Benlysta is Designed for - 2nd Common Ground ...
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Benlysta is
Designed for
Lupus
Benlysta is indicated for reducing disease activity in patients from 5 years of age with active
autoantibody positive systemic lupus erythematosus (SLE) who are receiving background therapy.
Benlysta has not been studied in patients with severe active central nervous system lupus or severe
active lupus nephritis.22
Do you consider using BENLYSTA earlier to improve
long-term treatment outcomes?
Treatment goals
CURRENT SLE TREATMENT GOALS
Damage
accrual
Time
Short-term goals 1,2
Long-term goals1-3
• Reduce disease activity • Reduce disease activity
• Improve health-related Key question: • Prevention of (severe) flares
quality of life (e.g., fatigue) When to start • Steroid sparing
• Reduce risk and number biologic (BENLYSTA) • Minimise damage accrual
of flares
therapy? • Address treatment-related
toxicities
Disease activity, flares and prolonged use of corticosteroids can all
contribute to organ damage.3, 5, 7
Long-term corticosteroid* therapy can cause irreversible organ damage.2
In fact, up to
80%
of late-stage damage Corticosteroid dose
could be attributed * Corticosteroid
dose should
to corticosteroid use.5 be minimized to ≤7.5 mg/day.2
2
Organ damage
DISEASE ACTIVITY, FLARES AND PROLONGED USE
OF CORTICOSTEROIDS CAN ALL CONTRIBUTE
TO ORGAN DAMAGE3-7
33% to 50% of SLE patients experience permanent organ
damage within 5 years of diagnosis7,8*
Percentage of patients with permanent organ damage (SDI†)8
100
90
% of patients with SDI ≥1 from diagnosis
80
70
60
50
40
30
20
10%
10 33% 51% 55% 65% 100%
(n=232) (n=232) (n=232) (n=143) (n=75) (n=6)
0
1 year 5 years 10 years 15 years 20 years 25 years
(from diagnosis)
Up to 80% of late-stage damage could be
attributed to corticosteroid use5
* Retrospective analysis of records for patients with ≥10 years of consistent follow-up presenting at the University College London Hospital SLE clinic.
Year 0 represents time of diagnosis. Mean age at diagnosis was 31.2 years; 95% of patients were female, 72% were white, 14% were black, 10%
were Asian (Indian), and 4% were “other”.8
† The Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SLICC/ACR DI; SDI) is the only
internationally agreed and validated measure of SLE damage. SDI differs from disease activity indices in that it does not distinguish whether damage
results from the disease, the medications used or other unrelated concomitant causes and is cumulative.9,10
3
EULAR recommendation
EULAR RECOMMENDED SLE TREATMENT GOALS2
“ To improve long-term patient outcomes, management should aim at remission
of disease symptoms and signs, prevention of damage accrual and minimisation of
”
drug side effects, as well as improvement of quality of life.
BELIMUMAB-SPECIFIC INFORMATION included in the updated
2019 EULAR recommendations for the treatment of SLE
Belimumab is recommended with Grade A level of evidence:2
• In patients with inadequate response to standard-of-care (combinations of hydroxychloroquine
and glucocorticoids with or without immunosuppressive agents), defined as residual
disease activity not allowing tapering of glucocorticoids and/or frequent relapses, add-on
treatment with belimumab should be considered
Drug treatments of non-renal SLE
Mild* Moderate* Severe*
1st line Refractory 1st line Refractory 1st line Refractory
Hydroxychloroquine (HCQ)
Glucocorticoids (GC) oral/IM Glucocorticoids (GC) oral/IV
Methotrexate/azathioprine (MTX/AZA)
Belimumab (BEL)
Calcineurin inhibitors (CNI)
Mycophenolate mofetil (MMF)
Cyclophosphamide (CYC)
Rituximab (RTX)
Grade A Grade B Grade C Grade D
Adapted from Fanouriakis A, et al.2
IM = intramuscular; IV = intravenous
* Mild disease: constitutional symptoms/mild arthritis/rash ≤9% body surface area (BSA)/platelets 50-100 x 103/mm3; SLEDAI ≤6; BILAG C or
≤1 BILAG B manifestation. Moderate disease: rheumatoid arthritis-like arthritis/rash 9-18% BSA/cutaneous vasculitis ≤18% BSA; platelets 20-50
x 103/mm3/serositis; SLEDAI 7-12; ≥2 BILAG B manifestations. Severe disease: major organ threatening disease (nephritis, cerebritis, myelitis,
pneumonitis, mesenteric vasculitis; thrombocytopenia with platelets 12; ≥1 BILAG A manifestations.
