Utilizing a Patients Own Fibroblasts to Reduce Wrinkles, A Summary of Dr. Mentz's et al FDA Study on Isolagen 

Objective: This paper reviews clinicians experience and data currently available on the efficacy and tolerability of this unique treatment based on the ongoing Phase III FDA clinical trial undertaken by Isolagen Technologies (Houston, TX).

Methods: One hundred forty-six patients with facial rhytids and scars were randomized to treatment with cultured autologous fibroblasts (Isolagen) and placebo. Efficacy and tolerability were then reviewed by patients and physicians at 1,2,4, and 6 months. Responders were categorized as patients who improved 2 or more levels on a 7 level photo scale.

Results: At one month 57% responded, at two months 79.6%, at four months 77.1% and at 6 months 81.6%. Most common side effects were edema and pain at injection site.

Conclusion: Autologous fibroblasts are a potentially efficacious and well-tolerated alternative for noninvasive facial rejuvenation.

Introduction:

Nonsurgical minimally invasive procedures for facial rejuvenation have become a mainstay of clinical practice for plastic surgeons and dermatologists. It has been reported that between 1992 and 2002 there has been a four-fold increase in fat injections, a two and one-half increase in collagen injections, and a four-fold increase in chemical peels.3 In addition, botulinum toxin type A (Botox) and hyaluronic acid (Restylane) are also highly sought therapies for patients who seek less invasive procedures.

Previously, the "gold standard" among injectable fillers was bovine collagen; however, with the advent of Restylane patients now have a therapeutic option that is better tolerated with less immunogenicity and potential hypersensitivity reactions, and offering a more "durable aesthetic".3,4,5,6 However, as with other fillers Restylane efficacy begins to decline at six months.3

Facial rejuvenation continues to advance. William Boss, MD began work in 1995 on autologous cultured fibroblasts for facial rejuvenation.2,8 In 1999 Deborah Watson, MD, et al reported a small study that showed potential efficacy for this therapeutic method with 9 out of 10 patients reporting a response to therapy.7 Building on these early findings of noncontrolled studies, and current use of Isolagen in Australia and the UK, the scope of research has been broadened and an FDA clinical trial is now under way to evaluate the efficacy and tolerability of cultured autologous fibroblasts for cosmetic dermal therapy. In addition, initial findings show a trend toward improved results over time, unlike other currently available dermal fillers.

Materials and Methods:

Isolagen is a clear gel consisting of autologous fibroblasts derived from a punch biopsy of the skin. The cells are expanded in-vitro, then harvested and injected into the patient’s skin as a suspension in Kreb’s ringers with 5% dextrose. In Phase III of this study a 1.2 cc syringe of sterile fibroblasts with a concentration of 20 million cells/cc is provided to the treating physician. Due to the autologous nature of this material no animal testing has been done.

The study was a double-blinded, randomized, placebo controlled trial conducted at ten sites in the United States. The study enrolled adult outpatients of both sexes requesting treatment for facial rhytids, and/or facial scars. Patients were not eligible for this study if they had concurrent or prior (6 months) cosmetic therapy to the area treated during the study. Other exclusion criteria included history of active autoimmune disease or organ transplantation, diagnosis of cancer, active or chronic skin disease, i.e. psoriasis, eczema, blistering skin disease, or local infection, also excluded were patients with active systemic infection, and chronic antibiotic or steroidal therapy.

At the initial screening visit, patients were evaluated, labs drawn, and written informed consent was taken. After patients were approved for the study areas of treatment were agreed upon by physician and patient. Eligible patients then underwent local anesthesia, and a 3mm postauricular punch biopsy was taken and the defect closed with absorbable suture. The patient’s sampled tissue was then sent to Isolagen laboratories for processing.

The lab extracted fibroblasts from the tissue sample and the cells were then washed, and exponentially expanded over a six week period. The final product is placed on ice, packaged in a Styrofoam container and shipped to the treating physician by priority overnight mail.

Local analgesia (ice, topical analgesics or local infiltration, and/or nerve block with 1% lidocaine) was provided prior to treatment at the discretion of the physician and patient. Patients were scheduled to return to clinic on the day of cultured fibroblast arrival, the physician, using a 30 gauge; 0.5-inch sterile needle injected the solution intradermally. These injections were repeated at two more clinic visits over 3 to 6 weeks. Areas treated were: glabellar crease, crow’s feet, nasolabial fold, labiomental crease, perioral rhytids, acne scarring, and other isolated facial scars.

Assessments were planned at 1,2,4,6, 9, and 12 months. At each follow-up visit the results were examined according to a photo guide assessment as the objective measure and a scale to evaluate patient satisfaction. These findings were recorded by both the physician and patient. The primary efficacy endpoint was the physician’s photo guide assessment (7-point ordinal scale) at the four month visit. Patients who improved two or more levels on the seven level photo scale were considered responders. (Fig – Photo Assessment) After all subjects had completed their four month visits the acute study database was locked and the study was unblinded. Subjects who had received treatment with placebo and requested further treatment, were given the opportunity to receive treatment with Isolagen.

Results:

The study enrolled 154 patients with a total of 146 patients completing the study. The primary reason for patients being discontinued was difficulty adhering to the study schedule. Of these, 107 patients were treated for facial rhytids (27 receiving placebo), and 47 were treated for facial scars including acne and traumatic scars (14 received placebo). The patients were 90.5% female and 9.5% male and the mean age was 46.8 years. Of these 91.5% were Caucasian, 4.4% Asian, 1.9% Hispanic, and 1.9% were black.

We present the data for 1, 2, 4, and 6 months. The results for 9 and 12 months are pending. The patients that were considered responders were those who improved more than 2 or more levels on the 7 level photo scale. The average placebo response was subtracted from responders in order to underscore the response results. Overall, the injected fibroblasts improved facial rhytids and scars, and the results improved with time. At 1 month 57% responded more than 2 levels, at 2 months 79.6%, 4 months 77.1%, and 6 months 81.6% (Fisher Exact Test p<0. 0001 at 2, 4, and 6 months). (Fig – Isolagen Response Graph) (Fig – Before and Afters)

The most common adverse events reported were injection site inflammation and injection site pain.

Conclusion:

Use of autologous cultured fibroblasts is potentially an efficacious and well-tolerated cosmetic dermal therapeutic option. Note that in figure () response to Isolagen improves with time. This is a unique finding compared to other fillers such as Restylane, which shows a decline in efficacy at 6 months.4 The clinical trial is still ongoing with results for nine month and twelve month pending. However, the trend as seen in figure one is clearly that of improvement over time.

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