Trial of Anifrolumab in Active Systemic Lupus Erythematosus

Design

Phase 3, randomized, double-blind, placebo-controlled, parallel-group trial

N= 362

Objective

To investigate anifrolumab for the treatment of systemic lupus erythematosus (SLE)

Study Groups

Anifrolumab (n= 180)

Placebo (n= 182)

Inclusion Criteria

Ages 18 to 70 years; fulfilled American College of Rheumatology classification criteria for SLE

Exclusion Criteria

Active severe lupus nephritis or neuropsychiatric SLE

Methods

Patients were randomized 1:1 to intravenous infusions of either placebo or anifrolumab (300 mg) every four weeks for 48 weeks. Aside from the glucocorticoid taper that was mandated by protocol, all other therapies remained consistent during the study. From week 8 to week 40, patients on oral prednisone or its equivalent at a dose of 10 mg or more daily had to try tapering to 7.5 mg or less. During the final 12 weeks of the experiment, glucocorticoid dosages were required to be stable.

Duration

From July, 2015 to September, 2018

Outcome Measures

Primary: Difference between the two groups in the percentage of patients who had a BICLA response at week 52

Secondary: BICLA response in patients with a high interferon gene signature at week 52; reductions in the glucocorticoid dose, in the severity of skin disease, and in counts of swollen and tender joints; and the annualized flare rate

Baseline Characteristics

Anifrolumab (n= 180)

Placebo (n= 182)

Age, years

Female

White

Geographic region

United States or Canada

Europe

64 (35.6%)

51 (28.3%)

68 (37.4%)

46 (25.3%)

Median time from initial SLE diagnosis

to randomization, months (range)

SLEDAI-2K

Global score

Score ≥ 10

11.4 ± 3.6

129 (71.7%)

11.5 ± 3.9

131 (72%)

BILAG-2004

≥ 1 A item

No A items and ≥ 2 B items

81 (45%)

91 (50.6%)

95 (52.2%)

78 (42.9%)

CLASI activity

8.3 ± 7.9

7.6 ± 7.8

Number of swollen joints

6.2 ± 5.7

7.4 ± 6.6

Number of tender joints

High type I interferon gene signature

Baseline treatment

Glucocorticoid

Antimalarial agent

Immunosuppresant agent

141 (78.3%)

119 (66.1%)

88 (48.9%)

151 (83%)

133 (73.1%)

86 (47.3%)

Abbreviations: SLEDAI-2K: Systemic Lupus Erythematosus Disease Activity Index 2000; BILAG: The British Isles Lupus Assessment Group 2004 Index; CLASI: Cutaneous Lupus Erythematosus Disease Area and Severity Index

Results

Endpoint

Anifrolumab (n= 180)

Placebo (n= 182)

Difference (95% CI)

p-Value

BICLA response at week 52

BICLA response in patients with a high interferon gene signature at week 52

Glucocorticoid reduction to target dose, sustained from week 40 to week 52

≥ 50% reduction in CLASI activity from baseline to week 12

≥ 50% reduction in both swollen and tender joints from baseline to week 52

Annualized flare rate through week 52

Adverse Events

Common Adverse Events: The most frequent adverse events in patients who received anifrolumab included upper respiratory tract infection (21.7%), nasopharyngitis (15.6%), infusion-related reaction (13.9%), bronchitis (12.2%), and herpes zoster (7.2%).

Serious Adverse Events: In the anifrolumab group, 8.3% of the patients had serious adverse events; 17.0% of the patients in the placebo group had serious adverse events, including pneumonia and worsening of SLE. There were six serious flares of SLE in the placebo group and one in the anifrolumab group.

Percentage that Discontinued due to Adverse Events: 2.8% of the patients in the anifrolumab group and in 7.1% in the placebo group, including three cases of worsening of SLE. One death due to pneumonia occurred in the anifrolumab group.

Study Author Conclusions

Monthly administration of anifrolumab resulted in a higher percentage of patients with a response (as defined by a composite end point) at week 52 than did placebo, in contrast to the findings of a similar phase 3 trial involving patients with SLE that had a different primary end point. The frequency of herpes zoster was higher with anifrolumab than with placebo.

