Practical Application of Genomics to the Development of a Topical Cosmetic Anti-aging Regimen

Joseph R. Kaczvinsky, PhD¹, Vince Bertucci, MD, FRCPC², Juian-juian Jan Fu, MD, PhD^3
1The Procter & Gamble Company, Cincinnati, OH, USA
²University of Toronto, Toronto, ON, Canada
³In private practice, Mason, OH, USA

Conflicts of Interest: Dr. Bertucci and Dr. Fu are paid consultants to Procter & Gamble. Dr. Kaczvinsky is employed by Procter & Gamble. This article has been adapted (with permission from the British Journal of Dermatology) from Fu JJ, Hillebrand GG, Raleigh P, et al. A randomized, controlled comparative study of the wrinkle reduction benefits of a cosmetic niacinamide/peptide/retinyl propionate product regimen vs. a prescription 0.02% tretinoin product regimen. Br J Dermatol 162(3):647-54 (2010 Mar).
ABSTRACT

The development of topical cosmetic anti-aging products is becoming increasingly sophisticated. This is demonstrated by the benefit agents selected and the scientific approaches used to identify them, treatment protocols that increasingly incorporate multi-product regimens, and the level of rigor in the clinical testing used to demonstrate efficacy. Consistent with these principles, a new cosmetic anti-aging regimen was recently developed. The key product ingredients were identified based on an understanding of the key mechanistic themes associated with aging at the genomic level coupled with appropriate in vitro testing. The products were designed to provide optimum benefits when used in combination in a regimen format. This cosmetic regimen was then tested for efficacy against the appearance of facial wrinkles in a 24-week clinical trial compared with 0.02% tretinoin, a recognized benchmark prescription treatment for facial wrinkling. The cosmetic regimen significantly improved wrinkle appearance after 8 weeks relative to tretinoin and was better tolerated. Wrinkle appearance benefits from the two treatments in cohorts of subjects who continued treatment through 24 weeks were also comparable.

Key Words:
cosmetics, aging skin, niacinamide, peptides, retinyl propionate, tretinoin, vitamin A, wrinkles

Background

The advent of new technologies in a variety of areas related to skin biology and clinical research is leading to an increasing level of sophistication in the development of topical cosmetic antiaging products. The development of reliable, accessible, and cost effective methods of measuring change in tissue gene expressionhas led to enhanced mechanistic understandings of skin disease and the skin aging process.^1-3 This, in turn, has led to better, more specific screening approaches to identify agents that can positively affect the key mechanisms identified via genomics.⁴ Finally, demands for more scientifically sound demonstrations of efficacy by dermatologists, patients, and oversight organizations have led to increased rigor in the clinical testing of cosmetic products. Adequate controls, appropriate statistical approaches, relevant treatment protocols, and the combination of both subjective and objective assessments are all important factors for more robust study designs. The composition and testing of a recently developed cosmetic anti-aging regimen⁵ reflects the influence of all the factors mentioned above.

Skin aging is a multifactorial process that combines intrinsic factors (i.e., genetically programmed decreases in cellular function over time) with the insults of extrinsic factors (e.g., exposure to ultraviolet [UV] radiation and environmental pollution). A genomic study of chronologically old and young skin provided insights into some of the biological mechanisms associated with chronological and photoaging.¹ Among the themes observed in chronologically aged skin were decreased expression of genes related to barrier repair, especially lipid biosynthesis and epidermal cellular differentiation pathways, and upregulation of inflammatory responses, cytokine activity, and protease activity. Many of these same pathways were found to also be enhanced in photoaged skin, especially those associated with inflammation, immune responses, and the degradation of elastin and extracellular matrix.

Consistent with these genomic themes, cosmetic anti-aging ingredients were identified via in vitro testing that 1) improve skin barrier function, 2) promote normal/natural exfoliation and skin turnover, 3) help control reactive oxygen species and oxidative stress, and 4) help maintain consistent synthesis and replacement of extracellular matrix components. Treatments containing some of these ingredients have been shown to improve the appearance of aged skin in previous clinical studies.^6-11 The ingredients, listed in Table 1, were incorporated into a comprehensive cosmetic product regimen. Given the multifactorial aspect of skin aging, it was felt that a combination regimen approach would provide the greatest treatment flexibility, as well as yield the opportunity to use optimum levels of potentially incompatible anti-aging ingredients. As shown in the table, this niacinamide/peptide/retinyl propionate (NPP) regimen consisted of a lotion intended for use during the day, which included sunscreen with sun protection factor (SPF) 30, a nighttime cream, and a specialized product for localized treatment of more prominently wrinkled areas of the face.

