New analyses of Phase II trial demonstrate improvement
of symptoms in multiple organ domains including skin and joints
8 June 2016
AstraZeneca and its global biologics research and development arm, MedImmune, today announced that they will present positive new data on anifrolumab, an investigational monoclonal antibody that blocks all type 1 interferons, being developed to treat moderate to severe systemic lupus erythematosus (SLE, or lupus), at the Annual European Congress of Rheumatology (EULAR 2016), taking place in London, U.K. from 8-11 June, 2016.
In five presentations — three oral and two posters — AstraZeneca and MedImmune will present results from the positive Phase II anifrolumab trial (known as MUSE) for the first time outside of the United States, as well as new analyses of the Phase II data demonstrating the broad effects of anifrolumab on multiple organ domains and on biomarkers of SLE, and other clinical evidence in lupus.1-5
Results from the Phase II MUSE trial in moderate to severe SLE demonstrate that anifrolumab reduced lupus disease activity across a wide range of clinical endpoints. In the analysis of the primary endpoint, significantly more anifrolumab-treated patients achieved an SLE Responder Index [SRI(4)] response at Day 169 with sustained reduction of oral corticosteroids (OCS) (<10 mg/day and ≤Day 1 dose from Day 85 to 169) compared to patients receiving placebo.1 Even greater effect sizes were observed in the 75% of patients who had a high type I interferon gene signature at baseline (Abstract OP0291, 11 June 2016, 09:47 am GMT).1
A new analysis of the Phase II trial revealed a greater reduction in disease activity with anifrolumab treatment versus placebo in individual organ domains frequently involved in lupus.2 At Week 52, changes in skin and joint activity (the mucocutaneous and musculoskeletal domains) were observed using the British Isles Lupus Assessment Group (BILAG) and SLE Disease Activity Index 2000 (SLEDAI-2K), with higher percentages of patients in the anifrolumab-treated groups showing improvement.2 Trends suggesting potential benefits were also observed in most of the other less frequently active organ domains, including cardiorespiratory, vascular, hematological and constitutional.2 (Abstract THU0295, 09 June 2016, 11:45 am–13:30 pm GMT).
Additional Company presentations at EULAR include:
- An additional analysis of the Phase II trial evaluating the effects of anifrolumab on immune cell dysregulation and complement system abnormalities of SLE.3 Results show that anifrolumab administration elicits a widespread impact on selected, peripheral biomarkers of patients with moderate to severe SLE. (Abstract OP0165, 10 June 2016, 11:20 am GMT).3
- Association between Systemic Lupus Erythematosus (SLE) Responder Index(4) (SRI4) and global, clinically-important benefit in patients with moderate-to-severe SLE, including broad improvements in clinical, laboratory and patient-reported outcome measures (Abstract OP0044, 09 June 2016, 11:10 am GMT).4
- Key factors for patient engagement in SLE and lupus nephritis trials in African-Americans, based on a clinical trial simulation (Abstract THU0355, 09 June 2016, 11:45 am–13:30 pm).5
Bing Yao, Senior Vice President, Research and Development for Respiratory, Inflammation and Autoimmunity, MedImmune, said: “Our Phase II trial has provided a strong foundation from which our Phase III trials were designed. We are actively enrolling in those Phase III trials now, and we look forward to further exploring the role of type I interferons in the treatment of lupus and building on these promising results.”
Principal Investigator Richard A. Furie, MD, Chief, Division of Rheumatology, Northwell Health, said: “Although there have been many recent treatment advances for autoimmune conditions, innovations in lupus therapies have lagged behind, leaving a significant need as most current options have limited efficacy or undesired side effects. I am excited to share compelling evidence that blocking type 1 interferons is a promising strategy for the treatment of SLE, providing needed hope for the lupus community.”
In the Phase II trial, anifrolumab treatment was well tolerated, and serious adverse events reported were similar across the three treatment groups.1 A dosage-dependent increase in Herpes zoster cases (Placebo: 2.0%; 300mg: 5.1%; 1000mg: 9.5%) and a greater number of events reported as influenza (placebo: 2.0%; 300mg: 6.1%; 1,000 mg: 7.6%) were observed for patients receiving anifrolumab.1
NOTES TO EDITORS
Anifrolumab is an investigational, fully human monoclonal antibody that binds to subunit 1 of the Type I IFN receptor, inhibiting the activity of all type I IFNs, which play a central role in lupus, including IFN-α, IFN-β, IFN-ω, and others.6 Anifrolumab is the only anti-type-I IFN receptor approach currently in development for SLE. Anifrolumab is currently in Phase III development for SLE.7 The US Food and Drug Administration has granted anifrolumab Fast- Track designation for SLE, which expedites the review process to facilitate the development of medicine candidates that treat serious conditions and fill an unmet medical need.8,9 A Phase II trial in lupus nephritis and a Phase I trial in a subcutaneous route of administration are also ongoing.10,11 Anifrolumab is being developed with a type I IFN gene signature test designed to identify patients who may be more likely to benefit from treatment.
