Taltz ® (ixekizumab) injektion

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Taltz® ▼ (ixekizumab): Användning i psoriasisartrit och tidigare cDMARD Användning

Ixekizumab var övelägsen placebo hos de patienter som tidigare använt cDMARDs, vilket fastställdes genom andelen patienter som uppnådde ACR20-svar.

Ixekizumab: Efficacy and Safety in Patients with Psoriatic Arthritis and Past cDMARD Use

Ixekizumab, alone or in combination with methotrexate, is indicated for the treatment of active psoriatic arthritis in adult patients who have responded inadequately to, or who are intolerant to one or more disease-modifying anti-rheumatic drug (DMARD) therapies.1

Short Answer Summary

  • Subgroup analyses stratified by baseline cDMARD use were conducted for the primary endpoint of ACR20 response rates at week 24 in the SPIRIT-P1 clinical trial.2,3

    • Patients included in this efficacy analysis did not receive a cDMARD during the study's double blind treatment period 

    • An additional secondary endpoint in the analysis included change from baseline in van der Heijde mTSS.3

  • Patients with past cDMARD use who received IXE had significantly higher ACR20 response rates than did patients who received placebo (IXE 80 mg Q2W, p<.05; IXE 80 mg Q4W, p<.01). 3


  • The numbers of patients who reported a TEAE in the cDMARD-experienced safety population (concomitant or past cDMARD users) were significantly greater for the IXE groups compared with the placebo group.3

cDMARD Use in SPIRIT-P1

The use of cDMARDs such as methotrexate, sulfasalazine, leflunomide, cyclosporine (ciclosporin) A, and azathioprine are recommended by EULAR for patients with PsA who had an inadequate response to NSAIDs.4

Specific inclusion eligibility criteria in SPIRIT-P1 included patients who

  • were cDMARD-naïve

  • were receiving no more than 1 cDMARD at baseline, or

  • had received a cDMARD in the past.2

Patients were excluded if they had used

  • cDMARDs other than methotrexate, leflunomide, sulfasalazine, or hydroxychloroquine in the 8 weeks prior to baseline, or

  • more than 1 cDMARD concomitantly at entry.3

A total of 89 patients (21.3%) reported past use of at least 1 cDMARD at baseline and were randomized to treatment 1:1:1:1 with

  • placebo

  • adalimumab 40 mg Q2W

  • IXE 80mg Q4W or

  • IXE 80mg Q2W.2 

The remaining enrolled patients were either cDMARD-naïve or were currently receiving treatment with a cDMARD at baseline.2 For a summary of the proportion of patients previously on cDMARDs and currently taking concomitant cDMARDs in each study, please refer to Table 1.

Efficacy Evaluation in Patients with Past cDMARD Use

ACR20 Response Rates

Subgroup analyses were stratified by past cDMARD use for the primary endpoint, ACR20.  These patients were not taking a cDMARD during the double blind treatment period of the study. The ACR20 response rates for these past users of cDMARDs were

  • 7/24 (29.2%) in the placebo group

  • 10/20 (50.0%) in the adalimumab 40 mg Q2W group

  • 16/22 (72.7%) in the IXE 80 mg Q4W group (p<.01 vs placebo), and

  • 14/23 (60.9%) in the IXE 80 mg Q2W group (p<.05 vs placebo).3

Change in mTSS

An additional subgroup analysis of the secondary endpoint, mTSS was also examined for past cDMARD use for ixekizumab vs placebo and adalimumab vs placebo. Please refer to Table 2 for results of this analysis.3

Safety Evaluations in SPIRIT-P1

Safety evaluations were performed for

  • the overall safety population, defined as all randomized patients who received at least 1 dose of study treatment, and

  • the cDMARD-experienced safety population, defined as all randomized patients who had cDMARD experience at baseline (concomitant or past cDMARD treatment) and who received at least 1 dose of study treatment.3 

One or more TEAEs were reported by

  • 65.1% of patients who received either regimen of IXE, and

  • 46.2% of patients who received placebo.3

Of the patients who discontinued from the study due to TEAEs,

  • 2 patients (2.2%) were in the IXE Q4W group

  • 4 patients (4.7%) were in the IXE Q2W group, and

  • 2 patients (2.2%) were in the placebo group.3

Serious adverse events were reported by

  • 5 patients (5.6%) in the IXE Q4W group 

  • no patients in the IXE Q2W group, and 

  • 2 patients (2.2%) in the placebo group.3

There were no statistically significant differences between either IXE group and the placebo group for the incidence of SAEs or discontinuations from the study due to adverse AEs.3 Safety analyses were not conducted for the past cDMARD-use-only subgroup.

