GSK submits regulatory application in Japan for belimumab in systemic lupus erythematosus
13 December 2016
Issued: London UK
GSK today announced the submission of a regulatory application to the Japanese Ministry of Health, Labor and Welfare (MHLW) for belimumab, in adult patients with active, autoantibody-positive systemic lupus erythematosus (SLE) who have an inadequate response to standard therapy.
Belimumab is a human monoclonal antibody that selectively targets B-lymphocyte stimulator (BLyS) an important factor in the survival of B cells.
The New Drug Application is based on results from two Phase III studies (Northeast Asia and BLISS-SC) and is seeking MHLW approval for belimumab in two formulations; administration via intravenous infusion and subcutaneous injection. The pivotal study of patients with SLE in Northeast Asia (Japan, China and South Korea) evaluated the efficacy and safety of 10mg/kg belimumab administered intravenously every four weeks, plus standard of care (SoC) relative to placebo plus SoC. BLISS-SC evaluated belimumab 200mg administered weekly via subcutaneous injection plus SoC compared to placebo plus SoC.
David Roth, Project Lead for belimumab at GSK said: “Lupus is a chronic and incurable inflammatory disease, which can affect almost any organ in the body. Current treatment options for lupus in Japan are very limited and there is no biologic medicine available that reduces active disease, so this regulatory submission for belimumab is very important progress. If approved, belimumab could address a great unmet medical need for lupus patients in Japan.”
Belimumab intravenous injection 10mg/kg is currently licensed for use in the US, EU and around 50 additional countries worldwide, with the approved trade name Benlysta®.
The subcutaneous formulation of belimumab is not currently approved for use anywhere in the world. Regulatory submissions in the US and EU were announced on 23 September 2016.
Benlysta is a trademark of the GlaxoSmithKline group of companies.
About Benlysta® (belimumab), for injection, for intravenous use only
Benlysta, a BLyS-specific inhibitor, is a human monoclonal antibody that binds to soluble BLyS. Benlysta does not bind B cells directly. By binding BLyS, Benlysta inhibits the survival of B cells, including autoreactive B cells, and reduces the differentiation of B cells into immunoglobulin-producing plasma cells.
Limitations of Use
The efficacy of Benlysta has not been evaluated in adult patients with severe active lupus nephritis or severe active central nervous system lupus. Benlysta has not been studied in combination with other biologics or intravenous cyclophosphamide. Use of Benlysta is not recommended in these situations.
Full prescribing information including Medication Guide for the US is available at: https://www.gsksource.com/pharma/content/dam/GlaxoSmithKline/US/en/Prescribing_Information/Benlysta/pdf/BENLYSTA-PI-MG.PDF
Benlysta is licensed in the European Union as an add-on therapy in adult patients with active autoantibody-positive SLE, with a high degree of disease activity (e.g. positive anti-dsDNA and low complement), despite standard therapy.
For the EU Summary of Product Characteristics for Benlysta, please visit www.ema.europa.eu
Benlysta is available as 120 mg in a 5-mL single-use vial and 400 mg in a 20-mL single-use vial for injection, for intravenous use only.
Important Safety Information for belimumab
Please consult the full Prescribing Information for all the labelled safety information for Benlysta (belimumab) for injection, for intravenous use only.
Benlysta is contraindicated in patients who have had anaphylaxis with belimumab.
WARNINGS AND PRECAUTIONS
There were more deaths reported with Benlysta than with placebo during the controlled period of the clinical trials. Out of 2,133 patients in three clinical trials, a total of 14 deaths occurred in the following groups: 3/675 in placebo, 5/673 in Benlysta 1 mg/kg, 0/111 in Benlysta 4 mg/kg, and 6/674 in Benlysta 10 mg/kg. No single cause of death predominated. Etiologies included infection, cardiovascular disease, and suicide.
Serious and sometimes fatal infections have been reported in patients receiving immunosuppressive agents, including Benlysta. Caution should be exercised when considering use in patients with severe or chronic infections. Consider interrupting therapy with Benlysta in patients who develop a new infection while receiving Benlysta and monitor these patients closely. The most frequent serious infections included pneumonia, urinary tract infection, cellulitis, and bronchitis.
Progressive Multifocal Leukoencephalopathy (PML): Cases of JC virus-associated PML resulting in neurological deficits, including fatal cases, have been reported in patients with SLE receiving immunosuppressants, including Benlysta. Patients presenting with new-onset or deteriorating neurological signs and symptoms should be evaluated for PML by an appropriate specialist. If PML is confirmed, consider stopping immunosuppressant therapy, including Benlysta.
The impact of treatment with Benlysta on the development of malignancies is not known. The mechanism of action of Benlysta could increase the risk for the development of malignancies.