The improvement in the appearance of facial wrinkles after treatment with this cosmetic regimen was compared to that from a prescription regimen including 0.02% tretinoin in an 8-week, randomized, and controlled clinical study, with cohorts from each treatment group using their regimen for an additional 16 weeks. Results of this clinical study were recently published¹² and are summarized below.

Clinical Study Findings

The study enrolled a total of 196 Caucasian female subjects aged 40 to 65 years with moderate to moderately severe periorbital wrinkles. Following a 2-week washout period in which the participants used a mild facial cleanser (Olay® Foaming Face Wash) ad libitum and a facial moisturizer (Olay® Complete All Day Moisture Lotion Sensitive Skin SPF 15) twice daily, the subjects were divided into two treatment groups. One group used the described cosmetic wrinkle regimen consisting of the SPF 30 lotion daily in the morning and the night cream daily in the evening, each over the entire face, and the specialized wrinkle product twice daily on areas of patient concern, while the other group used a morning application of a SPF 30 sunscreen and an evening application of 0.02% tretinoin in an emollient base. The tretinoin treatment dosing was escalated from every other evening to every evening over the first 2 weeks to minimize irritation. After 8 weeks of use, a cohort of 25 subjects from each treatment group (selected before treatment began) continued treatment for an additional 16 weeks (total of 24 weeks).

Figure 1: Improvement in the appearance of periorbital wrinkles for the full study population and 24-week cohort. Changes were determined by expert visual comparison of subject images before and after treatment, using a ±8 scale. Errors bars represent standard error. Entire population at 8 weeks: n=90 in the tretinoin regimen group; n=95 in the niacinamide/peptide/retinyl propionate (NPP) cosmetic wrinkle regimen group. Cohort at 8 weeks: n=25 in each group Cohort at 24 weeks: n=25 in the tretinoin regimen group; n=23 in the NPP cosmetic wrinkle regimen group

Figure 2: NPP cosmetic wrinkle regimen high responder before and after 8 weeks of treatment.

At baseline and after 8 and 24 weeks, standardized high resolution digital images were taken of both the left and right sides of the patients’ faces to capture the changes in facial wrinkles. These images were evaluated by expert grading for improved appearance of fine lines and wrinkles (+8 to -8 grading scale for improvement or worsening in the after treatment image) and were also assessed by computerized image analysis for changes in periorbital fine line and wrinkle area. Skin barrier integrity on each side of each subject’s face was determined via measurement of trans-epidermal water loss (TEWL) at the same time points. Subjects’ skin was also clinically graded for erythema and dryness periodically throughout the study, including baseline, 8 and 24 weeks, as well as intermediate times, to insure a thorough assessment of tolerance to treatment.

After 8 weeks, expert visual grading and wrinkle image analysis both showed that the cosmetic regimen was as effective as the 0.02% tretinoin regimen for reducing the appearance of fine lines and wrinkles. As seen in Figure 1, treatment with the cosmetic regimen significantly improved graded wrinkle appearance relative to treatment with the 0.02% tretinoin regimen (p<0.05). By image analysis, the cosmetic wrinkle regimen and tretinoin regimen produced 17% and 11% mean reductions in detectable fine line and wrinkle area, respectively (p=0.06). Figure 2 illustrates an example of a patient with a substantial response to cosmetic regimen treatment. Each of the 25-patient cohorts using their respective regimen for a total of 24 weeks showed continued improvement, with over 20% mean reductions in fine lines and wrinkles in both treatment groups after 24 weeks and comparable improvements in wrinkle appearance.

Consistent with its cosmetic design, the wrinkle regimen was well tolerated. The cosmetic wrinkle regimen produced little erythema or skin dryness overall and substantially less than the tretinoin regimen over the first 8 weeks of treatment. After 24 weeks, there was no significant difference in erythema and dryness from the two treatments. Additionally, as seen in Figure 3, skin barrier integrity was maintained after 8 weeks in the extended treatment patient cohort using the cosmetic wrinkle regimen, in contrast to the cohort using the tretinoin regimen. Patients in the cosmetic regimen cohort showed significant improvement in facial stratum corneum barrier function after 24 weeks of treatment.

Limitations to this study include the lack of subject blinding to treatment, possibly influencing self-assessment. Additionally, a larger 24-week sample size would have provided more statistical power and allowed more robust conclusions.

Conclusions

Topical tretinoin is considered a benchmark product for the mitigation of fine facial wrinkles.^13-15 However, a number of sideeffects (e.g., erythema and desquamation) are associated with tretinoin use, especially during the first few weeks, which may cause some patients to discontinue use.¹⁵

In contrast, cosmetic and cosmeceutical anti-wrinkle products are generally well-tolerated by the skin and pleasant for patients to use. While there are few published reports of direct comparative studies,¹⁶ it is generally presumed that such products do not have clinical efficacy comparable to that of prescription topical therapies.

