All content on this site is intended for healthcare professionals only. By acknowledging this message and accessing the information on this website you are confirming that you are a Healthcare Professional.

The Lupus Hub uses cookies on this website. They help us give you the best online experience. By continuing to use our website without changing your cookie settings, you agree to our use of cookies in accordance with our updated Cookie Policy
  TRANSLATE

The Lupus Hub website uses a third-party service provided by Google that dynamically translates web content. Translations are machine generated, so may not be an exact or complete translation, and the Lupus Hub cannot guarantee the accuracy of translated content. The Lupus Hub and its employees will not be liable for any direct, indirect, or consequential damages (even if foreseeable) resulting from use of the Google Translate feature. For further support with Google Translate, visit Google Translate Help.

Steering CommitteeAbout UsNewsletterContact
2022-09-16T11:26:24.000Z

Iberdomide in systemic lupus erythematosus: Results from a phase II study

Sep 16, 2022
Share:
Learning objective: After reading this article, learners will be able to cite a new clinical development in SLE.

Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune inflammatory disorder associated with the disruption of multiple innate and adaptive immune pathways.1

Iberdomide is a high affinity cereblon E3 ligase modulator that promotes proteasomal degradation of Ikaros (IKZF1) and Aiolos (IKZF3). Overexpression and genomic alteration of IKF1 and IKZF3 are strongly associated with the development of SLE.1

Here, we summarize the key findings from a phase II study (NCT03161483) of iberdomide in patients with active, moderate-to-severe SLE recently published by Merrill, et al.1 in the New England Journal of Medicine in 2022.

Study design

The trial was conducted at 117 sites in the United States, Canada, Europe, South America, Mexico, and Russia from July 6, 2017, to January 21, 2020, in patients with SLE.

Patients were included if they were aged 18 years with 6 points on the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI)-2K, a score of 4 on the clinical SLEDAI-2K (SLEDAI-2K without laboratory results), antinuclear antibody titers of at least 1:40, and seropositivity for anti-double-stranded DNA antibodies or anti-Smith antibodies.

Patients were treated once a day for 24 weeks with placebo (n = 83) or iberdomide at 0.45 mg (n = 82), 0.30 mg (n = 82), or 0.15 mg (n = 42).

Endpoints

  • Primary endpoint was a response on the SLE Responder Index (SRI-4) at Week 24
  • Secondary endpoints included the following: 
    • A decrease of ≥4 points from baseline in SLEDAI-2K score
    • No new A scores or >1 B score on British Isles Lupus Assessment Group (BILAG)-2004
    • No significant decrease in Physician Global Assessment (PGA) score, <0.3 change from baseline
    • Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI)-50 in the subgroup of patients with CLASI score ≥10 at baseline
    • Mean change from baseline in number of swollen joints or tender joints in the subgroup of patients with ≥2 affected joints at baseline
    • Adjusted mean change from baseline in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score
  • Exploratory endpoints included SRI-4 response in patients with a baseline SLEDAI-2K score of ≥10 and those with high expression of the Aiolos or type I interferon gene signatures
  • Safety

Results

Baseline characteristics

A total of 288 patients were treated with placebo (n = 83) or iberdomide at 0.45 mg (n = 81), 0.30 mg (n = 82) or 0.15 mg (n = 42), and 247 (86%) completed the 24-week placebo-controlled period. A higher percentage of the patients in the iberdomide 0.30 mg group discontinued treatment due to adverse events (AEs) or withdrew from the trial compared with the other groups. Baseline characteristics were balanced among the treatment groups (Table 1).

Table 1. Baseline and clinical characteristics*

Characteristic, %
(unless otherwise stated)

Ibe
0.45 mg
(n = 81)

Ibe
0.30 mg
(n = 82)

Ibe
0.15 mg
(n = 42)

Placebo
(n = 83)

Total
(N = 228)

Mean age, years

46.4

44.7

43.8

43.4

44.7

Female

98

94

98

98

97

Race

 

 

 

 

 

              Black

6

7

7

8

7

              White

74

72

69

72

72

              Other

20

21

24

19

20

Hispanic or Latino ethnic group

41

56

50

49

49

Geographic region

 

 

 

 

 

              US or Canada

22

24

21

19

22

              Europe

38

22

26

33

30

              Mexico or South America

36

48

48

42

43

              Russia

4

6

5

6

5

Median time from initial diagnosis of SLE to randomization (range), years

9.0
(0.531.7)

7.3
(0.535.8)

