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2019-11-11

AstraZeneca: Anifrolumab demonstrated superiority across multiple efficacy endpoints in patients with systemic lupus erythe...

Anifrolumab achieved a statistically significant reduction in disease
activity, a statistically significant reduction in oral
corticosteroid use and improvement in skin manifestations

AstraZeneca will tomorrow present detailed results from the positive
Phase III TULIP 2 trial for anifrolumab, a potential new medicine for
the treatment of moderate to severe systemic lupus erythematosus
(SLE), which demonstrated superiority across multiple efficacy
endpoints versus placebo, with both arms receiving standard of care.

On the primary endpoint, anifrolumab achieved a statistically
significant and clinically meaningful reduction in disease activity
at week 52, with 47.8% of patients receiving anifrolumab responding
compared with 31.5% of patients on placebo, as measured by the
British Isles Lupus Assessment Group-based Composite Lupus Assessment
(BICLA) composite measure.[1] The positive BICLA result in TULIP 2 is
consistent with results from pre-specified analyses using the BICLA
endpoint in the Phase III TULIP 1[2,3] and the Phase II MUSE
trials.[4]

The TULIP 2 trial also showed statistically significant differences in
multiple secondary endpoints.[1] 51.5% of anifrolumab patients
receiving oral corticosteroids (OCS) greater than or equal to 10mg
achieved a sustained reduction in OCS use compared with 30.2% of
patients on placebo. Additionally, 49% of patients receiving
anifrolumab with moderate to severe skin disease experienced improved
skin manifestations at week 12, the pre-specified timepoint, compared
with 25% of patients receiving placebo. Skin manifestations were
measured by the Cutaneous Lupus Erythematosus Disease Area and
Severity Index (CLASI).

Mene Pangalos, Executive Vice President, BioPharmaceuticals R&D, said:
"There has only been one new medicine approved for systemic lupus
erythematosus in the last 60 years, which is why we are so excited to
see the positive TULIP 2 results. There is now a strong body of
evidence demonstrating the benefit of anifrolumab, and we look
forward to bringing this potential new medicine to patients with
systemic lupus erythematosus as soon as possible."

Professor Eric F. Morand, Monash University, Australia, and Principal
Investigator on the TULIP 2 trial, said: "Systemic lupus
erythematosus is often difficult to treat, and innovative new
therapies are urgently needed. The TULIP 2 results demonstrated that,
by targeting the type I interferon receptor, anifrolumab reduces
overall disease activity, reduces corticosteroid use and improves
skin manifestations."

Dr. Richard Furie, Chief of the Division of Rheumatology at Northwell
Health, New York, US, and Principal Investigator on the TULIP 1 trial
and the Phase II MUSE trial, said: "The results across the MUSE and
TULIP trials are very important because they support anifrolumab's
potential to address systemic lupus erythematosus, an often
devastating disease that can impact almost any organ and even lead to
long-term organ damage and death."

The TULIP data are being presented at the American College of
Rheumatology (ACR) Annual Meeting 2019 in Atlanta, US. The TULIP 1
data were also published simultaneously in The Lancet Rheumatology.

As previously disclosed, TULIP 1 did not meet its primary endpoint
based on the SLE Responder Index 4 (SRI4) composite measure. However,
analyses of secondary endpoints show efficacy consistent with TULIP 2
on BICLA response, reduction in OCS use, and improvement in skin
disease activity.[2,3]

The safety and tolerability findings in TULIP 1 and TULIP 2 were
consistent with the known profile of anifrolumab.[1,2,3] There were
more commonly reported cases of herpes zoster in patients on
anifrolumab (TULIP 1: 5.6% vs.1.6%, TULIP 2: 7.2% vs.1.1%). Most
cases were mild to moderate in severity and all were cutaneous and
resolved with antiviral treatment.

About anifrolumab

Anifrolumab is a fully human monoclonal antibody that binds to subunit
1 of the type I interferon receptor, blocking the activity of all
type I interferons including IFN-alpha, IFN-beta and IFN-omega.[4]
Type I interferons are cytokines involved in the inflammatory
pathways.[5] Between 60% and 80% of adults with SLE have an increased
type I interferon gene signature, which has been shown to correlate
with disease activity.[5,6]

AstraZeneca acquired global rights to anifrolumab through an exclusive
license and collaboration agreement with Medarex, Inc. in 2004.
Medarex was acquired by Bristol-Myers Squibb in 2009.

About TULIP

The pivotal TULIP (Treatment of Uncontrolled Lupus via the Interferon
Pathway) programme includes two Phase III clinical trials, TULIP 1
and TULIP 2, that evaluated the efficacy and safety of anifrolumab
versus placebo in patients with moderately to severely active
autoantibody-positive SLE who are receiving standard of care
treatment.

