First long-term efficacy analysis on the effect of GSK’s Benlysta on rate of organ damage progression in SLE versus standard therapy alone

Issued: London / San Diego

GSK today announced results of the first study assessing levels of organ damage in patients with active systemic lupus erythematosus (SLE) treated with Benlysta (belimumab) plus standard of care (SoC) versus SoC alone. Patients with SLE are at risk of irreversible organ damage, which can accrue over time and is associated with increased risk of death. The data being presented at the 2017 American College of Rheumatology/Association for Rheumatology Health Professionals Annual Meeting (ACR/AHRP) shows that patients treated with belimumab plus SoC had significantly less organ damage over 5 years compared to those on SoC alone.

The propensity score (PS) matched study compared patients treated with belimumab plus SoC from the BLISS-76 US long-term extension study versus patients treated with SoC alone in the Toronto Lupus Cohort (TLC), a population of SLE patients with similar clinical characteristics to those in the BLISS pivotal studies for belimumab. Propensity Score is a composite value that allows clinically similar patients to be compared.

Results demonstrated that patients treated with belimumab plus SoC had significantly less SLE-related organ damage progression (0.44 smaller unit increase in SDI score), compared to patients in the TLC receiving SoC (p=0.001). This pattern of significantly lower organ damage progression started in the first year and continued every year of the analysis (through Year 5). Patients receiving belimumab plus SoC were 61% less likely to progress to a higher SDI score over any given year of follow-up, compared to SoC patients (p<0.001). Among patients whose levels of organ damage did increase, the magnitude of year-to-year progression also reduced compared to those on SoC alone (p=0.006).

Dr. Murray Urowitz, Professor of Medicine, University of Toronto and lead author on the study said, “These findings support results from a previous analysis of the BLISS long-term extension studies, published last year. Having an appropriate SLE comparator arm has enabled us to make the first formal evaluation of long-term belimumab treatment versus standard therapy alone. The results are encouraging and indicate the potential impact of belimumab on organ damage progression in patients living with this chronic condition.”

The results of the study were validated using an alternative method of analysis, based on inverse PS weighting, which showed similar results for the change in SDI score from baseline to Year 5 for belimumab plus SoC versus SoC alone.

The safety profile observed in the BLISS-76 long-term extension study was consistent with that observed in the overall BLISS clinical trial programme for belimumab.

About the study

This was the first long-term efficacy analysis on the effect of belimumab on the rate of organ damage progression in SLE, versus SoC alone. The study compared two groups of eligible patients with similar clinical characteristics; 259 patients who had taken part in the BLISS-76 pivotal trial US long-term extension (LTE) open labelled uncontrolled study and 706 patients from an external cohort (TLC). For the primary endpoint analysis 99 patients from the LTE study and 99 patients from the TLC were 1:1 matched and the results pertain to these 198 patients.

The primary endpoint of the study was the mean change in SLICC Damage Index [SDI] score (a validated score to quantify organ damage) from baseline to Year 5 between patients treated with belimumab plus SoC versus SoC, based on data from the BLISS LTE trial and the TLC. Secondary endpoints included time to first SDI worsening between patients treated with belimumab plus SoC versus SoC alone, and total SDI score at yearly intervals between patients treated with belimumab plus SoC versus SoC alone, as well as changes in SLEDAI score and steroid use.

One of the key limitations of this study was the time period during which patients were evaluated. The TLC has collected data on its patients for decades while the belimumab trials started in 2007. Therefore, an analysis could be confounded by change in treatment patterns over time. To minimise this possibility, TLC patients with index dates before 1990 were excluded.

About Benlysta (belimumab), for injection, for intravenous and subcutaneous use only

Benlysta is currently the only medicine specifically developed and approved for SLE. 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.

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 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 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.  In the EU, Benlysta is licensed for injection, for intravenous use only.

For the EU Summary of Product Characteristics for Benlysta, please visit www.ema.europa.eu

About systemic lupus erythematosus (SLE)

SLE is the most common form of lupus, affecting approximately 70 percent of an estimated 5 million people with lupus worldwide. SLE is a chronic, incurable, autoimmune disease associated with a range of symptoms that can fluctuate over time including painful or swollen joints, extreme fatigue, unexplained fever, skin rashes and organ damage.

Important Safety Information for belimumab

The following safety information is based on the US Prescribing Information. The Benlysta subcutaneous formulation is currently not approved in any country except the US and Japan. Please consult the full prescribing information in your country for all the labelled safety information for Benlysta (belimumab).

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 intravenous clinical trials. Out of 2,133 patients in 3 clinical trials, a total of 14 deaths occurred during the placebo-controlled, double-blind treatment periods: 3/675 (0.4%), 5/673 (0.7%), 0/111 (0%), and 6/674 (0.9%) deaths in the groups receiving placebo, BENLYSTA 1 mg/kg, BENLYSTA 4 mg/kg, and BENLYSTA 10 mg/kg, respectively. Etiologies included infection, cardiovascular disease, and suicide.

In the controlled clinical trial of BENLYSTA administered subcutaneously (N = 836), a total of 5 deaths occurred during the placebo-controlled, double-blind treatment period (0.7% [2/280] of patients receiving placebo and 0.5% [3/556] of patients receiving BENLYSTA). Infection was the most common cause of death.

