Status: BLA filing pending

Organizations involved:

Fibrocell Science Inc. –Manuf.; R&D; Tech.; USA mark.

Isolagen Inc. – Former

Description: Laviv is a formulation of autologous (patient's own) fibroblast skin-derived cells. The fibroblasts are extracted, cultured and re-injected as personalized therapy. Once prepared, it is injected into the skin over a few weeks to fill in lines, wrinkles, and scars. The cultured fibroblasts are viable, replication competent cells that are confirmed to contain collagen in vitro. The cells are injected intradermally at the intended treatment site.

The Bulk Drug Substance consists of expanded autologous fibroblasts, formulated to the target cell concentration and cryopreserved in cryovials. T he Drug Product consists of thawed and washed Drug Substance cells, resuspended to a concentration of 1.0 - 2.0 x 10.sup.7 cells/mL in sterile medium. The Drug Product is filled into 2 mL polypropylene cryovials, to contain 1.2 mL cell suspension, and shipped immediately at 2-8°C to the clinical site. The Drug Product is stable at 2-8°C for up to 48 hours prior to injection.

LAVIV (azficel-T) is the first and only FDA-approved therapy that uses autologous (patient's own) collagen-producing cells (fibroblasts) to improve the look of smile lines. Nomenclature: Fibroblasts, autologous [BIO]; Laviv [TR]; Isolagen Therapy [TR former]; azficel-T [USAN current]; azfibrocel-T [USAN preapproval]

Biological.: The rationale underlying Isolagen Therapy is to reinvigorate the microscopic structure of the skin through a biological mechanism, specifically, by injecting living fibroblasts into the area of the skin where an improvement in the skin’s appearance is desired. Following injection, the cultured fibroblasts are thought to synthesize new extracellular matrix and/or to stimulate the remodeling of existing tissue components, thereby altering the structure, texture and appearance of the skin at the site of injection. Although the exact mechanism of action is not known, it is believed that the injected fibroblasts deposit new extracellular matrix proteins and/or stimulate the remodeling of existing tissue components of the dermis.

Companies.: Laviv was developed by Isolagen Inc. In June 2009, declared bankruptcy and reorganized under Chapter 11 of the U.S. Bankruptcy Code, with the reorganized company renamed Fibrocell Science Inc. The company had run out of cash at a critical point, with its first product undergoing review by FDA. Isolagen stockholders were wiped out, and did not receive stock in the new company.

Manufacture: Isolagen Therapy is manufactured by propagation and expansion of dermal fibroblasts obtained from a small biopsy of the patient’s skin. Three 3-mm punch biopsies are collected by the treating physician from behind the ear, where the skin is likely to have received less sun exposure and where there are fewer concerns associated with possible scarring due to biopsy. Upon receipt, the biopsy is examined to ensure it meets Quality Control criteria for further processing. If acceptable, the tissue is washed in sterile medium containing antibiotics, and treated with a cocktail of digestive enzymes that release the cells from the biopsied tissue. The isolated cells are seeded into a tissue culture vessel and propagated and expanded by serial passage using cell culture techniques to obtain a quantity of cells sufficient for three consecutive treatments of the patient’s treatment area. Antibiotics are not used in the culture medium after the first cell feeding. When a sufficient number of cells have been obtained, the bulk cell suspension is cryopreserved until the patient can be scheduled at the physician’s office for their initial and subsequent treatments with Isolagen Therapy. One day prior to each scheduled visit, an aliquot of cryopreserved cells is thawed and washed in sterile medium. The cells are resuspended to a concentration of 1.0 – 2.0 x 10.sup.7 cells/mL in proprietary injection medium. Two vials of Isolagen Therapy Drug Product, each containing 1.2 mL cell suspension, are prepared for each treatment administration. This is a quantity sufficient to treat two nasolabial fold wrinkles with a total combined length of ≤ 20 cm, where Isolagen Therapy is injected in a volume of 0.1 mL/linear centimeter. The vials are shipped immediately upon manufacture to the clinical site using a controlled temperature (2-8ºC) shipping container and an overnight delivery service. The Drug Product is stable at 2-8°C for up to 48 hours prior to injection.

