilar tumor necrosis factor inhibitor (TNFi) products are no more immunogenic than their reference biologic counterparts in patients with rheumatoid arthritis, according to the results of two studies presented at the European Congress of Rheumatology.
Results of one study, which involved 544 RA patients, showed 33.1% treated with SB5, a biosimilar candidate for adalimumab (Humira), and 32% of those who were treated with reference adalimumab developed antidrug antibodies (ADAbs) after 24 weeks’ treatment.
In the second study, which involved 596 RA patients, significantly fewer treated with SB4, a biosimilar candidate for etanercept (Enbrel) developed ADAbs versus reference etanercept (0.7% vs. 13.1%, P less than .001).
In both studies the development of ADAbs with the biosimilar or reference products was found to attenuate the clinical responses seen, with trends towards lower American College of Rheumatology (ACR) scores with higher levels of ADAbs.
Dr. Kay observed that for both SB5 and adalimumab, efficacy at week 24 was higher among patients who achieved drug trough levels of 1.274 microg/mL or more than this threshold set for achieving a good EULAR response. At week 24, 32.9% and 43.2% of patients treated with the biosimilar adalimumab and reference adalimumab, respectively, had drug trough levels greater than or equal to the threshold, and achieved a good EULAR response, with 61.7% and 51.8% achieving a moderate EULAR response, and 5.4% and 5% no EULAR response. Dr. Kay also reported that similar percentages of patients treated with the biosimilar and reference adalimumab achieved a low disease activity (LDA) score or were in remission at 24 weeks if the drug trough levels were 1.274 microg/mL or above, at 32.9% and 43.2% for LDA and 20.8% and 25.9% for remission.
“Efficacy tended to be lower in patients with ADAbs,” Dr. Vencovský, who is vice-director of the Institute of Rheumatology, Charles University in Prague, Czech Republic, said. For both the ACR50 and ACR70 responses at week 24, no differences were seen between the patients who received biosimilar or reference etanercept. The impact on the ACR20 response could not be evaluated in the biosimilar group due to the low incidence of ADAbs, Dr. Vencovský said. The effect of injection site reactions on efficacy was also studied, and while no correlation was found between injection site reactions and the development of ADAbs, efficacy did tend to be slightly lower in some parameters measured in the patients who experienced injection site reactions. Dr. Vencovský reported that fewer patients treated with the biosimilar candidate experienced injection site reactions than those with the reference etanercept (3% vs. 16%).
The study presented by Dr. Kay is currently under consideration for publication and has previously been presented at the American College of Rheumatology.
Samsung Biopics sponsored the studies. The company has several biosimilar products in the pipeline, including SB2, which is a biosimilar for infliximab (Remicade) that was approved for use in the United States in April 2017. Although not yet available in the U.S., the company’s biosimilar adalimumab (SB5) is undergoing regulatory review by the European Medicines Agency (EMA) and it’s biosimilar etanercept is available in Europe as Benpali and Canada as Brenzys.
Dr. Kay has received research support paid to his institution from AbbVie, Genentech, Pfizer, Roche Laboratories, and UCB. He has also acted as a consultant to several companies that develop or market biosimilars including Samsung Bioepis who make the two biosimilar products mentioned in this report. Dr. Vencovský disclosed acting as a consultant to Samsung Bioepis and to Biogen, and acting as a speaker for UCB, Pfizer, AbbVie, MSD, Novartis, and Eli Lilly.
AT EULAR 2017
MADRID – Two biosimilar tumor necrosis factor inhibitor (TNFi) products are no more immunogenic than their reference biologic counterparts in patients with rheumatoid arthritis, according to the results of two studies presented at the European Congress of Rheumatology.
Results of one study, which involved 544 RA patients, showed 33.1% treated with SB5, a biosimilar candidate for adalimumab (Humira), and 32% of those who were treated with reference adalimumab developed antidrug antibodies (ADAbs) after 24 weeks’ treatment.
In the second study, which involved 596 RA patients, significantly fewer treated with SB4, a biosimilar candidate for etanercept (Enbrel) developed ADAbs versus reference etanercept (0.7% vs. 13.1%, P less than .001).
In both studies the development of ADAbs with the biosimilar or reference products was found to attenuate the clinical responses seen, with trends towards lower American College of Rheumatology (ACR) scores with higher levels of ADAbs.
Dr. Kay observed that for both SB5 and adalimumab, efficacy at week 24 was higher among patients who achieved drug trough levels of 1.274 microg/mL or more than this threshold set for achieving a good EULAR response. At week 24, 32.9% and 43.2% of patients treated with the biosimilar adalimumab and reference adalimumab, respectively, had drug trough levels greater than or equal to the threshold, and achieved a good EULAR response, with 61.7% and 51.8% achieving a moderate EULAR response, and 5.4% and 5% no EULAR response. Dr. Kay also reported that similar percentages of patients treated with the biosimilar and reference adalimumab achieved a low disease activity (LDA) score or were in remission at 24 weeks if the drug trough levels were 1.274 microg/mL or above, at 32.9% and 43.2% for LDA and 20.8% and 25.9% for remission.
“Efficacy tended to be lower in patients with ADAbs,” Dr. Vencovský, who is vice-director of the Institute of Rheumatology, Charles University in Prague, Czech Republic, said. For both the ACR50 and ACR70 responses at week 24, no differences were seen between the patients who received biosimilar or reference etanercept. The impact on the ACR20 response could not be evaluated in the biosimilar group due to the low incidence of ADAbs, Dr. Vencovský said. The effect of injection site reactions on efficacy was also studied, and while no correlation was found between injection site reactions and the development of ADAbs, efficacy did tend to be slightly lower in some parameters measured in the patients who experienced injection site reactions. Dr. Vencovský reported that fewer patients treated with the biosimilar candidate experienced injection site reactions than those with the reference etanercept (3% vs. 16%).
The study presented by Dr. Kay is currently under consideration for publication and has previously been presented at the American College of Rheumatology.
Samsung Biopics sponsored the studies. The company has several biosimilar products in the pipeline, including SB2, which is a biosimilar for infliximab (Remicade) that was approved for use in the United States in April 2017. Although not yet available in the U.S., the company’s biosimilar adalimumab (SB5) is undergoing regulatory review by the European Medicines Agency (EMA) and it’s biosimilar etanercept is available in Europe as Benpali and Canada as Brenzys.
Dr. Kay has received research support paid to his institution from AbbVie, Genentech, Pfizer, Roche Laboratories, and UCB. He has also acted as a consultant to several companies that develop or market biosimilars including Samsung Bioepis who make the two biosimilar products mentioned in this report. Dr. Vencovský disclosed acting as a consultant to Samsung Bioepis and to Biogen, and acting as a speaker for UCB, Pfizer, AbbVie, MSD, Novartis, and Eli Lilly.
Key clinical point:
Major finding: Around one-third of biosimilar and reference adalimumab-treated patients developed anti-drug antibodies, while significantly fewer patients treated with biosimilar etanercept versus reference etanercept did so (0.7% vs. 13/1%, P less than .001).
Data source: Two studies in patients with rheumatoid arthritis treated with biosimilar adalimumab or biosimilar etanercept or the reference products.
Disclosures: Samsung Bioepis sponsored the studies. Dr. Kay has received research support paid to his institution from AbbVie, Pfizer, Genentech, Roche Laboratories, and UCB. He has also acted as a consultant to several companies that develop or market biosimilars including Samsung Bioepis who make the two biosimilar products mentioned in this report. Dr. Vencovský disclosed acting as a consultant to Samsung Bioepis and to Biogen, and acting as a speaker for UCB, Pfizer, AbbVie, MSD, Novartis, and Eli Lilly.
Biologics, TNF-inhibitors confer no excess cancer risks upon RA patients
MADRID – Biologics and tumor necrosis factor–inhibitors confer very little – if any – risk of malignancy upon those who take them for rheumatoid arthritis, according to a large Swedish registry study.
A doubling in the risk of squamous cell carcinoma among those who took abatacept was the only significant finding in the 8-year study of almost 70,000 subjects, Hjalmar Wadstrom, said at the European Congress of Rheumatology. And while he said the finding could be spurious, he stressed that it can’t be ignored.
“We think this finding should be interpreted cautiously,” said Mr. Wadstrom, a doctoral student at the Karolinska Institute, Stockholm. “These patients are seen frequently, and this increase in sqaumous cell carcinoma could be related to this multiple screening, or due to study bias. But of course, we cannot disregard it. It should be validated and further examined.”
The study plumbed several national patient registries and administrative databases for its cohort. It comprised 22,500 patients who, from 2006 to 2014, took tocilizumab, abatacept, or rituximab; or a TNF-inhibitor as a first or second disease-modifying antirheumatic drug. These were compared to 46,600 patients who took synthetic DMARDS during the same period and to a matched general population cohort (107,500). The mean age of all groups was about 59 years.
The primary outcome was a first-ever solid or hematologic malignancy excluding nonmelanoma skin cancer. The fully adjusted risk model controlled for age, sex, educational level, comorbidities, seropositivity, number of hospitalizations and days spent in inpatient care, use of prednisone at baseline, use of nonsteroidal anti-inflammatory drugs at baseline, number of prescription drugs at baseline, and sick leave and disability.
A first invasive solid tumor or hematologic malignancy occurred in 50 patients taking tocilizumab; 61 taking abatacept; 141 taking rituximab; 478 taking a TNF-inhibitor as the first biologic DMARD; and 169 taking a TNF-inhibitor as the second DMARD. There was no statistically significant difference between any of these groups, when they were compared either to each other, to those taking a conventional synthetic DMARD, or to the general population.
The doubled risk of squamous cell carcinoma associated with abatacept (HR 2.2) was the only significant positive finding the secondary analysis, Dr. Wadstrom said.
He had no financial disclosures.
[email protected]
On Twitter @Alz_gal
MADRID – Biologics and tumor necrosis factor–inhibitors confer very little – if any – risk of malignancy upon those who take them for rheumatoid arthritis, according to a large Swedish registry study.
A doubling in the risk of squamous cell carcinoma among those who took abatacept was the only significant finding in the 8-year study of almost 70,000 subjects, Hjalmar Wadstrom, said at the European Congress of Rheumatology. And while he said the finding could be spurious, he stressed that it can’t be ignored.
“We think this finding should be interpreted cautiously,” said Mr. Wadstrom, a doctoral student at the Karolinska Institute, Stockholm. “These patients are seen frequently, and this increase in sqaumous cell carcinoma could be related to this multiple screening, or due to study bias. But of course, we cannot disregard it. It should be validated and further examined.”
The study plumbed several national patient registries and administrative databases for its cohort. It comprised 22,500 patients who, from 2006 to 2014, took tocilizumab, abatacept, or rituximab; or a TNF-inhibitor as a first or second disease-modifying antirheumatic drug. These were compared to 46,600 patients who took synthetic DMARDS during the same period and to a matched general population cohort (107,500). The mean age of all groups was about 59 years.
The primary outcome was a first-ever solid or hematologic malignancy excluding nonmelanoma skin cancer. The fully adjusted risk model controlled for age, sex, educational level, comorbidities, seropositivity, number of hospitalizations and days spent in inpatient care, use of prednisone at baseline, use of nonsteroidal anti-inflammatory drugs at baseline, number of prescription drugs at baseline, and sick leave and disability.
