Shelbi C. Jim On, MD; Madelaine Haddican, MD; Alex Yaroshinsky, PhD; Giselle Singer, BS; Mark Lebwohl, MD
Drs. Jim On and Haddican, Ms. Singer, and Dr. Lebwohl are from the Icahn School of Medicine at Mount Sinai, New York, New York. Dr. Yaroshinsky is from Vital Systems, Inc, Rolling Meadows, Illinois.
Drs. Jim On, Haddican, and Yaroshinsky and Ms. Singer report no conflict of interest. Dr. Lebwohl has been a consultant and investigator for LEO Pharma Inc and a consultant for Valeant Pharmaceuticals International, Inc.
This study was registered on April 17, 2013, at www.clinicaltrials.gov with the identifier NCT01836367.
This study was conducted at the Icahn School of Medicine at Mount Sinai. LEO Pharma Inc supplied the study drug and funded the costs of study-related tests and procedures.
Correspondence: Shelbi C. Jim On, MD, 5 E 98th St, 5th Floor, Box 1048, New York, NY 10029 (Shelbi.jimon@mountsinai.org).
Figure 3. Local skin reactions at 7 days after application of the first dose of ingenol mebutate gel 0.015% on the same site of the patient’s face in each cycle of treatment (cycle 1, day 8 [A]; cycle 2, day 36 [B]).
Visual analog scale scores for participant-perceived irritation were less than 50 on a scale of 0 to 100 during both application cycles. At 1 day and 3 days after application of the first dose of ingenol mebutate gel 0.015% in cycle 1, the mean (SD) VAS scores for irritation were 31.8 (37.06) and 37.9 (30.77), respectively. At the same time points in cycle 2, VAS scores were 44.2 (32.45) and 49.6 (26.90), respectively. No information was available regarding resolution of participant-perceived irritation, as irritation data were not collected after day 4 of each treatment cycle; therefore, P values were not determined. Participant satisfaction with treatment was high and nearly the same at the end of cycles 1 and 2 (VAS scores: 83.7 [12.73] and 83.8 [20.46], respectively).
Comment
Our findings show that a second course of treatment with ingenol mebutate gel 0.015% on the same site on the face or scalp produced a less intense inflammatory reaction than the first course of treatment. Composite LSR scores at each time point after the start of treatment were lower in cycle 2 than in cycle 1. The percentage of participants who demonstrated a severity score greater than 1 for any of the 6 components of the LSR assessment also was lower at time points in cycle 2 than in cycle 1. These results are consistent with the hypothesis that the activity of ingenol mebutate includes a mechanism that specifically targets transformed keratinocytes, which are reduced by the start of a second cycle of treatment.
The mechanism for the clinical efficacy of ingenol mebutate has not been fully described. Studies in preclinical models suggest at least 2 components, including direct cytotoxic effects on tumor cells and a localized inflammatory reaction that includes protein kinase C activation.11 Ingenol mebutate preferentially induces death in tumor cells and in proliferating undifferentiated keratinocytes.7,12 Cell death and protein kinase C activation lead to an inflammatory response dominated by neutrophils and other immunocompetent cells that add to the destruction of transformed cells.11
The reduced inflammatory response observed in participants during the second cycle of treatment in this study is consistent with the theory of a preferential action on transformed keratinocytes by ingenol mebutate. Once transformed keratinocytes are substantially cleared in cycle 1, fewer target cells remain, and therefore the inflammatory response is less intense in cycle 2. If ingenol mebutate were uniformly cytotoxic and inflammatory to all cells, the LSR scores in both cycles would be expected to be similar.
Assessment of participant-perceived irritation supplemented the measurement of the 6 visible manifestations of inflammation over each 4-week cycle. Participant-perceived irritation was recorded early in the cycles at 1 and 3 days after the first dose. Although it is difficult to standardize patient perceptions, VAS scores for irritation in cycle 2 were higher than those reported in cycle 1, which suggests an increased perception of irritation. The clinical relevance of this perception is not certain and may be due to the small number of participants and/or the time interval between the 2 treatment courses.
The results of this study were limited by the small patient sample. Additionally, LSR assessments were limited by the quality of the photographs. However, LSRs and AK clearance rates were similar to the pooled findings seen in the phase 3 studies of ingenol mebutate.3 Adverse events were predominantly conditions that occurred at the application site, as in phase 3 studies.3 Similarly, the time course of LSR development and resolution followed the same pattern as in those trials. The peak composite LSR score for the face and scalp was approximately 9 in both the present study (cycle 1) and in the pooled phase 3 studies.3
Conclusion
Ingenol mebutate gel 0.015% may specifically target and remove transformed proliferating keratinocytes, cumulatively reducing the burden of sun-damaged skin over the course of 2 treatment cycles. Patients may experience fewer LSRs on reapplication of ingenol mebutate to a previously treated site.
Acknowledgment
Editorial support was provided by Tanya MacNeil, PhD, of p-value communications, LLC, Cedar Knolls, New Jersey.
