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SAN DIEGO – An investigational human monoclonal antibody suggested a new approach to asthma treatment by showing evidence of anti-inflammatory activity and partial attenuation of early and late asthmatic responses in a proof-of-concept study of 31 patients with mild asthma.
Patients were randomized to intravenous treatment with AMG 157 or placebo for up to 3 months before undergoing allergen-induced challenge and testing. AMG 157 binds human thymic stromal lymphopoietin (TSLP), an epithelial-cell–derived cytokine that might be important in initiating allergic inflammation, and prevents receptor interaction.
By day 84, the maximum percentage decrease in the forced expiratory volume at 1 second (FEV1) during late asthmatic response (3-7 hours after allergy challenge) was 46% smaller in the treatment group, compared with placebo, a significant difference, Gail M. Gauvreau, Ph.D., and her associates reported at an international conference of the American Thoracic Society.
Among secondary outcomes, the area under the curve (AUC) of the time-adjusted percent decrease in FEV1 during the early asthmatic response was significantly smaller in the treatment group than the control group on day 84. Patients who got AMG 157 showed significantly lower levels of blood and sputum eosinophils before and after allergy challenge and in the fraction of exhaled nitric oxide.
Adverse events were reported in 15 patients on AMG 157 and 12 patients on placebo. No serious adverse events were seen, reported Dr. Gauvreau of the Firestone Institute of Respiratory Health at McMaster University, Hamilton, Ontario.
The study was published online by the New England Journal of Medicine (2014 May 20 [doi:10.1056/NEJMoa1402895]). "This proof-of-concept study suggests that TSLP is a pivotal cytokine not only in allergen-induced airway responses but also in persistent airway inflammation in patients with allergic asthma," the investigators wrote.
The company that is developing AMG 157 has started a phase II clinical trial, Dr. Gauvreau said in an interview at the meeting.
The population of mild asthmatics in the proof-of-concept study are not the kind of patients who might use this treatment, she said, but this potential treatment pathway offers hope for a new therapy for patients with steroid-resistant asthma. "They use an awful lot of resources and costs in terms of hospital emergency room care. They are the folks who have an unmet need to treat their asthma," she said.
Amgen, which is developing AMG 157, funded the study and analyzed the data. Dr. Gauvreau reported financial associations with Amgen and three other companies. Fourteen of her coinvestigators reported financial associations with Amgen and multiple other companies.
The magnitude of the effect of AMG 157 was sizable, similar to what could be achieved in allergen-induced asthma studies by blocking established asthma mediators such as the cysteinyl leukotrienes, Dr. Sven-Erik Dahlén wrote in an editorial accompanying Dr. Gauvreau’s article (N. Engl. J. Med.; 2014 May 20 [doi:10.1056/NEJMe1404737]).
The evidence of an effect from this highly selective anti-thymic stromal lymphopoietin [TSLP] antibody on both the early and late asthmatic responses might be because it directly inhibits interleukin-4 or interleukin-13 (two downstream cytokines induced by TSLP), this study and previous data suggest. There may be two ways to inhibit allergen-induced asthmatic responses, he suggested – direct antagonism of mast-cell mediators to block acute response, or long-term inhibition of regulatory networks. TSLP may be a "master switch" in the signaling between airway epithelium and other inflammatory cascades. Or, it may be part of action by several parallel pathways involving interleukins.
AMG 157 has "earned our respect" in this study, but it’s unclear whether this strategy will succeed in treating patients with asthma, Dr. Dahlén wrote. "We will first have to unravel the biologic mechanisms involved in this unexpected effect of AMG 157 and show why TSLP signaling" contributes to asthmatic responses.
Dr. Dahlén is a professor at the Center for Allergy Research, Institute of Environmental Medicine, Karolinska Institutet, Stockholm. He reported a financial association with AstraZeneca unrelated to this study.
The magnitude of the effect of AMG 157 was sizable, similar to what could be achieved in allergen-induced asthma studies by blocking established asthma mediators such as the cysteinyl leukotrienes, Dr. Sven-Erik Dahlén wrote in an editorial accompanying Dr. Gauvreau’s article (N. Engl. J. Med.; 2014 May 20 [doi:10.1056/NEJMe1404737]).
