TY - JOUR
T1 - Efficacy, patient-reported outcomes, and safety of the anti-granulocyte macrophage colony-stimulating factor antibody otilimab (GSK3196165) in patients with rheumatoid arthritis
T2 - a randomised, phase 2b, dose-ranging study
AU - Buckley, Christopher
AU - Simón-Campos, Jesus A
AU - Zhdan, Vyacheslav
AU - Becker, Brandon
AU - Davy, Katherine
AU - Fisheleva, Elena
AU - Gupta, Anubha
AU - Hawkes, Carol
AU - Inman, David
AU - Layton, Mark
AU - Mitchell, Nina
AU - Patel, Jatin
AU - Saurigny, Didier
AU - Williamson, Russell
AU - Tak, Paul P.
PY - 2020/11
Y1 - 2020/11
N2 - Background
The human monoclonal antibody otilimab inhibits
granulocyte-macrophage colony-stimulating factor (GM-CSF), a key driver in
immune-mediated inflammatory conditions. We aimed to evaluate the efficacy,
safety, and key patient-reported outcomes related to pain in patients with
active rheumatoid arthritis receiving otilimab.
Methods
This phase 2b, dose-ranging, multicentre, placebo-controlled
study was done at 64 sites across 14 countries. Patients aged 18 years or older
with rheumatoid arthritis who were receiving stable methotrexate were randomly
assigned (1:1:1:1:1:1) to subcutaneous placebo or otilimab 22·5 mg, 45 mg, 90
mg, 135 mg, or 180 mg, plus methotrexate, once weekly for 5 weeks, then every
other week until week 50. The randomisation schedule was generated by the
sponsor, and patients were assigned to treatment by interactive response
technology. Randomisation was blocked (block size of six) but was not
stratified. Investigators, patients, and the sponsor were blinded to treatment.
An unblinded administrator prepared and administered the study drug. The
primary endpoint was the proportion of patients who achieved disease activity
score for 28 joints with C-reactive protein (DAS28-CRP) <2·6 at week 24.
Patients who were not in the otilimab 180 mg group, without a good or moderate
European League Against Rheumatism response (week 12) or with DAS28-CRP >3·2
(week 24) escaped to otilimab 180 mg. Patients who escaped were treated as
non-responders in their original assigned group. Safety endpoints were
incidence of adverse events and serious adverse events, infections, and pulmonary
events. Efficacy and safety outcomes were assessed in the intention-to-treat
population. This study is registered with ClinicalTrials.gov, NCT02504671.
Findings
Between July 23, 2015, and Dec 29, 2017, 222 patients were
randomly assigned (37 to each group). 86 (49%) of 175 escaped to otilimab 180
mg at week 12 and 57 (69%) of 83 at week 24. At week 24, the proportion of
patients with DAS28-CRP <2·6 was two (5%) of 37 in the otilimab 22·5 mg
group, six (16%) of 37 in the 45 mg group, seven (19%) of 37 in the 90 mg
group, five (14%) of 37 in the 135 mg group, five (14%) of 37 in the 180 mg,
and one (3%) of 37 in the placebo group. The largest difference was achieved
with otilimab 90 mg (16·2%; odds ratio [OR] 8·39, 95% CI 0·98–72·14; p=0·053).
Adverse events were reported pre-escape in 19–24 (51–65%) patients and post
escape in 10–17 (40–61%) patients across otilimab dose groups and in 18 (49%)
of 37 and 22 (67%) of 33 in the placebo group. The most common adverse event
was nasopharyngitis: 3–9 (8–24%) in otilimab groups and one (3%) in the placebo
group pre-escape and 1–3 (4–10%) in otilimab groups and seven (21%) in the
placebo group post escape. Pre-escape serious adverse events were foot fracture
(otilimab 45 mg); arthralgia, myocardial infarction, dizziness (otilimab 90
mg); oesophageal spasm, acute pyelonephritis (otilimab 22·5 mg), and uterine
leiomyoma (otilimab 135 mg). Post-escape serious adverse events were ankle
fracture (placebo) and rheumatoid arthritis (otilimab 135 mg). There were no
deaths or pulmonary events of clinical concern, and rates of serious infection
were low.
Interpretation
Otilimab plus methotrexate was well tolerated and, despite
not achieving the primary endpoint of DAS28-CRP remission, there were
improvements compared with placebo in disease activity scores. Of note,
patients reported significant improvement in pain and physical function,
supporting further clinical development of otilimab in rheumatoid arthritis.
