CD40 ligand–binding protein safely lowered RA disease activity

A nonantibody scaffold protein that targets the CD40 ligand appears to dampen down autoimmune responses without the thromboembolic complications seen in trials of monoclonal antibodies against the CD40 ligand.

In a paper published in Science Translational Medicine, researchers presented the results of a phase 1a study in 59 healthy volunteers and phase 1b proof-of-concept study in 57 individuals with rheumatoid arthritis. Participants received either varying dosages of CD40 ligand (CD40L)–binding protein VIB4920 – a single dose in the healthy volunteers and seven doses in the phase 1b study – or placebo.

Jodi L. Karnell, PhD, of Viela Bio in Gaithersburg, Md., and coauthors, wrote that the CD40/CD40L pathway is known to play a key role in humoral immune responses and in the pathogenesis of several autoimmune diseases.

However, previous clinical trials of compounds targeting CD40L were stopped early because of an increased risk of adverse thromboembolic events related to platelet aggregation, despite showing potential benefits in lupus and immune thrombocytopenic purpura.

Preclinical studies of VIB4920 found that it blocked the expansion of CD40L-dependent human B cells without showing any signs of platelet aggregation. The authors said the platelet aggregation had been linked to a particular region of anti-CD40L monoclonal antibodies, but VIB4920 was engineered using a protein scaffold that did not contain that region.

In healthy volunteers, researchers saw a dose-dependent suppression of antibody production and reductions in B-cell proliferation, in recall response to a T cell–dependent antigen.

In individuals with rheumatoid arthritis, more than half of those treated with the two highest dosages of VIB4920 achieved low disease activity state or clinical remission by 12 weeks. Overall, there was also a significant decrease in disease activity, and dose-dependent decreases in rheumatoid factor autoantibodies and Vectra DA biomarker score, which is a composite of twelve rheumatoid arthritis–related biomarkers.

“The consistency of improvement across a variety of clinical and laboratory outcome measures further supports the potential clinical efficacy of VIB4920,” the authors wrote.

Researchers saw a similar rate of adverse events in the placebo and treatment arms of the study.

“VIB4920 represents an alternative to monoclonal antibody–based targeting of CD40L, which does not induce platelet aggregation in vitro and demonstrates a favorable safety profile in early clinical evaluation.”

The study was funded by MedImmune. All but one author were employees of MedImmune/AstraZeneca or of Viela Bio.

[email protected]

SOURCE: Karnell J et al. Sci Transl Med. 2019 April 24. doi: 10.1126/scitranslmed.aar6584

A nonantibody scaffold protein that targets the CD40 ligand appears to dampen down autoimmune responses without the thromboembolic complications seen in trials of monoclonal antibodies against the CD40 ligand.

In a paper published in Science Translational Medicine, researchers presented the results of a phase 1a study in 59 healthy volunteers and phase 1b proof-of-concept study in 57 individuals with rheumatoid arthritis. Participants received either varying dosages of CD40 ligand (CD40L)–binding protein VIB4920 – a single dose in the healthy volunteers and seven doses in the phase 1b study – or placebo.

Jodi L. Karnell, PhD, of Viela Bio in Gaithersburg, Md., and coauthors, wrote that the CD40/CD40L pathway is known to play a key role in humoral immune responses and in the pathogenesis of several autoimmune diseases.

However, previous clinical trials of compounds targeting CD40L were stopped early because of an increased risk of adverse thromboembolic events related to platelet aggregation, despite showing potential benefits in lupus and immune thrombocytopenic purpura.

Preclinical studies of VIB4920 found that it blocked the expansion of CD40L-dependent human B cells without showing any signs of platelet aggregation. The authors said the platelet aggregation had been linked to a particular region of anti-CD40L monoclonal antibodies, but VIB4920 was engineered using a protein scaffold that did not contain that region.

In healthy volunteers, researchers saw a dose-dependent suppression of antibody production and reductions in B-cell proliferation, in recall response to a T cell–dependent antigen.

In individuals with rheumatoid arthritis, more than half of those treated with the two highest dosages of VIB4920 achieved low disease activity state or clinical remission by 12 weeks. Overall, there was also a significant decrease in disease activity, and dose-dependent decreases in rheumatoid factor autoantibodies and Vectra DA biomarker score, which is a composite of twelve rheumatoid arthritis–related biomarkers.

“The consistency of improvement across a variety of clinical and laboratory outcome measures further supports the potential clinical efficacy of VIB4920,” the authors wrote.

Researchers saw a similar rate of adverse events in the placebo and treatment arms of the study.

“VIB4920 represents an alternative to monoclonal antibody–based targeting of CD40L, which does not induce platelet aggregation in vitro and demonstrates a favorable safety profile in early clinical evaluation.”

The study was funded by MedImmune. All but one author were employees of MedImmune/AstraZeneca or of Viela Bio.

[email protected]

SOURCE: Karnell J et al. Sci Transl Med. 2019 April 24. doi: 10.1126/scitranslmed.aar6584

A nonantibody scaffold protein that targets the CD40 ligand appears to dampen down autoimmune responses without the thromboembolic complications seen in trials of monoclonal antibodies against the CD40 ligand.

In a paper published in Science Translational Medicine, researchers presented the results of a phase 1a study in 59 healthy volunteers and phase 1b proof-of-concept study in 57 individuals with rheumatoid arthritis. Participants received either varying dosages of CD40 ligand (CD40L)–binding protein VIB4920 – a single dose in the healthy volunteers and seven doses in the phase 1b study – or placebo.

Jodi L. Karnell, PhD, of Viela Bio in Gaithersburg, Md., and coauthors, wrote that the CD40/CD40L pathway is known to play a key role in humoral immune responses and in the pathogenesis of several autoimmune diseases.

However, previous clinical trials of compounds targeting CD40L were stopped early because of an increased risk of adverse thromboembolic events related to platelet aggregation, despite showing potential benefits in lupus and immune thrombocytopenic purpura.

Preclinical studies of VIB4920 found that it blocked the expansion of CD40L-dependent human B cells without showing any signs of platelet aggregation. The authors said the platelet aggregation had been linked to a particular region of anti-CD40L monoclonal antibodies, but VIB4920 was engineered using a protein scaffold that did not contain that region.

In healthy volunteers, researchers saw a dose-dependent suppression of antibody production and reductions in B-cell proliferation, in recall response to a T cell–dependent antigen.

In individuals with rheumatoid arthritis, more than half of those treated with the two highest dosages of VIB4920 achieved low disease activity state or clinical remission by 12 weeks. Overall, there was also a significant decrease in disease activity, and dose-dependent decreases in rheumatoid factor autoantibodies and Vectra DA biomarker score, which is a composite of twelve rheumatoid arthritis–related biomarkers.

“The consistency of improvement across a variety of clinical and laboratory outcome measures further supports the potential clinical efficacy of VIB4920,” the authors wrote.

Researchers saw a similar rate of adverse events in the placebo and treatment arms of the study.

“VIB4920 represents an alternative to monoclonal antibody–based targeting of CD40L, which does not induce platelet aggregation in vitro and demonstrates a favorable safety profile in early clinical evaluation.”

The study was funded by MedImmune. All but one author were employees of MedImmune/AstraZeneca or of Viela Bio.

[email protected]

SOURCE: Karnell J et al. Sci Transl Med. 2019 April 24. doi: 10.1126/scitranslmed.aar6584