The evidence of an effect from this highly selective anti-thymic stromal lymphopoietin [TSLP] antibody on both the early and late asthmatic responses might be because it directly inhibits interleukin-4 or interleukin-13 (two downstream cytokines induced by TSLP), this study and previous data suggest. There may be two ways to inhibit allergen-induced asthmatic responses, he suggested – direct antagonism of mast-cell mediators to block acute response, or long-term inhibition of regulatory networks. TSLP may be a "master switch" in the signaling between airway epithelium and other inflammatory cascades. Or, it may be part of action by several parallel pathways involving interleukins.
AMG 157 has "earned our respect" in this study, but it’s unclear whether this strategy will succeed in treating patients with asthma, Dr. Dahlén wrote. "We will first have to unravel the biologic mechanisms involved in this unexpected effect of AMG 157 and show why TSLP signaling" contributes to asthmatic responses.
Dr. Dahlén is a professor at the Center for Allergy Research, Institute of Environmental Medicine, Karolinska Institutet, Stockholm. He reported a financial association with AstraZeneca unrelated to this study.
The magnitude of the effect of AMG 157 was sizable, similar to what could be achieved in allergen-induced asthma studies by blocking established asthma mediators such as the cysteinyl leukotrienes, Dr. Sven-Erik Dahlén wrote in an editorial accompanying Dr. Gauvreau’s article (N. Engl. J. Med.; 2014 May 20 [doi:10.1056/NEJMe1404737]).
The evidence of an effect from this highly selective anti-thymic stromal lymphopoietin [TSLP] antibody on both the early and late asthmatic responses might be because it directly inhibits interleukin-4 or interleukin-13 (two downstream cytokines induced by TSLP), this study and previous data suggest. There may be two ways to inhibit allergen-induced asthmatic responses, he suggested – direct antagonism of mast-cell mediators to block acute response, or long-term inhibition of regulatory networks. TSLP may be a "master switch" in the signaling between airway epithelium and other inflammatory cascades. Or, it may be part of action by several parallel pathways involving interleukins.
AMG 157 has "earned our respect" in this study, but it’s unclear whether this strategy will succeed in treating patients with asthma, Dr. Dahlén wrote. "We will first have to unravel the biologic mechanisms involved in this unexpected effect of AMG 157 and show why TSLP signaling" contributes to asthmatic responses.
Dr. Dahlén is a professor at the Center for Allergy Research, Institute of Environmental Medicine, Karolinska Institutet, Stockholm. He reported a financial association with AstraZeneca unrelated to this study.
SAN DIEGO – An investigational human monoclonal antibody suggested a new approach to asthma treatment by showing evidence of anti-inflammatory activity and partial attenuation of early and late asthmatic responses in a proof-of-concept study of 31 patients with mild asthma.
Patients were randomized to intravenous treatment with AMG 157 or placebo for up to 3 months before undergoing allergen-induced challenge and testing. AMG 157 binds human thymic stromal lymphopoietin (TSLP), an epithelial-cell–derived cytokine that might be important in initiating allergic inflammation, and prevents receptor interaction.
By day 84, the maximum percentage decrease in the forced expiratory volume at 1 second (FEV1) during late asthmatic response (3-7 hours after allergy challenge) was 46% smaller in the treatment group, compared with placebo, a significant difference, Gail M. Gauvreau, Ph.D., and her associates reported at an international conference of the American Thoracic Society.
Among secondary outcomes, the area under the curve (AUC) of the time-adjusted percent decrease in FEV1 during the early asthmatic response was significantly smaller in the treatment group than the control group on day 84. Patients who got AMG 157 showed significantly lower levels of blood and sputum eosinophils before and after allergy challenge and in the fraction of exhaled nitric oxide.
Adverse events were reported in 15 patients on AMG 157 and 12 patients on placebo. No serious adverse events were seen, reported Dr. Gauvreau of the Firestone Institute of Respiratory Health at McMaster University, Hamilton, Ontario.