Funding
GlaxoSmithKline.
AB - Background
The human monoclonal antibody otilimab inhibits
granulocyte-macrophage colony-stimulating factor (GM-CSF), a key driver in
immune-mediated inflammatory conditions. We aimed to evaluate the efficacy,
safety, and key patient-reported outcomes related to pain in patients with
active rheumatoid arthritis receiving otilimab.
Methods
This phase 2b, dose-ranging, multicentre, placebo-controlled
study was done at 64 sites across 14 countries. Patients aged 18 years or older
with rheumatoid arthritis who were receiving stable methotrexate were randomly
assigned (1:1:1:1:1:1) to subcutaneous placebo or otilimab 22·5 mg, 45 mg, 90
mg, 135 mg, or 180 mg, plus methotrexate, once weekly for 5 weeks, then every
other week until week 50. The randomisation schedule was generated by the
sponsor, and patients were assigned to treatment by interactive response
technology. Randomisation was blocked (block size of six) but was not
stratified. Investigators, patients, and the sponsor were blinded to treatment.
An unblinded administrator prepared and administered the study drug. The
primary endpoint was the proportion of patients who achieved disease activity
score for 28 joints with C-reactive protein (DAS28-CRP) <2·6 at week 24.
Patients who were not in the otilimab 180 mg group, without a good or moderate
European League Against Rheumatism response (week 12) or with DAS28-CRP >3·2
(week 24) escaped to otilimab 180 mg. Patients who escaped were treated as
non-responders in their original assigned group. Safety endpoints were
incidence of adverse events and serious adverse events, infections, and pulmonary
events. Efficacy and safety outcomes were assessed in the intention-to-treat
population. This study is registered with ClinicalTrials.gov, NCT02504671.
Findings
Between July 23, 2015, and Dec 29, 2017, 222 patients were
randomly assigned (37 to each group). 86 (49%) of 175 escaped to otilimab 180
mg at week 12 and 57 (69%) of 83 at week 24. At week 24, the proportion of
patients with DAS28-CRP <2·6 was two (5%) of 37 in the otilimab 22·5 mg
group, six (16%) of 37 in the 45 mg group, seven (19%) of 37 in the 90 mg
group, five (14%) of 37 in the 135 mg group, five (14%) of 37 in the 180 mg,
and one (3%) of 37 in the placebo group. The largest difference was achieved
with otilimab 90 mg (16·2%; odds ratio [OR] 8·39, 95% CI 0·98–72·14; p=0·053).
Adverse events were reported pre-escape in 19–24 (51–65%) patients and post
escape in 10–17 (40–61%) patients across otilimab dose groups and in 18 (49%)
of 37 and 22 (67%) of 33 in the placebo group. The most common adverse event
was nasopharyngitis: 3–9 (8–24%) in otilimab groups and one (3%) in the placebo
group pre-escape and 1–3 (4–10%) in otilimab groups and seven (21%) in the
placebo group post escape. Pre-escape serious adverse events were foot fracture
(otilimab 45 mg); arthralgia, myocardial infarction, dizziness (otilimab 90
mg); oesophageal spasm, acute pyelonephritis (otilimab 22·5 mg), and uterine
leiomyoma (otilimab 135 mg). Post-escape serious adverse events were ankle
fracture (placebo) and rheumatoid arthritis (otilimab 135 mg). There were no
deaths or pulmonary events of clinical concern, and rates of serious infection
were low.
Interpretation
Otilimab plus methotrexate was well tolerated and, despite
not achieving the primary endpoint of DAS28-CRP remission, there were
improvements compared with placebo in disease activity scores. Of note,
patients reported significant improvement in pain and physical function,
supporting further clinical development of otilimab in rheumatoid arthritis.
Funding
GlaxoSmithKline.
KW - Anti-GM-CSF
KW - CDAI
KW - GSK3196165
KW - DAS28(CRP)
KW - rheumatoid arthritis
KW - pain
KW - patient-reported outcomes
UR - http://www.scopus.com/inward/record.url?scp=85093700297&partnerID=8YFLogxK
U2 - 10.1016/S2665-9913(20)30229-0
DO - 10.1016/S2665-9913(20)30229-0
M3 - Article
SN - 2665-9913
VL - 2
SP - e677-e688
JO - The Lancet Rheumatology
JF - The Lancet Rheumatology
IS - 11
ER -