GSK today announced data at the Annual European Congress of Rheumatology (EULAR 2016) showing that patients with highly active systemic lupus erythematosus (SLE) experienced a significantly greater response to treatment with Benlysta (belimumab) 200mg administered via subcutaneous injection plus standard of care (SoC), compared to placebo plus SoC. High SLE disease activity is associated with symptom flares and a range of organ manifestations in lupus patients. The pre-specified analysis reviewed a subset of patients from the overall BLISS-SC Phase III pivotal study of belimumab subcutaneous formulation. This high disease activity sample is reflective of the licensed population for Benlysta intravenous formulation in the European Union.
Results showed that patients with highly active SLE (low C3/C4 complement and positive anti-double-stranded DNA) treated with belimumab administered subcutaneously plus SoC (belimumab group) had significantly greater reductions in disease activity as measured by the primary efficacy endpoint SRI4 (Systemic Lupus Responder Index) at Week 52, compared to placebo plus SoC (placebo group) (64.6% compared to 47.2%, p=0.0014). These findings are consistent with those observed in the pivotal Phase III BLISS clinical trial programme for belimumab administered intravenously.
For the pre-specified secondary endpoints, patients in the belimumab group showed a 62% reduction in their risk of experiencing a severe flare compared to those in the placebo group (Hazard Ratio = 0.38, p<0.0001). 14.1% of patients in the belimumab group had a severe flare during the course of the study compared to 31.5% in the placebo group. In patients receiving more than 7.5mg/day of prednisone (n=234), 20.7% of patients in the belimumab group were able to reduce their steroid dose by 25% or more to <7.5mg/day during Weeks 40-52, compared with 11.4% of those in the placebo group, but this was not statistically significant (p=0.0844).
“One of the major challenges facing clinicians managing patients with SLE is to predict the disease course, as it fluctuates and varies greatly between individuals, from relatively benign to rapidly progressive and even fatal”, said Professor Andrea Doria, University of Padua, Padua, Italy. “Research suggests that controlling this disease activity plays an important role in improving patient outcomes. The range of clinical benefits seen with Benlysta in this sub-set of patients with more active lupus provides valuable insights for clinicians about disease characteristics that may help inform the potential response to treatment and improve certain outcomes for patients living with this debilitating disease.”
The overall safety profile of belimumab in this subset population of BLISS-SC appears generally consistent with that observed in the two previous BLISS studies (BLISS-52 and BLISS-76). The overall incidence of adverse events (AEs) was 78.2% in the belimumab group vs 81.5% in the placebo group [the most common of which were infections and infestations (55.2% in the belimumab group compared with 54.6% in the placebo group)]. The percentage of patients experiencing a serious AE was 13.3% in the belimumab group compared with 23.1% in the placebo group.
BLISS-SC is the third successful Phase III study for belimumab in SLE.
Belimumab subcutaneous formulation is currently not approved for use anywhere in the world.
About the BLISS-SC study
BLISS-SC builds on an extensive clinical trial programme for belimumab, which is the largest clinical programme in SLE to date. BLISS-SC was 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.
Of the 836 patients enrolled into the study, 356 had low C3/C4 complement and positive anti-double-stranded DNA, characteristics of high SLE disease activity. Of these 248 were randomised to receive belimumab plus SoC and 108 were randomised to placebo plus SoC. 96.1% of this high disease activity population in the study were female.
The primary efficacy endpoint was 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 pre-specified 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.
Results for the overall study population, presented at the 2015 American College of Rheumatology/Association for Rheumatology Health Professionals Annual Meeting, showed that 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).
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 cells.
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.
Full US 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 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, for injection, for intravenous use only
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 common serious adverse reactions were serious infections (6.0% and 5.2% in patients receiving BENLYSTA and placebo, respectively). 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%; diarrhea 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: 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.
Populations not studied
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 worldwide. It is a chronic, incurable autoimmune disease producing autoantibodies that can attack almost any system in the body.
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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 2015.