Each lot of Bulk Drug Substance is confirmed to pass tests for sterility, mycoplasma contamination and endotoxin content. In addition, the Bulk Drug Substance is tested to verify the concentration, viability and purity of the cell suspension. Purity is evaluated based on the percentage of cells that stain positively with a fibroblast-specific cell surface marker. Typically, close to 100% of cells in the Bulk Drug Substance are found to express fibroblast-specific cell surface antigens.

The entire manufacturing process is conducted using aseptic processing techniques and microbiological controls for assurance of sterility of the Drug Product, and takes approximately three months using the commercial process.

FDA class: Biologics BLA

Status: Isolagen Therapy™ was sold commercially in the U.S. as a cosmetic treatment from Dec. 1995 to Feb. 1999. The product was manufactured at Isolagen’s New Jersey facility (which has since been closed) using a predecessor manufacturing process. Isolagen Therapy was also sold with limited distribution in the U.K. from 2002 to 2007 and in Australia from 2003 to 2004. Isolagen discontinued marketing of Isolagen Therapy in the U.S. in Feb. 1999 when FDA required all somatic cell therapies to file Investigational New Drug (IND) applications and follow a formal approval process. Isolagen initiated U.S. clinical trials of Isolagen Therapy under IND in 2003. The clinical indications: covered by the IND included treatment of rhytids, dermal depressions, and acne scars. The IND was narrowed at the request of the FDA to the treatment of facial rhytids (wrinkles) in Jan. 2003.

On March 9, 2009 Isolagen filed and on May 2009, FDA accepted a BLA for azfibrocel-T for the treatment of moderate to severe nasolabial fold wrinkles. The Prescription Drug User Fee Act (PDUFA) target date for FDA response was Jan. 4, 2010.

Azfibrocel-T for the treatment of moderate to severe nasolabial fold wrinkles in adults was the sole topic for discussion at the Cellular, Tissue and Gene Therapies Advisory Committee Meeting on Oct. 9, 2009. The committee voted 11 yes to 3 no that the data presented on azfibrocel-T demonstrated efficacy, and 6 yes to 8 no that the data demonstrated safety, both for the proposed indication.

In Dec. 2010, Fibrocell submitted its complete response to a Complete Response (CR) letter issued by FDA regarding the BLA for azficel-T for the treatment of moderate to severe nasolabial folds and wrinkles. One of the FDA requirements was to conduct a histopathological study examining skin after injections of azficel-T. The Company's response contained data from a 29-patient blinded study (IT-H-001). FDA participated in the design of the protocol, and consented to the unblinding of the study data. At three months, there were no unexpected results, and the study provided additional data to support the safety profile seen in the clinic. Azficel-T was directly compared to a placebo injection as well as untreated skin in each subject. The study results were consistent with previous clinical studies, while providing a detailed examination of azficel-T activity at the microscopic level after repeated injections. The study met all expectations, and raised no safety concerns. Trials: When previously marketed as a cosmetic, over 6,000 patients were treated with Isolagen Therapy in the U.K.; over 1,200 patients were treated in the U.S. prior to the submission of the IND; and 508 subjects have been treated under U.S. IND.

The azfibrocel-T pivotal Phase III safety and efficacy studies (IT-R-005; IT-R-006) evaluated a total of 421 individuals at 13 clinical sites in the U.S. Results demonstrated a significant difference in therapy results compared to placebo (p < 0.01). No serious adverse events were reported.

The pivotal clinical studies in support of the BLA were studies IT-R-005 and IT-R-006 which evaluated the efficacy of Isolagen Therapy™ in the treatment of moderate to severe nasolabial fold wrinkles. The pivotal clinical trials were conducted under identical clinical protocols that were developed in coordination with the FDA under a Special Protocol Assessment (SPA), whereby the Agency agreed that the pivotal study design was adequate to provide the primary basis of an efficacy claim. The pivotal studies were multicenter, randomized (1:1 by site), placebo-controlled, double-blind studies. The co-primary efficacy endpoints were based on the blinded Investigator’s live assessment of nasolabial fold wrinkle severity and the subject’s blinded live assessment of their satisfaction with the wrinkles on the lower part of the face compared to the respective Baseline assessments. Both endpoints were evaluated at six months following the third treatment visit for the primary efficacy analysis. Assessments were also performed at zero, two and four months after the third treatment visit for secondary analyses of efficacy. The co-primary efficacy analyses of both pivotal studies compared the proportion of responders in the Isolagen Therapy and placebo treatment groups based on the Evaluator’s wrinkle assessment and the subject’s wrinkle assessment.