A first invasive solid tumor or hematologic malignancy occurred in 50 patients taking tocilizumab; 61 taking abatacept; 141 taking rituximab; 478 taking a TNF-inhibitor as the first biologic DMARD; and 169 taking a TNF-inhibitor as the second DMARD. There was no statistically significant difference between any of these groups, when they were compared either to each other, to those taking a conventional synthetic DMARD, or to the general population.
The doubled risk of squamous cell carcinoma associated with abatacept (HR 2.2) was the only significant positive finding the secondary analysis, Dr. Wadstrom said.
He had no financial disclosures.
[email protected]
On Twitter @Alz_gal
MADRID – Biologics and tumor necrosis factor–inhibitors confer very little – if any – risk of malignancy upon those who take them for rheumatoid arthritis, according to a large Swedish registry study.
A doubling in the risk of squamous cell carcinoma among those who took abatacept was the only significant finding in the 8-year study of almost 70,000 subjects, Hjalmar Wadstrom, said at the European Congress of Rheumatology. And while he said the finding could be spurious, he stressed that it can’t be ignored.
“We think this finding should be interpreted cautiously,” said Mr. Wadstrom, a doctoral student at the Karolinska Institute, Stockholm. “These patients are seen frequently, and this increase in sqaumous cell carcinoma could be related to this multiple screening, or due to study bias. But of course, we cannot disregard it. It should be validated and further examined.”
The study plumbed several national patient registries and administrative databases for its cohort. It comprised 22,500 patients who, from 2006 to 2014, took tocilizumab, abatacept, or rituximab; or a TNF-inhibitor as a first or second disease-modifying antirheumatic drug. These were compared to 46,600 patients who took synthetic DMARDS during the same period and to a matched general population cohort (107,500). The mean age of all groups was about 59 years.
The primary outcome was a first-ever solid or hematologic malignancy excluding nonmelanoma skin cancer. The fully adjusted risk model controlled for age, sex, educational level, comorbidities, seropositivity, number of hospitalizations and days spent in inpatient care, use of prednisone at baseline, use of nonsteroidal anti-inflammatory drugs at baseline, number of prescription drugs at baseline, and sick leave and disability.
A first invasive solid tumor or hematologic malignancy occurred in 50 patients taking tocilizumab; 61 taking abatacept; 141 taking rituximab; 478 taking a TNF-inhibitor as the first biologic DMARD; and 169 taking a TNF-inhibitor as the second DMARD. There was no statistically significant difference between any of these groups, when they were compared either to each other, to those taking a conventional synthetic DMARD, or to the general population.
The doubled risk of squamous cell carcinoma associated with abatacept (HR 2.2) was the only significant positive finding the secondary analysis, Dr. Wadstrom said.
He had no financial disclosures.
[email protected]
On Twitter @Alz_gal
AT EULAR 2017
Key clinical point:
Major finding: A twofold increased risk of squamous cell carcinoma was associated with abatacept.
Data source: The Swedish study examined almost 70,000 people in various national registries and health care databases.
Disclosures: Mr. Wadstrom had no financial disclosures.
Obeticholic acid fails to prevent liver damage in an animal model of short-bowel syndrome
Obeticholic acid failed to prevent the development of short-bowel syndrome–associated liver disease in a preliminary study using piglet models. The findings were published in the July issue of Cellular and Molecular Gastroenterology and Hepatology (doi: 10.1016/j.jcmgh.2017.02.008).
Current treatment options for short-bowel syndrome-associated liver disease are limited, wrote Prue M. Pereira-Fantini, PhD, of Murdoch Childrens Research Institute, Victoria, Australia, and colleagues. However, the farnesoid X receptor, which regulates genes involved in bile acid synthesis, absorption, and transport in the intestine and liver, has shown promise as a pharmaceutical target.
“Recently, we described SBS-ALD-associated alterations in bile acid composition associated with disrupted farnesoid X receptor (FXR) signaling mechanisms,” the researchers said. Obeticholic acid (OCA) has been shown to prevent liver disease in mouse models and human disease, and the researchers explored whether it would be effective in the context of short-bowel syndrome associated liver disease (SBS-ALD).
The researchers randomized piglets into four groups to receive small-bowel resection or sham surgery, and either a daily dose of 2.4 mg/kg per day of OCA or no treatment. The pigs were euthanized 2 weeks after their surgeries, and the researchers collected portal plasma samples, bile samples, and liver samples.
OCA treatment in piglets in the SBS surgery group was associated with decreased stool fat that suggested improved fat absorption, but impacted liver morphology, the researchers noted. “Untreated, sham-operated piglets showed normal liver histology when compared with SBS piglets who showed decreased hepatic lobule area and small clusters of inflammatory cells together with mild-to-moderate vesicular zone 2 lipidosis,” they wrote.
Overall, OCA treatment prevented the depletion of taurine; taurine concentration was approximately 8 ng/mL for piglets with SBS treated with OCA compared with 8 ng/mL in the sham group, 9 ng/mL in the sham plus OCA group, and 3 ng/mL in the SBS-only group. However, bile acid dysmetabolism occurred as shown by HDCA levels, which increased with OCA treatment compared to sham controls but were significantly reduced in SBS piglets treated with OCA vs. untreated SBS piglets.
In addition, the researchers found that small-bowel resection did not impact gene expression levels of FXR targets in the intestine or liver. However, “intestinal FXR gene expression was 11-fold higher in untreated SBS piglets when compared with untreated sham piglets,” they wrote. OCA treatment had no significant impact on FXR gene expression in the OCA-treated group vs. the untreated group and in the OCA-treated SBS group.
Although the findings were limited by use of an animal model, the results suggest that OCA treatment may have clinical benefits for SBS patients by reducing fat malabsorption, which remains a challenge, the researchers wrote. However, OCA “did not prevent the development of SBS-ALD, thereby limiting the potential therapeutic benefit in patients with SBS,” they concluded.
The researchers had no financial conflicts to disclose. The study was supported in part by the National Health and Medical Research Council of Australia and by a research grant from the Science Foundation Ireland.
Obeticholic acid failed to prevent the development of short-bowel syndrome–associated liver disease in a preliminary study using piglet models. The findings were published in the July issue of Cellular and Molecular Gastroenterology and Hepatology (doi: 10.1016/j.jcmgh.2017.02.008).
Current treatment options for short-bowel syndrome-associated liver disease are limited, wrote Prue M. Pereira-Fantini, PhD, of Murdoch Childrens Research Institute, Victoria, Australia, and colleagues. However, the farnesoid X receptor, which regulates genes involved in bile acid synthesis, absorption, and transport in the intestine and liver, has shown promise as a pharmaceutical target.
“Recently, we described SBS-ALD-associated alterations in bile acid composition associated with disrupted farnesoid X receptor (FXR) signaling mechanisms,” the researchers said. Obeticholic acid (OCA) has been shown to prevent liver disease in mouse models and human disease, and the researchers explored whether it would be effective in the context of short-bowel syndrome associated liver disease (SBS-ALD).
The researchers randomized piglets into four groups to receive small-bowel resection or sham surgery, and either a daily dose of 2.4 mg/kg per day of OCA or no treatment. The pigs were euthanized 2 weeks after their surgeries, and the researchers collected portal plasma samples, bile samples, and liver samples.
OCA treatment in piglets in the SBS surgery group was associated with decreased stool fat that suggested improved fat absorption, but impacted liver morphology, the researchers noted. “Untreated, sham-operated piglets showed normal liver histology when compared with SBS piglets who showed decreased hepatic lobule area and small clusters of inflammatory cells together with mild-to-moderate vesicular zone 2 lipidosis,” they wrote.
Overall, OCA treatment prevented the depletion of taurine; taurine concentration was approximately 8 ng/mL for piglets with SBS treated with OCA compared with 8 ng/mL in the sham group, 9 ng/mL in the sham plus OCA group, and 3 ng/mL in the SBS-only group. However, bile acid dysmetabolism occurred as shown by HDCA levels, which increased with OCA treatment compared to sham controls but were significantly reduced in SBS piglets treated with OCA vs. untreated SBS piglets.
In addition, the researchers found that small-bowel resection did not impact gene expression levels of FXR targets in the intestine or liver. However, “intestinal FXR gene expression was 11-fold higher in untreated SBS piglets when compared with untreated sham piglets,” they wrote. OCA treatment had no significant impact on FXR gene expression in the OCA-treated group vs. the untreated group and in the OCA-treated SBS group.
Although the findings were limited by use of an animal model, the results suggest that OCA treatment may have clinical benefits for SBS patients by reducing fat malabsorption, which remains a challenge, the researchers wrote. However, OCA “did not prevent the development of SBS-ALD, thereby limiting the potential therapeutic benefit in patients with SBS,” they concluded.
The researchers had no financial conflicts to disclose. The study was supported in part by the National Health and Medical Research Council of Australia and by a research grant from the Science Foundation Ireland.
Obeticholic acid failed to prevent the development of short-bowel syndrome–associated liver disease in a preliminary study using piglet models. The findings were published in the July issue of Cellular and Molecular Gastroenterology and Hepatology (doi: 10.1016/j.jcmgh.2017.02.008).
Current treatment options for short-bowel syndrome-associated liver disease are limited, wrote Prue M. Pereira-Fantini, PhD, of Murdoch Childrens Research Institute, Victoria, Australia, and colleagues. However, the farnesoid X receptor, which regulates genes involved in bile acid synthesis, absorption, and transport in the intestine and liver, has shown promise as a pharmaceutical target.
“Recently, we described SBS-ALD-associated alterations in bile acid composition associated with disrupted farnesoid X receptor (FXR) signaling mechanisms,” the researchers said. Obeticholic acid (OCA) has been shown to prevent liver disease in mouse models and human disease, and the researchers explored whether it would be effective in the context of short-bowel syndrome associated liver disease (SBS-ALD).
The researchers randomized piglets into four groups to receive small-bowel resection or sham surgery, and either a daily dose of 2.4 mg/kg per day of OCA or no treatment. The pigs were euthanized 2 weeks after their surgeries, and the researchers collected portal plasma samples, bile samples, and liver samples.
OCA treatment in piglets in the SBS surgery group was associated with decreased stool fat that suggested improved fat absorption, but impacted liver morphology, the researchers noted. “Untreated, sham-operated piglets showed normal liver histology when compared with SBS piglets who showed decreased hepatic lobule area and small clusters of inflammatory cells together with mild-to-moderate vesicular zone 2 lipidosis,” they wrote.
Overall, OCA treatment prevented the depletion of taurine; taurine concentration was approximately 8 ng/mL for piglets with SBS treated with OCA compared with 8 ng/mL in the sham group, 9 ng/mL in the sham plus OCA group, and 3 ng/mL in the SBS-only group. However, bile acid dysmetabolism occurred as shown by HDCA levels, which increased with OCA treatment compared to sham controls but were significantly reduced in SBS piglets treated with OCA vs. untreated SBS piglets.
In addition, the researchers found that small-bowel resection did not impact gene expression levels of FXR targets in the intestine or liver. However, “intestinal FXR gene expression was 11-fold higher in untreated SBS piglets when compared with untreated sham piglets,” they wrote. OCA treatment had no significant impact on FXR gene expression in the OCA-treated group vs. the untreated group and in the OCA-treated SBS group.
Although the findings were limited by use of an animal model, the results suggest that OCA treatment may have clinical benefits for SBS patients by reducing fat malabsorption, which remains a challenge, the researchers wrote. However, OCA “did not prevent the development of SBS-ALD, thereby limiting the potential therapeutic benefit in patients with SBS,” they concluded.