InpharmD Researcher Critique

Time to first flare, Systemic Lupus Erythematosus Responder Index response, serologic alterations, and end points of persistent BICLA response were not formally evaluated for statistical significance, so no clinical conclusions can be made from that data. Investigators did not intend to assess risks or the longevity of the effects after 52 weeks.

Anifrolumab, an Anti-Interferon-α Receptor Monoclonal Antibody, in Moderate-to-Severe Systemic Lupus Erythematosus

Design

Randomized, double-blind, placebo,controlled study

N= 305

Objective

Study Groups

Placebo (n= 102)

Anifrolumab 300 mg (n= 99)

Anifrolumab 1,000 mg (n= 104)

Inclusion Criteria

Age 18 to 65 years, presence of SLE, weight ≥ 40 kg, fulfill at least 4 of the 11 American College of Rheumatology 1997 classification criteria for SLE, receiving treatment with oral prednisoone, azathioprine, antimalarial, mycophenolate mofetil/ mycophenolic acid, or methotrexate

Exclusion Criteria

Methods

Patients were randomized (1:1:1) to receive either intravenous infusion of placebo, anifrolumab 300 mg or anifrolumab 1,000 mg administered every 4 weeks for 48 weeks. Randomization was stratified based on SLE Disease Activity Index 2000 score (<10 or ≥10), oral corticosteroid dosage (<10 or ≥10 mg/day), and type I IFN gene signature test status (high or low).

Duration

Outcome Measures

Primary: Patients who achieved SLE Responder Index (SRI[4]) response at week 24 with sustained reduction of oral corticosteroids (<10 mg/day and less than or equal to the dose at week 1 from week 12 through 24)

Secondary: SRI[4] response at week 52, meeting oral corticosteroid taper criteria (reduction of oral corticosteroid dosage to ≤7.5 mg/day in patients who were receiving ≥10 mg/day at baseline), ≥ 50% improvement in Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) in patients who had a score of ≥ 10 at baseline

Baseline Characteristics

Placebo (n= 102)

Anifrolumab 300 mg (n= 99)

Age, years

Female

Race

White

African American

Asian

American Indian/Alaska Native

Other

40.2%

11.8%

12.7%

0

35.3%

35.4%

19.2%

3.0%

4.0%

38.4%

49.0%

9.6%

5.8%

1.0%

34.6%

Disease duration, months

Concomitant immunomodulatory medications

Corticosteroids

Antimalarials

Corticosteroids and antimalarials

Azathioprine

Methotrexate

Mycophenolate

86.3%

73.5%

61.8%

18.6%

15.7%

10.8%

79.8%

76.8%

59.6%

23.2%

19.2%

11.1%

87.5%

65.4%

53.8%

20.2%

24.0%

10.6%

Results

Endpoint

Placebo (n= 102)

Anifrolumab 300 mg (n= 99)

Odds ratio vs placebo (90% CI; p-Value)

SRI[4] (including oral corticosteroid taper) at week 24

High interferon gene signature

Low interferon gene signature

18 (17.6%)

10/76 (13.2%)

8/26 (30.8%)

34 (34.3%)

27/75 (36.0%)

7/24 (29.2%)

2.38 (1.33–4.26; 0.014)

3.55 (1.72–7.32; 0.004)

0.96 (0.34–2.74; 0.946)

30 (28.8%)

22/78 (28.2%)

8/26 (30.8%)

1.94 (1.08–3.49; 0.063)

2.65 (1.27–5.53; 0.029)

1.04 (0.37–2.88;0.953)

SRI[4] (excluding oral corticosteroid taper) at week 24

High interferon gene signature

Low interferon gene signature

41 (40.2%)

29/76 (38.2%)

12/26 (46.2%)

3 (53.5%)

41/75 (54.7%)

12/24 (50.0%)

1.77 (1.10–2.84; 0.047)

2.03 (1.17–3.52; 0.034)

1.13 (0.44–2.93; 0.832)

59 (56.7%)

47/78 (60.3%)

12/26 (46.2%)

1.98 (1.24–3.16; 0.016)