TULIP 1 randomised 457 eligible patients (1:2:2) to receive a
fixed-dose intravenous infusion of 150mg anifrolumab, 300mg
anifrolumab, or placebo every four weeks. TULIP 1 assessed the effect
of anifrolumab in reducing disease activity as measured by the SRI4.

TULIP 2 randomised 365 eligible patients (1:1) to receive a fixed-dose
intravenous infusion of 300mg anifrolumab or placebo every four
weeks. TULIP 2 assessed the effect of anifrolumab in reducing disease
activity as measured by the BICLA.

The SRI4 and the BICLA are both validated composite measures of SLE
disease activity, which have been used as primary endpoints in Phase
III lupus trials.[7] Each contain the same disease activity
assessment tools, British Isles Lupus Assessment Group (BILAG) index
and Systemic Lupus Erythematosus Disease Activity Index 2000
(SLEDAI-2K), but utilise different scoring systems.[7] The BICLA
requires improvement in all organs with disease activity from
baseline, with no new flares. It can capture clinically meaningful
partial improvements within an organ system. The SRI4 requires
complete resolution in a single `higher weight' lupus symptom or
complete resolution in multiple `lower weight' lupus symptoms, with
no new flares. It does not require improvement across all affected
organ systems.

In addition to the pivotal Phase III TULIP programme, anifrolumab is
being evaluated in a Phase III long-term extension trial in SLE and a
Phase II trial in lupus nephritis.

About SLE

Systemic lupus erythematosus (SLE) is an autoimmune disease in which
the immune system attacks healthy tissue in the body.[8 ]It is a
chronic and complex disease with a variety of clinical manifestations
that can impact many organs and can cause a range of symptoms
including pain, rashes, fatigue, swelling in joints, and fevers.[9]
It is associated with a greater risk of death from causes such as
infection and cardiovascular disease.[10] There has been only one new
medicine approved for SLE in the last 60 years.[11]

About AstraZeneca

AstraZeneca is a global, science-led biopharmaceutical company that
focuses on the discovery, development and commercialisation of
prescription medicines, primarily for the treatment of diseases in
three therapy areas - Oncology, Cardiovascular, Renal and Metabolism,
and Respiratory. AstraZeneca operates in over 100 countries and its
innovative medicines are used by millions of patients worldwide.
Please visit astrazeneca.com (http://www.astrazeneca.com/) and follow
the Company on Twitter @AstraZeneca
(https://twitter.com/AstraZeneca).

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References

1. Morand E, Furie R, Tanaka Y, et al. Efficacy and Safety of
Anifrolumab in Patients with Moderate to Severe Systemic Lupus
Erythematosus: Results of the Second Phase 3 Randomized Controlled
Trial [oral]. Presented at: ACR 2019 Annual Meeting; November 8-13,
2019. Abstract ID: 757228.
https://acrabstracts.org/abstract/efficacy-and-safety-of-anifrolumab-in-...
Accessed: November, 2019.

2. Furie R, Morand E, Bruce I, et al. A Phase 3 Randomized Controlled
Trial of Anifrolumab in Patients With Moderate to Severe Systemic
Lupus Erythematosus. Presented at: ACR 2019 Annual Meeting; November
8-13, 2019. Abstract ID: 1763.
https://acrabstracts.org/abstract/a-phase-3-randomized-controlled-trial-....
Accessed: October, 2019.

3. Furie R, Morand E, Bruce I, et al. Anifrolumab: Type I Interferon
Inhibitor Anifrolumab in Active Systemic Lupus Erythematosus
(TULIP-1): a Randomised, Controlled Phase 3 Trial, Lancet
Rheumatology 2019; doi.org/10.1016/S2665-9913(19)30076-1. Accessed
November 11, 2019.

4. Furie R, Khamashta M, Merrill J.T, et al. Anifrolumab, an
Anti-Interferon-? Receptor Monoclonal Antibody, in Moderate-to-Severe
Systemic Lupus Erythematosus. Arthritis & Rheumatology.
2017;69(2);376-386.

5. Lauwerys, B.R., Ducreux J, Houssiau F.A., et al. Type I Interferon
Blockade in Systemic Lupus Erythematosus: Where Do We Stand?
Rheumatology. 2013;53(8);1369-1376.

6. Crow, M. K., Type I Interferon in the Pathogenesis of Lupus, The
Journal of Immunology. 2014;192(12);5459-5468.

7. Mikdashi J, Nived O. Measuring Disease Activity in Adults with
Systemic Lupus Erythematosus: The Challenges of Administrative Burden
and Responsiveness to Patient Concern...

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