Ingenol Mebutate: A Succinct Review of a Succinct Therapy

Ingenol mebutate preferentially induces a rapid necrosis of the dysplastic keratinocytes of AK [13] through activation of the pro-apoptotic intracellular PKC, with subsequent mitochondrial swelling and rupture of the plasma membrane [12]. Keratinocytes that have undergone normal differentiation are resistant to the PKC mediated pro-apoptotic effects on the mitochondria for reasons that have yet to be defined [14].

In addition to having pro-apoptotic effects on dysplastic cells, ingenol mebutate also has immunostimulatory effects [15] which effectively ‘mop-up’ any dysplastic epidermal cells that might survive the immediate necrotic effects. Activated keratinocytes provide a milieu of cytokines that promote an infiltration of neutrophils into the area of application [16]. The neutrophils then activate reactive oxygen species and other cytotoxic mechanisms to lyse dysplastic cells [6]. This process is further enhanced by the action of ingenol mebutate functioning as an adjuvant [9], stimulating antibody production that stimulates cytotoxic T cells against dysplastic cells.

Siller and colleagues conducted a multicenter, randomized, double-blind, vehicle-controlled phase IIa trial of ingenol mebutate at concentrations of 0.0025%, 0.01% and 0.05%. Two doses were administered: one on day 1 and the second on either day 2 or day 8, and the response assessed at day 85. Patients that had five or more AK of 3–15 mm diameter were selected for the trial. A total of 58 patients and 285 lesions were assessed. Anatomically, the lesions were located predominantly on the upper limbs, scalp and face, in keeping with the usual areas of predilection of AK, and were distributed equitably across the treatment arms. Clinical efficacy was assessed on a per lesion and per patient basis, with complete clearance defined as no clinical evidence of disease and marked clearance being 50–90% lesion reduction. The greatest level of clinical efficacy was seen with the 0.05% concentration of ingenol mebutate gel. On a per lesion basis, 71% were completely cleared, while 67% of patients receiving the 0.05% dosage had clinical clearance of 80% or more of their lesions. Local skin responses (LSR) were seen in 47% of patients receiving the 0.05% concentration, and for the most part were assessed as mild/moderate, however, a total of 14 were recorded as severe. The most commonly seen effects were erythema, flaking/scaling/dryness and scabbing/crusting. Scarring and/or abnormal lesion proliferation did not occur in any of the subjects.

A phase IIb study examined the efficacy and safety outcomes of field therapy for non-facial AK lesions using ingenol mebutate at concentrations of 0.025% and 0.05%. Patients were randomized into four study cohorts. Treatment using 0.025% concentration was applied once daily for three consecutive days. Treatment with the 0.05% concentration was given daily to two groups: three consecutive days of treatment or day 1 vehicle treatment followed by 2 days of treatment. Vehicle treatment was applied for 3 days to the control group. The primary efficacy end point was the partial clearance rate. This was defined as the proportion of patients at the end of the study with at least 75% reduction in AK lesions in the area of field treatment, compared with those that were identified at baseline. This criterion was achieved for all three of the dosing regimens: 56.0% of the group receiving 0.025% for 3 days, 61.8% of the group receiving 0.05% for 2 days and 75.4% of the group receiving 0.05% for 3 days. Compared with the vehicle group, the results were statistically significant and indicated a dose-dependent response. Three secondary efficacy endpoints were included: the complete clearance rate (the number of patients at the end of the study with no clinically evident AK lesions in the field area), the baseline clearance rate (the number of patients with 100% reduction in the amount of AK lesions detected at baseline) and the percentage reduction of the number of AK lesions (the number of lesions at baseline minus the number at the end of the study divided by the number at baseline). These measures were all significantly higher in those patients who received any of the three ingenol mebutate regimes compared to those who received the vehicle treatment. The study also included subjective assessments of patient satisfaction with their treatment, all measures of which came back positive for ingenol mebutate compared with the vehicle treatment. Safety end points included the incidence and grade of LSRs, the incidence of AEs, changes in laboratory tests between screening and day 8, and the ‘global severity rating’ (GSR)—the examiner’s overall clinical impression of any local reactions observed (mild, moderate or severe). LSRs peaked from day 3 to 8, the most commonly observed responses being erythema, flaking/scaling and crusting. LSRs were scored on a scale from 0 to 4 and the individual scores were used to obtain a composite LSR score (sum of the individual scores at each examination in each treatment cohort). The mean composite LSR scores were at their highest at day 8 for the active treatment groups, but had declined substantially by the end of the study. The most common application site AEs were pruritus, pain and irritation, and were observed most frequently in the 0.05% for 3 days cohort, further indicating a dose-dependent response. All application site reactions had resolved spontaneously by 4 weeks, and nil serious AEs were noted during the follow-up period. No patients discontinued participation in the trial due to an AE. The GSR, as a function of observed LSRs, peaked at day 8 and dwindled towards the end of the study.