The researchers had no financial conflicts to disclose. The study was supported in part by the National Health and Medical Research Council of Australia and by a research grant from the Science Foundation Ireland.
FROM CMGH
Key clinical point: Treatment with obeticholic acid improved absorption and altered bile acid, but did not prevent liver damage in a piglet model of short-bowel syndrome.
Major finding: Overall, taurine concentration was approximately 8 ng/mL for piglets with SBS treated with OCA compared with 8 ng/mL in the sham surgery group, 9 ng/mL in the sham treated with OCA group, and 3 ng/mL in the SBS-only group.
Data source: The data come from piglets treated with obeticholic acid or untreated, and randomized to a small-bowel resection or a sham surgery.
Disclosures: The researchers had no financial conflicts to disclose,
Gene editing aims to recreate beneficial mutation in SCD, beta-thalassemia
MADRID – With some genetic sleight-of-hand, investigators hope to mimic a rare, naturally occurring mutation that protects some patients with beta-thalassemia or sickle-cell disease (SCD) from becoming symptomatic.
Although human studies have yet to begin, investigators in a biotech company report that they can use CRISPR/Cas9 gene editing to recreate the rare condition known as hereditary persistence of fetal hemoglobin, or HPFH, which causes some patients with SCD or beta-thalassemia to continue to produce the fully functional fetal rather than adult form of hemoglobin into adulthood.
To date, there have been no detectable undesirable off-target genetic modifications seen by targeted deep sequencing for the two leading guide RNAs (gRNA) in development, he said at the annual congress of the European Hematology Association.
“Patients with sickle-cell disease and beta-thalassemia are not sick when they are first born, but symptoms develop shortly after birth as the fetal hemoglobin levels decline, and as adult hemoglobin rises,” Dr. Lundberg said.
Fetal hemoglobin has been shown to reduce the risk of sickle events in SCD, and reduce symptoms and morbidity of beta-thalassemia.
“Modest amounts of fetal hemoglobin are beneficial, and more appears to be better,” he said.
In rare instances, the genetic switch to turn off fetal hemoglobin fails, leading to HPFH. It is this rare circumstance that the investigators hope to copy.
CRISPR/Cas9 technology copies a bacterial defense mechanism using clustered regularly interspaced short palindromic (CRISPR) repeats of DNA as a template for adaptive immunity against viruses and plasmids. The system allows bacteria to prevent the activation of invading nucleic acids by effectively snipping out target sequences of foreign DNA.
The investigators plan to harvest hematopoietic stem cells from patients with SCD and beta-thalassemia and use CRISPR/Cas9 technology to modify the cells to express the fetal form of hemoglobin. The reintroduced stem cells would, ideally, proliferate and help protect patients against painful crises and debilitating symptoms of the hemoglobinopathies.
Dr. Lundberg said that to date they have been able to edit blood stem cells with more than 80% on-target efficiency, and that the editing leads to “clinically meaningful” levels of protective fetal hemoglobin, in the range of 30%.
As noted, the investigators have to date seen no evidence of off-target editing that could lead to undesirable or dangerous complications. When introduced into an immunodeficient mouse model (NOD scid gamma, or NSG mice), the edited human cells persisted for long periods.
Finally, the investigators have been able to demonstrate that the modified stem cells are able to differentiate and reconstitute different types of cells in blood.
The company plans to submit a clinical trial application in 2017, and start clinical trials in 2018, Dr. Lundberg said.
At a media briefing where he discussed his research prior to his presentation of data in a symposium, Dr. Lundberg said that to date they have worked only with mouse models and with cells from healthy donors.
He pointed out, however, that there are many thousands of patients with inherited hemoglobin disorders worldwide and beta-thalassemia, and asked “how do you proceed to implement this very expensive treatment?”
Dr. Lundberg acknowledged that the diseases are common in both the developing world and in wealthy countries. He said that the technique relies as much as possible on existing technologies, and pointed out that if the treatment is successful, it’s costs could be at least partially offset by reducing the costs of other forms of therapy.
The work is supported by CRISPR Therapeutics. Dr. Lundberg is an employee and shareholder in the company. Dr. Hagenbeek reported having no relevant conflicts of interest.
MADRID – With some genetic sleight-of-hand, investigators hope to mimic a rare, naturally occurring mutation that protects some patients with beta-thalassemia or sickle-cell disease (SCD) from becoming symptomatic.
Although human studies have yet to begin, investigators in a biotech company report that they can use CRISPR/Cas9 gene editing to recreate the rare condition known as hereditary persistence of fetal hemoglobin, or HPFH, which causes some patients with SCD or beta-thalassemia to continue to produce the fully functional fetal rather than adult form of hemoglobin into adulthood.
To date, there have been no detectable undesirable off-target genetic modifications seen by targeted deep sequencing for the two leading guide RNAs (gRNA) in development, he said at the annual congress of the European Hematology Association.
“Patients with sickle-cell disease and beta-thalassemia are not sick when they are first born, but symptoms develop shortly after birth as the fetal hemoglobin levels decline, and as adult hemoglobin rises,” Dr. Lundberg said.
Fetal hemoglobin has been shown to reduce the risk of sickle events in SCD, and reduce symptoms and morbidity of beta-thalassemia.
“Modest amounts of fetal hemoglobin are beneficial, and more appears to be better,” he said.
In rare instances, the genetic switch to turn off fetal hemoglobin fails, leading to HPFH. It is this rare circumstance that the investigators hope to copy.
CRISPR/Cas9 technology copies a bacterial defense mechanism using clustered regularly interspaced short palindromic (CRISPR) repeats of DNA as a template for adaptive immunity against viruses and plasmids. The system allows bacteria to prevent the activation of invading nucleic acids by effectively snipping out target sequences of foreign DNA.
The investigators plan to harvest hematopoietic stem cells from patients with SCD and beta-thalassemia and use CRISPR/Cas9 technology to modify the cells to express the fetal form of hemoglobin. The reintroduced stem cells would, ideally, proliferate and help protect patients against painful crises and debilitating symptoms of the hemoglobinopathies.
Dr. Lundberg said that to date they have been able to edit blood stem cells with more than 80% on-target efficiency, and that the editing leads to “clinically meaningful” levels of protective fetal hemoglobin, in the range of 30%.
As noted, the investigators have to date seen no evidence of off-target editing that could lead to undesirable or dangerous complications. When introduced into an immunodeficient mouse model (NOD scid gamma, or NSG mice), the edited human cells persisted for long periods.
Finally, the investigators have been able to demonstrate that the modified stem cells are able to differentiate and reconstitute different types of cells in blood.
The company plans to submit a clinical trial application in 2017, and start clinical trials in 2018, Dr. Lundberg said.
At a media briefing where he discussed his research prior to his presentation of data in a symposium, Dr. Lundberg said that to date they have worked only with mouse models and with cells from healthy donors.
He pointed out, however, that there are many thousands of patients with inherited hemoglobin disorders worldwide and beta-thalassemia, and asked “how do you proceed to implement this very expensive treatment?”
Dr. Lundberg acknowledged that the diseases are common in both the developing world and in wealthy countries. He said that the technique relies as much as possible on existing technologies, and pointed out that if the treatment is successful, it’s costs could be at least partially offset by reducing the costs of other forms of therapy.
The work is supported by CRISPR Therapeutics. Dr. Lundberg is an employee and shareholder in the company. Dr. Hagenbeek reported having no relevant conflicts of interest.
MADRID – With some genetic sleight-of-hand, investigators hope to mimic a rare, naturally occurring mutation that protects some patients with beta-thalassemia or sickle-cell disease (SCD) from becoming symptomatic.
Although human studies have yet to begin, investigators in a biotech company report that they can use CRISPR/Cas9 gene editing to recreate the rare condition known as hereditary persistence of fetal hemoglobin, or HPFH, which causes some patients with SCD or beta-thalassemia to continue to produce the fully functional fetal rather than adult form of hemoglobin into adulthood.
To date, there have been no detectable undesirable off-target genetic modifications seen by targeted deep sequencing for the two leading guide RNAs (gRNA) in development, he said at the annual congress of the European Hematology Association.
“Patients with sickle-cell disease and beta-thalassemia are not sick when they are first born, but symptoms develop shortly after birth as the fetal hemoglobin levels decline, and as adult hemoglobin rises,” Dr. Lundberg said.
Fetal hemoglobin has been shown to reduce the risk of sickle events in SCD, and reduce symptoms and morbidity of beta-thalassemia.
“Modest amounts of fetal hemoglobin are beneficial, and more appears to be better,” he said.
In rare instances, the genetic switch to turn off fetal hemoglobin fails, leading to HPFH. It is this rare circumstance that the investigators hope to copy.
CRISPR/Cas9 technology copies a bacterial defense mechanism using clustered regularly interspaced short palindromic (CRISPR) repeats of DNA as a template for adaptive immunity against viruses and plasmids. The system allows bacteria to prevent the activation of invading nucleic acids by effectively snipping out target sequences of foreign DNA.
The investigators plan to harvest hematopoietic stem cells from patients with SCD and beta-thalassemia and use CRISPR/Cas9 technology to modify the cells to express the fetal form of hemoglobin. The reintroduced stem cells would, ideally, proliferate and help protect patients against painful crises and debilitating symptoms of the hemoglobinopathies.
Dr. Lundberg said that to date they have been able to edit blood stem cells with more than 80% on-target efficiency, and that the editing leads to “clinically meaningful” levels of protective fetal hemoglobin, in the range of 30%.
As noted, the investigators have to date seen no evidence of off-target editing that could lead to undesirable or dangerous complications. When introduced into an immunodeficient mouse model (NOD scid gamma, or NSG mice), the edited human cells persisted for long periods.
Finally, the investigators have been able to demonstrate that the modified stem cells are able to differentiate and reconstitute different types of cells in blood.
The company plans to submit a clinical trial application in 2017, and start clinical trials in 2018, Dr. Lundberg said.
At a media briefing where he discussed his research prior to his presentation of data in a symposium, Dr. Lundberg said that to date they have worked only with mouse models and with cells from healthy donors.
He pointed out, however, that there are many thousands of patients with inherited hemoglobin disorders worldwide and beta-thalassemia, and asked “how do you proceed to implement this very expensive treatment?”
Dr. Lundberg acknowledged that the diseases are common in both the developing world and in wealthy countries. He said that the technique relies as much as possible on existing technologies, and pointed out that if the treatment is successful, it’s costs could be at least partially offset by reducing the costs of other forms of therapy.
The work is supported by CRISPR Therapeutics. Dr. Lundberg is an employee and shareholder in the company. Dr. Hagenbeek reported having no relevant conflicts of interest.
AT EHA 2017
Key clinical point: The fetal form of hemoglobin is protective against symptoms of sickle-cell disease (SCD) and beta-thalassemia.
Major finding: Human blood stem cells modified by CRISPR/Cas9 gene editing produced fetal hemoglobin without observable off-target effects.
Data source: Summary of preclinical studies with blood from healthy human volunteers and mouse models.
Disclosures: The work is supported by CRISPR Therapeutics. Dr. Lundberg is an employee and shareholder in the company. Dr. Hagenbeek reported having no relevant conflicts of interest.
Oral insulin matches glargine in phase II trial
SAN DIEGO – In an industry-funded phase II trial, researchers say they’ve shown for the first time that oral basal insulin tablets can safely decrease plasma glucose in patients with type 2 diabetes (T2DM).
