GSK announces regulatory submissions for subcutaneous formulation of Benlysta® (belimumab) for patients with systemic lupus disease

Issued: London

GSK today announced that it has filed regulatory submissions in the US and Europe for Benlysta® (belimumab) for approval as a subcutaneous formulation in patients with active, autoantibody-positive systemic lupus erythematosus (SLE). The submissions comprise:

  • A Biologics Licence Application (BLA) to the US Food and Drug Administration for belimumab administered subcutaneously for the treatment of adult patients with active, autoantibody‑positive SLE who are receiving standard therapy
  • An extension Marketing Authorisation Application (MAA) to the European Medicines Agency for belimumab administered subcutaneously as 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.

Benlysta is a human monoclonal antibody which is currently licensed for use intravenously as a one-hour infusion every four weeks1. The regulatory submissions for the subcutaneous formulation in the US and Europe are based on results from the BLISS-SC Phase III pivotal study, which evaluated belimumab 200mg administered weekly via subcutaneous injection plus standard of care (SoC) compared to placebo plus SoC, in patients with active autoantibody-positive SLE.

Paul-Peter Tak, Chief Immunology Officer and Senior Vice President Research & Development Pipeline said: “Lupus is a complex and debilitating disease, mainly affecting women of working age, and its symptoms and impact vary from person to person. If approved, a subcutaneous formulation of Benlysta would provide an alternative approach to treatment administration, helping to address the individual needs of lupus patients.”

The BLA and extension MAA are seeking approval for the Benlysta subcutaneous formulation in 2 presentations, a single-dose prefilled syringe and a single-dose autoinjector.

Regulatory filings in other countries are planned during the course of 2016 and 2017. The subcutaneous formulation of Benlysta is currently not approved for use anywhere in the world.

About Benlysta® (belimumab), for injection, for intravenous use only

Benlysta is the first medicine specifically developed and approved for SLE in over 50 years. It is a human monoclonal antibody that selectively targets B-lymphocyte stimulator (BLyS), an important factor in the survival of B cells1,4-7.

Benlysta is indicated in the US for the treatment of adult patients with active, autoantibody‑positive, systemic lupus erythematosus (SLE) who are receiving standard therapy.

Limitations of Use

The efficacy of Benlysta has not been evaluated in 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 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.

CONTRAINDICATION

Benlysta is contraindicated in patients who have had anaphylaxis with belimumab.

WARNINGS AND PRECAUTIONS

MORTALITY

There were more deaths reported with Benlysta than with placebo during the controlled period of the clinical trials. Out of 2133 patients in 3 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 INFECTIONS

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 a history of chronic infections. Patients receiving therapy for a chronic infection should not receive Benlysta. Consider interrupting therapy with Benlysta in patients who develop a new infection while receiving Benlysta. 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.

MALIGNANCY

The impact of treatment with Benlysta on the development of malignancies is not known. The mechanism of action of Benlysta could increase the risk 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.

DEPRESSION

In clinical trials, psychiatric events (primarily depression, insomnia, and anxiety) were reported more frequently with Benlysta than with placebo. Serious psychiatric events, serious depression, and two suicides were also reported. 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.

IMMUNISATION

Live vaccines should not be given for 30 days before or concurrently with Benlysta. Benlysta may interfere with the response to immunisations.

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.

ADVERSE REACTIONS

The most commonly reported adverse reactions (≥5%) were nausea, diarrhea, pyrexia, nasopharyngitis, bronchitis, insomnia, pain in extremity, depression, migraine, and pharyngitis.

Other Important Information for Benlysta

USE IN SPECIFIC POPULATIONS

Pregnancy: Category C. Benlysta should be used during pregnancy only if the potential benefit outweighs the risk. Women of childbearing potential should use adequate contraception during treatment with Benlysta and for at least 4 months after the last dose.

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
  • HIV
  • 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 2 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 worldwide8. It is a chronic, incurable autoimmune disease producing autoantibodies that can attack almost any system in the body9-12

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Registered in England & Wales:Cautionary statement regarding forward-looking statements

GSK cautions investors that any forward-looking statements or projections made by GSK, including those made in this announcement, are subject to risks and uncertainties that may cause actual results to differ materially from those projected. Such factors include, but are not limited to, those described under Item 3.D 'Risk factors' in the company's Annual Report on Form 20-F for 2014.

References

  1. GlaxoSmithKline. BENLYSTA Summary of Product Characteristics. November 2014.
  2. Navarra SV, Guzmán RM, Gallacher AE, et al. Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-controlled, phase 3 trial. Lancet. 2011;377:722-24.
  3. Furie R, Petri M, Zamani O, et al. A Phase III, randomized, placebo-controlled study of belimumab, a monoclonal antibody that inhibits B lymphocyte stimulator, in patients with systemic lupus erythematosus. Arthritis Rheum. 2011;63:3922.
  4. Cancro MP et al. The role of B lymphocyte stimulator (BLyS) in systemic lupus erythematosus. J Clin Invest. 2009;119: 1066–73
  5. Baker KP et al. Generation and Characterization of LymphoStat-B, a Human Monoclonal Antibody That Antagonizes the Bioactivities of B Lymphocyte Stimulator. (0413) Arthritis & Rheumatism 2003;48(11): 3253–3265
  6. Petri M, Stohl W, Chatham W, McCune WJ, Chevrier M, Ryel J, Recta V, Zhong J, Freimuth W. Association of plasma B lymphocyte stimulator levels and disease activity in systemic lupus erythematosus. Arthritis & Rheumatism 2008;58(8): 2453–2459
  7. Petri M, et al.Baseline predictors of systemic lupus erythematosus flares: data from the combined placebo groups in the Phase 3 belimumab trials Arthritis Rheum 2013;Epub: na
  8. Lupus Foundation of America. Statistics on lupus. Available at: http://www.lupus.org/about/statistics-on-lupus Last accessed August 2016
  9. American College of Rheumatology Ad Hoc Committee on Systemic Lupus Erythematosus Guidelines. Guidelines for referral and management of systemic lupus erythematosus in adults. Arthritis Rheum 1999;42:1785–96.
  10. McElhone K, Abbott J, Gray J, et al. Patient perspective of systemic lupus erythematosus in relation to health-related quality of life concepts: a qualitative study. Lupus 2010;19:1640–8.
  11. Danchenko N, Satia JA, Anthony MS. Epidemiology of systemic lupus erythematosus: a comparison of worldwide disease burden. Lupus 2006;15:308–18.
  12. Lerang K, Gilboe I, Garen T, et al. High incidence and prevalence of systemic lupus erythematosus in Norway. Lupus 2012;21:1362-9.

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