Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: Selective immunosuppressants, ATC code: L04AA26 
Mechanism of action

Belimumab is a human IgG1λ monoclonal antibody specific for soluble human B Lymphocyte Stimulator protein (BLyS, also referred to as BAFF and TNFSF13B). Belimumab blocks the binding of soluble BLyS, a B cell survival factor, to its receptors on B cells. Belimumab does not bind B cells directly, but by binding BLyS, belimumab inhibits the survival of B cells, 

including autoreactive B cells, and reduces the differentiation of B cells into immunoglobulin- producing plasma cells.

BLyS levels are elevated in patients with SLE and other autoimmune diseases. There is an association between plasma BLyS levels and SLE disease activity. The relative contribution of BLyS levels to the pathophysiology of SLE is not fully understood.

Pharmacodynamic effects

Median IgG levels at Week 52 were reduced by 11% in patients with SLE receiving Benlysta compared with an increase of 0.7% in patients receiving placebo.

In patients with anti-dsDNA antibodies at baseline, median anti-dsDNA antibodies levels at Week 52 were reduced by 56% in patients receiving Benlysta compared with 41% in patients receiving placebo. In patients with anti-dsDNA antibodies at baseline, by Week 52, 18% of patients treated with Benlysta had converted to anti-dsDNA negative compared with 15% of the patients receiving placebo.

In patients with SLE with low complement levels, normalization of C3 and C4 was observed by Week 52 in 42% and 53% of patients receiving Benlysta and in 21% and 20% of patients receiving placebo, respectively.

Benlysta significantly reduced circulating overall, transitional, naïve, and SLE B cells, as well as plasma cells at Week 52. Reductions in naïve and transitional B cells, as well as the SLE B cell subset were observed as early as Week 8. Memory cells increased initially and slowly declined toward baseline levels by Week 52.

The B cell and IgG response to long term treatment with intravenous Benlysta was assessed in an uncontrolled SLE extension study. After 7 and a half years of treatment (including the 72- week parent study), a substantial and sustained decrease in various B cell subsets was observed leading to 87% median reduction in naïve B cells, 67% in memory B cells, 99% in activated B cells, and 92% median reduction in plasma cells after more than 7 years of treatment. After about 7 years, a 28% median reduction in IgG levels was observed, with 1.6% of subjects experiencing a decrease in IgG levels to below 400 mg/dL. Over the course of the study, the reported incidence of AEs generally remained stable or declined.

In patients with active lupus nephritis, following treatment with Benlysta (10 mg/kg intravenously) or placebo, there was an increase in serum IgG levels which was associated with decreased proteinuria. Relative to placebo, smaller increases in serum IgG levels were observed in the Benlysta group as expected with the known mechanism of belimumab. At Week 104, the median percent increase from baseline in IgG was 17% for Benlysta and 37% for placebo.
Reductions in autoantibodies, increases in complement, and reductions in circulating total B cells and B-cell subsets observed were consistent with the SLE studies.

Immunogenicity

In the subcutaneous study where serum samples from more than 550 patients with SLE were tested, no anti-belimumab antibodies were detected during or after treatment with belimumab 200 mg subcutaneously. In the lupus nephritis study where 224 patients received Benlysta 10 mg/kg intravenously, no anti-belimumab antibodies were detected.

Clinical efficacy and safety

SLE
Subcutaneous injection
The efficacy of Benlysta administered subcutaneously was evaluated in a randomised, double-blind, placebo-controlled 52-week Phase III study (HGS1006-C1115; BEL112341) in 836 adult patients with a clinical diagnosis of SLE according to the American College of Rheumatology classification criteria. Eligible patients had active SLE disease, defined as a SELENA-SLEDAI score ≥8 and positive anti-nuclear antibody (ANA or anti-dsDNA) test results (ANA titre ≥1:80 and/or a positive anti-dsDNA [≥30 units/mL]) at screening. Patients were on a stable SLE treatment regimen (standard of care) consisting of any of the following (alone or in combination): corticosteroids, anti-malarials, NSAIDs or other immunosuppressives. Patients were excluded from the study if they had severe active central nervous system lupus or severe active lupus nephritis.