“Oral basal insulin appears safe and efficacious in insulin-naive patients with type 2 [diabetes] insufficiently controlled with medications. It improves glycemic control to a similar extent as does glargine,” said study lead author Leona Plum-Mörschel, MD, CEO of the German clinical research organization Profil Mainz, in an oral presentation at the scientific sessions of the American Diabetes Association. A statement from Novo Nordisk, the maker of the investigational medication, says the company discontinued development of the product due to its low bioavailability and concerns about the costs of producing it.
According to Dr. Plum-Mörschel, researchers have been searching for an oral insulin treatment for almost a century without success.
In the new phase IIa study, researchers tested a basal insulin analog tablet called OI338GT. It uses a technology platform called Gipet by Merrion Pharmaceuticals that aims to boost the absorption of injectable drugs when they are given in oral form.
Researchers recruited 50 insulin-naive patients with T2DM (mean age 61 ± 7 years, mean BMI 30.5 ± 3.7 kg/m²) whose diabetes wasn’t properly controlled by metformin by itself or in conjunction with other drugs. All had hemoglobin A1c (HbA1c) levels between 7% and 10%.
The patients were randomly assigned (1:1) to the investigational oral medication or subcutaneous insulin glargine (IGlar). They took the drugs once a day for 8 weeks in addition to their existing drug regimen.
The researchers increased the doses on a weekly basis with a goal of reaching fasting plasma glucose (FPG) of 80-126 mg/dL. Daily doses of the investigational drug (nmol/kg) began at a mean 30 ± 11 and reached 114 ± 51 by the end of the study; daily mean doses of IGlar (U/kg) began at 0.11 ± 0.03 and ended at 0.33 ± 0.15.
Both medications boosted glycemic control at about the same level, the researchers report, based on levels of FPG, HbA1c, and fructosamine levels at 8 weeks.
Mean FPG levels (mg/dL), the primary endpoint, declined in investigational medication and IGlar from 175 ± 50 and 164 ± 31, respectively, at baseline to 129 ± 33 and 121 ± 17, respectively, at end of treatment. The treatment difference (investigational medication – IGlar) was 5.2 mg/dL [–8.8;19.1], 95% CI, P = .4567.
In a post hoc analysis, mean HbA1c levels declined from 8.1 ± 0.6% and 8.2 ± 0.8% at baseline in investigational medication and IGlar, respectively, to 7.3 ± 0.8% and 7.1 ± 0.6%, respectively. The treatment difference (investigational medication – IGlar) was 0.30% [–0.03;0.63], 95% CI, P = .0774.
In another post hoc analysis, mean fructosamine levels (micromol/L) dipped from 275 ± 44 and 273 ± 50 in investigational medication and IGlar, respectively, to 235 ± 45 and 223 ± 34, respectively. The treatment difference (investigational medication – IGlar)
was 9.6 micromol/L [–11.7;30.9], 95% CI, P = .3700. None of the patients reported severe hypoglycemia. In the investigational group, 6 subjects suffered 7 events of hypoglycemia that emerged or worsened during treatment; 11 events occurred in 6 subjects in the IGlar group. Researchers report similar levels of adverse events in both groups: 31 in 15 patients treated with the investigational drug and 37 in 17 patients treated with IGlar.
“After termination of treatment, plasma glucose rebounded to baseline levels within a couple of weeks,” Dr. Plum-Mörschel said.
Novo Nordisk funded the trial. Dr. Plum-Mörschel reports no disclosures.
SAN DIEGO – In an industry-funded phase II trial, researchers say they’ve shown for the first time that oral basal insulin tablets can safely decrease plasma glucose in patients with type 2 diabetes (T2DM).
“Oral basal insulin appears safe and efficacious in insulin-naive patients with type 2 [diabetes] insufficiently controlled with medications. It improves glycemic control to a similar extent as does glargine,” said study lead author Leona Plum-Mörschel, MD, CEO of the German clinical research organization Profil Mainz, in an oral presentation at the scientific sessions of the American Diabetes Association. A statement from Novo Nordisk, the maker of the investigational medication, says the company discontinued development of the product due to its low bioavailability and concerns about the costs of producing it.
According to Dr. Plum-Mörschel, researchers have been searching for an oral insulin treatment for almost a century without success.
In the new phase IIa study, researchers tested a basal insulin analog tablet called OI338GT. It uses a technology platform called Gipet by Merrion Pharmaceuticals that aims to boost the absorption of injectable drugs when they are given in oral form.
Researchers recruited 50 insulin-naive patients with T2DM (mean age 61 ± 7 years, mean BMI 30.5 ± 3.7 kg/m²) whose diabetes wasn’t properly controlled by metformin by itself or in conjunction with other drugs. All had hemoglobin A1c (HbA1c) levels between 7% and 10%.
The patients were randomly assigned (1:1) to the investigational oral medication or subcutaneous insulin glargine (IGlar). They took the drugs once a day for 8 weeks in addition to their existing drug regimen.
The researchers increased the doses on a weekly basis with a goal of reaching fasting plasma glucose (FPG) of 80-126 mg/dL. Daily doses of the investigational drug (nmol/kg) began at a mean 30 ± 11 and reached 114 ± 51 by the end of the study; daily mean doses of IGlar (U/kg) began at 0.11 ± 0.03 and ended at 0.33 ± 0.15.
Both medications boosted glycemic control at about the same level, the researchers report, based on levels of FPG, HbA1c, and fructosamine levels at 8 weeks.
Mean FPG levels (mg/dL), the primary endpoint, declined in investigational medication and IGlar from 175 ± 50 and 164 ± 31, respectively, at baseline to 129 ± 33 and 121 ± 17, respectively, at end of treatment. The treatment difference (investigational medication – IGlar) was 5.2 mg/dL [–8.8;19.1], 95% CI, P = .4567.
In a post hoc analysis, mean HbA1c levels declined from 8.1 ± 0.6% and 8.2 ± 0.8% at baseline in investigational medication and IGlar, respectively, to 7.3 ± 0.8% and 7.1 ± 0.6%, respectively. The treatment difference (investigational medication – IGlar) was 0.30% [–0.03;0.63], 95% CI, P = .0774.
In another post hoc analysis, mean fructosamine levels (micromol/L) dipped from 275 ± 44 and 273 ± 50 in investigational medication and IGlar, respectively, to 235 ± 45 and 223 ± 34, respectively. The treatment difference (investigational medication – IGlar)
was 9.6 micromol/L [–11.7;30.9], 95% CI, P = .3700. None of the patients reported severe hypoglycemia. In the investigational group, 6 subjects suffered 7 events of hypoglycemia that emerged or worsened during treatment; 11 events occurred in 6 subjects in the IGlar group. Researchers report similar levels of adverse events in both groups: 31 in 15 patients treated with the investigational drug and 37 in 17 patients treated with IGlar.
“After termination of treatment, plasma glucose rebounded to baseline levels within a couple of weeks,” Dr. Plum-Mörschel said.
Novo Nordisk funded the trial. Dr. Plum-Mörschel reports no disclosures.
SAN DIEGO – In an industry-funded phase II trial, researchers say they’ve shown for the first time that oral basal insulin tablets can safely decrease plasma glucose in patients with type 2 diabetes (T2DM).
“Oral basal insulin appears safe and efficacious in insulin-naive patients with type 2 [diabetes] insufficiently controlled with medications. It improves glycemic control to a similar extent as does glargine,” said study lead author Leona Plum-Mörschel, MD, CEO of the German clinical research organization Profil Mainz, in an oral presentation at the scientific sessions of the American Diabetes Association. A statement from Novo Nordisk, the maker of the investigational medication, says the company discontinued development of the product due to its low bioavailability and concerns about the costs of producing it.
According to Dr. Plum-Mörschel, researchers have been searching for an oral insulin treatment for almost a century without success.
In the new phase IIa study, researchers tested a basal insulin analog tablet called OI338GT. It uses a technology platform called Gipet by Merrion Pharmaceuticals that aims to boost the absorption of injectable drugs when they are given in oral form.
Researchers recruited 50 insulin-naive patients with T2DM (mean age 61 ± 7 years, mean BMI 30.5 ± 3.7 kg/m²) whose diabetes wasn’t properly controlled by metformin by itself or in conjunction with other drugs. All had hemoglobin A1c (HbA1c) levels between 7% and 10%.
The patients were randomly assigned (1:1) to the investigational oral medication or subcutaneous insulin glargine (IGlar). They took the drugs once a day for 8 weeks in addition to their existing drug regimen.
The researchers increased the doses on a weekly basis with a goal of reaching fasting plasma glucose (FPG) of 80-126 mg/dL. Daily doses of the investigational drug (nmol/kg) began at a mean 30 ± 11 and reached 114 ± 51 by the end of the study; daily mean doses of IGlar (U/kg) began at 0.11 ± 0.03 and ended at 0.33 ± 0.15.
Both medications boosted glycemic control at about the same level, the researchers report, based on levels of FPG, HbA1c, and fructosamine levels at 8 weeks.
Mean FPG levels (mg/dL), the primary endpoint, declined in investigational medication and IGlar from 175 ± 50 and 164 ± 31, respectively, at baseline to 129 ± 33 and 121 ± 17, respectively, at end of treatment. The treatment difference (investigational medication – IGlar) was 5.2 mg/dL [–8.8;19.1], 95% CI, P = .4567.
In a post hoc analysis, mean HbA1c levels declined from 8.1 ± 0.6% and 8.2 ± 0.8% at baseline in investigational medication and IGlar, respectively, to 7.3 ± 0.8% and 7.1 ± 0.6%, respectively. The treatment difference (investigational medication – IGlar) was 0.30% [–0.03;0.63], 95% CI, P = .0774.
In another post hoc analysis, mean fructosamine levels (micromol/L) dipped from 275 ± 44 and 273 ± 50 in investigational medication and IGlar, respectively, to 235 ± 45 and 223 ± 34, respectively. The treatment difference (investigational medication – IGlar)
was 9.6 micromol/L [–11.7;30.9], 95% CI, P = .3700. None of the patients reported severe hypoglycemia. In the investigational group, 6 subjects suffered 7 events of hypoglycemia that emerged or worsened during treatment; 11 events occurred in 6 subjects in the IGlar group. Researchers report similar levels of adverse events in both groups: 31 in 15 patients treated with the investigational drug and 37 in 17 patients treated with IGlar.
“After termination of treatment, plasma glucose rebounded to baseline levels within a couple of weeks,” Dr. Plum-Mörschel said.
Novo Nordisk funded the trial. Dr. Plum-Mörschel reports no disclosures.
AT THE ADA ANNUAL SCIENTIFIC SESSIONS
Key clinical point: In 8-week trial, oral insulin tablets produce similar glucose control to injectable glargine (IGlar) in patients with type 2 diabetes (T2DM).
Major finding: Mean levels fasting plasma glucose (FPG, mg/dL) declined from 175 ± 50 to 129 ± 33 (investigational medication) and from 164 ± 31 to 121 ± 17 (IGlar). The treatment difference (investigational medication – IGlar) was 5.2 mg/dL [–8.8;19.1], 95% CI, P = .4567.
Data source: 50 insulin-naive patients with T2DM randomly assigned (1:1) to daily doses of investigational oral medication or IGlar for 8 weeks, titrated to reach target FPG of 80-126 mg/dL.
Disclosures: Novo Nordisk funded the trial. Dr. Plum-Mörschel reports no disclosures.
