GSK today announced publication of a new long-term analysis showing that patients with moderate-to-severe systemic lupus erythematosus (SLE) treated with Benlysta (belimumab) plus standard of care (SoC) over five years experienced low rates of organ damage progression, regardless of their baseline level of damage. Patients with SLE are at risk of irreversible organ damage which will accrue over time and is associated with increased risk of death1.
Results from this analysis of two pooled, open-label, continuation studies published in Lupus, showed that for the primary endpoint (change in SLICC Damage Index [SDI] from baseline, a validated score to quantify organ damage, at study years 5-6), 85.1% patients had no change in organ damage and the mean change in SDI from baseline was 0.2 (0.48, n=403). In patients without organ damage at baseline, 87.6% had no change in SDI and the mean change was 0.2 (0.44, n=241). In patients with organ damage at baseline, 81.5% had no change in SDI and the mean change was 0.2 (0.53, n=162).The overall probability of patients maintaining their SDI score was 0.83 (95% confidence interval [CI]: 0.79, 0.86) and the median time to first worsening was 677 days (n=117).
Professor Ian Bruce, University of Manchester, UK, said: “This is the first analysis to investigate Benlysta’s long-term effect on organ damage. Whilst this is an open-label continuation study, the results are very encouraging and suggest that use of more targeted therapies may slow progression of irreversible long-term damage for lupus patients. Further studies to examine this question further would be warranted.”
The long-term safety observed in the analysis was consistent with the known safety profile of Benlysta. The majority (96.5%) of patients in the modified intent-to-treat population (MITT) experienced an adverse event (AE) any time post baseline. The incidence of AEs decreased from 87.4% to 52.7% during the study. 313 (31.4%) patients experienced a serious AE. Overall, 433 (43.4%) patients experienced a drug-related AE. The most commonly reported drug-related AEs were infections/infestations (282, 28.3%) and gastrointestinal disorders (139, 13.9%).Opportunistic infections were reported in 23 (2.3%) patients, four cases of which were serious, and herpes zoster infection was reported for 87 (8.7%) patients, seven cases of which were serious. 11 deaths occurred during the study period and three additional deaths occurred after study exit.
This data is an interim analysis of two open-label, non-randomised, uncontrolled extension studies with no placebo (SoC) data for comparison.
Results of the analysis are available at http://lup.sagepub.com/content/early/2016/02/18/0961203315625119.full.pdf+html
About the analysis
This analysis pooled data from two ongoing open-label, long-term, continuation studies that enrolled 998 patients (MITT) who completed the parent Phase III studies, BLISS-52 and BLISS-76. The BLISS studies were large randomised, controlled, clinical trials that were pivotal in the regulatory approval of Benlysta2,3,4.
BLISS-52 and BLISS-76 patients were randomised to belimumab 1 mg/kg, belimumab 10 mg/kg, or placebo plus SoC for 52 or 76 weeks. Patients in the long-term continuation studies were included regardless of whether they received 10 mg/kg or 1 mg/kg (unlicensed dose) belimumab in the BLISS studies. All patients receiving 1 mg/kg in the BLISS studies subsequently transitioned to 10 mg/kg in the continuation studies. The BLISS studies excluded patients who had active Central Nervous System (CNS) Lupus or who had severe lupus kidney disease, or who had active nephritis.
At baseline (defined as prior to the first dose of belimumab), 940 (94.2%) patients were female, with a mean (SD) age of 38.7 (11.49) years and disease duration of 6.69 (6.24) years. Systemic Lupus International Collaborating Clinics (SLICC) Damage Index (SDI) values were assessed every 48 weeks (yearly interval).
Overall 427 (42.8%) patients withdrew. Of those who withdrew, ‘patient request’ was the most common reason (168, 16.8%); where provided, the two reasons most cited by patients were a desire to conceive and logistical reasons. Other common reasons for withdrawal were AEs (85, 8.5%), other (70, 7.0%) and investigator decision (48, 4.8%).
About Benlysta® (belimumab), for injection, for intravenous use only
Benlysta was the first medicine specifically developed and approved for SLE in over 50 years when its regulatory licence was granted in 2011. It is a human monoclonal antibody that selectively targets B-lymphocyte stimulator (BLyS), an important factor in the survival of B cells2,5-8.
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 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 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.
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.
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.
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.
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
∙ 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 worldwide9. It is a chronic, incurable autoimmune disease producing autoantibodies that can attack almost any system in the body10-13.
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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.
- Nossent J, Kiss E, Rozman B, et al. Disease activity and damage accrual during the early disease course in a multinational inception cohort of patients with systemic lupus erythematosus. Lupus 2010;19:949–56.
- GlaxoSmithKline. BENLYSTA Summary of Product Characteristics. November 2014.
- 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.
- 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.
- Cancro MP et al. The role of B lymphocyte stimulator (BLyS) in systemic lupus erythematosus. J Clin Invest. 2009;119: 1066–73
- 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
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- 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.
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- Lerang K, Gilboe I, Garen T, et al. High incidence and prevalence of systemic lupus erythematosus in Norway. Lupus 2012;21:1362-9.