A review of the TEAEs, including frequency, severity, and seriousness, did not identify any notable differences between the overall safety population and the cDMARD-experienced safety population.3

SPIRIT clinical trials

The safety and efficacy of ixekizumab were assessed in two randomised, double-blind, placebo-controlled phase III studies in 780 patients with active psoriatic arthritis (≥3 swollen and ≥3 tender joints). Patients in these studies had a diagnosis of psoriatic arthritis (Classification Criteria for Psoriatic Arthritis [CASPAR] criteria) for a median of 5.33 years.

Randomised patients also had current plaque psoriasis skin lesions (94.0%) or a documented history of plaque psoriasis, with 12.1% of patients with moderate to severe plaque psoriasis at baseline.

Over 58.9% and 22.3% of the psoriatic arthritis patients had enthesitis and dactylitis at baseline, respectively.

For both studies, the primary endpoint was American College of Rheumatology (ACR) 20 response at Week 24.1

In Psoriatic Arthritis Study 1 (SPIRIT-P1), patients naive to biologic therapy with active psoriatic arthritis were randomised to subcutaneous injections of placebo, adalimumab 40 mg once every 2 weeks (active control reference arm), ixekizumab 80 mg once every 2 weeks (Q2W), or 80 mg once every 4 weeks (Q4W). Both ixekizumab regimens included a 160 mg starting dose.

85.3% of patients in this study had received prior treatment with ≥1 cDMARD. 53% of patients had concomitant use of MTX at a mean weekly dose of 15.8 mg. 67% of patients who had concomitant use of MTX had a dose of 15 mg or greater.

Patients in all treatment groups with an inadequate response at week 16 received rescue therapy (modification to background therapy). Patients on ixekizumab Q2W or Q4W remained on their originally assigned dose of ixekizumab. Patients receiving adalimumab or placebo were re-randomised 1:1 to ixekizumab Q2W or Q4W at week 16 or 24 based on responder status. 1

Psoriatic Arthritis Study 2 (SPIRIT-P2) enrolled patients who were previously treated with an anti-TNF agent and discontinued the anti-TNF agent for either lack of efficacy or intolerance (anti-TNF-IR patients). Patients were randomised to subcutaneous injections of placebo, ixekizumab 80 mg once every 2 weeks (Q2W), or 80 mg once every 4 weeks (Q4W).  Both ixekizumab regimens included a 160 mg starting dose.

56% and 35% of patients were inadequate responders to 1 anti-TNF or 2 anti-TNF, respectively. 

SPIRIT-P2 evaluated 363 patients, of whom 41% had concomitant use of MTX at a mean weekly dose of 16.1 mg. 73.2% of patients who had concomitant use of MTX had a dose of 15 mg or greater.

Patients in all treatment groups with an inadequate response at week 16 received rescue therapy (modification to background therapy). Patients in ixekizumab Q2W or Q4W remained on their originally assigned dose of ixekizumab. Patients receiving placebo were re-randomised 1:1 to ixekizumab Q2W or Q4W at week 16 or 24 based on responder status.1

Posology

Psoriatic arthritis

The recommended dose is 160 mg by subcutaneous injection (two 80 mg injections) at Week 0, followed by 80 mg (one injection) every 4 weeks thereafter.1

For psoriatic arthritis patients with concomitant moderate to severe plaque psoriasis, the recommended dosing regimen is the same as for plaque psoriasis.1

Consideration should be given to discontinuing treatment in patients who have shown no response after 16 to 20 weeks of treatment.1

Some patients with initially partial response may subsequently improve with continued treatment beyond 20 weeks.1