The study was published online by the New England Journal of Medicine (2014 May 20 [doi:10.1056/NEJMoa1402895]). "This proof-of-concept study suggests that TSLP is a pivotal cytokine not only in allergen-induced airway responses but also in persistent airway inflammation in patients with allergic asthma," the investigators wrote.
The company that is developing AMG 157 has started a phase II clinical trial, Dr. Gauvreau said in an interview at the meeting.
The population of mild asthmatics in the proof-of-concept study are not the kind of patients who might use this treatment, she said, but this potential treatment pathway offers hope for a new therapy for patients with steroid-resistant asthma. "They use an awful lot of resources and costs in terms of hospital emergency room care. They are the folks who have an unmet need to treat their asthma," she said.
Amgen, which is developing AMG 157, funded the study and analyzed the data. Dr. Gauvreau reported financial associations with Amgen and three other companies. Fourteen of her coinvestigators reported financial associations with Amgen and multiple other companies.
SAN DIEGO – An investigational human monoclonal antibody suggested a new approach to asthma treatment by showing evidence of anti-inflammatory activity and partial attenuation of early and late asthmatic responses in a proof-of-concept study of 31 patients with mild asthma.
Patients were randomized to intravenous treatment with AMG 157 or placebo for up to 3 months before undergoing allergen-induced challenge and testing. AMG 157 binds human thymic stromal lymphopoietin (TSLP), an epithelial-cell–derived cytokine that might be important in initiating allergic inflammation, and prevents receptor interaction.
By day 84, the maximum percentage decrease in the forced expiratory volume at 1 second (FEV1) during late asthmatic response (3-7 hours after allergy challenge) was 46% smaller in the treatment group, compared with placebo, a significant difference, Gail M. Gauvreau, Ph.D., and her associates reported at an international conference of the American Thoracic Society.
Among secondary outcomes, the area under the curve (AUC) of the time-adjusted percent decrease in FEV1 during the early asthmatic response was significantly smaller in the treatment group than the control group on day 84. Patients who got AMG 157 showed significantly lower levels of blood and sputum eosinophils before and after allergy challenge and in the fraction of exhaled nitric oxide.
Adverse events were reported in 15 patients on AMG 157 and 12 patients on placebo. No serious adverse events were seen, reported Dr. Gauvreau of the Firestone Institute of Respiratory Health at McMaster University, Hamilton, Ontario.
The study was published online by the New England Journal of Medicine (2014 May 20 [doi:10.1056/NEJMoa1402895]). "This proof-of-concept study suggests that TSLP is a pivotal cytokine not only in allergen-induced airway responses but also in persistent airway inflammation in patients with allergic asthma," the investigators wrote.
The company that is developing AMG 157 has started a phase II clinical trial, Dr. Gauvreau said in an interview at the meeting.
The population of mild asthmatics in the proof-of-concept study are not the kind of patients who might use this treatment, she said, but this potential treatment pathway offers hope for a new therapy for patients with steroid-resistant asthma. "They use an awful lot of resources and costs in terms of hospital emergency room care. They are the folks who have an unmet need to treat their asthma," she said.
Amgen, which is developing AMG 157, funded the study and analyzed the data. Dr. Gauvreau reported financial associations with Amgen and three other companies. Fourteen of her coinvestigators reported financial associations with Amgen and multiple other companies.
AT ATS 2014
Key clinical point: A proof-of-concept study suggests that there may be a new asthma treatment pathway, to be tested next in a phase II clinical trial.
Major finding: The maximum percentage decrease in the FEV1 3-7 hours after allergy challenge was 46% smaller in the treatment group, compared with placebo on day 84 (P = .02)
Data source: A double-blind, placebo-controlled study of 31 patients with mild asthma treated with 3 months of intravenous AMG 157 or placebo assessed after allergen challenge.
Disclosures: Amgen, which is developing AMG 157, funded the study and analyzed the data. Dr. Gauvreau reported financial associations with Amgen and three other companies. Fourteen of her coinvestigators reported financial associations with Amgen and multiple other companies.
