MedImmune, the global biologics research and development arm of
AstraZeneca, today announced it will be presenting positive data from a
Phase IIb study on sifalimumab, a novel monoclonal antibody targeting
interferon being investigated for treatment in patients with moderate to
severe systemic lupus erythematosus (SLE or lupus), at the American
College of Rheumatology (ACR) 2014 Annual Meeting in Boston, MA.
The study met its primary endpoint of percentage of subjects that
responded as measured by the SLE Responder Index (SRI-4) at week 52. In
addition, statistically significant improvements were seen in multiple
other clinical measures of disease activity. Study results will be
presented in a late-breaking oral presentation on Tuesday, November 18
at 3:15 pm.
The efficacy and safety of sifalimumab were assessed in a Phase IIb,
randomized double-blind placebo-controlled study in subjects with
moderate to severe SLE. The study evaluated 431 patients receiving
sifalimumab at monthly doses of 200, 600 or 1200 mg, plus their current
standard of care, or placebo along with standard of care. The results
show that the percentage of patients achieving improvement as measured
by the SLE Responder Index (SRI-4) at week 52 was significantly higher
for sifalimumab at all doses versus placebo plus standard of care
(placebo/SOC, 45.4%; 200 mg, 58.3%; 600 mg, 56.5%; 1200 mg, 59.8%).
Sifalimumab targets interferon-α subtypes, inflammatory cytokines in the
body known to play a critical role in the pathogenesis of SLE. The Phase
IIb study on sifalimumab is the first to demonstrate efficacy in
moderate to severe systemic lupus patients across multiple endpoints
with an anti-interferon molecule.
Most commonly reported adverse events (AEs) were similar across groups
including worsening SLE (sifalimumab 30.0% vs placebo 34.3%), urinary
tract infection (17.6% vs 13.9%) and headache (13.3% vs 13.9%). Serious
AEs were reported in 18.3% (sifalimumab) vs 17.6% (placebo) of subjects.
An increase in subjects reporting Herpes zoster was seen in subjects
receiving sifalimumab, particularly in the 1200 mg group (placebo, 0.9%;
200 mg, 4.6%; 600 mg, 3.7%; 1200 mg, 8.4%).
“The sifalimumab data we’re presenting at ACR represent some of the most
encouraging Phase II data to date in systemic lupus,” said Bing Yao,
Senior Vice President and Head of Respiratory, Inflammation and
Autoimmunity Innovative Medicines Unit, MedImmune. “Developing new
treatments for lupus patients is challenging, as is evidenced by the
fact that only one new drug has been introduced in close to 60 years.
MedImmune is committed to Type I interferon inhibition in our quest to
bring new medicines to patients, and we are excited by the positive data
on sifalimumab as well as the early data on our other investigational
molecule, anifrolumab.”
The trial shows robust responses across multiple endpoints, as evident
by greater differences relative to placebo both with SRI-4 and more
stringent response criteria such as SRI-6, 7 or 8 with statistically
significant effects for all sifalimumab groups at week 52. Furthermore,
in a different composite disease activity measure, the BILAG-based
Combined Lupus Assessment (BICLA), improvements over placebo were shown
in all three dose groups, with a statistically significant effect for
1200 mg group at 52 weeks.
Improvements in organ-specific outcomes also seen
The study also shows positive results in clinically important
organ-specific outcome measures including skin (rash) and joint
involvement (swollen and tender joints). Skin rashes were assessed by
the Cutaneous Lupus Erythematosus Disease Area and Severity Index
(CLASI), with the study demonstrating that a significantly higher
percentage of subjects with moderate to severe skin involvement had a ≥4
point decrease in CLASI on sifalimumab 200 mg and 1200 mg (72.7%, 73.1%)
versus placebo/SOC (48.6%) at 52 weeks. Furthermore, a statistically
significant higher percentage of patients with moderate to severe joint
involvement had a joint response (50% reduction in the number of swollen
and tender joints) for all three doses of sifalimumab compared with
placebo/SOC at 52 weeks.