Last Reviewed: 28 January 2019

References

1. Taltz [summary of product characteristics]. Eli Lilly Nederland B.V., The Netherlands.

2. Mease PJ, van der Heijde D, Ritchlin CT, et al. Ixekizumab, an interleukin-17A specific monoclonal antibody, for the treatment of biologic-naive patients with active psoriatic arthritis: results from the 24-week randomised, double-blind, placebo-controlled and active (adalimumab)-controlled period of the phase III trial SPIRIT-P1. Ann Rheum Dis. 2017;76(1):79-87. http://dx.doi.org/10.1136/annrheumdis-2016-209709

3. Data on file, Eli Lilly and Company and/or one of its subsidiaries.

4. Gossec L, Smolen JS, Ramiro S, et al. European League Against Rheumatism (EULAR) recommendations for the management of psoriatic arthritis with pharmacological therapies: 2015 update. Ann Rheum Dis 2016 75(3):499-510. http://dx.doi.org/10.1136/annrheumdis-2015-208337

Glossary

ACR20 = 20% improvement from baseline in American College of Rheumatology Index

AE = adverse event

cDMARD = conventional disease-modifying antirheumatic drug

EULAR = European League Against Rheumatism

IXE = ixekizumab

mTTS = modified Total Sharp Score

NSAID = nonsteroidal anti-inflammatory drug

PsA = psoriatic arthritis

Q2W = every 2 weeks

Q4W = every 4 weeks

SAE = serious adverse event

TEAE = treatment-emergent adverse event

Appendix

Table 1. Background cDMARD Therapy Baseline Characteristics2

 

PBO

N=106

ADA 40 mg Q2W

N=101

IXE 80 mg Q4W

N=107

IXE 80 mg Q2W

N=103

cDMARD naïve, n(%)

13 (12.3)

14 (13.9)

17 (15.9)

17 (16.5)

cDMARD past use, n(%)

24 (22.6)

20 (19.8)

22 (20.6)

23 (22.3)

cDMARD current use, n(%)

69 (65.1)

67 (66.3)

68 (63.6)

63 (61.2)

Methotrexate use, n(%)a

Yes

59 (55.7)

57 (56.4)

57 (53.3)

53 (51.5)

No

47 (44.3)

44 (43.6)

50 (46.7)

50 (48.5)

Abbreviations; ADA = adalimumab; cDMARD = conventional disease-modifying antirheumatic drug; IXE = ixekizumab; Q2W = every 2 weeks; Q4W = every 4 weeks; PBO = placebo.

a Methotrexate use among those patients with cDMARD current use at baseline.

Table 2. Modified Total Sharp Score at Baseline and at Week 24 in Patients with Past Use of a cDMARD 3

Study Visit 

PBO (N=106) 

IXE 80mg Q4W (N=107)

IXE 80mg Q2W (N= 103)

n

Mean (SD)

n

Mean (SD) 

n

Mean (SD)

Baselinea mTSS 

23

13.8 (21.4)

21

21.3 (29.9)

22

12.1 (20.1)

Week 24 mTSS (observed)b

12

11.8 (16.6)

18

17.0 (26.3)

17

10.0 (15.9) 

Change from baseline at week 24 (observed)

14

0.58 (1.19)

19

0.32 (1.40)

17

0.03 (0.21) 

Change from baseline at week 24 (linear extrapolation) 

23

0.48 (1.06)

21

0.22 (1.38) 

21

0.06 (0.25) 

LSM change from baseline (95% CI) at week 24 (linear extrapolation)c 

23

0.50 (0.13, 0.86)d

21

0.16 (-0.22, 0.55)

21

0.08 (-0.30, 0.47)

LSMD (95% CI) vs PBO at week 24 

23

---

21

-0.33 (-0.87, 0.20)

21

-0.41 (-0.94, 0.12)

Abbreviations: cDMARD = conventional disease-modifying antirheumatic drug; IXE = ixekizumab; LSM=least squares mean; LSMD = least squares mean difference; mTSS = van der Heijde modified Total Sharp Score; PBO = placebo; Q2W = every 2 weeks; Q4W = every 4 weeks.

a Last value on or prior to the date of first injection of study treatment.

b Inadequate responders at week 16 and all patients who discontinued from the study at or prior to week 24 are defined as nonresponders. Observed data after week 16 for inadequate responders at week 16 are excluded.

c LSM, LSMD, CI, and within-group p value used analysis of covariance model.

d p=.009.

This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions.

Datum fӧr senaste ӧversyn 2019 M01 28


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