Company Announcements

First Patients Dosed in IRIS Phase III Trial Evaluating Anifrolumab in Lupus Nephritis

Anifrolumab is a first-in-class type I interferon receptor antibody

WILMINGTON, Del.--(BUSINESS WIRE)--May 27, 2022-- The first patients have been dosed in the IRIS Phase III clinical trial of anifrolumab in lupus nephritis (LN).

Up to 60% of patients with lupus develop kidney involvement. In more severe cases, this can develop into LN.1 LN is characterized by kidney inflammation and is one of the most common severe organ manifestations in systemic lupus erythematosus (SLE),2 a chronic and complex autoimmune disease in which the immune system attacks healthy tissue in the body.3 Patients with LN are at a substantial increased risk of dialysis and early mortality.4-6 Patients with LN have been shown to have elevated levels of type I interferons in the blood and kidneys.7,8

Eduardo Mysler, Medical Director and Rheumatologist at the Organización Médica de Investigación, Buenos Aires, Argentina, and the international coordinating investigator in the anifrolumab clinical development program for LN, said, “The Phase II results of anifrolumab in lupus nephritis provided important evidence suggesting that blocking type I interferons is a potentially promising strategy for the treatment of lupus nephritis. I look forward to contributing to the next phase of anifrolumab’s development in this severe and often debilitating complication of lupus where new therapeutic options are needed.”

Mene Pangalos, Executive Vice President, BioPharmaceuticals R&D, AstraZeneca, said: “Lupus nephritis continues to represent a significant burden to patients worldwide. Following the approval of anifrolumab as the first new treatment for systemic lupus erythematosus in over a decade, the start of our IRIS Phase III trial in lupus nephritis is another important step forward in our ambition to bring anifrolumab to more patients with diseases where type I interferon is a central driver.”

Results from the TULIP-LN1 Phase II proof of concept, dose-finding trial of anifrolumab were published in Annals of the Rheumatic Diseasesin February 2022.9 The primary endpoint was the change in a measure of kidney function (baseline 24-hour urine protein creatinine ratio) at week 52 for combined anifrolumab versus placebo groups. Although the trial’s primary endpoint was not met (69% versus 70%, p=0.905), the higher dose tested showed clinically meaningful numeric improvements across multiple secondary and exploratory endpoints versus placebo (with all patients also receiving standard therapy).9 The adverse events that were more common (≥5% difference) in the combined anifrolumab versus placebo groupswere herpes zoster, urinary tract infection, and influenza.9

INDICATION AND LIMITATIONS OF USE for SAPHNELO™ (anifrolumab-fnia)

SAPHNELO is indicated for the treatment of adult patients with moderate to severe systemic lupus erythematosus (SLE), who are receivingstandard therapy.

Limitations of Use: The efficacy of SAPHNELO has not been evaluated in patients with severe active lupus nephritis or severe active central nervous system lupus. Use is not recommended in these situations.

IMPORTANT SAFETY INFORMATION

CONTRAINDICATION

Known history of anaphylaxis with SAPHNELO.

WARNINGS AND PRECAUTIONS

  • Serious Infections: Serious and sometimes fatal infections have occurred in patients receiving immunosuppressive agents, including SAPHNELO. SAPHNELO increases the risk of respiratory infections and herpes zoster. Use caution in patients with severe or chronic infections. Avoid initiating treatment during an active infection and consider interrupting therapy in patients who develop a new infection during treatment
  • Hypersensitivity Reaction Including Anaphylaxis: Serious hypersensitivity reactions (including anaphylaxis) have been reported following SAPHNELO administration. Events of angioedema have also been reported. Other hypersensitivity reactions and infusion-related reactions have occurred following administration of SAPHNELO. SAPHNELO should be administered by healthcare providers prepared to manage hypersensitivity reactions, including anaphylaxis and infusion-related reactions, if they occur. Immediately interrupt administration and initiate appropriate therapy if a serious infusion-related or hypersensitivity reaction (eg, anaphylaxis) occurs
  • Malignancy: There is an increased risk of malignancies with the use of immunosuppressants. The impact of SAPHNELO on the potential development of malignancies is not known
  • Immunization: Avoid the use of live or live-attenuated vaccines in patients treated with SAPHNELO
  • Use With Biologic Therapies: SAPHNELO is not recommended for use in combination with other biologic therapies, including B-cell targeted therapies

ADVERSE REACTIONS

The most common adverse reactions (incidence ≥5%) are nasopharyngitis, upper respiratory tract infections, bronchitis, infusion-related reactions, herpes zoster and cough.

In the controlled clinical trials, the incidence of infusion-related reactions was 9.4% in patients while on treatment with SAPHNELO and 7.1% in patients on placebo. Infusion-related reactions were mild to moderate in intensity; the most common symptoms were headache, nausea, vomiting, fatigue, and dizziness.