HYPERSENSITIVITY REACTIONS (INCLUDING ANAPHYLAXIS) AND INFUSION REACTIONS
Acute hypersensitivity reactions, including anaphylaxis and death, have been reported with Benlysta. These events generally occurred within hours of the infusion; however, they may occur later. Non-acute hypersensitivity reactions including rash, nausea, fatigue, myalgia, headache, and facial edema, have been reported and typically occurred up to a week following the most recent infusion. Hypersensitivity, including serious reactions, has occurred in patients who have previously tolerated infusions of Benlysta. Patients with a history of multiple drug allergies or significant hypersensitivity may be at increased risk. Some patients received premedication; however, there is insufficient evidence to determine whether premedication diminishes the frequency or severity of these reactions.
Healthcare providers should be aware of the risk of hypersensitivity reactions, which may present as infusion reactions, and monitor patients closely. Manifestations of hypersensitivity included hypotension, angioedema, urticaria or other rash, pruritus, and dyspnea. In the event of a serious hypersensitivity reaction, discontinue Benlysta immediately and administer appropriate medical therapy. Infusion-associated adverse events were also reported. Serious infusion reactions included bradycardia, myalgia, headache, rash, urticaria, and hypotension. In the event of an infusion reaction, the infusion rate may be slowed or interrupted.
Patients should be informed of the signs and symptoms of an acute hypersensitivity reaction and be instructed to seek immediate medical care should a reaction occur.
In clinical trials, psychiatric events (primarily depression-related events, insomnia, and anxiety) were reported more frequently with Benlysta than with placebo. Serious psychiatric events and serious depression were reported in both groups. Two suicides were reported in patients receiving Benlysta. It is unknown if treatment with Benlysta is associated with increased risk for these events. Patients should be instructed to contact their healthcare provider if they experience new or worsening depression, suicidal thoughts, or other mood changes.
Live vaccines should not be given for 30 days before or concurrently with Benlysta. Benlysta may interfere with the response to immunizations.
USE WITH BIOLOGIC THERAPIES OR IV CYCLOPHOSPHAMIDE
Benlysta has not been studied in combination with other biologic therapies, including B-cell targeted therapies, or IV cyclophosphamide. Therefore, use of Benlysta is not recommended in combination with these therapies.
The most common serious adverse reactions were serious infections (6.0% and 5.2% in patients receiving Benlysta and placebo, respectively), some of which were fatal. Adverse reactions, regardless of causality, occurring in at least 3% of patients with SLE who received Benlysta 10 mg/kg and placebo respectively and, at an incidence at least1% greater than that observed with placebo in the 3 controlled studies were: nausea 15% and 12%; diarrhoea 12% and 9%; pyrexia 10% and 8%; nasopharyngitis 9% and 7%; bronchitis 9% and 5%; insomnia 7% and 5%; pain in extremity 6%, and 4%; depression 5% and 4%; migraine 5% and 4%, pharyngitis 5% and 3%; cystitis 4% and 3%; leukopenia 4% and 2%; viral gastroenteritis 3% and 1%.
Other Important Information for Benlysta
USE IN SPECIFIC POPULATIONS
Pregnancy: There are insufficient data on use of Benlysta in pregnancy women to determine whether there is drug-associated risk for major birth defects or miscarriage. Following an assessment of benefit versus risk, if prevention is warranted, women of childbearing potential should use adequate contraception during treatment and for at least four months after the final treatment,
Lactation: There is no information available on the presence of belimumab in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Benlysta and any potential adverse effects on the breastfed child from Benlysta or from the underlying maternal condition.
Populations not studied: Benlysta has not been studied in the following patient groups, and is not recommended in patients with:
- severe active central nervous system lupus
- severe active lupus nephritis
- a history of, or current, hepatitis B or C
- hypogammaglobulinaemia (IgG <400 mg/dl) or IgA deficiency (IgA <10 mg/dl)
- a history of major organ transplant or hematopoietic stem / cell / marrow transplant or renal transplant
Effect in black/African American patients: In exploratory analyses of two Phase III trials, response rates were lower for black patients (N=148) in the groups receiving Benlysta relative to black patients in the placebo group. In the Phase II trial, black patients (N=106) in the groups receiving Benlysta did not appear to have a different response than the rest of the study population. Although no definitive conclusions can be drawn from these analyses, caution should be used when considering Benlysta for black/African American patients.
About systemic lupus erythematosus (SLE)
Systemic lupus erythematosus (SLE) is the most common form of lupus, affecting approximately 70 percent of an estimated 5 million people with lupus worldwide. It is a chronic, incurable autoimmune disease producing autoantibodies that can attack almost any system in the body.
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