To our knowledge, this is the first published long-term clinical study comparing a cosmetic anti-aging regimen against a recognized prescription topical treatment for improving the appearance of facial wrinkling. The results of this study show that the efficacy of a prescription product for improving the appearance of facial fine lines and wrinkles can be achieved with an appropriately designed cosmetic regimen, while providing additional benefits in aesthetics, skin tolerance, and potential patient compliance.

As cosmetic and cosmeceutical anti-aging products continue to become more sophisticated, we anticipate that the use of cuttingedge scientific approaches (e.g., genomics to identify potentially fruitful benefit targets) and the technical rigor associated with clinical testing of the products that are eventually developed (e.g., comparison to accepted benchmarks) will continue to grow.

Figure 3: Changes in facial skin TEWL for the extended treatment cohorts after 8 and 24 weeks of treatment. Similar results were seen in the full study population after 8 weeks. At 8 weeks n=25 for both groups. At 24 weeks, n=25 for the tretinoin regimen cohort and n=23 for NPP cosmetic wrinkle regimen cohort.

References

1. Robinson MK, Binder RL, Griffiths CE. Genomic-driven insights into changes in aging skin. J Drugs Dermatol 8(7 Suppl):s8-11 (2009 Jul).
2. Clemmensen A, Andersen KE, Clemmensen O, et al. Genome-wide expression analysis of human in vivo irritated epidermis: differential profiles induced by sodium lauryl sulfate and nonanoic acid. J Invest Dermatol 130(9):2201-10 (2010 Sep).
3. Marionnet C, Bernerd F, Dumas A, et al. Modulation of gene expression induced in human epidermis by environmental stress in vivo. J Invest Dermatol 121(6):1447-58 (2003 Dec).
4. Osborne R, Mullins LA, Jarrold BB. Understanding metabolic pathways for skin anti-aging. J Drugs Dermatol 8(7 Suppl):s4-7 (2009 Jul).
5. Kaczvinsky JR, Jr., Grimes PE. Practical applications of genomics research for treatment of aging skin. J Drugs Dermatol 8(7 Suppl):s15-8 (2009 Jul).
6. Bissett DL, Oblong JE, Saud A, et al. Topical niacinamide provides skin aging appearance benefits while enhancing barrier function. J Clin Dermatol 32S:9-18 (2003).
7. Bissett DL, Miyamoto K, Sun P, et al. Topical niacinamide reduces yellowing, wrinkling, red blotchiness, and hyperpigmented spots in aging facial skin. Int J Cosmet Sci 26(5):231-8 (2004 Oct).
8. Robinson LR, Fitzgerald NC, Doughty DG, et al. Topical palmitoyl pentapeptide provides improvement in photoaged human facial skin. Int J Cosmet Sci 27(3):155-60 (2005 Jun).
9. Osborne R, Mullins LA, Jarrold BB, et al. In vitro skin structure benefits with a new antiaging peptide, Pal-KT. J Am Acad Dermatol 58(Suppl 2):AB25 (2008 May).
10. Hipkiss AR. Carnosine, a protective, anti-ageing peptide? Int J Biochem Cell Biol 30(8):863-8 (1998 Aug).
11. Oblong JE, Bissett DL. Retinoids. In: Draelos ZD (ed). Procedures in cosmetic dermatology series: Cosmeceuticals. Philadelphia: Elsevier Saunders, p35-42 (2005).
12. Fu JJ, Hillebrand GG, Raleigh P, Li J, et al. A randomized, controlled comparative study of the wrinkle reduction benefits of a cosmetic niacinamide/peptide/retinyl propionate product regimen vs. a prescription 0.02% tretinoin product regimen. Br J Dermatol 162(3):647-54 (2010 Mar).
13. Kang S, Fisher GJ, Voorhees JJ. Photoaging and topical tretinoin: therapy, pathogenesis, and prevention. Arch Dermatol 133(10):1280-4 (1997 Oct).
14. Nyirady J, Bergfeld W, Ellis C, et al. Tretinoin cream 0.02% for the treatment of photodamaged facial skin: a review of 2 double-blind clinical studies. Cutis 68(2):135-42 (2001 Aug).
15. Weiss JS, Ellis CN, Headington JT, et al. Topical tretinoin in the treatment of aging skin. J Am Acad Dermatol 19(1 Pt 2):169-75 (1988 Jul).
16. Draelos ZD, Ertel KD, Berge CA. Facilitating facial retinization through barrier improvement. Cutis 78(4):275-81 (2006 Oct).