This study was conducted in the US, South America, Europe and Asia. Patient median age was 37 years (range: 18 to 77 years), and the majority (94%) were female. Background medicinal products included corticosteroids (86%; >7.5 mg/day prednisone equivalent 60%), immunosuppressives (46%), and anti-malarials (69%). Patients were randomised in a 2:1 ratio to receive belimumab 200 mg or placebo subcutaneously once weekly for 52 weeks.

At baseline 62.2% of patients had high disease activity (SELENA SLEDAI score ≥10), 88% of patients had mucocutaneous, 78% had musculoskeletal, 8% had haematological, 12% had renal, and 8% had vascular organ involvement.

The primary efficacy endpoint was a composite endpoint (SLE Responder Index) that defined response as meeting each of the following criteria at Week 52 compared with baseline: 
• ≥ 4-point reduction in the SELENA-SLEDAI score, and
• no new British Isles Lupus Assessment Group (BILAG) A organ domain score or 2 new BILAG B organ domain scores, and
• no worsening (< 0.30 point increase) in Physician’s Global Assessment score (PGA) 
The SLE Responder Index measures improvement in SLE disease activity, without worsening in any organ system, or in the patient’s overall condition.
Table 1. Response rate at Week 52
Response1                             Placebo2          Benlysta2
200 mg weekly
(n=279)            (n=554)

SLE responder index                                      48.4%               61.4% (p = 0.0006)

Observed difference vs. placebo                                             12.98% 
Odds ratio (95% CI) vs. placebo
1.68
(1.25, 2.25)

Components of SLE responder index

Percent of patients with reduction in                    49.1%              62.3% SELENA-                                                                   (p=0.0005) SLEDAI ≥ 4

Percent of patients with no worsening by                 74.2%              80.9% BILAG index                                                               (p=0.0305) 
Percent of patients with no worsening by                 72.8%              81.2% PGA                                                                       (p=0.0061) 

1
Analyses excluded any subject missing a baseline assessment for any of the components (1 for placebo; 2 for Benlysta).
2
All patients received standard therapy.

The differences between the treatment groups were apparent by Week 16 and sustained through Week 52 (Figure 1).

Figure 1. Proportion of SRI responders by visit
Responders (%)



Benlysta + Standard therapy (n = 554)
Placebo + Standard therapy (n = 279)
* P < 0.05


Time (weeks)
Flares in SLE were defined by the modified SELENA SLEDAI SLE Flare Index. The risk of first flare was reduced by 22% during the 52 weeks of observation in the group receiving Benlysta compared with the group receiving placebo (hazard ratio=0.78; p=0.0061). The median time to the first flare among patients having a flare was delayed in patients receiving Benlysta compared with placebo (190 days vs. 141 days). Severe flares were observed in 10.6% of patients in the group receiving Benlysta compared with 18.2% of patients in the group receiving placebo over the 52 weeks of observation (observed treatment difference = -7.6%).
The risk of severe flares was reduced by 49% during the 52 weeks of observation in the group receiving Benlysta compared with the group receiving placebo (hazard ratio=0.51; p=0.0004).
The median time to the first severe flare among patients having a severe flare was delayed in patients receiving Benlysta compared with placebo (171 days vs. 118 days).

The percentage of patients receiving greater than 7.5 mg/day prednisone (or equivalent) at baseline whose average corticosteroid dose was reduced by at least 25% from baseline to a dose equivalent to prednisone ≤7.5 mg/day during Weeks 40 through 52, was 18.2% in the group receiving Benlysta and 11.9% in the group receiving placebo (p=0.0732).

Benlysta demonstrated improvement in fatigue compared with placebo measured by the FACIT-Fatigue Scale. The adjusted mean change of score at Week 52 from baseline is significantly greater with Benlysta compared to placebo (4.4 vs. 2.7, p=0.0130).

