Anifrolumab is a first-in-class type I
interferon receptor antibody
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 Diseases in 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 groups were 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
receiving standard 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 indication beyond 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
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Company.
AstraZeneca is an established leader in respiratory care with a
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With common pathways and underlying disease drivers across
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Company’s growing presence in immunology is focused on five mid- to
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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
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References
- 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]
- Medscape. Lupus nephritis. Available at:
https://emedicine.medscape.com/article/330369-overview. [Last
accessed: March 2022]
- Centers for Disease Control and Prevention. Systemic Lupus
Erythematosus (SLE). Available at:
https://www.cdc.gov/lupus/facts/detailed.html [Last accessed: March
2022]
- Almaani S, et al. Update on Lupus Nephritis. Clin J Am Soc
Nephrol. 2017; 12 (5): 825-835.
- 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
- 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)
- 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.
- Ding X, et al. IFN-I Mediates Lupus Nephritis From the
Beginning to Renal Fibrosis. Front Immunol. 2021; 12: 676082
- 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
- The Lupus Foundation of America. What is Lupus Nephritis?
Available at:
https://www.lupus.org/resources/what-is-lupus-nephritis [Last
accessed: March 2022]
- ClinicalTrials.gov. Phase 3 Study of Anifrolumab in Adult
Patients With Active Proliferative Lupus Nephritis (IRIS).
Available at: https://clinicaltrials.gov/ct2/show/NCT05138133 [Last
accessed: March 2022]
- 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]
- 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.
- Lauwerys BR, et al. Type I interferon blockade in systemic
lupus erythematosus: where do we stand? Rheumatol. 2014; 53:
1369-1376.
- 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.
- Jefferies CA. Regulating IRFs in IFN Driven Disease. Front
Immunol. 2019; 10: 325.
- 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.
- López de Padilla CM, et al. The Type I Interferons: Basic
Concepts and Clinical Relevance in Immune-mediated Inflammatory
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- R�nnblom L, et al. Interferon pathway in SLE: one key to
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e000270.
- Crow MK. Type I Interferon in the Pathogenesis of Lupus. J
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https://www.clinicaltrials.gov/ct2/show/NCT02794285 [Last accessed:
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- ClinicalTrials.gov. Subcutaneous Anifrolumab in Adult Patients
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https://clinicaltrials.gov/ct2/show/NCT04877691 [Last accessed:
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