USE IN SPECIFIC POPULATIONS

Pregnancy: A pregnancy exposure registry monitors pregnancy outcomes in women exposed to SAPHNELO during pregnancy. For more information about the registry or to report a pregnancy while on SAPHNELO, contact AstraZeneca at 1-877-693-9268.

There are insufficient data on the use of SAPHNELO in pregnant women to establish whether there is drug-associated risk for major birth defects or miscarriage. Advise female patients to inform their healthcare provider if they intend to become pregnant during therapy, suspect they are pregnant or become pregnant while receiving SAPHNELO.

Lactation: No data are available regarding the presence of SAPHNELO in human milk, the effects on the breastfed child, or the effects on milk production.

Pediatric Use: The safety and efficacy of SAPHNELO in pediatric patients less than 18 years of age has not been established.

Please see full Prescribing Information, including Patient Information.

Notes

Lupus nephritis
LN is more common in women than in men, and there is a higher prevalence and severity of the disease among African American, Asian and Hispanic women between 15-44, who tend to develop the disease earlier and experience more serious complications.10

IRIS
The IRIS Phase III trial is a two-year, multicenter, multinational, randomized, double-blind, placebo-controlled study expected to enroll up to 360 participants aged 18 to 70.11 The aim of the study is to evaluate the efficacy and safety of anifrolumab versus placebo when added to standard therapy (consisting of mycophenolate mofetil and glucocorticoids) in adults diagnosed with active Class III or IV LN (with or without concomitant Class V).11 Active LN will be confirmed by kidney biopsy during screening visits using the 2003 International Society of Nephrology/Renal Pathology Society criteria, and clinically active kidney disease.11

TULIP-LN1
This Phase II double-blinded TULIP-LN1 study randomized 147 patients to receive monthly intravenous anifrolumab basic regimen (300 mg), intensified regimen (900 mg ×3, 300 mg thereafter) or placebo, alongside standard therapy (oral glucocorticoids, mycophenolate mofetil). 12 The primary endpoint was change in baseline 24-hour urine protein–creatinine ratio at week 52 for combined anifrolumab versus placebo groups. The secondary endpoint was complete renal response at week 52.12 Exploratory endpoints included more stringent complete renal response definitions and sustained glucocorticoid reductions (≤7.5 mg/day, weeks 24–52). Safety was analyzed descriptively.12

SAPHNELO
SAPHNELO (anifrolumab) is a fully human monoclonal antibody that binds to subunit 1 of the type I IFN receptor, blocking the activity of type I IFN.13 Type I IFNs, such as IFN-alpha, IFN-beta and IFN-kappa, are cytokines involved in regulating the inflammatory pathways implicated in SLE.14-19 The majority of adults with moderate to severe SLE have increased type I IFN signaling, which is associated with increased disease activity and severity.14,20

SAPHNELO is approved for the treatment of moderate to severe SLE in the US, Japan, Europe and Canada, with regulatory reviews ongoing in other countries worldwide. This is the first Phase III trial of SAPHNELO in a potential new indicationbeyond SLE. The IRIS Phase III trial will be conducted in multiple countries involving adult patients with active LN.11

In SLE, SAPHNELO continues to be evaluated in a long-term extension Phase III trial and a Phase III trial assessing subcutaneous delivery.21,22

Additional Phase III trials are planned investigating SAPHNELO in diseases where type I IFN plays a key role, including cutaneous lupus erythematosus and myositis.23

AstraZeneca in Respiratory & Immunology
Respiratory & Immunology, part of BioPharmaceuticals, is one of AstraZeneca’s main disease areas and is a key growth driver for the Company.

AstraZeneca is an established leader in respiratory care with a 50-year heritage. The Company aims to transform the treatment of asthma and chronic obstructive pulmonary disease (COPD) by focusing on earlier biology-led treatment, eliminating preventable asthma attacks and removing COPD as a top-three leading cause of death. The Company’s early respiratory research is focused on emerging science involving immune mechanisms, lung damage and abnormal cell-repair processes in disease and neuronal dysfunction.

With common pathways and underlying disease drivers across respiratory and immunology, AstraZeneca is following the science from chronic lung diseases to immunology-driven disease areas. The Company’s growing presence in immunology is focused on five mid- to late-stage franchises with multi-disease potential, in areas including rheumatology (including SLE), dermatology, gastroenterology, and systemic eosinophilic-driven diseases. AstraZeneca’s ambition in Respiratory & Immunology is to achieve disease modification and durable remission for millions of patients worldwide.