Subgroup analysis of the primary endpoint demonstrated that the greatest benefit was observed in patients with higher disease activity at baseline including patients with SELENA SLEDAI scores ≥ 10 or patients requiring steroids to control their disease or patients with low complement levels.

An additional, previously identified serologically active group, those patients with low complement and positive anti-dsDNA at baseline, also demonstrated a greater relative response, see Table 2 for results of this example of a higher disease activity group.


Table 2. Patients with low complement and positive anti-dsDNA at baseline Subgroup                                     Anti-dsDNA positive AND low complement

Placebo            Benlysta
200 mg weekly
(n=108)            (n=246)

SRI response rate at Week 521 (%)                      47.2           64.6 (p=0.0014) 
Observed treatment difference vs. placebo (%)                              17.41 
Severe flares over 52 weeks:                          (n=108)             (n=248) 
Patients experiencing a severe flare (%)               31.5                 14.1 
Observed treatment difference vs. placebo (%)                               17.4 
Time to severe flare [Hazard ratio (95% CI)]                          0.38 (0.24, 0.61) (p<0.0001)
(n=70)               (n=164)

Prednisone reduction by ≥25% from baseline             11.4           20.7 (p=0.0844) to ≤7.5 mg/day during weeks 24 through 522
(%)
9.3
Observed treatment difference vs. placebo (%)
(n=108)             (n=248)
FACIT-fatigue score improvement from
2.4           4.6 (p=0.0324) baseline at Week-52 (mean):
Observed treatment difference vs. placebo
2.1
(median difference)
1
Analysis of SRI response rate at Week 52 excluded any subject missing a baseline assessment (2 for Benlysta).
2
Among patients with baseline prednisone dose >7.5 mg/day


The efficacy and safety of Benlysta in combination with a single cycle of rituximab have been studied in a Phase III, randomised, double-blind, placebo-controlled 104-week study including 292 patients (BLISS-BELIEVE). The primary endpoint was the proportion of subjects with a state of disease control defined as a SLEDAI-2K score ≤ 2, achieved without immunosuppressants and with corticosteroids at a prednisone equivalent dose of ≤ 5 mg/day at Week 52. This was achieved in 19.4 % (n = 28/144) of the patients treated with Benlysta in combination with rituximab and in 16.7 % (n = 12/72) of the patients treated with Benlysta in combination with placebo (odds ratio 1.27; 95 % CI: 0.60, 2.71; p = 0.5342). A higher frequency of adverse events (91.7 % vs. 87.5 %), serious adverse events (22.2 % vs. 13.9 %) and serious infections (9.0 % vs. 2.8 %) were observed in patients treated with Benlysta in combination with rituximab as compared to Benlysta in combination with placebo.


Lupus nephritis
Subcutaneous injection
The efficacy and safety of Benlysta S.C. 200 mg administered subcutaneously to patients with active lupus nephritis is based on data from administration of Benlysta 10 mg/kg intravenously and pharmacokinetic modelling and simulation (see section 5.2).
In the subcutaneous SLE study, described above, patients who had severe active lupus nephritis were excluded; however, 12% of patients had renal organ domain involvement at baseline (based on SELENA SLEDAI assessment). The following study in active lupus nephritis has been conducted.

Intravenous infusion
The efficacy and safety of Benlysta 10 mg/kg administered intravenously over a 1-hour period on Days 0, 14, 28, and then every 28 days, were evaluated in a 104-week randomised (1:1), double-blind, placebo-controlled, Phase III study (BEL114054) in 448 patients with active lupus nephritis. The patients had a clinical diagnosis of SLE according to ACR classification criteria, biopsy proven lupus nephritis Class III, IV, and/or V and had active renal disease at screening requiring standard therapy. Standard therapy included corticosteroids, 0 to 3 intravenous administrations of methylprednisolone (500 to1000 mg per administration), followed by oral prednisone 0.5 to1 mg/kg/day with a total daily dose ≤60 mg/day and tapered to ≤10 mg/day by Week 24, with:
• mycophenolate mofetil 1 to 3 g/day orally or mycophenolate sodium 720 to 2160 mg/day orally for induction and maintenance, or
• cyclophosphamide 500 mg intravenously every 2 weeks for 6 infusions for induction followed by azathioprine orally at a target dose of 2 mg/kg/day for maintenance.

