Phase IIb study on sifalimumab met primary endpoint of reduction in global SLE disease activity score (SRI-4) and demonstrated clinically important improvements in skin, joints, and patient-reported outcomes
Studies on both sifalimumab and anifrolumab confirm the promise of targeting the interferon pathway
Gaithersburg, MD – November 17, 2014 – 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
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.
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.
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-a, IFN-b and IFN-w. 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.
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.
Susannah Budington, MedImmune
Tracy Rossin, MedImmune