Developments on the malaria front
Progress is being made in the battle against malaria. From engineering a mosquito-killing fungus to discovering new anti-malaria targets, scientists are making advances on multiple malaria fronts.
And US aid to combat malaria is having a positive impact on reducing childhood mortality in 19 sub-Saharan countries. A few of the recent developments are described here.
Genetic engineering
Scientists developed a genetic technique that disrupts the heme synthesis pathway in Plasmodium berghei parasites, which could be an effective way to target Plasmodium parasites in the liver.
Heme synthesis is essential for P berghei development in mosquitoes that transmit the parasite between rodent hosts. However, the pathway is not essential during a later stage of the parasite’s development in the bloodstream.
So researchers produced P berghei parasites capable of expressing the FC gene. The FC (ferrochelatase) gene allows P berghei to produce heme. The parasites could develop properly in mosquitoes, but produced some FC-deficient parasites once they infected mouse liver cells.
FC-deficient parasites were unable to complete their liver development phase.
The team says this approach would be prophylactic, since malaria symptoms aren't apparent until the parasite leaves the liver and begins its bloodstream phase.
The team published its findings in PLOS Pathogens.
Mosquito-killing fungi
In a report that sounds almost like a science fiction story, researchers genetically engineered a fungus to kill mosquitoes by producing spider and scorpion toxins.
They suggest this method could serve as a highly effective biological control mechanism to fight malaria-carrying mosquitoes.
The researchers isolated genes that express neurotoxins from the venom of scorpions and spiders. They then engineered the genes into the fungus's DNA.
The researchers used the fungus Metarhizium pingshaensei, which is a natural killer of mosquitoes.
The fungus was originally isolated from a mosquito and previous evidence suggests it is specific to disease-carrying mosquito species, including Anopheles gambiae and Aedes aegypti.
When spores of the fungus contact a mosquito's body, the spores germinate and penetrate the insect's exoskeleton, eventually killing the insect host from the inside out.
And the most potent fungal strains, Brian Lovett, a graduate student at the University of Maryland in College Park, explained, “are able to kill mosquitoes with a single spore."
He added that the fungi also stop mosquitoes from blood feeding. Taken together, this means “that our fungal strains are capable of preventing transmission of disease by more than 90 percent of mosquitoes after just 5 days."
The fungus is specific to mosquitoes and does not pose a risk to humans. The study results also suggest the fungus is safe for honeybees and other insects.
The researchers plan to expand on-the-ground testing in Burkina Faso.
For more on this mosquito-killing approach, see their study published in Scientific Reports.
Potential new target
Researchers have described a new protein, the transcription factor PfAP2-I, which they say may turn out to be an effective target to combat drug-resistant malaria parasites.
PfAP2-I regulates genes involved with the parasite's invasion of red blood cells. This is a critical part of the parasite's 3-stage life cycle that could be targeted by new anti-malarial drugs.
“Most multi-celled organisms have hundreds of these regulators,” said lead author Manuel Llinás, PhD, of Penn State University in State College, Pennsylvania, “but it turns out, so far as we can recognize, the [Plasmodium] parasite has a single family of transcription factors called Apicomplexan AP2 proteins. One of these transcription factors is PfAP2-I."
PfAP2-I is the first known regulator of invasion genes in Plasmodium falciparum.
The new study also indicates that PfAP2-I likely recruits another protein, Bromodomain Protein 1 (PfBDP1), which was previously shown to be involved in the invasion of red blood cells.
The two proteins may work together to regulate gene transcription during this critical stage of infection.
For more on this potential new target, see their study published in Cell Host & Microbe.
Parasite diversity
Not all malaria infections result in life-threatening anemia and organ failure, and so a research team led by Matthew B. B. McCall, MD, PhD, of Erasmus Medical Center in Rotterdam, the Netherlands, set out to determine why.
They exposed 23 healthy human volunteers to sets of 5 mosquitoes carrying the NF54, NF135.C10, or NF166.C8 isolates of P falciparum.
All volunteers developed parasitemia, were treated with anti-malarial drugs, and recovered, although some strains caused more severe symptoms.
The investigators found that 3 geographic and genetically diverse forms of the parasite each demonstrated a distinct ability to infect liver cells.
They also observed the degree of infection in human liver cells growing in culture was closely correlated with parasite loads in the bloodstream.
The investigators believe the variability among parasite types suggests that malaria vaccines should use multiple strains.
In addition, the infectivity of different parasite strains could vary in populations previously exposed to malaria.
For more details on parasite diversity, see the team’s findings in Science Translational Medicine.
Malaria test
A new malaria test can diagnose malaria faster and more reliably than current methods, according to a report in the NL Times.
The new test uses an algorithm that can diagnose malaria at a rate of 120 blood tests per hour. It is 97% accurate.
Rather than search for the parasite itself in blood samples, the new test analyzes the effect the infection has on the blood, such as shape and density of red blood cells, hemoglobin level, and 27 other parameters simultaneously.
The developers won the European Inventor Award for the rapid malaria test, which will be further developed by Siemens.
Aid to combat malaria
The US malaria initiative in 19 sub-Saharan African countries has contributed to a 16% reduction in the annual risk of mortality for children under 5 years, according to a new study published in PLOS Medicine.
Thirteen sub-Saharan countries did not receive funding from the initiative, which allowed researchers to compare and analyze the impact of the intervention.
Because the study may have had confounding variables that were not measured, however, the results could not be definitively interpreted as causal evidence of the reduction in child mortality rates.
However, they do indicate an association between the receipt of funding and mortality.
The funding went to support malaria prevention technologies, such as insecticide-treated nets and indoor residual spraying.
The authors believe further investment in these interventions “may translate to additional lives saved, reduced household financial burdens associated with caring for ill household members and lost wages, and less strain on health systems associated with treating malaria cases.”
Countries that received funding included: Angola, Benin, Congo DRC, Ethiopia, Ghana, Guinea, Kenya, Liberia, Madagascar, Malawi, Mali, Mozambique, Nigeria, Rwanda, Senegal, Tanzania, Uganda, Zambia, and Zimbabwe.
Comparison countries include: Burkina Faso, Burundi, Cameroon, Chad, Congo, Cote d’Ivoire, Gabon, Namibia, Niger, Sierra Leone, Swaziland, The Gambia, and Togo. 
Progress is being made in the battle against malaria. From engineering a mosquito-killing fungus to discovering new anti-malaria targets, scientists are making advances on multiple malaria fronts.
And US aid to combat malaria is having a positive impact on reducing childhood mortality in 19 sub-Saharan countries. A few of the recent developments are described here.
Genetic engineering
Scientists developed a genetic technique that disrupts the heme synthesis pathway in Plasmodium berghei parasites, which could be an effective way to target Plasmodium parasites in the liver.
Heme synthesis is essential for P berghei development in mosquitoes that transmit the parasite between rodent hosts. However, the pathway is not essential during a later stage of the parasite’s development in the bloodstream.
So researchers produced P berghei parasites capable of expressing the FC gene. The FC (ferrochelatase) gene allows P berghei to produce heme. The parasites could develop properly in mosquitoes, but produced some FC-deficient parasites once they infected mouse liver cells.
FC-deficient parasites were unable to complete their liver development phase.
The team says this approach would be prophylactic, since malaria symptoms aren't apparent until the parasite leaves the liver and begins its bloodstream phase.
The team published its findings in PLOS Pathogens.
Mosquito-killing fungi
In a report that sounds almost like a science fiction story, researchers genetically engineered a fungus to kill mosquitoes by producing spider and scorpion toxins.
They suggest this method could serve as a highly effective biological control mechanism to fight malaria-carrying mosquitoes.
The researchers isolated genes that express neurotoxins from the venom of scorpions and spiders. They then engineered the genes into the fungus's DNA.
The researchers used the fungus Metarhizium pingshaensei, which is a natural killer of mosquitoes.
The fungus was originally isolated from a mosquito and previous evidence suggests it is specific to disease-carrying mosquito species, including Anopheles gambiae and Aedes aegypti.
When spores of the fungus contact a mosquito's body, the spores germinate and penetrate the insect's exoskeleton, eventually killing the insect host from the inside out.
And the most potent fungal strains, Brian Lovett, a graduate student at the University of Maryland in College Park, explained, “are able to kill mosquitoes with a single spore."
He added that the fungi also stop mosquitoes from blood feeding. Taken together, this means “that our fungal strains are capable of preventing transmission of disease by more than 90 percent of mosquitoes after just 5 days."
The fungus is specific to mosquitoes and does not pose a risk to humans. The study results also suggest the fungus is safe for honeybees and other insects.
The researchers plan to expand on-the-ground testing in Burkina Faso.
For more on this mosquito-killing approach, see their study published in Scientific Reports.
Potential new target
Researchers have described a new protein, the transcription factor PfAP2-I, which they say may turn out to be an effective target to combat drug-resistant malaria parasites.
PfAP2-I regulates genes involved with the parasite's invasion of red blood cells. This is a critical part of the parasite's 3-stage life cycle that could be targeted by new anti-malarial drugs.
“Most multi-celled organisms have hundreds of these regulators,” said lead author Manuel Llinás, PhD, of Penn State University in State College, Pennsylvania, “but it turns out, so far as we can recognize, the [Plasmodium] parasite has a single family of transcription factors called Apicomplexan AP2 proteins. One of these transcription factors is PfAP2-I."
PfAP2-I is the first known regulator of invasion genes in Plasmodium falciparum.
The new study also indicates that PfAP2-I likely recruits another protein, Bromodomain Protein 1 (PfBDP1), which was previously shown to be involved in the invasion of red blood cells.
The two proteins may work together to regulate gene transcription during this critical stage of infection.
For more on this potential new target, see their study published in Cell Host & Microbe.
Parasite diversity
Not all malaria infections result in life-threatening anemia and organ failure, and so a research team led by Matthew B. B. McCall, MD, PhD, of Erasmus Medical Center in Rotterdam, the Netherlands, set out to determine why.
They exposed 23 healthy human volunteers to sets of 5 mosquitoes carrying the NF54, NF135.C10, or NF166.C8 isolates of P falciparum.
All volunteers developed parasitemia, were treated with anti-malarial drugs, and recovered, although some strains caused more severe symptoms.
The investigators found that 3 geographic and genetically diverse forms of the parasite each demonstrated a distinct ability to infect liver cells.
They also observed the degree of infection in human liver cells growing in culture was closely correlated with parasite loads in the bloodstream.
The investigators believe the variability among parasite types suggests that malaria vaccines should use multiple strains.
In addition, the infectivity of different parasite strains could vary in populations previously exposed to malaria.
For more details on parasite diversity, see the team’s findings in Science Translational Medicine.
Malaria test
A new malaria test can diagnose malaria faster and more reliably than current methods, according to a report in the NL Times.
The new test uses an algorithm that can diagnose malaria at a rate of 120 blood tests per hour. It is 97% accurate.
Rather than search for the parasite itself in blood samples, the new test analyzes the effect the infection has on the blood, such as shape and density of red blood cells, hemoglobin level, and 27 other parameters simultaneously.
The developers won the European Inventor Award for the rapid malaria test, which will be further developed by Siemens.
Aid to combat malaria
The US malaria initiative in 19 sub-Saharan African countries has contributed to a 16% reduction in the annual risk of mortality for children under 5 years, according to a new study published in PLOS Medicine.
Thirteen sub-Saharan countries did not receive funding from the initiative, which allowed researchers to compare and analyze the impact of the intervention.