7.3
(0.935.7)

5.7
(0.535.8)

7.2
(0.535.8)

Antinuclear antibody level ≥1:80

98

100

100

100

99

Mean SLEDAI-2K global score

9.5

9.6

9.5

9.8

9.6

BILAG-2004, 1 A score or >1 B score§

73

73

83

78

76

Mean PGA score

1.7

1.7

1.7

1.7

1.7

Mean CLASI-A activity

7.2

7.1

7.2

6.3

6.9

Cutaneous lupus subtype

 

 

 

 

 

                  Acute/subacute/chronic

47/15/36

52/11/28

71/21/33

60/20/22

56/16/29

Number of affected joints

 

 

 

 

 

                  Swollen/tender

5.5/8.2

7.2/9.8

7.2/8.6

6.4/8.7

6.5/8.9

High gene signature

 

 

 

 

 

                  Aiolos/type 1
                  interferon/Ikaros

44/70/79

39/60/65

33/60/67

33/58/68

38/62/70

Elevated anti-dsDNA antibody level

36

28

31

33

32

Baseline treatment for SLE

 

 

 

 

 

                  Any dose of oral
                  glucocorticoid

72

78

74

77

75

                  Oral glucocorticoid
                  ≥10 mg/day

40

37

40

37

38

                  Antimalarial agent

62

77

67

80

72

                  Immunosuppressant
                  agent

46

44

52

41

45

BILAG-2004, British Isles Lupus Assessment Group 2004; CLASI-A, Cutaneous Lupus Erythematosus Disease Area and Severity Index-Activity; dsDNA, double-stranded DNA; PGA, Physician Global Assessment; SLE, systemic lupus erythematosus; SLEDAI-2K; systemic Lupus Erythematosus Disease Activity Index-2000.
*Adapted from Merrill, et al.1
Race and ethnicity were reported by the patients.
SLEDAI-2K is a 24-item weighted score of lupus activity that ranges from 0 to 105, with higher scores indicating greater disease activity. However, in individual patients with severe disease, the score rarely exceeds 20.
§
BILAG-2004 is an assessment of 97 clinical and laboratory variables covering nine organ systems, with scores ranging from A (severe) to E (never involved) for each organ system.
PGA of disease activity uses a visual-analog scale, with scores ranging from 0 (no disease activity) to 3 (maximal disease).
CLASI-A score is a measure of skin-disease severity. Scores range from 0 to 70, with higher scores representing more severe disease activity. Individual patients rarely have scores exceeding 20.

Primary and secondary endpoints

At Week 24, a higher percentage of patients in the iberdomide 0.45 mg treatment group achieved an SRI-4 response than in the placebo group. The primary endpoint was not met with the other doses of iberdomide (0.30 mg and 0.15 mg) (Figure 1).

Figure 1. SLE Responder Index at Week 24 in the intention-to-treat population* 


CI, confidence interval; SRI-4, Subcutaneous Lupus Erythematosus Responder Index.                                  *Adapted from Merrill, et al.1
Difference between treatment group and placebo.

Secondary endpoints in the iberdomide groups versus placebo are summarized in Table 2.

Table 2. Secondary efficacy endpoints at Week 24 in the intention-to-treat population*

Endpoint, difference in % points

Iberdomide 0.45 mg vs placebo

Iberdomide 0.30 mg vs placebo

Iberdomide 0.15 mg vs placebo

Decrease of ≥4 points from baseline in SLEDAI-2K score

19.3

6.5

10.3

No new A scores or >1 B score on BILAG-2004

8.0

−5.3

12.4

No significant decrease in PGA score, <0.3 change from baseline

6.8

−4.3

12.1

CLASI-50 in a subgroup of patients with CLASI score ≥10 at baseline

14.2

5.3

24.0

Mean change from baseline in no. of swollen joints in a subgroup of patients with ≥2 swollen or tender joints at baseline

0.1

0.7

0.7

Mean change from baseline in no. of tender joints in a subgroup of patients with ≥2 swollen or tender joints at baseline

0.3

1.3

1.1

Adjusted mean change from baseline in FACIT-Fatigue score

1.4

−0.6

−1.1

Glucocorticoid dose reduced by week 16 to <10 mg/day from a dose ≥10 mg/day at baseline