About the Phase II Anifrolumab Trial (MUSE)
The efficacy and safety of anifrolumab were evaluated in a Phase II, randomized, double-blind, placebo-controlled trial, known as MUSE, in which 305 adults with seropositive moderate to severe SLE receiving standard-of-care medications were randomized to receive intravenous (IV) anifrolumab 300 mg or 1,000 mg Q4W or placebo (PBO) every four weeks for 48 weeks.1 Patients were stratified by SLE Disease Activity Index (SLEDAI) score, OCS (oral corticosteroid) dosage, and IFN gene signature (IFN high vs. IFN low) based on a 4-gene expression assay.1 The trial met its primary endpoint of difference in the percentage of patients who achieved response as measured by the SLE Responder Index 4 (SRI4) at Day 169, along with a sustained reduction of oral corticosteroid (OCS) use between Day 85 and day 169.1The trial also met both secondary efficacy endpoints measuring responses at Day 365.1
The SLE Responder Index is recognised as an endpoint for SLE clinical trials by health authorities and combines criteria from three internationally validated disease activity measures, representing a clinically significant improvement in lupus disease activity.12 To achieve SRI4 response, an individual must have at least a 4-point improvement on the SLE Disease Activity-2K (SLEDAI-2K) score and have no worsening on the Physician Global Assessment of disease activity and the BILAG (British Isles Lupus Assessment Group) disease activity index.12 Disease activity was also assessed by Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI), BICLA, and 28-joint count.1
About the Phase III TULIP Programme7,13
The TULIP (Treatment of Uncontrolled Lupus via the Interferon Pathway) programme includes two Phase III clinical trials that will evaluate the efficacy and safety of anifrolumab versus placebo in patients with moderately to severely active, autoantibody-positive SLE, while receiving standard of care treatments. The Phase III trials will assess the effects of anifrolumab in reducing disease activity (as measured by the SRI), decreasing use of OCS, improving skin manifestations (as measured by Cutaneous Lupus Erythematosus Disease Area and Severity Index - CLASI) and reducing flares.
About Systemic Lupus Erythematosus (SLE)
Systemic lupus erythematosus (SLE), or lupus, is an autoimmune disease in which the immune system produces antibodies that, instead of targeting viruses or other foreign invaders, attack healthy tissues in the body, including skin, joints, the kidney, brain and blood vessels. SLE can cause a range of manifestations, including pain, rashes, fatigue, swelling in joints, and fevers.14,15 It is associated with increased morbidity and mortality from the disease itself, medications used to control disease activity, infections and cardiovascular disease.16
About Respiratory, Inflammation and Autoimmunity
Respiratory, Inflammation and Autoimmunity (RIA) is one of AstraZeneca’s main therapy areas, and we have a growing portfolio of medicines that reached more than 17 million patients in 2015. Our strong pipeline has the potential to deliver up to seven launches between 2016 and 2020. In respiratory disease, our aim is to transform asthma and COPD treatment through inhaled combinations at the core of care, biologics for the unmet needs of specific patient populations, and scientific advancements in disease modification. We are building on a 40-year heritage in respiratory disease, and our capability in inhalation technology spans both pressurised metered-dose inhalers (pMDIs) and dry powder inhalers (DPIs), as well as our unique Co-SuspensionTM Technology.
In Inflammation and Autoimmunity, our aim is to develop innovative therapies for the treatment of autoimmune and rheumatologic diseases, with a lead programme in systemic lupus erythematosus. Across respiratory, inflammation and autoimmune diseases, our research is focused on four key biological pathways: eosinophilic disease, Th2-driven disease, epithelial-driven pathobiology, and autoimmunity.
MedImmune is the global biologics research and development arm of AstraZeneca, a global, innovation-driven biopharmaceutical business that focuses on the discovery, development and commercialization of small molecule and biologic prescription medicines. MedImmune is pioneering innovative research and exploring novel pathways across key therapeutic areas, including oncology; respiratory, inflammation and autoimmunity; cardiovascular and metabolic disease; and infection and vaccines. The MedImmune headquarters is located in Gaithersburg, Md., one of AstraZeneca’s three global R&D centers, with additional sites in Cambridge, UK and Mountain View, CA. For more information, please visit www.medimmune.com.