Because the study may have had confounding variables that were not measured, however, the results could not be definitively interpreted as causal evidence of the reduction in child mortality rates.
However, they do indicate an association between the receipt of funding and mortality.
The funding went to support malaria prevention technologies, such as insecticide-treated nets and indoor residual spraying.
The authors believe further investment in these interventions “may translate to additional lives saved, reduced household financial burdens associated with caring for ill household members and lost wages, and less strain on health systems associated with treating malaria cases.”
Countries that received funding included: Angola, Benin, Congo DRC, Ethiopia, Ghana, Guinea, Kenya, Liberia, Madagascar, Malawi, Mali, Mozambique, Nigeria, Rwanda, Senegal, Tanzania, Uganda, Zambia, and Zimbabwe.
Comparison countries include: Burkina Faso, Burundi, Cameroon, Chad, Congo, Cote d’Ivoire, Gabon, Namibia, Niger, Sierra Leone, Swaziland, The Gambia, and Togo.
Progress is being made in the battle against malaria. From engineering a mosquito-killing fungus to discovering new anti-malaria targets, scientists are making advances on multiple malaria fronts.
And US aid to combat malaria is having a positive impact on reducing childhood mortality in 19 sub-Saharan countries. A few of the recent developments are described here.
Genetic engineering
Scientists developed a genetic technique that disrupts the heme synthesis pathway in Plasmodium berghei parasites, which could be an effective way to target Plasmodium parasites in the liver.
Heme synthesis is essential for P berghei development in mosquitoes that transmit the parasite between rodent hosts. However, the pathway is not essential during a later stage of the parasite’s development in the bloodstream.
So researchers produced P berghei parasites capable of expressing the FC gene. The FC (ferrochelatase) gene allows P berghei to produce heme. The parasites could develop properly in mosquitoes, but produced some FC-deficient parasites once they infected mouse liver cells.
FC-deficient parasites were unable to complete their liver development phase.
The team says this approach would be prophylactic, since malaria symptoms aren't apparent until the parasite leaves the liver and begins its bloodstream phase.
The team published its findings in PLOS Pathogens.
Mosquito-killing fungi
In a report that sounds almost like a science fiction story, researchers genetically engineered a fungus to kill mosquitoes by producing spider and scorpion toxins.
They suggest this method could serve as a highly effective biological control mechanism to fight malaria-carrying mosquitoes.
The researchers isolated genes that express neurotoxins from the venom of scorpions and spiders. They then engineered the genes into the fungus's DNA.
The researchers used the fungus Metarhizium pingshaensei, which is a natural killer of mosquitoes.
The fungus was originally isolated from a mosquito and previous evidence suggests it is specific to disease-carrying mosquito species, including Anopheles gambiae and Aedes aegypti.
When spores of the fungus contact a mosquito's body, the spores germinate and penetrate the insect's exoskeleton, eventually killing the insect host from the inside out.
And the most potent fungal strains, Brian Lovett, a graduate student at the University of Maryland in College Park, explained, “are able to kill mosquitoes with a single spore."
He added that the fungi also stop mosquitoes from blood feeding. Taken together, this means “that our fungal strains are capable of preventing transmission of disease by more than 90 percent of mosquitoes after just 5 days."
The fungus is specific to mosquitoes and does not pose a risk to humans. The study results also suggest the fungus is safe for honeybees and other insects.
The researchers plan to expand on-the-ground testing in Burkina Faso.
For more on this mosquito-killing approach, see their study published in Scientific Reports.
Potential new target
Researchers have described a new protein, the transcription factor PfAP2-I, which they say may turn out to be an effective target to combat drug-resistant malaria parasites.
PfAP2-I regulates genes involved with the parasite's invasion of red blood cells. This is a critical part of the parasite's 3-stage life cycle that could be targeted by new anti-malarial drugs.
“Most multi-celled organisms have hundreds of these regulators,” said lead author Manuel Llinás, PhD, of Penn State University in State College, Pennsylvania, “but it turns out, so far as we can recognize, the [Plasmodium] parasite has a single family of transcription factors called Apicomplexan AP2 proteins. One of these transcription factors is PfAP2-I."
PfAP2-I is the first known regulator of invasion genes in Plasmodium falciparum.
The new study also indicates that PfAP2-I likely recruits another protein, Bromodomain Protein 1 (PfBDP1), which was previously shown to be involved in the invasion of red blood cells.
The two proteins may work together to regulate gene transcription during this critical stage of infection.
For more on this potential new target, see their study published in Cell Host & Microbe.
Parasite diversity
Not all malaria infections result in life-threatening anemia and organ failure, and so a research team led by Matthew B. B. McCall, MD, PhD, of Erasmus Medical Center in Rotterdam, the Netherlands, set out to determine why.
They exposed 23 healthy human volunteers to sets of 5 mosquitoes carrying the NF54, NF135.C10, or NF166.C8 isolates of P falciparum.
All volunteers developed parasitemia, were treated with anti-malarial drugs, and recovered, although some strains caused more severe symptoms.
The investigators found that 3 geographic and genetically diverse forms of the parasite each demonstrated a distinct ability to infect liver cells.
They also observed the degree of infection in human liver cells growing in culture was closely correlated with parasite loads in the bloodstream.
The investigators believe the variability among parasite types suggests that malaria vaccines should use multiple strains.
In addition, the infectivity of different parasite strains could vary in populations previously exposed to malaria.
For more details on parasite diversity, see the team’s findings in Science Translational Medicine.
Malaria test
A new malaria test can diagnose malaria faster and more reliably than current methods, according to a report in the NL Times.
The new test uses an algorithm that can diagnose malaria at a rate of 120 blood tests per hour. It is 97% accurate.
Rather than search for the parasite itself in blood samples, the new test analyzes the effect the infection has on the blood, such as shape and density of red blood cells, hemoglobin level, and 27 other parameters simultaneously.
The developers won the European Inventor Award for the rapid malaria test, which will be further developed by Siemens.
Aid to combat malaria
The US malaria initiative in 19 sub-Saharan African countries has contributed to a 16% reduction in the annual risk of mortality for children under 5 years, according to a new study published in PLOS Medicine.
Thirteen sub-Saharan countries did not receive funding from the initiative, which allowed researchers to compare and analyze the impact of the intervention.
Because the study may have had confounding variables that were not measured, however, the results could not be definitively interpreted as causal evidence of the reduction in child mortality rates.
However, they do indicate an association between the receipt of funding and mortality.
The funding went to support malaria prevention technologies, such as insecticide-treated nets and indoor residual spraying.
The authors believe further investment in these interventions “may translate to additional lives saved, reduced household financial burdens associated with caring for ill household members and lost wages, and less strain on health systems associated with treating malaria cases.”
Countries that received funding included: Angola, Benin, Congo DRC, Ethiopia, Ghana, Guinea, Kenya, Liberia, Madagascar, Malawi, Mali, Mozambique, Nigeria, Rwanda, Senegal, Tanzania, Uganda, Zambia, and Zimbabwe.
Comparison countries include: Burkina Faso, Burundi, Cameroon, Chad, Congo, Cote d’Ivoire, Gabon, Namibia, Niger, Sierra Leone, Swaziland, The Gambia, and Togo.
Safety data review finds no increased risk of infection from abatacept
MADRID – Abatacept doesn’t appear to increase the risk of opportunistic infections among patients with rheumatoid arthritis, Kevin Winthrop, MD, reported at the European Congress of Rheumatology.
After reviewing all of the extant safety data on the drug – all of its clinical trial and open-label study data, and case reports of abatacept-associated adverse events – Dr. Winthrop concluded that infections, including tuberculosis, fungal overgrowth, herpes simplex and herpes zoster, occur either with similar frequency or less often than among those taking placebo.
“In fact, there is a sense that abatacept is actually safer,” than some other disease-modifying antirheumatic drugs,” said Dr. Winthrop, an infectious disease specialist at Oregon Health and Science University, Portland. However, there are few data comparing safety among the agents – something he said should be examined in more detail.
His review encompassed 16 clinical trials comprising 7,044 patients who took the drug (21,330 patient/years of abatacept exposure) and 1,485 patients who took placebo. He conducted two analyses: one for opportunistic bacterial and fungal infections, and one for herpes simplex and herpes zoster.
The first analysis found 45 opportunistic bacterial or fungal infections among those taking abatacept – an incidence rate of 0.21/ 100 person-years. There were seven such infections in the placebo group – an incidence rate of 0.56/100 person-years. This difference was statistically significant.
In the abatacept cohort, there were two cases of bronchopulmonary aspergilliosis (IR 0.01) and three fungal eye infections (IR 0.01). There was also one case of gastrointestinal candidiasis; one fungal esophagitis; one cryptococcal meningitis; two pneumonias (one pseudomonal and one caused by Pneumocystis jirovecii); and two cases of respiratory monoliasis. All of these infections had an incidence rate of less than 0.01/100 person-years.
There were 17 tuberculosis cases (IR 0.08/100 person-years). Three cases were latent. Six of the cases were pulmonary and five were extrapulmonary. Two cases were unspecified. All occurred in regions with high or moderate endemic tuberculosis levels.
A meta-regression analysis examined the risk of opportunistic infections in the patients taken from the placebo-controlled clinical trials only (2,653 abatacept, 1,485 placebo). The estimated frequency of an opportunistic infection was 0.15% among those taking the drug and 0.48% among those taking placebo.
The herpes analysis examined the placebo-controlled clinical trial population as well. There were 57 cases of herpes simplex (IR 2.5/100 person-years) among those taking abatacept and 22 among those taking placebo (IR 1.8/100 person-years). The difference was not statistically significant.
There were 44 cases of herpes zoster among those taking abatacept (IR 1.9/100 person-years) and 21 among those taking placebo (IR 1.7/100 person-years).
“Basically, I think what we’re seeing here is a whole lot of nothing,” Dr. Winthrop said.
Dr. Winthrop has been a consultant for Pfizer, AbbVie, Bristol-Myers Squibb, UCB Pharma, Roche/Genentech, Amgen, Galapagos, and Eli Lilly.
[email protected]
On Twitter @Alz_gal
MADRID – Abatacept doesn’t appear to increase the risk of opportunistic infections among patients with rheumatoid arthritis, Kevin Winthrop, MD, reported at the European Congress of Rheumatology.
After reviewing all of the extant safety data on the drug – all of its clinical trial and open-label study data, and case reports of abatacept-associated adverse events – Dr. Winthrop concluded that infections, including tuberculosis, fungal overgrowth, herpes simplex and herpes zoster, occur either with similar frequency or less often than among those taking placebo.
“In fact, there is a sense that abatacept is actually safer,” than some other disease-modifying antirheumatic drugs,” said Dr. Winthrop, an infectious disease specialist at Oregon Health and Science University, Portland. However, there are few data comparing safety among the agents – something he said should be examined in more detail.
His review encompassed 16 clinical trials comprising 7,044 patients who took the drug (21,330 patient/years of abatacept exposure) and 1,485 patients who took placebo. He conducted two analyses: one for opportunistic bacterial and fungal infections, and one for herpes simplex and herpes zoster.
The first analysis found 45 opportunistic bacterial or fungal infections among those taking abatacept – an incidence rate of 0.21/ 100 person-years. There were seven such infections in the placebo group – an incidence rate of 0.56/100 person-years. This difference was statistically significant.