This study was conducted in Asia, North America, South America, and Europe. Patient median age was 31 years (range: 18 to 77 years); the majority (88%) were female.

The primary efficacy endpoint was Primary Efficacy Renal Response (PERR) at Week 104 defined as a response at Week 100 confirmed by a repeat measurement at Week 104 of the following parameters: urinary protein:creatinine ratio (uPCR) ≤700 mg/g (79.5 mg/mmol) and estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2 or no decrease in eGFR of >20% from pre-flare value.

The major secondary endpoints included:
• Complete Renal Response (CRR) defined as a response at Week 100 confirmed by a repeat measurement at Week 104 of the following parameters: uPCR <500 mg/g (56.8 mg/mmol) and eGFR ≥90 mL/min/1.73 m2 or no decrease in eGFR of >10% from pre-flare value.
• PERR at Week 52.
• Time to renal-related event or death (renal-related event defined as first event of end-stage renal disease, doubling of serum creatinine, renal worsening [defined as increased proteinuria, and/or impaired renal function], or receipt of renal disease-related prohibited therapy).

For PERR and CRR endpoints, steroid treatment had to be reduced to ≤10 mg/day from Week 24 to be considered a responder. For these endpoints, patients who discontinued treatment early,
received prohibited medication, or withdrew from the study early were considered non-responders.

The proportion of patients achieving PERR at Week 104 was significantly higher in patients receiving Benlysta compared with placebo. The major secondary endpoints also showed significant improvement with Benlysta compared with placebo (Table 3).


Table 3. Efficacy results in adult patients with lupus nephritis

Efficacy endpoint          Placebo     Benlysta    Observed      Odds/Hazard        P- 10 mg/kg    difference     ratio vs.       value vs.        placebo
(n = 223)   (n = 223)    placebo       (95 % CI)
PERR at Week 104       1
OR 1.55
Responders                  32.3%       43.0%          10.8%     (1.04, 2.32)     0.0311 Components of PERR
Urine                                                             OR 1.54 protein:creatinine         33.6%       44.4%          10.8%     (1.04, 2.29)     0.0320 ratio ≤700 mg/g
(79.5 mg/mmol) eGFR≥60 mL/min/1.73m2 or no decrease in                                                    OR 1.32 eGFR from pre-flare        50.2%       57.4%          7.2%      (0.90, 1.94)     0.1599 value of >20%
Not treatment                                                     OR 1.65 failure³                   74.4%       83.0%          8.5%      (1.03, 2.63)     0.0364 CRR at Week 1041                                                   OR 1.74 Responders                  19.7%       30.0%          10.3%     (1.11, 2.74)     0.0167 
Components of CRR
Urine                                                             OR 1.58 protein:creatinine         28.7%       39.5%          10.8%     (1.05, 2.38)     0.0268 ratio <500 mg/g
(56.8 mg/mmol) eGFR≥90 mL/min/1.73m2 or                                                  OR 1.33 no decrease in             39.9%       46.6%          6.7%      (0.90, 1.96)     0.1539 eGFR from pre-flare value of >10%
Not treatment                                                     OR 1.65 failure³                   74.4%       83.0%          8.5%      (1.03, 2.63)     0.0364 
PERR at Week 521                                                   OR 1.59 Responders                  35.4%       46.6%          11.2%     (1.06, 2.38)     0.0245 Time to renal- related event or death1
Percentage of               28.3%       15.7%            - patients with event2
HR 0.51
Time to event                                          -          (0.34, 0.77)     0.0014 [Hazard ratio (95%
CI)]
1
PERR at Week 104 was the primary efficacy analysis; CRR at Week 104, PERR at Week 52 and time to renal-related event or death were included in the pre-specified testing hierarchy.
2
When excluding deaths from the analysis (1 for Benlysta; 2 for placebo), the percentage of patients with a renal-related event was 15.2% for Benlysta compared with 27.4% for placebo (HR = 0.51; 95% CI: 0.34, 0.78).
³ Treatment failure: Patients who took protocol-prohibited medication.