2.50 (1.45–4.32; 0.006)

0.96 (0.38–2.44; 0.943)

SRI[4] (including oral corticosteroid taper) at week 52

High interferon gene signature

Low interferon gene signature

26 (25.5%)

15/76 (19.7%)

11/26 (42.3%)

51 (51.5%)

39/75 (52.%)

12/24 (50.0%)

3.08 (1.86–5.09; <0.001)

4.30 (2.34–7.91; <0.001)

1.47 (0.55–3.93; 0.514)

40 (38.5%)

30/78 (38.5%)

10/26 (38.5%)

1.84 (1.11–3.04; 0.048)

2.52 (1.37–4.64; 0.013)

0.89 (0.34–2.35; 0.849)

SRI[4] (excluding oral corticosteroid taper) at week 52

High interferon gene signature

Low interferon gene signature

41 (40.2%)

27/76 (35.5%)

14/26 (53.8%)

62 (62.6%)

45/75 (60.0%)

17/24 (70.8%)

2.66 (1.64–4.31; <0.001)

2.98 (1.69–5.24; 0.001)

2.07 (0.77–5.53; 0.225)

56 (53.8%)

43/78 (55.1%)

13/26 (50.0%)

1.78 (1.11–2.85; 0.043)

2.33 (1.34–4.04; 0.012)

0.85 (0.34–2.12; 0.765)

Meeting oral corticosteroid taper criteria

17/64 (26.6%)

31/55 (56.4%)

3.59 (1.87–6.89; 0.001)

20/63 (31.7%)

1.23 (0.64–2.37; 0.595)

≥ 50% improvement in CLASI

8/26 (30.8%)

17/27 (63.0%)

4.49 (1.67–12.12; 0.013)

14/24 (58.3%)

2.97 (1.08–8.19; 0.077)

Adverse Events

The percentages of patients experiencing adverse events and serious adverse events were generally similar across the placebo, anifrolumab 300mg, and anifrolumab 1000mg groups. Certain infections like herpes zoster occurred more frequently in the anifrolumab groups compared to placebo (5.1% anifrolumab 300 mg; 9.5% anifrolumab 1,000 mg; 2.0% placebo), but responded well to treatment.

Study Author Conclusions

Anifrolumab substantially reduced disease activity compared with placebo across multiple clinical end points in the patients with moderate‐to‐severe SLE.

InpharmD Researcher Critique

Anifrolumab for Moderate and Severe Muco-Cutaneous Lupus Erythematosus: A Monocentric Experience and Review of the Current Literature

Design

Case #1 presentation

A 37-year-old woman with a four-year history of systemic lupus erythematosus (SLE) was phototype III, and had positive anti-nuclear antibodies (ANA), anti-DNA antibodies (ADNA), and low complement. Cutaneous manifestations were refractory to antimalarials, corticosteroids, mycophenolate mofetil, methotrexate, cyclosporine A, azathioprine, belimumab, baricitinib, and evobrutinib. Thus, the patient was started on anifrolumab in addition to her ongoing therapy with mycophenolate mofetil, corticosteroids, and hydroxychloroquine. Rapid clinical improvement was observed within the first month of therapy, and after four months exhibited clinical improvement (CLASI-A score 27 to 3). Her prednisone dose was reduced from 10 mg daily to 3 mg daily. Complement levels remained low despite ADNA levels decreasing below the laboratory positive threshold. One episode of herpes labialis and one episode of vaginal candidiasis was reported over 23 weeks of treatment.

Case #2 presentation

A 25-year-old woman with a 12-year history of SLE and phototype III had positive ANA, ADNA, anticardiolipin antibodies, and low complement. Mycophenolate mofetil and cyclophosphamide were useful in treating systemic manifestations; however, the patient had persistent steroid dependency to control manifestations of photosensitive rashes and chronic urticaria/angioedema. The patient began treatment with anifrolumab, to which clinical improvement was observed (CLASI-A 12 to 0) within the first month of therapy and maintained after 46 weeks. Slightly lower C4 levels compared to baseline were reported at last observation, although C3 and ADNA levels were stable. One episode of vaginal candidiasis was reported during treatment, which resolved once the patient temporarily discontinued mycophenolate mofetil and treated with systemic antifungals.