4
Disease activity reduction
SUPERIOR DISEASE ACTIVITY REDUCTION (SRI-4)
VS. STANDARD THERAPY ALONE AT WEEK 5211, 12, 16*
SRI-4 achieved significant improvement at Week 52
100 Placebo + standard therapy HDA and non-HDA patients†
90 BENLYSTA + standard therapy
80
SRI-4 Response Rate (%)
70
60
17.4%
50 13.7%
40 19.8%
30
20
10
47.2% 64.6% 31.7% 51.5% 40.1% 53.8%
(n=108) (n=248) (n=287) (n=305) (n=217) (n=446)
0
BLISS-SC† BLISS-IV NE Asia‡
P=0.0014 (52/76 pooled data)† P
Flare reduction
ADDING BENLYSTA REDUCED THE RISK OF SEVERE
FLARES BY 40-60% VS. STANDARD THERAPY ALONE11, 12, 16*
% of patients having ≥1 severe flare over 52 weeks
50 HDA and non-HDA patients
Placebo + standard therapy
40 BENLYSTA + standard therapy
% of patients
30
20
10
31.5% 14.1% 29.6% 19.0% 22.1% 12.0%
(n=108) (n=248) (n=287) (n=305) (n=226) (n=451)
0
BLISS-SC† BLISS-IV NE ASIA‡
HR=0.38 (95% CI: 0.24, 0.61) (52/76 POOLED DATA)† HR=0.50 (95% CI: 0.34, 0.73)
P0.5 mg/kg/day, or hospitalization) for CNS SLE, or vasculitis, or
nephritis, or myositis, or platelets 0.5 mg/kg/day, or new immunosuppressant, or an increase in PGA score to >2.5, or a change in SELENA-SLEDAI to >12 accompanied by
at least one of the items above.17
† High disease activity patients. High disease activity (HDA) defined as positive anti-dsDNA (≥30 IU/mL) and low C3 and/or C4 complement. 62% of
patients had HDA at baseline in BLISS-SC and 52% in BLISS-IV (52/76 pooled data).
‡ Includes HDA and non-HDA patients.
6Steroid reduction
IN 4 PIVOTAL CLINICAL TRIALS:
NUMERICAL REDUCTION IN STEROID DOSE
OVER WEEKS 40-52 VS. STANDARD THERAPY ALONE+
GC dose reduction by ≥25% from baseline to ≤7.5 mg/day during weeks 40-52 in patients
receiving >7.5 mg/day at baseline
Placebo + SOC Benlysta + SOC P-value
BLISS-5213* 12.0% 18.6% ns
BLISS-76 * 14
12.7% 17.5% ns
BLISS-SC 15
11.9% 18.2% ns
Asia12
10.9% 15.6% ns
* Pooled data BLISS 52/7622 12.3% 17.9% 0.045
OBSErve SWITZERLAND: CHANGES IN
CORTICOSTEROID D
OSE SEEN20
Reduction in mean corticosteroid dose at 6 months
“
18
Glucocorticoids can provide rapid
16
Mean corticosteroid dose (mg/day)
symptom relief, but the medium to
14
long term aim should be to minimise
12
daily dose to ≤7.5 mg/day prednisone
10 equivalent or to discontinue them,
8 because long term GC therapy can
49%
have various detrimental effects
”
6
4 including irreversible organ damage.
2
11.6 5.9
(n=42) (n=42)
- EULAR Recommendations – 2019 Update2
0
Baseline Month 6
These results are consistent with those observed in the randomized, clinical trials.20
These results were not statistically significant.
OBSErve study: Evaluation of use of Belimumab in clinical practice settings. Multicentre, observational cohort study to
retrospectively analyse real-world information on the short-term outcomes of Benlysta use in SLE patients.
+ SOC = Standard of care
7Safety | Long-term organ damage
ADDING BENLYSTA IV LED TO A HIGHER
PERCENTAGE OF PATIENTS WITH NO WORSENING
OF ORGAN DAMAGE AT YEAR 5-621*
100 HDA and non-HDA patients
80
% of patients
60
40
20
85.1% 11.4% 3.2% 0.2%
(n=343) (n=46) (n=13) (n=1)
0
No change +1 +2 +3
Primary endpoint: Change in baseline SDI score at Year 5-6
85.1% of patients had no change in SDI score21
* Includes HDA and non-HDA patients. High disease activity (HDA) defined as positive anti-dsDNA (≥30 IU/mL) and low C3 and/or C4
complement. 62% of patients had HDA at baseline in BLISS-SC and 52% in BLISS-IV (52/76 pooled data).
