Friday, 15 Feb 2019

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POSTURE Study: Apremilast Fails in Ankylosing Spondylitis

ClinicalTrials.gov has listed the results of the POSTURE study, a large randomized placebo-controlled trial wherein apremilast was found to yield no benefit (compared to placebo) in treating ankylosing spondylitis (AS) (32.5% vs. 36.6% ASAS20 at week 16) patients. These findings make it unlikely that Celgene will pursue AS as an indication for apremilast.

This was a 490 patient trial wherein active AS patients were randomized to receive placebo, Apremilast 20 mg or apremilast 30 mg bid for 24 weeks, with a planned 5 year open-label extension. The primary endpoint was the percentage achieving an Assessment of Spondyloarthritis ASAS20 response at week 16 (comparing those on placebo and apremilast 30 mg BID).

ASAS20 Response at Week 16

Placebo

(n 164)

Apremilast 30 mg

(n 163)

36.6%

32.5%

P =0.438

While many of the details have yet to be published or presented, the primary endpoint was not met. Dropouts were low (10-15%) and nearly 30% of each group had an early exit a week 16.  Interestingly these patients had a wide diversity in disease duration with 42% having less than 5 years disease duration and 38% had > 10 yrs. disease duration. It is not known how many of these patients had axial only disease or how many had peripheral arthritis or enthesitis.

The toxicity profile appears to be in line with that reported in other trials, including 9-12% diarrhea on apremilast and 3% on placebo.  Overall adverse events were not different between groups, but the 30 mg apremilast patients had more serious adverse events (6 vs. 1) and adverse events leading to drug withdrawal (12 vs 6) than patients on placebo. 

Apremilast is a phosphodiesterase-4 inhibitor (PDE-4) that has been approved for the treatment of moderate to severe plaque psoriasis or active psoriatic arthritis in adults. In RCTs it was shown to yield 32-41% ACR20 responses in PsA and 29-33% PASI75 responses in psoriasis patients after 16 weeks of therapy.

The drug failed as add-on therapy in a phase II rheumatoid arthritis patient trial where in methotrexate incomplete responders received either placebo, apremilast 20 mg or 30 mg bid (Citation source http://buff.ly/2eO4qYo). After 16 weeks, apremilast (28-33%) was no better than placebo (34%) at achieving an ACR20 response.

An early pilot study of 36 active, NSAID-treated ankylosing spondylitis (AS) patients showed a nonsignificant trend toward improved BASDAI and BASMI scores compared to placebo. Interestingly there was a significant decline in biomarkers of bone biology (RANKL, sclerostin) in the apremilast treated cohort. (Citation source: http://buff.ly/2dYzjtR)

In summary, apremilast may be effective in psoriatic disease, but does not have any proven efficacy in anklyosing spondylitis that would support its use and make its future study unlikely.

The data tables for the POSTURE study are shown below:

 Baseline

Measures

  Placebo

(n 164)

  Apremilast 20 mg

(n 163)

  Apremilast 30 mg

(n 163)

  Total

(n 490)

Mean Age  (yrs)

 44.0 

 45.2 

 44.8

 44.7 

Male 

 124 

 121 

 107 

 352 

AS duration (yrs)

 10.39 

 11.06

 10.31

 10.59 

≤ 2 yrs 

 41 

 48 

 40 

 129 

> 2 to ≤ 5 yrs 

 29 

 23 

 26 

 78 

Ø  5 to ≤10 yrs 

 33 

 29 

 33 

 95 

> 10 yrs 

 61 

 63 

 64 

 188 

 

 

  Placebo

  Apremilast 20 mg

  Apremilast 30 mg

STARTED 

 164 

 163 

 163 

Received Treatment 

 164 

 163 

 163 

Completed Week 16 

 150 

 151 

 144 

Early Escape at Week 16 

 51

 49 

 49

Completed Week 24

 145 

 147 

 138 

Dropouts 

 19 

 16 

 25 

Adverse Event 

              6 

              7 

              12 

Lack of Efficacy 

              3 

              2 

              5 

Non-compliance with study drug 

              1 

              1 

              0 

Withdrawal by Subject 

              8 

              3 

              5 

Lost to Follow-up 

              1 

              2 

              0 

Protocol Violation 

              0 

              0 

              3 

Unspecified 

              0 

              1 

              0 

 

 Adverse Events

  Placebo

  Apremilast 20 mg

  Apremilast 30 mg

Overall Participants  

 164 

 163 

 163 

Any Treatment Emergent Adverse Event (TEAE) 

 82 

 89 

 85 

Any drug-related TEAE 

 21 

 43 

 49 

Any severe TEAE 

 0 

 2 

 5 

Any serious TEAE 

 1 

 3 

 6 

Any serious drug-related TEAE 

 0 

 0 

 3 

Any TEAE leading to drug interruption 

 13 

 12 

 13 

Any TEAE leading to drug withdrawal 

 6 

 9 

 12 

Disclosures: 
The author has received research/grant financial support on this subject
The author has received compensation as an advisor or consultant on this subject

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