Isolagen Therapy has been tested for the treatment of facial wrinkles and creases in two Phase II studies and five Phase III studies). Studies IT-R-005 (N=175) and IT-R-006 (N=197) are the pivotal clinical trials for the treatment of moderate to severe nasolabial fold wrinkles in adults ≥ 18 years of age. The earliest trials, IT-R-001 (N=40) and IT-R-002 (N=151), provided exploratory data that guided the design of the subsequent, larger-scale, Phase III studies. Studies IT-R-003A (N=107) and IT-R-003B (N=106) provide robust, well-controlled data supporting the efficacy and safety of Isolagen Therapy for the treatment of facial contour deformities. Study IT-R-007 (N=45) provides additional data in support of the safety of Isolagen Therapy administration to the face.

In both pivotal studies, a higher proportion of responders was observed among Isolagen Therapy-randomized subjects compared to placebo-randomized subjects on both the Evaluator and subject assessment scales, where all subjects with missing data were treated as non-responders. The differences in response rates between treatment groups were statistically significant in all cases, with p-values below 0.01. Thus, the co-primary efficacy endpoints for each pivotal clinical study, as agreed upon under the SPA, were met. These data not only definitively demonstrate the treatment effect of Isolagen Therapy relative to placebo, but also the clinical effect of Isolagen Therapy..

Safety results for 508 Isolagen Therapy-treated subjects and 354 placebo-treated subjects were included in the BLA analysis. Injection site reactions were by far the most commonly reported adverse events in the studies. The most frequent adverse events associated with treatment with Isolagen Therapy or placebo were injection site erythema (16%), injection site swelling (14%), injection site bruising (11%), injection site pain (6%), and injection site edema (4%). Injection site reactions were slightly more frequent among Isolagen Therapy-treated subjects than placebo-treated subjects. Injection site reactions were largely of mild or moderate intensity and of short duration.

Fibrocell Science plans to continue studies for additional aesthetic and therapeutic indications: for azfibrocel-T.. In early 2009, Isolagen completed its Phase II/III trial for the treatment of acne scars with statistically significant efficacy results.

Medical: The dose regimen for the treatment of nasolabial fold wrinkles is up to 2 mL of autologous cell suspension at a concentration of 1.0-2.0 x 10.sup.7 cells/mL, administered at 0.1 mL per linear centimeter (up to 20 centimeters total treatment area). A full course of treatment involves three doses administered at an interval of five weeks ± one week.

Isolagen Therapy is a somatic cell therapy that is distinct in composition and mechanism of action from currently marketed dermal filler products for the treatment of facial rhytids. Dermal fillers are widely employed by plastic surgeons and dermatologists to temporarily correct the appearance of nasolabial fold wrinkles and other facial rhytids. These products, containing collagen or hyaluronic acid (see related entries) or other polymeric substances, achieve wrinkle correction through a space-filling effect at the site of injection. Although newer generation products have achieved a longer duration of effect and a reduced risk of hypersensitivity reactions compared to the early collagen-based fillers, the polymers within all fillers naturally degrade over time and are not replenished. Thus, wrinkle correction is temporary and re-treatment is necessary to maintain the desired appearance. In contrast, Isolagen Therapy provides wrinkle correction through a biological mechanism employing the patient’s own cells to modify the microstructure of the skin at the site of injection. The onset of Isolagen Therapy effect is not immediate but develops over a period of weeks, and the duration of effect is potentially long-lasting.

Market: Laviv will have to compete against Botox, collagens, hyaluronic acids and other products used for treatment of nasolabial folds.

Isolagen will provide Isolagen Therapy only to trained practitioners who are specially certified in the Isolagen Therapy Program. The Program includes biopsy and Isolagen Therapy injection training.