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The TULIP extension trial of anifrolumab in SLE: 3-year results

Jan 25, 2023
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Learning objective: After reading this article, learners will be able to cite a new clinical development in systemic lupus erythematosus.

At the American College of Rheumatology (ACR) Convergence 2022, Kalunian1 presented results from the 3-year extension phase of the TULIP trials. The TULIP-1 and -2 phase III trials investigated anifrolumab, a human IgG1κ monoclonal antibody that inhibits type 1 IFN signaling, which is  approved by the U.S. Food and Drug Administration (FDA) for the treatment of systemic lupus erythematosus (SLE).2 In both trials, patients were randomized to anifrolumab 300 mg, 150 mg, or placebo.1

The Lupus Hub has previously produced a visual abstract focused on glucocorticoid tapering in the TULIP studies. The extension phase of TULIP (NCT02794285) is the first long-term placebo-controlled safety study of anifrolumab.1

Patient disposition1

During the 3-year extension, patients received either anifrolumab 300 mg or placebo every 4 weeks, in addition to standard of care treatment. Patient disposition is shown in Figure 1. Fewer patients treated with placebo in the long-term extension completed this phase (48.2%) compared with patients treated with anifrolumab in the long-term extension, who had received either anifrolumab 300 mg (69.3%), anifrolumab 150 mg (61.2%), or placebo (62.2%) in the initial TULIP studies.

Figure 1. Patient disposition in the TULIP studies and extension* 

LTE, long-term extension.
*Adapted from Kalunian.1

Safety results1

Safety results for patients who received either anifrolumab 300 mg or placebo in TULIP-1 or -2 and remained on the same treatment in the long-term extension are shown in Table 1.

 Table 1. Incidence of adverse events* 

AE, EAIR per 100 patient-years (unless otherwise stated)

Anifrolumab 300 mg
(n = 257)

Placebo
(n = 112)

Exposure, years

683.5

250.3

Any AE

33.1

37.6

Any serious AE

8.5

11.2

Any AE leading to death

0.4

0.4

Any AE leading to treatment discontinuation

2.5

3.2

Non-opportunistic serious infections

3.7

3.6

Opportunistic infections

0

1.2

Herpes zoster infection

3.4

2.8

Latent tuberculosis

2.3

0.8

Influenza

2.2

0.8

MACE

0.7

1.2

Malignancy

0.3

0.8

Most common AEs

 

 

              Nasopharyngitis

9.7

5.5

              Urinary tract infection

8.5

6.3

              Upper respiratory tract infection

8.3

7.2

AE, adverse event; EAIR, exposure-adjusted incidence rate; MACE, major adverse cardiovascular event.
*Adapted from Kalunian.1

Overall, 12 deaths occurred in the TULIP studies and long-term extension, nine of which were during the extension. Ten deaths were in patients treated with anifrolumab and two were in patients treated with placebo.

COVID-19 safety

Study drug exposure was higher in patients who received anifrolumab during the COVID-19 pandemic (227.7 patient-years; n = 325) than those who received placebo (42.7 patient-years; n = 64).

COVID-19-related adverse events were reported in 10.2% of patients who received anifrolumab and 6.3% of patients who received placebo. Serious COVID-19-related adverse events occurred in 4.9% and 1.6% of patients in the anifrolumab and placebo groups, respectively. Additionally, following adjustment for exposure and time-at-risk during the pandemic, rates of COVID-19-related serious adverse events were higher in patients treated with anifrolumab compared with placebo. However, no COVID-19-related events occurred following full vaccination, and all three deaths due to COVID-19 occurred during the first 6 months of the pandemic.

Efficacy results1

In patients who were treated with either anifrolumab 300 mg or placebo in the TULIP trials and remained on the same treatment in the long-term extension, the mean improvement in the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) at Week 52 of the extension was greater in those receiving anifrolumab compared with placebo, with improvements sustained over time. In addition, the mean glucocorticoid dose was lower at the end of the long-term extension for patients treated with anifrolumab than placebo, with an increase in the number of patients not requiring glucocorticoids in the anifrolumab group.

Figure 2. Glucocorticoid doses from baseline to Year 4 in the TULIP trials and long-term extension* 

LTE, long-term extension
*Adapted from Kalunian.1

In each treatment year, fewer patients in the anifrolumab arm required the highest glucocorticoid dose (>7.5 mg/day) compared with placebo. Furthermore, the reduction from baseline to Year 4 in the proportion of patients treated with the highest glucocorticoid dose was greater in the anifrolumab arm than in the placebo arm.

Conclusion

This 3-year extension showed that anifrolumab is safe and effective when used long-term for the treatment of SLE. Rates of serious adverse events and serious infections were similar between the anifrolumab and placebo groups. However, rates of COVID-19-related serious adverse events were higher in patients treated with anifrolumab than placebo, highlighting the need for further studies into the safety of using anifrolumab in patients with COVID-19. Anifrolumab showed good efficacy in the long-term extension, with a reduction in the number of patients requiring high-dose glucocorticoids (>7.5 mg/day) and greater mean improvements in SLEDAI-2K compared with placebo.

  1. Kalunian K. Long-term safety and efficacy of anifrolumab in adult patients with systemic lupus erythematosus: A multicenter, randomized, double-blind, placebo-controlled 3-year TULIP extension study. Oral abstract #1652. American College of Rheumatology Convergence 2022; Nov 14, 2022. Philadelphia, US.
  2. Burki T. FDA approval for anifrolumab in patients with lupus. Lancet Rheumatol. 2021;3(10):E689. DOI: 1016/S2665-9913(21)00291-5