8Safety | Long-term organ damage
EVIDENCE FOR BENLYSTA ON REDUCTION
OF ORGAN DAMAGE PROGRESSION
Propensity score-matched analysis of organ damage in pooled
BLISS-LTE trials vs. the Toronto Lupus observational cohort19
Baseline = first belimumab dose
(1 mg/kg or 10 mg/kg)
Up to 6.5 years of exposure
BLISS-76 BLISS-LTE for the time-to-event analysis
Year 1 2 3 4 5
Week 52 76 (48) (48) (48)
≥5 years of exposure for primary endpoint
Baseline = SLEDAI-2K ≥6
Up to 14 years of exposure
Toronto Lupus Cohort = SoC for the time-to-event analysis
≥5 years of exposure for primary endpoint
Limitations:
• PSM can only match patients based on known variables
• Non-observable differences may cause some degree of residual confounding
• Patients could not be matched by year of entry
• Post-hoc analysis
This study should be interpreted in the context of its design limitations.
LTE = long-term extension; SLEDAI-2K = SLE Disease Activity Index-2000; SoC = standard of care; SDI = SLICC/ACR Damage Index;
SLICC/ACR = Systemic Lupus International Collaborating Clinics/American College of Rheumatology; PMS = propensity score matching
9Safety | Long-term organ damage
ADDING BENLYSTA IV LED TO SIGNIFICANTLY
LESS CHANGE IN ORGAN DAMAGE (SDI) AT
YEAR 5 VS. STANDARD THERAPY 19*
Primary endpoint results
0.8 HDA and non-HDA patients
0.7
Change in SDI score at Year 5
0.6
0.5
0.4
0.3
0.2
0.1
0.717 0.283
(n=99) (n=99)
0
Standard therapy BENLYSTA
(95% CI: -0.667, -0.201)
PSafety | Long-term organ damage
DIFFERENCE IN TIME TO ORGAN DAMAGE
PROGRESSION IN PATIENTS WITH ≥1 YEAR
OF FOLLOW-UP (SECONDARY ENDPOINT)19*
HDA and non-HDA patients
100
BENLYSTA exponential
HR 0.036
(95% CI: 0.025, 0.051)
% of patients without organ damage
75
Standard therapy KM
50
BENLYSTA KM
Standard therapy
HR 0.391 exponential
(95% CI: 0.253, 0.605) HR 0.091
25
(95% CI: 0.072, 0.115)
0
0 1 2 3 4 5 6 7 8
Years since baseline (years are 48 weeks in length) PSafety/tolerability
IN 4 PIVOTAL CLINICAL TRIALS, BENLYSTA WAS
WELL TOLERATED*
Adverse events (AEs): 3 IV studies and 1 SC study22†‡
System organ class Frequency Adverse events§
Infections and infestations Very common Bacterial infections, e.g., bronchitis,
urinary tract infection
Common Gastroenteritis viral, pharyngitis,
nasopharyngitis, viral upper respiratory
tract infection
Blood and lymphatic system disorders Common Leucopenia
Immune system disorders Common Hypersensitivity reactions¶
Uncommon Anaphylactic reaction
Rare Delayed-type, non-acute
hypersensitivity reactions
Psychiatric disorders Common Depression
Uncommon Suicidal behaviour, suicidal ideation
Nervous system disorders Common Migraine
Gastrointestinal disorders Very common Diarrhoea, nausea
Skin and subcutaneous tissue disorders Common Injection site reactions (SC formulation only)
Uncommon Angioedema, urticaria, rash
Musculoskeletal and connective tissue disorders Common Pain in extremity
General disorders and administration Common Infusion or injection-related systemic
site conditions reactions,§ pyrexia
Very common ≥1/10; common ≥1/100 toDosing Benlysta SC
BENLYSTA SC IS AVAILABLE IN A SINGLE AND
MONTHLY PACK.22
Age >18 years
Benlysta 200 mg Autoinjector
RECOMMENDED DOSING FOR BENLYSTA SC22
Weight-independent dosage of 200 mg once a week.
Subcutaneous injection into abdomen or thigh.
It is recommended that at least the first subcutaneous injection be carried out under medical
supervision in an environment adequately equipped for the management of any hypersensitivity
reactions. The physician must adequately train the patient in the technique of subcutaneous
injection and educate him or her about the signs and symptoms of hypersensitivity reactions.
After adequate information and training of the patient, the injection can be carried out by the
patient himself on medical prescription.
Children and adolescents
Sufficient experience of belimumab administered subcutaneously to children and adolescents
under 18 years of age is not available.