Case #3 presentation

A 36-year-old woman with a history of Class IV lupus nephritis and phototype II had positive ADNA, anti-Sm, anti-Ro, anti-RNP antibodies, and lupus anticoagulant, as well as low complement. Thirteen years prior, she was diagnosed with posterior reversible encephalopathy syndrome. Cyclophosphamide, mycophenolate mofetil, and B-cell depleting agents were useful in controlling non-cutaneous manifestations; however, the patient's malar rash and photosensitivity persisted despite treatment with medium-dose steroids. Thus, the patient was started on anifrolumab in addition to her ongoing therapy with mycophenolate mofetil, corticosteroids, and topical pimecrolimus. A modest response was observed by week 10, and complete lesion resolution was reported after the fourth infusion. Clinical improvement was observed (CLASI-A 5 to 1) after 16 weeks. No anifrolumab-related adverse events were reported.

Case #4 presentation

A 44-year-old woman with a 9-year history of SLE and phototype II had positive ANA, ADNA, anti-phospholipid antibodies and low complement. Mucocutaneous manifestations were refractory to mycophenolate mofetil, belimumab, hydroxychloroquine, and corticosteroids; corticosteroid dosages could not be raised and maintained due to the patient's concomitant osteoporosis. The patient was then started on anifrolumab, where partial response was observed after 8 weeks of treatment, with complete resolution by week 12 (CLASI-A 17 to 2). ADNA remained positive, while complement levels returned to normal. No anifrolumab-related adverse events were reported.

Study Author Conclusions

Growing real-life evidence corroborated by data from a series of consecutive patients with SLE and refractory CLE supports the use of anifrolumab as a rapid, effective treatment for lupus skin manifestations and confirms its relatively good safety profile. Further studies are necessary to identify other potential areas of selective anifrolumab efficacy and possibly extend its indication to patients with skin-limited lupus besides patients with SLE. In this context, the use of domain-specific clinimetrics including CLA-IGA might have a non-redundant role in accurately measure treatment response.

Type I interferon inhibitor anifrolumab in active systemic lupus erythematosus (TULIP-1): a randomised, controlled, phase 3 trial

Design

Prospective, double-blind, randomized, multi-center, placebo-controlled, phase 3 trial

N= 457

Objective

To confirm the efficacy of anifrolumab versus placebo in a phase 3 trial of adult patients with systemic lupus erythematosus (SLE) and moderate-to-severe disease activity despite standard-of-care treatment

Study Groups

Placebo (n= 184)

Anifrolumab 150 mg (n= 93)

Anifrolumab 300 mg (n= 180)

Inclusion Criteria

Aged 18 to 70 years; moderate-to-severe SLE at least 24 weeks before enrollment; weight ≥ 40 kg; ongoing stable treatment with either prednisone or equivalent, an antimalarial, azathioprine, mizoribine, mycophenolate mofetil or mycophenolic acid, or methotrexate

Exclusion Criteria

Severe lupus nephritis, central nervous system lupus, pediatric patients

Methods

Patients were randomized (2:1:2) to receive placebo, anifrolumab 150 mg, or anifrolumab 300 mg intravenously (IV) q4w for 48 weeks total. Standard of care treatment continued with the addition of corticosteroid tapering for patients who were on concomitant prednisone or equivalent of 10 mg/day or greater. Tapering attempts were required between weeks 8 and 40 for patients on doses ≥ 10 mg/day; tapering could also be considered for patients on smaller steroid doses.

Final assessment was on week 52, where patients could then enroll in a separate long-term extension study or continue for 8 more weeks for a 12-week safety follow-up after the last medication dose.