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 severe or chronic infections. Consider interrupting therapy with BENLYSTA in patients who develop a new infection while receiving BENLYSTA and monitor these patients closely.

In controlled clinical trials of BENLYSTA administered intravenously, serious infections occurred in 6.0% and 5.2% of patients receiving BENLYSTA and placebo, respectively. The most frequent serious infections included pneumonia, urinary tract infection, cellulitis, and bronchitis. Infections leading to discontinuation of treatment occurred in 0.7% and 1.0% of patients receiving BENLYSTA and placebo, respectively. Infections resulting in death occurred in 0.3% (4/1,458) and 0.1% (1/675) of patients receiving BENLYSTA and placebo, respectively. In the controlled trials of BENLYSTA administered subcutaneously (N = 836), serious infections occurred in 4.1% and 5.4% of patients receiving BENLYSTA and placebo, respectively.

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. Risk factors for PML include treatment with immunosuppressant therapies and impairment of immune function. Consider the diagnosis of PML in any patient presenting with new-onset or deteriorating neurological signs and symptoms and consult with a neurologist or other appropriate specialist as clinically indicated. In patients with confirmed PML, consider stopping immunosuppressant therapy, including BENLYSTA.

HYPERSENSITIVITY REACTIONS (INCLUDING ANAPHYLAXIS)

Acute hypersensitivity reactions, including anaphylaxis and death, have been reported in association 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. Limited data suggest that patients with a history of multiple drug allergies or significant hypersensitivity may be at increased risk.

In the controlled clinical trials of BENLYSTA administered intravenously, hypersensitivity reactions occurring on the day of the infusion were reported in 13% (191/1,458) and 11% (76/675) of patients receiving BENLYSTA and placebo, respectively. Anaphylaxis was observed in 0.6% (9/1,458) and 0.4% (3/675) of patients receiving BENLYSTA and placebo, respectively. Manifestations included hypotension, angioedema, urticaria or other rash, pruritus, and dyspnea.

Some patients (13%) received premedication, which may have mitigated or masked a hypersensitivity response. 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 and be prepared to manage anaphylaxis. In the event of a serious hypersensitivity reaction, discontinue BENLYSTA immediately and administer appropriate medical therapy. Patients should be monitored during and for an appropriate period of time after the intravenous administration of BENLYSTA, 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 the controlled trial of BENLYSTA administered subcutaneously (N = 836), the incidence and severity of systemic hypersensitivity reactions were similar to those observed in the intravenous clinical trials.

INFUSION REACTIONS

In the controlled clinical trials, infusion reactions occurring on the day of the infusion were reported in 17% (251/1,458) and 15% (99/675) of patients receiving BENLYSTA and placebo, respectively. Serious infusion reactions (excluding hypersensitivity reactions) were reported in 0.5% and 0.4% of patients receiving BENLYSTA and placebo, respectively. Serious infusion reactions included bradycardia, myalgia, headache, rash, urticaria, and hypotension. The most common infusion reactions occurring in ≥3% of patients receiving BENLYSTA were headache, nausea, and skin reactions.

Some patients (13%) received premedication, which may have mitigated or masked an infusion reaction; however, there is insufficient evidence to determine whether premedication diminishes the frequency or severity of these reactions. BENLYSTA should be administered by healthcare providers prepared to manage infusion reactions. The infusion rate may be slowed or interrupted if the patient develops an infusion reaction. Healthcare providers should be aware of the risk of hypersensitivity reactions, which may present as infusion reactions, and monitor patients closely.

DEPRESSION

In controlled clinical trials of BENLYSTA administered intravenously, serious psychiatric events were reported in 0.8% and 0.4% of patients receiving BENLYSTA and placebo, respectively. Serious depression was reported in 0.4% and 0.1% of patients receiving BENLYSTA and placebo, respectively. Two suicides were reported in patients receiving BENLYSTA. In the controlled trial of BENLYSTA administered subcutaneously, serious psychiatric events were reported in 0.2% of patients receiving BENLYSTA and in no patients receiving placebo. 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.

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 for the development of malignancies.

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

Intravenous administration

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 least 1% 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%.

Subcutaneous administration

The safety profile observed for BENLYSTA administered subcutaneously was consistent with the known safety profile of BENLYSTA administered intravenously, with the exception of local injection site reactions, which occurred in 6.1% and 2.5% of patients receiving BENLYSTA and placebo, respectively.

OTHER IMPORTANT INFORMATION FOR BENLYSTA

USE IN SPECIFIC POPULATIONS

Pregnancy: There are insufficient data on use of BENLYSTA in pregnant women to establish 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 effective contraception during treatment and for at least 4 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.

Black/African American Patients: In controlled clinical trials of BENLYSTA administered intravenously, SLE Responder Index-4 (SRI-4) response rates were lower for black/African American patients receiving BENLYSTA relative to black/African American patients receiving placebo.

In the controlled trial of BENLYSTA administered subcutaneously, SRI-4 response was slightly higher for black/African American patients receiving BENLYSTA relative to black/African American patients receiving placebo, but the treatment difference was not as great as that observed in the overall population. Use with caution in black/African American patients.

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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 'Principal risks and uncertainties' in the company's Annual Report on Form 20-F for 2016.