13Dosing Benlysta IV
BENLYSTA IV IS AVAILABLE IN TWO PACK SIZES.22
Age >5 years
Benlysta 400 mg
Benlysta 120 mg
RECOMMENDED DOSING FOR BENLYSTA IV22
10
mg/kg
10
mg/kg
10
mg/kg
10
mg/kg
Every Every
Every 4 weeks
2 weeks 2 weeks
First 3 doses Subsequent doses
The dosage is weight dependent with 10 mg/kg body weight. After a saturation phase, the
following infusions are administered monthly.
There are no data on efficacy and safety for children under 6 years.
14BENLYSTA powder for making an infusion solution, solution for malignancies. Before treatment with belimumab, the patient’s risk
subcutaneous injection. AI: Belimumab. I: Reduction of disease for depression or suicide must be carefully evaluated and the
activity in patients aged 5 years and older (infusion solution) and patient must be monitored accordingly during treatment. The
in patients aged 18 years and older (subcutaneous injection) physician must be contacted in the event of new or worsening
respectively with active autoantibody positive systemic lupus psychiatric symptoms. Application in combination with other
erythematosus (SLE) who are receiving standard therapy. Belimumab B-cell‑targeted therapy or cyclophosphamide i.v. was not studied.
has not been studied in patients with severe active central nervous Live vaccines should not be given for 30 days before or concurrently
system lupus or severe active lupus nephritis. D: Patients ≥5 years: with Belimumab. IA: No drug interaction studies have been
Infusion solution: 10 mg/kg on Days 0, 14, 28, and at 4weeks conducted. Evidence of increased clearance of belimumab i.v.
intervals thereafter. I.v.-infusion over a 1 h period; must not be when co-administrated with steroids and ACE inhibitors. P/L: Pregnancy:
administered as an i.v. push or bolus. Premedication with an oral Belimumab should only be used if the potential benefit to the
antihistamine, with or without an antipyretic, may be administered. mother justifies the potential risk to the foetus. If indicated, women
Patients should be monitored during and for an appropriate period of childbearing age should use adequate contraceptive measures
of time after administration. Patients ≥18 years: Solution for while being treated and for at least four months after the last
subcutaneous injection: 200 mg once a week, on the same day of treatment. Lactation: Safety not verified. In consideration of all
the week (independent of body weight). S.c.-injection (abdomen aspects it is recommended to consider discontinuing breast-feeding.
or thigh). Suitable training of patient in the technique associated UE: Very common: Infections, nausea, diarrhoea. Common:
with s.c. injection and the perception of signs and symptoms of Hypersensitivity-, infusion- and injection-related reaction, pyrexia,
hypersensitivity reactions. Switch from i.v.- to s.c.-treatment: first (rhino)pharyngitis, bronchitis, cystitis, gastroenteritis viral, pain in
s.c. dose approx. 2 weeks after the last i.v. dose. General: consider extremity, insomnia, depression, migraine, leukopenia; reactions
discontinuing treatment if there is no improvement in the control at the administration site (s.c.-injection). Uncommon: a. o. bradycardia,
of the disease after 6 months. For elderly patients and patients anaphylactic reaction, angioedema, Suicidal thoughts, suicidal
with renal impairment, dosage adjustment is not recommended. behavior, rash. Store: at + 2 °C to + 8 °C, do not freeze. P: Powder
Hepatic impairment: see product information. CI: Hypersensitivity for making an infusion solution: 120 mg and 400 mg vial. Solution
to one of the ingredients. W/P: Infusion-, injection- and hypersensitivity for subcutaneous injection: Autoinjector 200 mg (1 ml) ×1 and ×4.
reactions are possible, which can be severe, or fatal (delay in onset, DC: Vial: A. Autoinjector: B. Last updated: February 2020
and recurrence after initial resolution possible). Patients should be (infusion solution), October 2019 (subcutaneous injection).
made aware of potential risks and signs of such reactions. Increased GlaxoSmithKline AG, 3053 Münchenbuchsee. Detailed information
risk of infection possible. Presenting neurological symptoms, you can find under www.swissmedicinfo.ch. Please report adverse
possibility of progressive multifocal leukoencephalopathy (PML) drug reactions under pv.swiss@gsk.com.
should be considered. Increased potential risk for development of
References: 1. van Vollenhoven RF, Mosca M, Bertsias G, et al. Treat-to-target in systemic lupus erythematosus: recommendations from an
international task force. Ann Rheum Dis. 2014:73:958-67. 2. Fanouriakis A, Kostopoulou M, Alunno A, et al. 2019 update of the EULAR
recommendations for the management of systemic lupus erythematosus. Ann Rheum Dis. 2019;78:736–745. 3. Doria A, Gatto M, Zen M, et al.