Duration

48 weeks

Between June 9, 2015 and June 16, 2017

Outcome Measures

Primary: Difference between groups for the proportion of patients who achieved an SLE responder index-4 (SRI-4) response at week 52

Secondary: Proportion of patients in the interferon gene signature test-high subgroup who achieved SRI-4 at week 52; proportion of patients on 10 mg/day or more corticosteroids at baseline who achieved a sustained dose reduction to 7.5 mg/day or less from week 40 to 52; proportion of patients with a cutaneous lupus erythematosus disease area and severity index (CLASI) activity score of 10 or higher at baseline who achieved a 50% or more reduction in CLASI score by week 12; proportion of patients who achieved SRI-4 at week 24; annualised flare rate through week 52

Baseline Characteristics

Placebo (n= 184)

Anifrolumab 150 mg (n= 93)

Age, years

Female

White

Baseline disease characteristics

SLEDAI-2K global score

BILAG-2004 at least one A item

BILAG-2004 no A and at least two B items

CLASI activity score

High type I interferon gene signature

Increased anti-DS DNA antibodies

11.5

46%

46%

8.1

82%

45%

11.0

43%

52%

7.7

82%

47%

11.3

52%

44%

8.5

82%

45%

Abnormal complement concentration

C3

C4

35%

21%

37%

23%

32%

19%

Baseline SLE treatments

PO corticosteroid (prednisone or equivalent)

PO corticosteroid ≥10 mg/day

Antimalarials

Azathioprine

Methotrexate

Mycophenolate

NSAIDs

83%

55%

73%

18%

21%

12%

19%

84%

52%

82%

17%

15%

10%

17%

83%

57%

69%

18%

12%

17%

17%

Abbreviations: CLASI, cutaneous lupus erythematosus disease area and severity index; DS, double-stranded; NSAID, non-steroidal anti-inflammatory drugs; PO, oral

Results

Endpoint

Placebo (n= 184)

Anifrolumab 300 mg (n= 180)

Difference (95% CI)*

p-value**

SRI-4 week 52

SRI-4 week 52 in interferon gene signature test-high patients

SRI-4 week 24

Sustained oral corticosteroid dose
reduction to target at week 52^‡

≥50% reduction in CLASI activity score from baseline to week 12^§

Annualised flare rate through week 52^¶

Any adverse event

Serious adverse event

78%

16%

85%

11%

89%

14%

Abbreviations: CI, confidence interval

* The response rates, the differences in response rates, and associated 95% CIs were adjusted for the factors for which randomisation was stratified using the stratified Cochran-Mantel-Haenszel method, so with these adjustments, proportions do not always equal n/N.

** As the primary endpoint was not reached, nominal p-values presented for key secondary endpoints should not be used to conclude statistical significance.

‡ In patients with baseline oral corticosteroid use of at least 10 mg/day (prednisone or equivalent)

§ In patients with CLASI activity score of at least 10 at baseline

¶ Defined as either at least one new BILAG-2004 A item or at least two new BILAG-2004 B items compared with the previous visit (i.e., a worsening from an E, D, or C score to a B score in at least two organ systems or a worsening from an E, D, C, or B score to an A score in any one organ system compared with the previous visit); calculation of flare rate does not involve restricted medications; therefore, values for the prespecified and post-hoc analyses are the same. Difference is expressed as a rate ratio.

Adverse Events

Common Adverse Events: Nasopharyngitis (placebo 12% vs. anifrolumab 150 mg 15% vs. anifrolumab 300 mg 20%), upper respiratory tract infection (10% vs. 17% vs. 12%), urinary tract infection (15% vs. 10% vs. 12%), infusion-related reaction (7% vs. 10% vs. 9%)

Serious Adverse Events: 16% vs. 11% vs. 14%; malignancies were reported in 1 patient, 1 patient, and 3 patients of the respective arms. Malignancies were squamous cell carcinoma of the cervix in the placebo group; invasive breast carcinoma in the anifrolumab 150 mg group; and squamous cell carcinoma, squamous cell carcinoma of skin, and B-cell lymphoma in the anifrolumab 300 mg group.

Percentage that Discontinued due to Adverse Events: 3% vs. 5% vs. 6%. One death due to encephalitis occurred in the placebo group, although due to it occurring outside the 28-day window for treatment-emergent adverse events, it was not counted. One death due to pneumonia occurred in the 300 mg group, where the patient received two doses of anifrolumab 300 mg.