This study looked at four double-blinded trials: two trials considered lesions of the face and scalp while the other two focused on lesions of the trunk and extremities. Patients with facial or scalp lesions were given either a placebo or 0.015% ingenol mebutate gel to apply for three consecutive days while those with lesions elsewhere on the trunk and extremities were provided with either a vehicle treatment or 0.05% ingenol mebutate to be applied for 2 days. In both cases, patients were to self-apply the gel to a 25 cm² contiguous area once daily. The facial lesion cohort was assessed for safety at day 3 while the trunk and extremities group was assessed on day 4, and both were then assessed at days 8, 15, 29 and 57. In both cohorts, efficacy was assessed at baseline and at day 57. The primary end point assessment of efficacy was complete clearance of all clinically detectable AK lesions in the field area by the end of the study. Complete clearance was observed in 42.2% of the face and scalp cohort (compared to 3.7% with placebo) and 34.1% of the trunk and extremities cohort (versus 4.7% with placebo). The secondary endpoint was partial clearance: a reduction of >75% of clinically detectable AK lesions by the end of the study. Partial clearance was achieved in 63.9% of the face and scalp group (compared with 7.4% with placebo) and 49.1% among the trunk and extremities group (versus 6.9% with placebo). A further secondary end point was the percentage difference in the amount of AK lesions detected compared to the baseline. The percentage change was zero among all patients receiving placebo in all trials. A median reduction of 83% of lesions was noted in the face and scalp cohort and 75% in the trunk and extremities cohort. Overall, the number needed to treat value for ingenol mebutate to achieve complete and partial clearance among the face and scalp cohort was 2.6 and 1.8, respectively, while for the trunk and extremities cohort the number needed to treat to achieve complete and partial clearance was 3.4 and 2.4, respectively. Safety end points that were considered were similar in method to that of Anderson et al. [10] described above: AEs, composite LSR scores, scarring and pigmentation. However, the GSR was not used in this study design. The most common AEs reported across all four trials were application site-specific pruritus, irritation and pain, which is consistent with the findings of Anderson et al. [10]. None of the four trials highlighted any incidences of scarring or changes in pigmentation. In the face and scalp cohort, day 4 was the peak of the composite LSR score, which then declined as the study progressed. Individual LSR scores for erythema were greater than 3 (on a scale of 0–4) in 69.7% of participants compared with 2.2% in the placebo group, and a small group of the active treatment group had a score greater than 3 for flaking or scaling, crusting, swelling, vesiculation or ulceration. In the trunk and extremities group, the composite LSR had three peaks in a decrescendo pattern at day 3, day 8 and day 15. Individual LSR scores for erythema and flaking or scaling were above 2 for the majority of subjects. Vesiculation occurred in 43.6% of those on active treatment and ulceration in 25.8%. The patients who had complete clearance in the two trials involving lesions of the face, as well as those patients in one of the trials involving body lesions, were monitored for a further 12 months.

This is the follow-up study of the patients who had achieved complete clearance in the above study. These patients were seen at three monthly intervals up to 12 months, during which time further field therapy was not administered, however, lesion-directed therapy was available if the assessors deemed necessary. Information was also recorded on possible confounders such as concomitant treatments and conditions that could alter immune function. AK lesions in the field area were counted at each three monthly visit: the primary end point in this follow-up study was recurrence of AK lesions in the field area. Sustained clearance was defined as a field area free of AK lesions after a 12-month period. For the face and scalp cohort, the sustained clearance rate was 46.1% and for the trunk and extremities group was 44.0%. A second end point was sustained lesion reduction, defined as the total percentage reduction of AK lesions in the field area at 12 months compared to the baseline. For the face and scalp this was 87.2% and for the trunk and extremities this was 86.8%.

Based on the number of recurrences recorded at each follow-up, the estimated median time for new or recurrent lesions to occur in the field area was calculated: 365 days for the face and scalp and 274 days for the trunk and extremities. AEs in the field area were also assessed. Three patients suffered adverse symptoms in the field area during the follow-up period; however, the investigators did not consider these to be related to the application of ingenol mebutate. All three events resolved completely. This absence of any AEs supports the idea that ingenol mebutate has an excellent safety profile.

This study is an evaluation of the results of three phase I trials in which ingenol mebutate was applied to normal skin to determine its sensitization potential, photo irritation potential and photo allergic (photosensitizing) potential, respectively. In the dermal sensitization study, none of the subjects experienced reactions that would indicate an allergic response. In the photo irritation study, very mild erythema was observed in the field area following irradiation that was considered statistically significant compared to non-irradiated areas. However, the erythema was clinically at a level so mild that it did not reflect photo irritation. Moderate erythema was observed in the irradiated field area when assessing for photo allergic potential, however, since mild erythema is an accepted LSR for ingenol mebutate; this was not considered to be an AE. Thus, these three pharmacology trials provide further evidence for the safety profile of ingenol mebutate: ingenol mebutate does not appear to have any potential for skin sensitization, photo irritation or photoallergy.