GSK Announces Positive Results From Phase III BLISS-SC Study of Benlysta® (Belimumab) Administered Subcutaneously In Patients With Systemic Lupus Erythematosus (SLE)

SAN FRANCISCO and LONDON, Nov. 10, 2015 /PRNewswire/ -- On Saturday, Nov. 7, GSK announced results from the BLISS-SC Phase III pivotal study in patients with active, autoantibody-positive systemic lupus erythematosus (SLE). These results, which are being presented at the American College of Rheumatology/Association for Rheumatology Health Professionals Annual Meeting, showed that Benlysta^® (belimumab) 200mg administered weekly via subcutaneous injection plus standard of care (SoC), showed significantly greater reductions in disease activity compared to placebo plus SoC.

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For the primary efficacy endpoint (Systemic Lupus Erythematosus Responder Index (SRI) at Week 52), significantly more patients treated with belimumab administered subcutaneously plus SoC (60.8%) showed reduced disease activity compared to placebo plus SoC (48.47%, p=0.0011). SRI is a comprehensive composite endpoint measure, used in the pivotal Phase III BLISS clinical trial programme for belimumab administered intravenously. The SRI components measure reduction in disease activity defined as clinical improvement (SELENA-SLEDAI) with no significant worsening in any organ system (BILAG) and no worsening in overall patient condition (PGA).

For the two pre-specified secondary efficacy endpoints, the study showed that the time to severe flare was significantly delayed in patients receiving belimumab administered subcutaneously plus SoC (170 days, p=0.0003) compared to those on placebo plus SoC (116.5 days). In addition, in patients receiving more than 7.5mg/day of prednisone (n=503),18.2% of patients receiving belimumab administered subcutaneously plus SoC in the study were able to reduce their steroid dose by 25% or more to <7.5mg/day during Weeks 40-52, compared with 11.9% of those on placebo plus SoC, but this did not reach statistical significance (p=0.0732).

"Despite use of current standard of care, such as glucocorticosteroids and immunosuppressants, about 60% of lupus patients continue to experience persistent symptoms and severe disease flares," said Paul-Peter Tak, Senior Vice-President and Head of the Immuno-Inflammation Therapy Area Unit at GSK. "This is GSK's third successful Phase III study of belimumab in patients with lupus, the results of which reinforce our belief in the BLyS pathway as a means of reducing underlying disease activity. On the basis of these data, we expect to progress towards global regulatory filings for a belimumab subcutaneous formulation, which if approved, will provide appropriate patients with a new approach to treatment administration."

The overall safety profile of belimumab in BLISS-SC was consistent with that observed in the two previous BLISS studies (BLISS-52 and BLISS-76). The overall incidence of treatment-related adverse events (AEs) was 31.3% with belimumab administered subcutaneously plus SoC vs 26.1% with placebo plus SoC [the most common of which were infections/infestations (belimumab administered subcutaneously plus SoC 18.7% vs placebo plus SoC 18.9%) and general disorders and administration site conditions, primarily injection site-related events (belimumab administered subcutaneously plus SoC 6.3% vs placebo plus SoC 3.6%)]. Incidence of AEs leading to discontinuation in the belimumab administered subcutaneously plus SoC group was 7.2% compared to 8.9% with placebo plus SoC. The percentage of patients experiencing a serious AE was 10.8% with belimumab administered subcutaneously plus SoC compared with 15.7% with placebo plus SoC. A total of 5 deaths were reported; 3 (0.5%) with belimumab administered subcutaneously plus SoC, and 2 (0.7%) with placebo plus SoC. The overall incidence of death in all the randomised controlled studies of belimumab in lupus was 0.7% for the belimumab group, which is similar to that in the placebo group (0.5%).

Belimumab subcutaneous formulation is currently not approved for use anywhere in the world.

About the BLISS-SC study
BLISS-SC builds on a robust clinical trial programme for belimumab, which is the largest conducted in SLE to date^1-3. BLISS-SC is a Phase III, multi-centre, randomised, double-blind, placebo-controlled, 52-week study to evaluate the efficacy and safety of belimumab administered subcutaneously to patients with active, autoantibody-positive SLE who are receiving standard therapy. The primary efficacy endpoint is the SRI response rate at Week 52. This is a composite measure which comprises a number of elements including:

• ≥ 4 point reduction from baseline in SELENA SLEDAI score AND
• no worsening (increase of < 0.30 points) in Physician's Global Assessment (PGA) AND
• no worsening in disease activity as measured by  British Isles Lupus Assessment Group of SLE Clinics (BILAG) organ domain score (No new A or 2 new BILAG B organ domain scores compared with baseline)
• Drop outs and treatment failures were included as non-responders in the primary analysis. 

The two major secondary efficacy endpoints included the time to first severe flare (as measured by the modified SLE Flare Index (SFI)) and the percentage of patients whose average prednisone dose was reduced by ≥ 25% from baseline to ≤ 7.5 mg/day during weeks 40 to 52 in patients receiving greater than 7.5 mg/day at baseline.

Of the 836 patients enrolled into the study, 556 were randomised to receive belimumab plus SoC and 280 were randomised to placebo plus SoC. Ninety-four percent of the overall population in the study were female.

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 cells^1,4-7.

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. Instruct patients to contact their healthcare provider if they experience new or worsening depression, suicidal thoughts, or other mood changes.

IMMUNIZATION
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.

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:

• 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 five million people with lupus worldwide⁸. It is a chronic, incurable autoimmune disease producing autoantibodies that can attack almost any system in the body^9-12

GSK – one of the world's leading research-based pharmaceutical and healthcare companies – is committed to improving the quality of human life by enabling people to do more, feel better and live longer.  For further information please visit www.gsk.com.

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. May 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 October 2015.
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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