About AstraZeneca
AstraZeneca is a global, science-led biopharmaceutical company that focuses on the discovery, development and commercialization of prescription medicines in Oncology, Rare Diseases and BioPharmaceuticals, including Cardiovascular, Renal & Metabolism, and Respiratory & Immunology. Based in Cambridge, UK, AstraZeneca operates in over 100 countries, and its innovative medicines are used by millions of patients worldwide. For more information, please visit www.astrazeneca-us.com and follow us on Twitter @AstraZenecaUS.

©2022 AstraZeneca. All rights reserved. Used with permission.

References

  1. Lupus Foundation of America. The Expert Series: Kidney health and lupus. Available at: https://www.lupus.org/resources/the-expert-series-kidney-health-and-lupus. [Last accessed: May 2022]
  2. Medscape. Lupus nephritis. Available at: https://emedicine.medscape.com/article/330369-overview. [Last accessed: March 2022]
  3. Centers for Disease Control and Prevention. Systemic Lupus Erythematosus (SLE). Available at: https://www.cdc.gov/lupus/facts/detailed.html [Last accessed: March 2022]
  4. Almaani S, et al. Update on Lupus Nephritis. Clin J Am Soc Nephrol. 2017; 12 (5): 825-835.
  5. Kostopoulou M, et al. Management of lupus nephritis: a systematic literature review informing the 2019 update of the joint EULAR and European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations. RMD Open 2020; 6: e001263
  6. Arriens C, et al. Increased Risk of Progression to Lupus Nephritis for Lupus Patients with Elevated Interferon Signature [abstract]. Arthritis Rheumatol. 2019; 71 (suppl 10)
  7. Castellano G, et al. Local synthesis of interferon-alpha in lupus nephritis is associated with type I interferons signature and LMP7 induction in renal tubular epithelial cells. Arthritis Res Ther. 2015; 17 (1): 72.
  8. Ding X, et al. IFN-I Mediates Lupus Nephritis From the Beginning to Renal Fibrosis. Front Immunol. 2021; 12: 676082
  9. Jayne D, et al. Phase II randomised trial of type I interferon inhibitor anifrolumab in patients with active lupus nephritis. Annals of the Rheumatic Diseases Published Online First: 10 February 2022. doi: 10.1136/annrheumdis-2021-221478
  10. The Lupus Foundation of America. What is Lupus Nephritis? Available at: https://www.lupus.org/resources/what-is-lupus-nephritis [Last accessed: March 2022]
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  12. ClinicalTrials.gov. Safety and Efficacy of Two Doses of Anifrolumab Compared to Placebo in Adult Subjects With Active Proliferative Lupus Nephritis (TULIP-LN1). Available at: https://www.clinicaltrials.gov/ct2/show/NCT02547922. [Last accessed: May 2022]
  13. Riggs JM, et al. Characterisation of anifrolumab, a fully human anti-interferon receptor antagonist antibody for the treatment of systemic lupus erythematosus. Lupus Sci Med. 2018; 5 (1): e000261.
  14. Lauwerys BR, et al. Type I interferon blockade in systemic lupus erythematosus: where do we stand? Rheumatol. 2014; 53: 1369-1376.
  15. Sarkar MK, et al. Photosensitivity and type I IFN responses in cutaneous lupus are driven by epidermal-derived interferon kappa. Ann Rheum Dis. 2018; 77: 1653-1664.
  16. Jefferies CA. Regulating IRFs in IFN Driven Disease. Front Immunol. 2019; 10: 325.
  17. Mai L, et al. The baseline interferon signature predicts disease severity over the subsequent 5 years in systemic lupus erythematosus. Arthritis Res Ther. 2021; 23: 29.
  18. López de Padilla CM, et al. The Type I Interferons: Basic Concepts and Clinical Relevance in Immune-mediated Inflammatory Diseases. Gene. 2016; 576 (101): 14-21.
  19. Rönnblom L, et al. Interferon pathway in SLE: one key to unlocking the mystery of the disease. Lupus Sci Med. 2019; 6 (1): e000270.
  20. Crow MK. Type I Interferon in the Pathogenesis of Lupus. J Immunol. 2014; 192 (12): 5459-5468.
  21. ClinicalTrials.gov. Long Term Safety of Anifrolumab in Adult Subjects With Active Systemic Lupus Erythematosus (TULIP SLE LTE). https://www.clinicaltrials.gov/ct2/show/NCT02794285 [Last accessed: March 2022].
  22. ClinicalTrials.gov. Subcutaneous Anifrolumab in Adult Patients With Systemic Lupus Erythematosus (Tulip SC). Available at: https://clinicaltrials.gov/ct2/show/NCT04877691 [Last accessed: March 2022]
  23. AstraZeneca plc. Saphnelo (anifrolumab) approved in the US for moderate to severe systemic lupus erythematosus. Available at: https://www.astrazeneca.com/media-centre/press-releases/2021/saphnelo-approved-in-the-us-for-sle.html [Last accessed: March 2022]

 

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