Study Author Conclusions

TULIP-1 did not achieve the primary endpoint of SRI-4. However, treatment with anifrolumab 300 mg every 4 weeks in patients with moderate-to-severe SLE was associated with improvements in several secondary endpoints, including BICLA response, sustained oral corticosteroid reduction to target dose, and organ-specific measures (eg, skin and joints). Future trials in patients with SLE should carefully select endpoints that are relevant to target biology, appropriate for the patient population, and sensitive to clinically meaningful improvements.

InpharmD Researcher Critique

Despite improvements in secondary endpoints, as the primary endpoint was never met, results are exploratory and highlight the need for further research to provide more robust data. Still, the inclusion of patients with background medication use as well as the double-blinded and randomized design are strengths of the study that enhance its validity. 

Long‐Term Safety and Efficacy of Anifrolumab in Adults With Systemic Lupus Erythematosus: Results of a Phase II Open‐Label Extension Study

Design

Open-label extension of a phase IIb prospective, randomized, multi-center, placebo-controlled trial

N= 218

Objective

To investigate long‐term safety and tolerability of anifrolumab, a human monoclonal antibody to the type I interferon (IFN) receptor subunit 1, in patients with moderate‐to‐severe systemic lupus erythematosus (SLE)

Study Groups

Cohort in the open‐label extension (N= 218)

Inclusion Criteria

Completed the randomized controlled trial (RCT) treatment and follow‐up; aged 18 to 65 years; fulfilled ≥4 of the 11 American College of Rheumatology (ACR) classification criteria for SLE

Exclusion Criteria

Active and severe lupus nephritis or neuropsychiatric SLE; underwent major surgery within 8 weeks or elective major surgery planned; received azathioprine (>200 mg/day), mycophenolate mofetil/mycophenolic acid (>2.0 g/day), or methotrexate (>25 mg/week); received any vaccine within 4 weeks; received BCG vaccine within 1 year

Methods

Patients who completed RCT treatment with anifrolumab or placebo to day 337 and finished follow-up on day 422 were eligible to continue treatment via the open-label extension. Standard‐of‐care treatments were allowed and modified at the discretion of the investigator. All patients received intravenous (IV) anifrolumab 1,000 mg q4w, then reduced to 300 mg q4w.

Duration

Follow-up: 85 days

Outcome Measures

Incidence of adverse events

Baseline Characteristics

Study cohort (N= 218)

Age, years

Female

White

Disease activity

SLEDAI‐2K global score

SDI score

ANA positive

Anti‐dsDNA positive

Abnormal (low) complement C3

Abnormal (low) complement C4

4.9 ± 3.9

0.6 ± 1.0

203/212 (95.8%)

57/205 (27.8%)

61/206 (29.6%)

49/206 (23.8%)

SLE medication

Glucocorticoids

Antimalarial

Methotrexate

Azathioprine

Mycophenolate

Leflunomide

159 (72.9%)

149 (68.3%)

45 (20.6%)

34 (15.6%)

25 (11.5%)

1 (0.5%)

Of the patients, 153 (70.2%) had received anifrolumab a nd 65 (29.8%) had received placebo in the RCT.

Results

Endpoint

Study cohort (N= 218)

Any adverse event

Top adverse events in ≥5% of patients

Nasopharyngitis

Bronchitis

Headache

Upper respiratory tract infection

Diarrhea

24 (11.0%)

21 (9.6%)

14 (6.4%)

14 (6.4%)

10 (4.6%)

≥1 serious adverse event

50 (22.9%)

Changes in efficacy by week 168

SLEDAI‐2K global score

C3 levels, mg/dL

C4 levels, mg/dL

-0.9

8.54 ± 17.5

1.98 ± 3.5

15 patients (6.9%) discontinued due to adverse events; 1 patient died prior to study completion. SDI levels generally remained stable over the years.

Adverse Events

See Results

Study Author Conclusions

This open‐label extension reaffirmed the safety profile observed in the 1‐year parent study and, more importantly, showed that these results were maintained with long‐term exposure to anifrolumab. These findings suggest that long‐term inhibition of the type I IFN pathway with anifrolumab may provide a promising novel therapeutic strategy in addition to currently available treatments for patients with SLE.

