Apremilast (1) – Otezla®

• Clinical trials
  • For the indication of plaque psoriasis, the two double-blind, placebo-controlled trials (PSOR-008/ESTEEM 1 and PSOR-009/ESTEEM 2), which had comparable study designs, were assessed by the EMA as part of the authorisation procedure.
  • The PSOR-010 study was not yet available for marketing authorisation.

a) Psoriatic arthritis in adult patients who have responded inadequately to, or are intolerant of, prior DMARD therapy

• Justification: In order to identify studies demonstrating the additional benefit of apremilast for the treatment of psoriatic arthritis compared with the appropriate comparator therapy, the pharmaceutical manufacturer conducted a bibliographic literature search as well as a search of clinical trial registries. Only placebo-controlled studies were found. Consequently, there are no direct comparative studies of apremilast against the appropriate comparator therapy (etanercept, adalimumab, infliximab or golimumab, where applicable in combination with MTX).
• However, the pharmaceutical manufacturer has made no effort to identify any studies that might have allowed for an indirect comparison of apremilast with one of the comparator therapies.
• Consequently, it is not possible to assess the relative value of apremilast compared with other treatment options for psoriatic arthritis.
• In the absence of a direct comparison, the pharmaceutical manufacturer presents the (pooled) results of the placebo-controlled studies PSA-002, PSA-003 and PSA-004 in its benefit assessment dossier.
• However, as these placebo-controlled trials do not allow for a comparison with an appropriate comparator therapy, no conclusions regarding additional benefit can be drawn from the analyses presented.
• Consequently, the additional benefit of apremilast for the treatment of psoriatic arthritis is not proven.
• Morbidity – HAQ-DI (Health Assessment Questionnaire)
  • Furthermore, the EPAR stated that the results of the study programme were insufficient to support the originally proposed additional claim: ‘[…] Otezla improves physical functioning.’
  • For the HAQ-DI (Health Assessment Questionnaire) endpoint supporting this claim, the minimum clinically important difference (MCID) for the psoriasis arthritis indication was not sufficiently established, and the differences compared with the placebo group were only minor.

b) Adult patients with moderate to severe chronic plaque psoriasis who have not responded to another systemic therapy, such as ciclosporin or methotrexate or psoralen in combination with UVA light (PUVA), or for whom such therapy is contraindicated or who have been unable to tolerate it

• The additional benefit of apremilast over the appropriate comparator therapy (adalimumab, ustekinumab or infliximab) is not proven.
• Rationale: In order to identify studies demonstrating the additional benefit of apremilast compared with the appropriate comparator therapy, the pharmaceutical manufacturer conducted a bibliographic literature search as well as a search of trial registries. This search identified only placebo-controlled studies, as well as a three-arm study comparing etanercept with placebo.
• Consequently, there are no direct comparative studies of apremilast against the appropriate comparator therapy (adalimumab, ustekinumab or infliximab).
• However, the pharmaceutical manufacturer has made no effort to identify studies that might have allowed for an indirect comparison of apremilast with one of the comparator therapies.
• Consequently, it is not possible to assess the relative value of apremilast compared with other treatment options for plaque psoriasis.
• In the absence of a direct comparison, the pharmaceutical manufacturer presents the (pooled) results of studies PSOR-008, PSOR-009 and PSOR-010 in its benefit assessment dossier, showing the study arms with placebo and apremilast respectively.
• However, placebo is not part of the appropriate comparator therapy, which is why no conclusions regarding additional benefit can be drawn from the analyses presented.
• Consequently, the additional benefit of apremilast is not proven.
• The EMA criticised the absence of an active comparator on the grounds that it was not possible to assess apremilast within the treatment cascade in relation to other available treatment options for plaque psoriasis.
• Furthermore, the EMA states the following regarding the efficacy of apremilast: “The efficacy demonstrated in the treatment of plaque psoriasis is modest; however, given the favourable safety and tolerability profile, together with the benefit of an oral route of administration, this could result in better patient compliance with treatment.”
• Due to the minor efficacy of apremilast compared with placebo, it cannot be conclusively assessed whether other active systemic therapies may have greater efficacy than apremilast.
• Morbidity – PASI score (Psoriasis Area and Severity Index)
  • Furthermore, the EMA considers the need for long-term data (from the PSOR-008 and PSOR-009 studies) in order to better assess why, in a significant proportion of patients, the improvement in PASI 75 or PASI 50 observed at the start of treatment with apremilast regresses by week 32.

Courtesy translation only, please refer to the German original.