In the abatacept cohort, there were two cases of bronchopulmonary aspergilliosis (IR 0.01) and three fungal eye infections (IR 0.01). There was also one case of gastrointestinal candidiasis; one fungal esophagitis; one cryptococcal meningitis; two pneumonias (one pseudomonal and one caused by Pneumocystis jirovecii); and two cases of respiratory monoliasis. All of these infections had an incidence rate of less than 0.01/100 person-years.
There were 17 tuberculosis cases (IR 0.08/100 person-years). Three cases were latent. Six of the cases were pulmonary and five were extrapulmonary. Two cases were unspecified. All occurred in regions with high or moderate endemic tuberculosis levels.
A meta-regression analysis examined the risk of opportunistic infections in the patients taken from the placebo-controlled clinical trials only (2,653 abatacept, 1,485 placebo). The estimated frequency of an opportunistic infection was 0.15% among those taking the drug and 0.48% among those taking placebo.
The herpes analysis examined the placebo-controlled clinical trial population as well. There were 57 cases of herpes simplex (IR 2.5/100 person-years) among those taking abatacept and 22 among those taking placebo (IR 1.8/100 person-years). The difference was not statistically significant.
There were 44 cases of herpes zoster among those taking abatacept (IR 1.9/100 person-years) and 21 among those taking placebo (IR 1.7/100 person-years).
“Basically, I think what we’re seeing here is a whole lot of nothing,” Dr. Winthrop said.
Dr. Winthrop has been a consultant for Pfizer, AbbVie, Bristol-Myers Squibb, UCB Pharma, Roche/Genentech, Amgen, Galapagos, and Eli Lilly.
[email protected]
On Twitter @Alz_gal
MADRID – Abatacept doesn’t appear to increase the risk of opportunistic infections among patients with rheumatoid arthritis, Kevin Winthrop, MD, reported at the European Congress of Rheumatology.
After reviewing all of the extant safety data on the drug – all of its clinical trial and open-label study data, and case reports of abatacept-associated adverse events – Dr. Winthrop concluded that infections, including tuberculosis, fungal overgrowth, herpes simplex and herpes zoster, occur either with similar frequency or less often than among those taking placebo.
“In fact, there is a sense that abatacept is actually safer,” than some other disease-modifying antirheumatic drugs,” said Dr. Winthrop, an infectious disease specialist at Oregon Health and Science University, Portland. However, there are few data comparing safety among the agents – something he said should be examined in more detail.
His review encompassed 16 clinical trials comprising 7,044 patients who took the drug (21,330 patient/years of abatacept exposure) and 1,485 patients who took placebo. He conducted two analyses: one for opportunistic bacterial and fungal infections, and one for herpes simplex and herpes zoster.
The first analysis found 45 opportunistic bacterial or fungal infections among those taking abatacept – an incidence rate of 0.21/ 100 person-years. There were seven such infections in the placebo group – an incidence rate of 0.56/100 person-years. This difference was statistically significant.
In the abatacept cohort, there were two cases of bronchopulmonary aspergilliosis (IR 0.01) and three fungal eye infections (IR 0.01). There was also one case of gastrointestinal candidiasis; one fungal esophagitis; one cryptococcal meningitis; two pneumonias (one pseudomonal and one caused by Pneumocystis jirovecii); and two cases of respiratory monoliasis. All of these infections had an incidence rate of less than 0.01/100 person-years.
There were 17 tuberculosis cases (IR 0.08/100 person-years). Three cases were latent. Six of the cases were pulmonary and five were extrapulmonary. Two cases were unspecified. All occurred in regions with high or moderate endemic tuberculosis levels.
A meta-regression analysis examined the risk of opportunistic infections in the patients taken from the placebo-controlled clinical trials only (2,653 abatacept, 1,485 placebo). The estimated frequency of an opportunistic infection was 0.15% among those taking the drug and 0.48% among those taking placebo.
The herpes analysis examined the placebo-controlled clinical trial population as well. There were 57 cases of herpes simplex (IR 2.5/100 person-years) among those taking abatacept and 22 among those taking placebo (IR 1.8/100 person-years). The difference was not statistically significant.
There were 44 cases of herpes zoster among those taking abatacept (IR 1.9/100 person-years) and 21 among those taking placebo (IR 1.7/100 person-years).
“Basically, I think what we’re seeing here is a whole lot of nothing,” Dr. Winthrop said.
Dr. Winthrop has been a consultant for Pfizer, AbbVie, Bristol-Myers Squibb, UCB Pharma, Roche/Genentech, Amgen, Galapagos, and Eli Lilly.
[email protected]
On Twitter @Alz_gal
AT EULAR 2017
Key clinical point:
Major finding: The overall incidence rate for opportunistic infection was 0.21/100 person-years for abatacept and 0.56 for placebo.
Data source: The review comprised 7,044 who took abatacept and 1,485 who took placebo.
Disclosures: Dr. Winthrop has been a consultant for Pfizer, AbbVie, Bristol-Myers Squibb, UCB Pharma, Roche/Genentech, Amgen, Galapagos, and Eli Lilly.
Midostaurin improves survival in new AML
Adding the multitargeted kinase inhibitor midostaurin to standard chemotherapy led to significantly longer overall and event-free survival, compared with placebo and standard chemotherapy in newly diagnosed acute myeloid leukemia (AML) patients with FLT3 gene mutations, according to phase III trial results published in the New England Journal of Medicine.*
About 30% of AML patients have mutations to the FLT3 gene – with three-quarters of those internal tandem duplication (ITD) mutations, which involves duplication of between 3 and 100 amino acids in the juxtamembrane region. These mutations are linked with a high relapse rate and poor prognosis, especially when there is a high ratio of these mutations to wild-type FLT3. About 8% of patients with newly diagnosed AML have an FLT3 point mutation in the tyrosine kinase domain (TKD), but the effect of these on prognosis isn’t clear.
In the trial, called RATIFY and conducted at 225 sites in 17 countries, 360 patients were randomized to the midostaurin group and 357* to placebo, and they were treated from 2008 to 2013. In all, 29.8% of patients were “ITD high,” meaning their ITD FLT3 mutation to wild-type FLT3 ratio was higher than 0.7, and 47.6% were “ITD low,” with a mutation-to-wild-type FLT3 ratio of 0.5 to 0.7. A total of 22.6% of patients had TKD mutations.
Patients received standard induction chemotherapy, with daunorubicine and cytarabine, and on days 8 through 21 either 50 mg of midostaurin or placebo orally twice a day. Patients were given an identical second cycle of induction therapy, with midostaurin or placebo, if they showed definitive clinically significant residual leukemia after the first induction treatment.
Those who achieved complete remission after induction were given 4, 28-day cycles of consolidation treatment, with midostaurin or placebo on days 8 through 21. If they stayed in remission after that, they were given maintenance of 12, 28-day cycles of midostaurin or placebo.
They were not required to receive hematopoetic stem cell transplantation (HSCT), but it was performed at investigator discretion.
Midostaurin improved survival but not rates of complete remission as defined in the trial protocol, researchers reported.
The hazard ratio for death in the midostaurin group was 0.78 (95% CI, 0.63 to 0.96; one-sided P = .0009). The 4-year overall survival rate was 51.4% for the midostaurin group and 44.3% for the placebo group. Midostaurin was shown to benefit all mutation subgroups, but with no greater benefit in one group than another.
Patients in the midostaurin group had a 21.6% lower likelihood of having an event, defined as failure to achieve protocol-defined complete remission, relapse or death without relapse.
There was no significant difference between the groups in complete remission, which under protocol had to occur by day 60.
HSCT was performed in 57% of patients – during the first complete remission in 28.1% of the midostaurin group and in 22.7% during the first complete remission in the placebo group. For those who were transplanted after the first complete remission, no treatment effect was seen.
Researchers noted that there was a therapeutic benefit even among patients with ITD mutations but with a low allelic burden, in whom the disease might be due largely to mutations other than FLT3.
“It is possible that the benefit of midostaurin, which is a multitargeted kinase inhibitor, might lie beyond its ability to inhibit FLT3,” possibly through inhibition of KIT, researchers said.
They also noted that as the trial went on, more and more investigators decided to treat patients with hematopoietic stem cell transplantation, based on newly reported data elsewhere. Since midostaurin was discontinued at the time of transplant, that could have limited exposure to the drug and limited its effect.
*CORRECTION 7/5/2017: An earlier version of this article misstated the number of patients in the placebo group as well as where the study originally appeared.
Adding the multitargeted kinase inhibitor midostaurin to standard chemotherapy led to significantly longer overall and event-free survival, compared with placebo and standard chemotherapy in newly diagnosed acute myeloid leukemia (AML) patients with FLT3 gene mutations, according to phase III trial results published in the New England Journal of Medicine.*
About 30% of AML patients have mutations to the FLT3 gene – with three-quarters of those internal tandem duplication (ITD) mutations, which involves duplication of between 3 and 100 amino acids in the juxtamembrane region. These mutations are linked with a high relapse rate and poor prognosis, especially when there is a high ratio of these mutations to wild-type FLT3. About 8% of patients with newly diagnosed AML have an FLT3 point mutation in the tyrosine kinase domain (TKD), but the effect of these on prognosis isn’t clear.
In the trial, called RATIFY and conducted at 225 sites in 17 countries, 360 patients were randomized to the midostaurin group and 357* to placebo, and they were treated from 2008 to 2013. In all, 29.8% of patients were “ITD high,” meaning their ITD FLT3 mutation to wild-type FLT3 ratio was higher than 0.7, and 47.6% were “ITD low,” with a mutation-to-wild-type FLT3 ratio of 0.5 to 0.7. A total of 22.6% of patients had TKD mutations.
Patients received standard induction chemotherapy, with daunorubicine and cytarabine, and on days 8 through 21 either 50 mg of midostaurin or placebo orally twice a day. Patients were given an identical second cycle of induction therapy, with midostaurin or placebo, if they showed definitive clinically significant residual leukemia after the first induction treatment.
Those who achieved complete remission after induction were given 4, 28-day cycles of consolidation treatment, with midostaurin or placebo on days 8 through 21. If they stayed in remission after that, they were given maintenance of 12, 28-day cycles of midostaurin or placebo.
They were not required to receive hematopoetic stem cell transplantation (HSCT), but it was performed at investigator discretion.
Midostaurin improved survival but not rates of complete remission as defined in the trial protocol, researchers reported.
The hazard ratio for death in the midostaurin group was 0.78 (95% CI, 0.63 to 0.96; one-sided P = .0009). The 4-year overall survival rate was 51.4% for the midostaurin group and 44.3% for the placebo group. Midostaurin was shown to benefit all mutation subgroups, but with no greater benefit in one group than another.
Patients in the midostaurin group had a 21.6% lower likelihood of having an event, defined as failure to achieve protocol-defined complete remission, relapse or death without relapse.
There was no significant difference between the groups in complete remission, which under protocol had to occur by day 60.
HSCT was performed in 57% of patients – during the first complete remission in 28.1% of the midostaurin group and in 22.7% during the first complete remission in the placebo group. For those who were transplanted after the first complete remission, no treatment effect was seen.
Researchers noted that there was a therapeutic benefit even among patients with ITD mutations but with a low allelic burden, in whom the disease might be due largely to mutations other than FLT3.
“It is possible that the benefit of midostaurin, which is a multitargeted kinase inhibitor, might lie beyond its ability to inhibit FLT3,” possibly through inhibition of KIT, researchers said.
They also noted that as the trial went on, more and more investigators decided to treat patients with hematopoietic stem cell transplantation, based on newly reported data elsewhere. Since midostaurin was discontinued at the time of transplant, that could have limited exposure to the drug and limited its effect.