A numerically greater percentage of patients receiving Benlysta achieved PERR beginning at Week 24 compared with placebo, and this treatment difference was maintained through to Week 104. Beginning at Week 12, a numerically greater percentage of patients receiving Benlysta achieved CRR compared with placebo and the numerical difference was maintained through to Week 104 (Figure 2).


Figure 2. Response rates in adults with lupus nephritis by visit
Primary Efficacy Renal Response (PERR)
Responders (%) +/- SE



Benlysta + Standard therapy (n = 223)
Placebo + Standard therapy (n = 223)

Time (weeks)


Complete Renal Response (CRR)
Responders (%) +/- SE


Benlysta + Standard therapy (n = 223)
Placebo + Standard therapy (n = 223)


Time (weeks)


In descriptive subgroup analyses, key efficacy endpoints (PERR and CRR) were examined by induction regimen (mycophenolate or cyclophosphamide) and biopsy class (Class III or IV, Class III + V or Class IV + V, or Class V) (Figure 3).


Figure 3. Odds ratio of PERR and CRR at Week 104 across subgroups
Subgroup                                                                                 Response Rate Benlysta (n) versus Placebo (n)                                                       Placebo   Benlysta    Odds atio (%)       (%)      (95% CI)

Induction regimen                        Favours Placebo            Favours Benlysta 
Mycophenolate (164 vs. 164)
34        46     1.6 (1.0, 2.5)
20        34     2.0 (1.2, 3.4)

Cyclophosphamide (59 vs. 59)
27        34     1.5 (0.7, 3.5)
19        19     1.1 (0.4, 2.8)
Biopsy class

Class III or Class IV (126 vs. 132)                                                       32        48     1.8 (1.1, 3.1) 19        31     1.8 (1.0, 3.2)

Class III + V or Class IV + V (61 vs. 55)                                                 27        38     1.8 (0.8, 4.0) 15        26     2.8 (1.0, 7.7)

Class V (36 vs. 36)
42        36     0.6 (0.2, 1.9)
31        33     0.8 (0.3, 2.6)

0.1   0.2   0.5   1    2    4      8
Odds Ratio
Primary Efficacy Renal Response (PERR)
Complete Renal Response (CRR)


Age and race

There were no observed differences in efficacy or safety in SLE patients ≥ 65 years who received Benlysta intravenously or subcutaneously compared to the overall population in placebo-controlled studies; however, the number of patients aged ≥ 65 years (62 patients for efficacy and 219 for safety) is not sufficient to determine whether they respond differently to younger patients.

There were too few black patients enrolled in the placebo-controlled studies with subcutaneous Benlysta to draw meaningful conclusions about the effects of race on clinical outcomes.

The safety and efficacy of Benlysta administered intravenously have been studied in black patients. The currently available data are described in the Summary of Product Characteristics of Benlysta I.V.120 mg and 400 mg powder for concentrate for solution for infusion.

Pharmacokinetic Properties

5.2    Pharmacokinetic properties

The subcutaneous pharmacokinetic parameters below are based on population parameter estimates from 661 subjects, comprised of 554 SLE patients and 107 healthy subjects, who received Benlysta subcutaneously.