−3.2

BILAG-2004, British Isles Lupus Assessment Group 2004 Index; CLASI-A, Cutaneous Lupus Erythematosus Disease Area and Severity Index-Activity; FACIT-Fatigue, Functional Assessment of Chronic Illness Therapy-Fatigue; PGA, Physician Global Assessment; SLE, systemic lupus erythematosus; SLEDAI-2K; Systemic Lupus Erythematosus Disease Activity Index-2000.
*Adapted from Merrill, et al.1
For the mean changes from baseline in the numbers of swollen or tender joints, the subgroup consisted of a placebo group (n = 62), iberdomide 0.15 mg group (n = 33), iberdomide 0.30 mg group (n = 54), and iberdomide 0.45 mg group (n = 56).
The FACIT-Fatigue is a 13-item questionnaire with individual questions scored from 0 (not at all) to 4 (very much) and total scores ranging from 0 to 52.

At Week 24, a higher percentage of patients in the iberdomide 0.45 mg treatment group achieved a secondary endpoint compared with the placebo group.

  • A decrease in SLEDAI-2K score of ≥4 points from baseline was observed in 56% of patients who received 0.45 mg compared with 36% of patients who received placebo.
  • CLASI-50 was achieved in 68% of patients in the 0.45 mg group compared with 50% in the placebo group.
  • The adjusted mean change from baseline in FACIT-Fatigue score was 5.2 in the 0.45 mg group compared with 3.8 in the placebo group.

No meaningful differences were observed in the BILAG-2004 and PGA scores at Week 24.

Exploratory endpoints

According to biomarkers at baseline, an SRI-4 response was observed in the iberdomide 0.45 mg, 0.30 mg, 0.15 mg, and placebo groups at the frequencies listed below.

  • High Aiolos gene signature: 64%, 28%, 36% and 33%, respectively
  • High type I interferon gene signature: 60%, 43%, 60%, and 33%, respectively
  • High Ikaros expression: 55%, 40%, 43%, and 38%, respectively

Safety

Overall, 78%, 78%, 74%, and 65% in the 0.45 mg, 0.30 mg, 0.15 mg, and placebo groups, respectively, reported any AE (Table 3). Most events were mild to moderate severity. The most frequent AEs in the iberdomide groups were urinary tract infections, upper respiratory tract infections, neutropenia, and influenza. Serious AEs occurred in 6% of patients who received iberdomide and 8% of patients who received placebo (SLE flares). No deaths were reported in the iberdomide groups and one death was reported in the placebo group due to pulmonary embolism after SLE exacerbation and an acute viral respiratory infection. In the iberdomide groups, seven AEs led to withdrawal by >1 patient (neutropenia [n = 4] and rash [n = 3]), and in the placebo group, two patients withdrew due to herpes zoster infection.

Table 3. Adverse events during the intervention*

Event, %

Iberdomide
0.45 mg
(n = 81)

Iberdomide
0.30 mg
(n = 82)

Iberdomide
0.15 mg
(n = 42)

Placebo
(n = 83)

Any AE

78

78

74

65

Any intervention-related AE

40

44

33

29

Any serious AE

7

5

7

8

Any severe AE

1

5

7

6

Any AE leading to interruption of intervention

28

17

24

18

Any AE leading to the withdrawal of intervention

5

13

5

7

Death

0

0

0

1

AE with a frequency of ≥5%

 

 

 

 

              Urinary tract
              infection

10

16

5

4

              Upper respiratory
              tract infection

12

9

7

5

              Neutropenia

11

7

5

2

              Influenza

6

5

7

4

              Nasopharyngitis

9

1

7

1

              Leukopenia

6

4

2

1

              Diarrhea

4

2

7

0

              Sinusitis

6

0

2

1

              Headache

0

0

5

6

AE, adverse event.
*Adapted from Merrill, et al.1
Patients may have had >1 AE. Rash was reported in 4% of patients in the iberdomide 0.45 mg and 0.30 mg groups each, with one case in each of these dose groups considered to be severe but not resulting in the withdrawal of the intervention.

Conclusion

The study showed the promising efficacy and safety of iberdomide in patients with SLE. At 24 weeks, significantly higher SRI-4 response was observed with the highest dose of iberdomide (0.45 mg) compared with placebo, but not with the lower doses. The findings are preliminary and further long-term trials are required to confirm the clinical efficacy and safety of iberdomide in patients with SLE.

  1. Merrill JT, Werth VP, Furie R, et al. Phase 2 trial of iberdomide in systemic lupus erythematosus. N Engl J Med. 2022;386:1034-1045. DOI: 1056/NEJMoa2106535

Newsletter

Subscribe to get the best content related to lupus delivered to your inbox