*CORRECTION 7/5/2017: An earlier version of this article misstated the number of patients in the placebo group as well as where the study originally appeared.
Adding the multitargeted kinase inhibitor midostaurin to standard chemotherapy led to significantly longer overall and event-free survival, compared with placebo and standard chemotherapy in newly diagnosed acute myeloid leukemia (AML) patients with FLT3 gene mutations, according to phase III trial results published in the New England Journal of Medicine.*
About 30% of AML patients have mutations to the FLT3 gene – with three-quarters of those internal tandem duplication (ITD) mutations, which involves duplication of between 3 and 100 amino acids in the juxtamembrane region. These mutations are linked with a high relapse rate and poor prognosis, especially when there is a high ratio of these mutations to wild-type FLT3. About 8% of patients with newly diagnosed AML have an FLT3 point mutation in the tyrosine kinase domain (TKD), but the effect of these on prognosis isn’t clear.
In the trial, called RATIFY and conducted at 225 sites in 17 countries, 360 patients were randomized to the midostaurin group and 357* to placebo, and they were treated from 2008 to 2013. In all, 29.8% of patients were “ITD high,” meaning their ITD FLT3 mutation to wild-type FLT3 ratio was higher than 0.7, and 47.6% were “ITD low,” with a mutation-to-wild-type FLT3 ratio of 0.5 to 0.7. A total of 22.6% of patients had TKD mutations.
Patients received standard induction chemotherapy, with daunorubicine and cytarabine, and on days 8 through 21 either 50 mg of midostaurin or placebo orally twice a day. Patients were given an identical second cycle of induction therapy, with midostaurin or placebo, if they showed definitive clinically significant residual leukemia after the first induction treatment.
Those who achieved complete remission after induction were given 4, 28-day cycles of consolidation treatment, with midostaurin or placebo on days 8 through 21. If they stayed in remission after that, they were given maintenance of 12, 28-day cycles of midostaurin or placebo.
They were not required to receive hematopoetic stem cell transplantation (HSCT), but it was performed at investigator discretion.
Midostaurin improved survival but not rates of complete remission as defined in the trial protocol, researchers reported.
The hazard ratio for death in the midostaurin group was 0.78 (95% CI, 0.63 to 0.96; one-sided P = .0009). The 4-year overall survival rate was 51.4% for the midostaurin group and 44.3% for the placebo group. Midostaurin was shown to benefit all mutation subgroups, but with no greater benefit in one group than another.
Patients in the midostaurin group had a 21.6% lower likelihood of having an event, defined as failure to achieve protocol-defined complete remission, relapse or death without relapse.
There was no significant difference between the groups in complete remission, which under protocol had to occur by day 60.
HSCT was performed in 57% of patients – during the first complete remission in 28.1% of the midostaurin group and in 22.7% during the first complete remission in the placebo group. For those who were transplanted after the first complete remission, no treatment effect was seen.
Researchers noted that there was a therapeutic benefit even among patients with ITD mutations but with a low allelic burden, in whom the disease might be due largely to mutations other than FLT3.
“It is possible that the benefit of midostaurin, which is a multitargeted kinase inhibitor, might lie beyond its ability to inhibit FLT3,” possibly through inhibition of KIT, researchers said.
They also noted that as the trial went on, more and more investigators decided to treat patients with hematopoietic stem cell transplantation, based on newly reported data elsewhere. Since midostaurin was discontinued at the time of transplant, that could have limited exposure to the drug and limited its effect.
*CORRECTION 7/5/2017: An earlier version of this article misstated the number of patients in the placebo group as well as where the study originally appeared.
FROM NEJM
Key clinical point: Multitargeted kinase inhibitor midostaurin combined with standard chemotherapy improved survival in newly diagnosed acute myeloid leukemia patients.
Major finding: The 4-year overall survival rate was 51.4% for the midostaurin group and 44.3% for the placebo group. Midostaurin was shown to benefit all mutation subgroups — internal tandem mutations and point mutations in the tyrosine kinase domain – but with no greater benefit in one group than another.
Data source: A multicenter, multinational, randomized, double-blind, placebo-controlled trial.
Disclosures: The trial was funded by the National Cancer Institute and Novartis. Researchers reported receiving personal fees from Novartis and other companies.
Ibrutinib dons new anti-GVHD hat
MADRID – Talk about versatility: Ibrutinib (Imbruvica), a drug with marked activity against B-cell malignancies, also appears to be a safe and acceptable option for the treatment of patients with chronic graft vs. host disease (cGVHD) for whom frontline therapies have failed.
Among 42 patients in a phase II study with steroid-refractory cGVHD, the overall response rate with ibrutinib was 67%, with one-third of responders having a complete response, reported Iskra Pusic, MD, from Washington University School of Medicine in St. Louis.
Corticosteroids are the most commonly used therapy for cGVHD in the United States, but for those patients for whom corticosteroids are a bust, there is no established second-line therapy, and patients with refractory cGVHD are usually recommended for clinical trials, Dr. Pusic said.
The therapeutic rationale underpinning the use of ibrutinib in cGVHD, a condition marked by extensive immune dysregulation, is that the agent is an irreversible inhibitor of Bruton’s tyrosine kinase and interleukin-2 inducible T-cell kinase, and thus has wide-ranging immune-dampening activity, Dr. Pusic said.
She and colleagues in a multicenter study enrolled 42 patients with cGVHD that corticosteroids had failed to treat adequately, and treated them with oral ibrutinib 420 mg daily until cGVHD progression or unacceptable toxicity.
At a median follow-up of 13.9 months, a total of 28 patients (67%) had a response according to 2005 National Institutes of Health (NIH) criteria, including nine with a complete response, and 19 with partial responses.
Of the patients with responses, 79% had a response at the time of the first assessment for response, and 71% of responders had responses lasting at least 5 months.
Among patients with multiorgan involvement, responses were seen in two or more organs.
Grade 3 or greater adverse events included fatigue, diarrhea, muscles spasms, pneumonia, pyrexia, and headache. Two patients died on study, one from multilobular pneumonia and one from bronchopulmonary aspergillosis.
In general, the safety profile of ibrutinib was similar to that seen in studies of the drug in B-cell malignancies and to that seen with corticosteroid therapy for patients with cGVHD, Dr. Pusic said.
Investigators are currently enrolling patients in a double-blind clinical trial comparing ibrutinib or placebo in combination with corticosteroids in patients with newly diagnosed cGVHD, she noted.
The study was supported by Pharmacyclics. Dr. Pusic did not report disclosures.
MADRID – Talk about versatility: Ibrutinib (Imbruvica), a drug with marked activity against B-cell malignancies, also appears to be a safe and acceptable option for the treatment of patients with chronic graft vs. host disease (cGVHD) for whom frontline therapies have failed.
Among 42 patients in a phase II study with steroid-refractory cGVHD, the overall response rate with ibrutinib was 67%, with one-third of responders having a complete response, reported Iskra Pusic, MD, from Washington University School of Medicine in St. Louis.
Corticosteroids are the most commonly used therapy for cGVHD in the United States, but for those patients for whom corticosteroids are a bust, there is no established second-line therapy, and patients with refractory cGVHD are usually recommended for clinical trials, Dr. Pusic said.
The therapeutic rationale underpinning the use of ibrutinib in cGVHD, a condition marked by extensive immune dysregulation, is that the agent is an irreversible inhibitor of Bruton’s tyrosine kinase and interleukin-2 inducible T-cell kinase, and thus has wide-ranging immune-dampening activity, Dr. Pusic said.
She and colleagues in a multicenter study enrolled 42 patients with cGVHD that corticosteroids had failed to treat adequately, and treated them with oral ibrutinib 420 mg daily until cGVHD progression or unacceptable toxicity.
At a median follow-up of 13.9 months, a total of 28 patients (67%) had a response according to 2005 National Institutes of Health (NIH) criteria, including nine with a complete response, and 19 with partial responses.
Of the patients with responses, 79% had a response at the time of the first assessment for response, and 71% of responders had responses lasting at least 5 months.
Among patients with multiorgan involvement, responses were seen in two or more organs.
Grade 3 or greater adverse events included fatigue, diarrhea, muscles spasms, pneumonia, pyrexia, and headache. Two patients died on study, one from multilobular pneumonia and one from bronchopulmonary aspergillosis.
In general, the safety profile of ibrutinib was similar to that seen in studies of the drug in B-cell malignancies and to that seen with corticosteroid therapy for patients with cGVHD, Dr. Pusic said.
Investigators are currently enrolling patients in a double-blind clinical trial comparing ibrutinib or placebo in combination with corticosteroids in patients with newly diagnosed cGVHD, she noted.
The study was supported by Pharmacyclics. Dr. Pusic did not report disclosures.
MADRID – Talk about versatility: Ibrutinib (Imbruvica), a drug with marked activity against B-cell malignancies, also appears to be a safe and acceptable option for the treatment of patients with chronic graft vs. host disease (cGVHD) for whom frontline therapies have failed.
Among 42 patients in a phase II study with steroid-refractory cGVHD, the overall response rate with ibrutinib was 67%, with one-third of responders having a complete response, reported Iskra Pusic, MD, from Washington University School of Medicine in St. Louis.
Corticosteroids are the most commonly used therapy for cGVHD in the United States, but for those patients for whom corticosteroids are a bust, there is no established second-line therapy, and patients with refractory cGVHD are usually recommended for clinical trials, Dr. Pusic said.
The therapeutic rationale underpinning the use of ibrutinib in cGVHD, a condition marked by extensive immune dysregulation, is that the agent is an irreversible inhibitor of Bruton’s tyrosine kinase and interleukin-2 inducible T-cell kinase, and thus has wide-ranging immune-dampening activity, Dr. Pusic said.
She and colleagues in a multicenter study enrolled 42 patients with cGVHD that corticosteroids had failed to treat adequately, and treated them with oral ibrutinib 420 mg daily until cGVHD progression or unacceptable toxicity.
At a median follow-up of 13.9 months, a total of 28 patients (67%) had a response according to 2005 National Institutes of Health (NIH) criteria, including nine with a complete response, and 19 with partial responses.
Of the patients with responses, 79% had a response at the time of the first assessment for response, and 71% of responders had responses lasting at least 5 months.
Among patients with multiorgan involvement, responses were seen in two or more organs.
Grade 3 or greater adverse events included fatigue, diarrhea, muscles spasms, pneumonia, pyrexia, and headache. Two patients died on study, one from multilobular pneumonia and one from bronchopulmonary aspergillosis.
In general, the safety profile of ibrutinib was similar to that seen in studies of the drug in B-cell malignancies and to that seen with corticosteroid therapy for patients with cGVHD, Dr. Pusic said.
Investigators are currently enrolling patients in a double-blind clinical trial comparing ibrutinib or placebo in combination with corticosteroids in patients with newly diagnosed cGVHD, she noted.
The study was supported by Pharmacyclics. Dr. Pusic did not report disclosures.
AT EHA 2017
Key clinical point: The tyrosine kinase inhibitor ibrutinib was associated with complete and partial responses in two-thirds of patients with steroid-refractory chronic graft vs. host disease (cGVHD).
Major finding: A total of 28 patients (67%) had responses, including 9 complete responses.
Data source: Phase II clinical trial in 42 patients with cGVHD for whom corticosteroids had failed.
Disclosures: The study was supported by Pharmacyclics. Dr. Pusic did not report disclosures.