Absorption

Benlysta in pre-filled pen or pre-filled syringe is administered by subcutaneous injection.
Following subcutaneous administration the bioavailability of belimumab was approximately 74%. Steady-state exposure was reached after approximately 11 weeks of subcutaneous administration. The maximum serum concentration (Cmax) of belimumab at steady state was 108 µg/mL.
Distribution

Belimumab was distributed to tissues with steady-state volume (Vss) of distribution of approximately 5 litres.

Biotransformation

Belimumab is a protein for which the expected metabolic pathway is degradation to small peptides and individual amino acids by widely distributed proteolytic enzymes. Classical biotransformation studies have not been conducted.

Elimination

Following subcutaneous administration, belimumab had a terminal half-life of 18.3 days. The systemic clearance was 204 mL/day.

Lupus nephritis study

A population pharmacokinetic analysis was conducted in 224 adult patients with lupus nephritis who received Benlysta 10 mg/kg intravenously (Days 0, 14, 28, and then every 28 days up to 104 weeks). In patients with lupus nephritis, due to renal disease activity, belimumab clearance was initially higher than observed in SLE studies; however, after 24 weeks of treatment and throughout the remainder of the study, belimumab clearance and exposure were similar to that observed in adult patients with SLE who received belimumab 10 mg/kg intravenously.

Based on population pharmacokinetic modelling and simulation, the steady-state average concentrations of subcutaneous administration of belimumab 200 mg once weekly in adults with lupus nephritis are predicted to be similar to those observed in adults with lupus nephritis receiving belimumab 10 mg/kg intravenously every 4 weeks.


Special Patient Populations
Paediatric population: No pharmacokinetic data are available for subcutaneous administration of Benlysta in paediatric patients.

Elderly: Benlysta has been studied in a limited number of elderly patients. Age did not affect belimumab exposure in the subcutaneous population pharmacokinetic analysis. However, given the small number of subjects ≥65, an effect of age cannot be ruled out conclusively.

Renal impairment: No specific studies have been conducted to examine the effects of renal impairment on the pharmacokinetics of belimumab. During clinical development, Benlysta was studied in a limited number of SLE patients with mild (creatinine clearance [CrCl] ≥60 and <90 mL/min), moderate (CrCl ≥30 and <60 mL/min), or severe (CrCl ≥15 and <30 mL/min) renal impairment: 121 patients with mild renal impairment and 30 patients with moderate renal impairment received Benlysta subcutaneously; 770 patients with mild renal impairment, 261 patients with moderate renal impairment and 14 patients with severe renal impairment received Benlysta intravenously.

No clinically significant reduction in systemic clearance as a result of renal impairment was observed. Therefore, no dose adjustment is recommended for patients with renal impairment 
Hepatic impairment: No specific studies have been conducted to examine the effects of hepatic impairment on the pharmacokinetics of belimumab. IgG1 molecules such as belimumab are catabolised by widely distributed proteolytic enzymes, which are not restricted to hepatic tissue and changes in hepatic function are unlikely to have any effect on the elimination of belimumab.

Body weight/Body mass index (BMI)

The effects of body weight and BMI on belimumab exposure after subcutaneous administration were not considered clinically meaningful. There was no significant impact on efficacy and safety based on weight. Therefore, no dose adjustment is recommended.


Transitioning from intravenous to subcutaneous administration
SLE
Patients with SLE transitioning from 10 mg/kg intravenously every 4 weeks to 200 mg subcutaneously weekly using a 1 to 4 week switching interval had pre-dose belimumab serum concentrations at their first subcutaneous dose close to their eventual subcutaneous steady-state trough concentration (see section 4.2).

Based on simulations with population PK parameters the steady-state average belimumab concentrations for 200 mg subcutaneous every week were similar to 10 mg/kg intravenous every 4 weeks.

Lupus nephritis
One to 2 weeks after completing the first 2 intravenous doses, patients with lupus nephritis transitioning from 10 mg/kg intravenously to 200 mg subcutaneously weekly, are predicted to have average belimumab serum concentrations similar to patients dosed with 10 mg/kg intravenously every 4 weeks based on population PK simulations (see section 4.2).