Pilot trial of first in kind biologic shows RA treatment potential

 

The novel biologic mavrilimumab that targets the GM-CSF pathway has shown therapeutic potential in the treatment of rheumatoid arthritis in a proof-of-concept trial, particularly in patients who have failed to respond to biologics that target other pathways.

Writing in the Annals of the Rheumatic Diseases, researchers led by Gerd R. Burmester, MD, director and professor of medicine in the department of rheumatology and clinical immunology at Charité University Hospital and the Free University and Humboldt University of Berlin, noted that despite the success of the currently available biologics to treat rheumatoid arthritis (RA), a considerable number of patients do not achieve long-term responses (Ann Rheum Dis. 2017 Feb 17. doi: 10.1136/annrheumdis-2016-210624).

“Consequently, new treatments employing different mechanisms of action from those currently available, such as GM-CSFR [granulocyte-macrophage colony-stimulating factor receptor] antagonism, are needed,” they wrote.

Mavrilimumab is a fully human monoclonal antibody that blocks GM-CSFR and is the first biologic of its kind to target the GM-CSF pathway, they noted.

The multicenter, phase IIb, randomized trial EARTH EXPLORER 1 involved 305 patients with moderate to severe RA who were randomized in a ratio of 1:1:1:1 to subcutaneous mavrilimumab 150 mg, 100 mg, 30 mg, or placebo every other week plus methotrexate for 24 weeks.

The results showed that the GM-CSFR blocker met one of its primary endpoints by significantly reducing the 28-joint Disease Activity Score based on C-reactive protein (DAS28–CRP) from baseline to week 12 when compared with placebo. The amount of reduction increased with the dose, from –1.37 with 30 mg, to –1.64 with 100 mg, to –1.90 with 150 mg, compared with –0.68 with placebo (P less than .001 for all vs. placebo).

The biologic also met its other primary endpoint of achieving ACR20 level of response by 24 weeks in significantly more patients than with placebo: 73.4% for 150 mg, 61.2% for 100 mg, and 50.6% for 30 mg vs. 24.7% for placebo (P less than .001).

Adverse events were reported in all treatment dose groups (42%-54% of patients in each group), and no treatment-related safety signals were observed. Only one case each of pneumonia and angioedema were considered to be related to treatment by the investigators.

The research team suggested that the blocking of GM-CSF signaling could be applicable to patients who have failed treatment with biologics that target other pathways or for people with other inflammatory or autoimmune diseases.

“This proof-of-concept study confirms that inhibition of GM-CSF activity is a promising and novel therapeutic approach for patients with RA, including those who do not adequately respond to currently available therapies,” they concluded.

The study was funded by AstraZeneca/MedImmune. Several of the authors are employees of MedImmune and several reported financial ties to other pharmaceutical companies.

 

The novel biologic mavrilimumab that targets the GM-CSF pathway has shown therapeutic potential in the treatment of rheumatoid arthritis in a proof-of-concept trial, particularly in patients who have failed to respond to biologics that target other pathways.

Writing in the Annals of the Rheumatic Diseases, researchers led by Gerd R. Burmester, MD, director and professor of medicine in the department of rheumatology and clinical immunology at Charité University Hospital and the Free University and Humboldt University of Berlin, noted that despite the success of the currently available biologics to treat rheumatoid arthritis (RA), a considerable number of patients do not achieve long-term responses (Ann Rheum Dis. 2017 Feb 17. doi: 10.1136/annrheumdis-2016-210624).

“Consequently, new treatments employing different mechanisms of action from those currently available, such as GM-CSFR [granulocyte-macrophage colony-stimulating factor receptor] antagonism, are needed,” they wrote.

Mavrilimumab is a fully human monoclonal antibody that blocks GM-CSFR and is the first biologic of its kind to target the GM-CSF pathway, they noted.

The multicenter, phase IIb, randomized trial EARTH EXPLORER 1 involved 305 patients with moderate to severe RA who were randomized in a ratio of 1:1:1:1 to subcutaneous mavrilimumab 150 mg, 100 mg, 30 mg, or placebo every other week plus methotrexate for 24 weeks.