Optimizing outcome in SLE: treating‑to‑target and definition of treatment goals. Autoimmun Rev. 2014;13(7):770-7. 4. Lopez R, Davidson
JE, Beeby MD, et al. Lupus disease activity and the risk of subsequent organ damage and mortality in a large lupus cohort. Rheumatology
(Oxford). 2012;51(3):491‑8. 5. Gladman DD, Urowitz MB, Rahman P, et al. Accrual of organ damage over time in patients with systemic lupus
erythematosus. J Rheumatol. 2003;30(9):1955‑9. 6. Stoll T, Sutcliffe N, Mach J, et al. Analysis of the relationship between disease activity and
damage in patients with systemic lupus erythematosus—a 5-yr prospective study. Rheum. 2004;43:1039-44. 7. Urowitz MB, Gladman DD,
Ibañez D, et al. Evolution of disease burden over five years in a multicenter inception systemic lupus erythematosus cohort. Arth Care and
Res. 2012;64(1);132-7. 8. Chambers SA, Allen E, Rahman A, et al. Damage and mortality in a group of British patients with systemic
lupus erythematosus followed up for over 10 years. Rheumatology (Oxford). 2009;48:673-5. 9. Feld J, Isenberg D. Why and how should
we measure disease activity and damage in lupus? Presse Med. 2014;43(6 Pt 2):e151-6. 10. Gladman D, Ginzler E, Goldsmith C,
et al. The development and initial validation of the Systemic Lupus International Collaborating Clinics/American College of Rheumatology
damage index for systemic lupus erythematosus. Arthritis Rheum. 1996;39(3):363-9. 11. Doria A, Stohl W et al. Efficacy and safety of
subcutaneous belimumab in anti-dsDNA-positive, hypocomplementemic patients with systemic lupus erythematosus. Arthritis Rheumatol.
2018;70(8):1256-64. 12. Zhang F, Bae SC, Bass D, et al. A pivotal phase III, randomised, placebo-controlled study of belimumab in
patients with systemic lupus erythematosus located in China, Japan and South Korea. Ann Rheum Dis. 2018;77:355-63. 13. Navarra SV,
Guzman RM, Gallacher AE, et al. Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomized,
placebo-controlled, phase 3 trial. Lancet. 2011;377(9767):721-31. 14. 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(12):3918-30. 15. Stohl W, Schwarting A, Okada M, et al. Efficacy and safety of subcutaneous
belimumab in systemic lupus erythematosus: a fifty-two-week randomized, double-blind, placebo-controlled study. Arthritis Rheumatol.
2017;69(5):1016-27. 16. van Vollenhoven RF, Petri MA, Cervera R, et al. Belimumab in the treatment of systemic lupus erythematosus:
high disease activity predictors of response. Ann Rheum Dis. 2012;71(8):1343-9. 17. Petri M, Buyon J, Kim M. Classification and
definition of major flares in SLE clinical trials. Lupus 1999,8:685-691. 18. Wallace DJ, Ginzler EM, Merrill JK, et al. Safety and
efficacy of belimumab plus standard therapy for up to 13 years in patients with systemic lupus erythematosus. Arthritis Rheumatol.
2019:1-10. 19. Urowitz MB, Ohsfeldt RL, Wielage RC, et al. Organ damage in patients treated with belimumab versus standard of
care: a propensity score-matched comparative analysis. Ann Rheum Dis. 2019;78(3):372-9. 20. von Kempis J, Clinical outcomes in
patients with systemic lupus erythematosus treated with belimumab in clinical practice settings: a retrospective analysis of results from
the OBSErve study in Switzerland, Swiss Med Wkly. 2019; 149:w20022. 21. Bruce IN, Urowitz M, van Vollenhoven R. et al. Long-term
organ damage accrual and safety in patients with SLE treated with belimumab plus standard of care. Lupus. 2016; 25(7):699-709.
22. Fachinformation Benlysta, www.swissmedicinfo.ch.
15BENLYSTA: DESIGNED FOR LUPUS
When standard therapy is not enough,
why not choose BENLYSTA early?
Compared to standard therapy alone, BENLYSTA offers:
Superior reduction in Well tolerated safety profile22
disease activity at week 5222
Evidence on reduction of
Reduced risk of severe SLE organ damage progression19
flares over 52 weeks22
One molecule,
two formulations22*
Steroid reduction 22, 20
* T he SC formulation of BENLYSTA has not been studied in paediatric patients.
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Tel. +41 31 862 21 11,Fax +41 31 862 22 00, www.glaxosmithkline.ch
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