GSK presents new results showing low rates of organ damage with long term use of Benlysta

Patients with SLE are at risk of irreversible damage across multiple organ systems because of both active disease and medication toxicities.  The severity and frequency of damage increases over time, and patients with damage have consistently been shown to be at risk of accruing additional damage. If left untreated, this can lead to serious and even fatal complications, particularly in patients with vital organ involvement such as heart, kidney, lungs or central nervous systems.

Gijs van den Brink, Head, Immuno-Inflammation Therapy Area R&D, GSK said: “It is important that we continue to generate evidence that increases our understanding of SLE and the benefits that Benlysta may bring to patients with this chronic condition. Using the rich data set from the long-term extension studies, these two new analyses support the potential long-term benefits of Benlysta not only to help manage the symptoms of lupus, but also to reduce the rate of organ damage.”

As the only approved biological treatment for SLE, Benlysta demonstrated a clinically meaningful reduction in SLE disease activity in the phase III BLISS pivotal trials. Assessing the level of organ damage in patients receiving Benlysta expands the understanding of its benefits when used long-term. Both analyses, which used data from the long-term extension studies from the pivotal BLISS studies, showed low rates of organ damage with Benlysta treatment.  The data in patients receiving Benlysta also provides further evidence of the importance of B-lymphocyte stimulator (BLyS, an important factor in the survival of B cells) in the development of symptoms of SLE, including longer-term organ damage.

• The long-term organ damage analysis (Van Vollenhoven RF et al) reports data from the long-term single-arm extension study in 735 non-US patients treated with Benlysta for up to 9 years.
  • For the efficacy endpoint (change in SLICC Damage Index [SDI] from baseline, a validated score to quantify organ damage, at study year 8), 87.7% patients treated with Benlysta had no increase in organ damage.
  • The incidence of adverse events (including infections, malignancies, depression, suicide, self-injury and death) remained stable or declined over time.

• The propensity score (PS) matched analysis (Urowitz M et al) reports the comparison of pooled data from the BLISS long-term extension studies with data from the Toronto Lupus Cohort (TLC) over 5 years. The PS is a composite value that allows clinically similar patients to be compared.
  • Patients treated with Benlysta plus standard of care (SoC) had significantly less progression of SLE-related organ damage (0.45 smaller unit increase in SDI score), compared with patients in the TLC receiving SoC (N=181, p<0.001).

• Patients treated with Benlysta plus SoC were 60% less likely to progress to a worse SDI score over any given year of follow‑up compared with SoC patients (N=323, p<0.001).
• A patient receiving Benlysta plus SoC has a 3.1% annual probability of organ damage progression compared with a 7.5% annual probability with SoC (N=323).

The long-term safety observed in both analyses was consistent with the known safety profile of Benlysta.  For further details see Important Safety Information below.

About the analyses

The analyses used data from two open-label, Benlysta long-term extension studies (BEL112233 and BEL112234) that enrolled patients who completed the pivotal phase III studies, BLISS-52 (BEL110752) and BLISS-76 (BEL110751). The BLISS studies were large randomised, controlled, clinical trials that were pivotal in the regulatory approval of Benlysta.

• Long-term organ damage analysis: analysed data from non-US patients that completed the BLISS pivotal phase III studies and continued in the long-term extension study (BEL112234). The study had no formal comparison to a standard of care arm since the long-term extension BLISS studies were single-armed with no control arm. Interim results (5-6 year data) were previously announced in March 2016.

• Propensity score matched analysis: analysed pooled data from patients that completed the BLISS long-term extension studies (BEL112233 and BEL112234). The pooled data was compared with data from an external registry, the Toronto Lupus Cohort, with patients who have similar clinical characteristics to those in the BLISS pivotal studies. Results in US patients were previously announced in November 2017. One of the key limitations of this study was the time period during which patients were evaluated. The TLC 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 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

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 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

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

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 , Canada 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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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 2017.