The results showed that the GM-CSFR blocker met one of its primary endpoints by significantly reducing the 28-joint Disease Activity Score based on C-reactive protein (DAS28–CRP) from baseline to week 12 when compared with placebo. The amount of reduction increased with the dose, from –1.37 with 30 mg, to –1.64 with 100 mg, to –1.90 with 150 mg, compared with –0.68 with placebo (P less than .001 for all vs. placebo).

The biologic also met its other primary endpoint of achieving ACR20 level of response by 24 weeks in significantly more patients than with placebo: 73.4% for 150 mg, 61.2% for 100 mg, and 50.6% for 30 mg vs. 24.7% for placebo (P less than .001).

Adverse events were reported in all treatment dose groups (42%-54% of patients in each group), and no treatment-related safety signals were observed. Only one case each of pneumonia and angioedema were considered to be related to treatment by the investigators.

The research team suggested that the blocking of GM-CSF signaling could be applicable to patients who have failed treatment with biologics that target other pathways or for people with other inflammatory or autoimmune diseases.

“This proof-of-concept study confirms that inhibition of GM-CSF activity is a promising and novel therapeutic approach for patients with RA, including those who do not adequately respond to currently available therapies,” they concluded.

The study was funded by AstraZeneca/MedImmune. Several of the authors are employees of MedImmune and several reported financial ties to other pharmaceutical companies.

 

The novel biologic mavrilimumab that targets the GM-CSF pathway has shown therapeutic potential in the treatment of rheumatoid arthritis in a proof-of-concept trial, particularly in patients who have failed to respond to biologics that target other pathways.

Writing in the Annals of the Rheumatic Diseases, researchers led by Gerd R. Burmester, MD, director and professor of medicine in the department of rheumatology and clinical immunology at Charité University Hospital and the Free University and Humboldt University of Berlin, noted that despite the success of the currently available biologics to treat rheumatoid arthritis (RA), a considerable number of patients do not achieve long-term responses (Ann Rheum Dis. 2017 Feb 17. doi: 10.1136/annrheumdis-2016-210624).

“Consequently, new treatments employing different mechanisms of action from those currently available, such as GM-CSFR [granulocyte-macrophage colony-stimulating factor receptor] antagonism, are needed,” they wrote.

Mavrilimumab is a fully human monoclonal antibody that blocks GM-CSFR and is the first biologic of its kind to target the GM-CSF pathway, they noted.

The multicenter, phase IIb, randomized trial EARTH EXPLORER 1 involved 305 patients with moderate to severe RA who were randomized in a ratio of 1:1:1:1 to subcutaneous mavrilimumab 150 mg, 100 mg, 30 mg, or placebo every other week plus methotrexate for 24 weeks.

The results showed that the GM-CSFR blocker met one of its primary endpoints by significantly reducing the 28-joint Disease Activity Score based on C-reactive protein (DAS28–CRP) from baseline to week 12 when compared with placebo. The amount of reduction increased with the dose, from –1.37 with 30 mg, to –1.64 with 100 mg, to –1.90 with 150 mg, compared with –0.68 with placebo (P less than .001 for all vs. placebo).

The biologic also met its other primary endpoint of achieving ACR20 level of response by 24 weeks in significantly more patients than with placebo: 73.4% for 150 mg, 61.2% for 100 mg, and 50.6% for 30 mg vs. 24.7% for placebo (P less than .001).

Adverse events were reported in all treatment dose groups (42%-54% of patients in each group), and no treatment-related safety signals were observed. Only one case each of pneumonia and angioedema were considered to be related to treatment by the investigators.

The research team suggested that the blocking of GM-CSF signaling could be applicable to patients who have failed treatment with biologics that target other pathways or for people with other inflammatory or autoimmune diseases.

“This proof-of-concept study confirms that inhibition of GM-CSF activity is a promising and novel therapeutic approach for patients with RA, including those who do not adequately respond to currently available therapies,” they concluded.

The study was funded by AstraZeneca/MedImmune. Several of the authors are employees of MedImmune and several reported financial ties to other pharmaceutical companies.