“This study is the first successful Phase II clinical trial targeting
IFN-alpha in SLE and therefore represents very encouraging news for
patients with lupus for whom currently available treatments are not
working well,” said principal investigator Munther Khamashta, MD, PhD,
FRCP, Graham Hughes Lupus Research Laboratory, King’s College, London,
UK. “The efficacy of sifalimumab is supported by the primary endpoint of
SRI-4 as well as other organ-specific outcomes, with results supporting
IFN-alpha as an important therapeutic target in SLE.”
Additional studies confirm interferon inhibition by both
sifalimumab and anifrolumab
MedImmune also shared results from two open-label Phase II studies, one
with sifalimumab and one with anifrolumab, MedImmune’s other anti-Type I
interferon monoclonal antibody currently under investigation as a
potential treatment for SLE. The studies evaluated the pharmacokinetic
and pharmacodynamics effects of both molecules in the blood of adult SLE
Japanese patients.
Sifalimumab binds to and neutralizes the IFN-α subtypes but not other
Type 1 interferons, whereas anifrolumab targets the Type I Interferon
receptor blocking all Type 1 interferon signaling.
In the studies presented at ACR, both molecules were confirmed to affect
the Type I IFN pathway through suppression of the IFN gene signature,
one measure of IFN activity in the body. Anifrolumab showed more
profound and more sustained gene suppression than sifalimumab,
suggesting the first-in-class receptor approach represented by
anifrolumab may be more effective at blocking the signalling of all Type
I IFN subtypes.
There were no major safety issues in the small trials; overall safety
will be further studied in larger, double-blind controlled studies.
NOTES TO EDITORS
About Lupus
Lupus is an autoimmune disease in which the immune system produces
antibodies that, instead of targeting viruses or other foreign invaders,
attacks healthy tissue in the body, including skin, joints, the brain,
and blood vessels. Lupus can cause a range of symptoms, including pain,
rashes, fatigue, swelling in joints, and fevers, and is associated with
a higher risk of death from causes such as infection and cardiovascular
disease.
The SRI-4 Responder Index combines criteria from three internationally
validated indices, representing a clinically significant improvement in
lupus disease activity assessment that more accurately reflects recent
advances in lupus research. To achieve SRI-4 response, a person with
lupus must have at least a 4 point improvement on the SLE Disease
Activity Index – 2K (SLEDAI-2K) score, a validated measure of disease
activity and have no worsening on the Physician Global Assessment of
disease activity or the BILAG (British Isles Lupus Assessment Group)
disease activity index.
About Sifalimumab
Sifalimumab (formerly MEDI-545) is an investigational human monoclonal
antibody that targets IFN-α subtypes, inflammatory cytokines in the body
known to play a role in the development of SLE. Previous studies have
shown that elevated levels of IFN-α are correlated with more severe
disease activity in SLE patients and early studies of sifalimumab have
demonstrated that this agent inhibits signaling of interferon alpha
subtypes.
About Anifrolumab
Anifrolumab (formerly MEDI-546) is an investigational human monoclonal
antibody that binds to subunit 1 of the Type I IFN receptor, inhibiting
the activity of all Type I IFNs including IFN-α, IFN-β and IFN-ω.
Anifrolumab is the only anti-Type I IFN receptor approach currently in
development for SLE. It is being studied in an ongoing Phase IIb
clinical study in patients with moderate to severe SLE, with full
results anticipated to be presented in 2015.
About MedImmune
MedImmune is the worldwide biologics research and development arm of
AstraZeneca. MedImmune is pioneering innovative research and exploring
novel pathways across key therapeutic areas, including respiratory,
inflammation and autoimmunity; cardiovascular and metabolic disease;
oncology; neuroscience; and infection and vaccines. The MedImmune
headquarters is located in Gaithersburg, Md., one of AstraZeneca’s three
global R&D centres. For more information, please visit www.medimmune.com.
Copyright Business Wire 2014