InpharmD Researcher Critique

The timeline for switch from 1,000 mg to 300 mg anifrolumab is vague. Patient data on adverse events are pooled together from both placebo and anifrolumab groups, making it difficult to discern whether serious adverse events are treatment-related. Lack of blinding and selection bias are also limitations of this study.

A Randomized, Placebo‐Controlled Phase III Extension Trial of the Long‐Term Safety and Tolerability of Anifrolumab in Active Systemic Lupus Erythematosus

Design

Long-term randomized, placebo-controlled, double-blind extension of a phase III study

N= 369

Objective

To explore long‐term safety and tolerability of anifrolumab 300 mg compared with placebo in patients with systemic lupus erythematosus (SLE) who completed a Treatment of Uncontrolled Lupus via the Interferon Pathway (TULIP) trial and enrolled in the placebo‐controlled 3‐year long‐term extension (LTE) study

Study Groups

Anifrolumab 300 mg (n= 257)

Placebo (n= 112)

Inclusion Criteria

Complete the previous 52‐week treatment period (TULIP trial); repeat tuberculosis test showing no active tuberculosis (or if newly positive for latent tuberculosis, prophylaxis treatment was required); negative HIV test; repeated Pap smear test without malignancy

Exclusion Criteria

Any condition that would interfere with study data; concurrently enrolled in another clinical study; above‐standard clinical doses of azathioprine; mycophenolate mofetil; mycophenolic acid; oral, subcutaneous, or intramuscular methotrexate; or mizoribine within the preceding 60 days

Methods

During enrollment, patients who were patients previously treated with anifrolumab 300 mg continued receiving that dosage. If patients were receiving anifrolumab 150 mg in TULIP‐1, they were switched to anifrolumab 300 mg. Patients who were previously randomized to placebo were re-randomized (1:1) to receive either anifrolumab 300 mg or placebo. The overall ratio of anifrolumab to placebo was 4:1. A total of up to 39 doses were given q4w after LTE start. Use of concomitant cyclophosphamide, other biologic drugs, intravenous (IV) immunoglobulin, or IV glucocorticoids was not permitted.

Duration

3 years

Follow-up: 8 weeks after last dose

Outcome Measures

Long‐term safety and tolerability as assessed by rates of adverse events

Baseline Characteristics

Anifrolumab 300 mg (n= 257)

Placebo (n= 112)

Age, years

Female

White

Disease activity

SLEDAI‐2K

SDI global score

Type I IFN gene signature high

ANA positive

Anti‐dsDNA positive

Abnormal (low) complement C3

Abnormal (low) complement C4

Baseline SLE treatments

GCs (prednisone or equivalent)

Antimalarials

Azathioprine

Methotrexate

Mycophenolate

NSAIDs

Abbreviations: SLEDAI‐2K, SLE Disease Activity Index 2000; SDI, Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index; IFN, interferon; ANA, antinuclear antibody; anti‐dsDNA, anti–double‐stranded DNA; GCs, glucocorticoids; NSAIDs, nonsteroidal antiinflammatory drugs; AE, adverse events

Results

Endpoint

Anifrolumab 300 mg (n= 257)

Placebo (n= 112)

p-value

Any AE

Any SAE (including events with outcome of death)

Any DAE

Any AESI

Non‐opportunistic serious infections

Herpes zoster

Latent tuberculosis*

Influenza

Major acute cardiovascular events**

Malignancy

Anaphylaxis

Opportunistic infections

Vasculitis

* Latent tuberculosis was defined as a positive interferon‐γ release assay result. All patients were required to be tested at least annually, if not more. No active cases of tuberculosis were reported.

** Per the cardiovascular event adjudication committee

Adverse Events

See Results

Study Author Conclusions

This LTE study represents the longest placebo‐controlled clinical trial performed in SLE to date. No new safety findings were identified in the LTE study, supporting the favorable benefit–risk profile of anifrolumab for patients with moderate‐to‐severe SLE receiving standard therapy.

InpharmD Researcher Critique

Patients were partially randomized, as those who received anifrolumab prior continued treatment with anifrolumab.