AstraZeneca is a global, innovation-driven biopharmaceutical business that focuses on the discovery, development and commercialisation of prescription medicines, primarily for the treatment of cardiovascular, metabolic, respiratory, inflammation, autoimmune, oncology, infection and neuroscience diseases. AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. For more information, please visit: www.astrazeneca.com.
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1. Furie R, et. al. Anifrolumab, an Anti-Interferon-Alpha Receptor Monoclonal Antibody, in Moderate to Severe Systemic Lupus Erythematosus. Abstract OP0291 [Oral Presentation]. Presented at the Annual European Congress of Rheumatology (EULAR 2016), 8-11 June 2016, London.
2. Merrill JT, et. al. Anifrolumab reduces disease activity in multiple organ domains in Moderate to Severe Systemic Lupus Erythematosus. Abstract THU0295 [Poster Presentation]. Presented at the Annual European Congress of Rheumatology (EULAR 2016), 8-11 June 2016, London.
3. Guo X, et. al. Beneficial effects of an anti-IFNAR1 monoclonal antibody on immune cell dysregulation and complement system abnormalities of systemic lupus erythematosus: an exploratory analysis of a Phase IIb clinical trial of anifrolumab. Abstract OP0165 [Oral Presentation]. Presented at the Annual European Congress of Rheumatology (EULAR 2016), 8-11 June 2016, London.
4. Furie R, et. al. Systemic Lupus Erythematosus (SLE) responder index [SRI(4)] response is associated with global benefit in patients with moderate to severe SLE. Abstract OP0044 [Oral Presentation]. Presented at the Annual European Congress of Rheumatology (EULAR 2016), 8-11 June 2016, London.
5. Lim SS, et. al. Clinical trial simulation identifies factors for patient engagement in systemic lupus erythematosus and lupus nephritis trials in African-Americans. Abstract THU0355 [Poster Presentation]. Presented at the Annual European Congress of Rheumatology (EULAR 2016), 8-11 June 2016, London.
6. Furie R, et. al. Anifrolumab, an Anti-Interferon-Alpha Receptor Monoclonal Antibody, in Moderate to Severe Systemic Lupus Erythematosus. Arthritis and Rheumatology. 2016 [TBD pending publication]
7. National Institutes of Health. Efficacy and Safety of Two Doses of Anifrolumab Compared to Placebo in Adult Subjects With Active Systemic Lupus Erythematosus. Available at: https://clinicaltrials.gov/ct2/show/NCT02446912. Accessed May 2016.
8. AstraZeneca. Q3 2015 results. Available from: https://www.astrazeneca.com/content/dam/az/our-company/investor-relations/presentations-and-webcast/AstraZeneca%20Results%20Presentation%20Q3%202015.pdf. Accessed June 2016.
9. FDA. Fast Track. Available from: http://www.fda.gov/ForPatients/Approvals/Fast/ucm405399.htm. Accessed June 2016
10. National Institutes of Health. Safety and Efficacy of Two Doses of Anifrolumab Compared to Placebo in Adult Subjects With Active Proliferative Lupus Nephritis (TULIP-LN1). Available at: https://clinicaltrials.gov/ct2/show/NCT02547922. Accessed June 2016.
11. National Institutes of Health. A Study to Assess the Pharmacokinetics and Safety of Single Doses of Anifrolumab in Healthy Subjects. Available at: https://clinicaltrials.gov/ct2/show/NCT02601625. Accessed June 2016.
12. EMA. Guideline on clinical investigation of medicinal products for the treatment of systemic lupus erythematosus and lupus nephritis. Available at: http://www.fdanews.com/ext/resources/files/03-15/03-27-15-EMAlupusguideline.pdf?1427471226 . Accessed June 2016
13. National Institutes of Health. Efficacy and Safety of Anifrolumab Compared to Placebo in Adult Subjects With Active Systemic Lupus Erythematosus. Available at: https://clinicaltrials.gov/ct2/show/NCT02446899. Accessed June 2016.
14. Alliance for Lupus Research. What is lupus. Available at: http://www.lupusresearch.org/lupus/what-is.html. Accessed June 2016.
15. Lateef A, et. al. Unmet medical needs in systemic lupus erythematosus. Arthritis Research & Therapy. 2012;14(suppl4): S4.
16. Lisnevskaia L, et. al. Systemic lupus erythematosus. Lancet. 2014;384(9957):1878-1888.