Ingenolmebutat (2) – Picato®

• Clinical trials
  • Study LP0041-1120 is a randomised, open-label, multicentre, two-arm parallel-group study in which topical treatment with ingenol mebutate was compared with topical therapy with diclofenac-hyaluronic acid.

a) Adult patients with non-hyperkeratotic, non-hypertrophic actinic keratoses on the face and/or scalp

• For adult patients with non--hyperkeratotic, non-hypertrophic actinic keratoses on the face and/or scalp, there is a hint of a non-quantifiable additional benefit for ingenol mebutate compared with the appropriate comparator therapy, diclofenac-hyaluronic acid.
• Overall, the effects of ingenol mebutate in the population described here, with actinic keratosis on the face and/or scalp, are therefore classified as non-quantifiable, taking into account the severity of the condition and the therapeutic objective in treating the condition.
• Taken as a whole, the uncertainties described justify classifying the certainty of the evidence as a hint of additional benefit.
• mortality
  • In the presented study, no deaths occurred in the ingenol mebutate arm, whilst two events occurred in the diclofenac-hyaluronic acid arm.
  • There was no statistically significant difference between the treatment groups for the endpoint of overall mortality.
• Morbidity – Complete resolution of visible lesions
  • Complete resolution of visible lesions is a patient-relevant endpoint.
  • For the endpoint of complete resolution of visible lesions, a statistically significant difference in favour of ingenol mebutate compared with the comparator treatment of diclofenac-hyaluronic acid was observed at 17 weeks: among patients treated with ingenol mebutate, 45.1% showed complete regression at week 17, whilst among those treated with diclofenac-hyaluronic acid, this occurred in 23.5% of patients [RR: 1.92; 95% CI [1.48; 2.50]; p < 0.001].
  • Limitations must be taken into account when interpreting the results. For instance, 26% of patients in the ingenol mebutate arm who were lesion-free at week 8 developed new lesions within 8 weeks.
  • This indicates that, for a proportion of patients, lasting or long-term freedom from lesions was not achieved.
  • For patients receiving diclofenac-hyaluronic acid therapy, no data are available on the occurrence of lesions between weeks 8 and 17, nor on recurrences after week 17, as neither a visit at week 8 nor follow-up beyond the end of the study was planned (a priori).
  • Furthermore, it remains unclear overall, for patients in both the ingenol mebutate and diclofenac-hyaluronic acid arms, how many patients experienced further recurrences or lesions after week 17.
  • The long-term durability of the effect cannot therefore be conclusively assessed.
  • Furthermore, when interpreting the results, it should be borne in mind that the optimal therapeutic effect of diclofenac-hyaluronic acid may not be achieved until 120 days (i.e. at the end of the study).
• Morbidity – squamous cell carcinoma of the skin
  • Actinic keratosis, as a precancerous condition, is a disease associated with a risk of developing squamous cell carcinoma.
  • The treatment of actinic keratosis is undertaken, in particular, with the aim of reducing the long-term incidence of squamous cell carcinoma.
  • The study presented does not address this relevant issue.
  • Consequently, there are no usable data available overall for the patient-relevant endpoint ‘squamous cell carcinoma of the skin’.
  • The data from the study documentation cannot be interpreted for the purpose of benefit assessment, both due to the lack of long-term follow-up beyond 17 weeks and due to insufficient information on the location of the squamous cell carcinomas.
  • Monitoring the development of squamous cell carcinomas from actinic keratosis is relevant and would therefore have been of particular importance for assessing the additional benefit of ingenol mebutate compared with diclofenac-hyaluronic acid.
• quality of life
  • Health-related quality of life was not assessed in the LP0041-1120 study.
• Side effects – SAE, discontinuation due to AE
  • For the SAE endpoint, there was no statistically significant difference between ingenol mebutate and diclofenac-hyaluronic acid at week 17.
  • The results for the endpoint ‘discontinuation of treatment due to AEs’ are not interpretable due to the different durations of administration for ingenol mebutate (3 days) compared with diclofenac hyaluronic acid (90 days).
• Overall assessment
  • For adult patients with non-hyperkeratotic, non-hypertrophic actinic keratoses on the scalp and/or face, data are available from the randomised, open-label RCT LP0041-1120.
  • This study provides results on mortality, morbidity and side effects.
  • In summary, in the endpoint categories of mortality and side effects, there are no statistically significant advantages or disadvantages for ingenol mebutate compared with the appropriate comparator therapy, diclofenac-hyaluronic acid.
  • In the morbidity category, data on the patient-relevant incidence of squamous cell carcinomas are lacking.
  • Nevertheless, for the endpoint of complete regression of visible lesions at week 17, there is a statistically significant advantage of ingenol mebutate over the appropriate comparator therapy, diclofenac-hyaluronic acid.
  • No data on quality of life were collected.
  • Consequently, for adult patients with non-hyperkeratotic, non-hypertrophic actinic keratoses on the face and/or scalp, the morbidity endpoint category for ingenol mebutate compared with the appropriate comparator therapy, diclofenac-hyaluronic acid in the context of the study, exclusively positive effects were observed in the endpoint ‘complete regression of visible lesions’.
  • This is not offset by any negative results from other categories.
  • Due to the lack of long-term follow-up, it is not possible to assess either the sustainability of the positive effect or the potential impact of topical therapy on the development of squamous cell carcinomas.

b) Adult patients with non-hyperkeratotic, non-hypertrophic actinic keratoses on the trunk and/or extremities

• For adult patients with non-hyperkeratotic, non-hypertrophic actinic keratoses on the trunk and/or extremities, the additional benefit of ingenol mebutate compared with the appropriate comparator therapy is not proven.
• For the patient population covered by the marketing authorisation – adult patients with non-hyperkeratotic, non--hypertrophic actinic keratoses on the trunk and/or extremities, the pharmaceutical manufacturer has not submitted any study that would have been suitable for assessing the additional benefit of topical therapy with ingenol mebutate compared with the appropriate comparator therapy.

Courtesy translation only, please refer to the German original.