19.6  Product Summary Basis of Approval Reviews

vein occlusion (BRVO) or central retinal vein occlusion (CRVO). It is a biodegradable implant containing 0.7 mg dexamethasone that is injected into the vitreous humor using a specifically designed injector. On 10 January 2005, the agency granted Allergan with a Fast Track Designation for the dexamethasone Intravitreal implant stating that there were no approved drug products indicated for patients with macular edema secondary to BRVO or CRVO at that time. The drug product is a rod-shaped intravitreal implant loaded into a standard 22-G thin wall hypodermic needle of a single-use applicator that delivers the implant directly to the posterior segment of the eye. It contains the active drug in a biodegradable poly (D,L-lactide- co-glycolide) (PLGA) matrix. Consistent in vitro release rates were demonstrated and these showed good correlation with the in vivo release rates in rabbits and monkeys. Additionally, the sterility and endotoxin limits were specified and accepted by the agency.

Dexamethasone is a synthetic derivative of hydrocortisone that acts as a potent anti-inflammatory agent and inhibits the expression of VEGF leading to an inhibition of VEGF-induced vascular leakage in a rabbit model of blood-retinal and blood-aqueous barrier breakdown (Edelman et al., 2005). This was confirmed in a 10-week study evaluating the primary pharmacodynamics of the dexamethasone intravitreal implant. A dose-dependent inhibition of VEGF-induced blood-retinal- barrier (BRB) breakdown was observed with 0.35 and 0.7 mg dexamethasone implants with the higher dose producing a more pronounced inhibitory effect compared to lower dose.

In addition to the pharmacology studies, the submission included a condensed nonclinical safety program (PKDM and toxicology studies) because dexamethasone had been marketed in the United States for decades and its systemic ADME (absorption, distribution, metabolism, and excretion) and toxicology profile had been well established. Five single dose ocular absorption and distribution studies with the dexamethasone implant were conducted in rabbits and one single dose study was conducted in monkeys. Dexamethasone concentrations were generally lower in monkeys compared to rabbits and lasted for a longer period of time with the implant releasing >90% dexamethasone by 3 months and containing detectable levels in the vitreous humor up to 6 months. These concentrations were higher than the EC50 values obtained from cell-based potency assays supporting the 6-month clinical dosing interval. In vitro, dexamethasone did not bind to synthetic melanin suggesting that it does not accumulate in pigmented ocular tissues following repeated dosing. Tissue distribution studies using radiolabeled dexamethasone containing implants showed that the drug distribution in the posterior segment of the eye was relatively higher than its distribution in the anterior segment of the eye following intravitreal injection. Dexamethasone also exhibited negligible metabolism in an in vitro study using human ocular tissues and in in vivo ocular metabolism studies in rabbits and monkeys. Since the characteristics and metabolism of the matrix PLGA polymers had been extensively studied during the past few decades and these polymers had been approved by the FDA for human use, no additional studies were conducted to characterize the metabolism of these polymers. Since the

systemic use of dexamethasone had been reported for several decades, systemic distribution, metabolism, and excretion studies were not conducted. In addition, the plasma concentrations of dexamethasone following intravitreal administration were minimal, alleviating any concerns of systemic side effects.

Ocular and systemic safety of the dexamethasone implant was evaluated in three single dose toxicity studies in rabbits and in repeat dose toxicity studies each (two injections, 3 months apart) in rabbits and monkeys. Even though some transient and expected dexamethasone-related systemic adverse effects in rabbits were observed, the repeat dose toxicity study in monkeys did not exhibit any significant ocular or systemic toxicity at doses up to two 0.7 mg implants, 3 months apart. The 0.7 mg dose was substantially lower than the maximal doses in animal studies reported without adverse ocular findings for single intravitreal injection (4.8 mg) or for implanted sustained release dexamethasone devices (5.0 mg). Furthermore, dexamethasone had been widely used in ophthalmology for many decades (Gordon 1959a, b). Since the plasma concentrations of dexamethasone following intravitreal administration were minimal and the systemic use of dexamethasone had been well documented, additional toxicity studies via the systemic route of administration, genetic toxicology studies, reproductive toxicology studies, and carcinogenicity studies were not conducted because the data were either not needed (due to adequate systemic safety margins following intravitreal injection) or was available in the literature, resulting in significant savings of time, money, and resources. Furthermore, since the use of PLGA polymers was well documented in humans with no safety concerns, no toxicity studies were needed to prove the safety of the PLGA matrix alone.

The clinical development program included Phase I emergency and compassionate use studies, Phases I and II dose ranging trials and two Phase III multicenter, masked, randomized, sham-controlled, safety and efficacy studies in patients with macular edema following BRVO or CRVO. The clinical data showed that 0.7 mg implant had greater efficacy and longer duration of effect than the 0.35 mg implant suggesting a dose response. The safety endpoints (mostly class effects related to steroids) did not exhibit a dose response and the overall incidence of adverse events was significantly higher when compared to sham, but was not statistically significant between the two dose groups. Overall there was substantial evidence of safety and efficacy to file an NDA application with the FDA. Following the NDA application, OZURDEX™ was approved in June 2009.

In addition to these studies, the sponsor requested a Pediatric Waiver at one of the two pre-NDA meetings based on the justification that pediatric studies with dexamethasone implants are highly impractical due to the fact that macular edema associated with BRVO or CRVO is mainly found in adults and the number of pediatric patients with this indication is very small. This request was granted by the FDA. The sponsor also held additional meetings with the FDA that included a pre-IND meeting, an EOP2 clinical trial meeting , clinical meetings and discussions throughout the drug development program to obtain relevant guidance on the nonclinical and clinical plans.

19.6.2  LUCENTIS™

LUCENTIS™ (Ranibizumab) is a recombinant, humanized monoclonal IgG1 antibody antigen-binding fragment (Fab) designed to bind and inhibit all active forms of human VEGF and indicated for neovascular (wet) ARMD. It is approximately 48 kilodaltons (kDa) and is produced by an Escherichia coli expression system. It is administered as a 0.05-mL (0.5 mg) intravitreal injection of the sterile, colorless to pale yellow solution once a month. In pharmacology studies, ranibizumab showed high binding affinity to different isoforms of rhVEGF. This was confirmed in a guinea-pig skin model where ranibizumab significantly inhibited VEGF-induced vascular permeability in a dose-dependent manner.

Analytical methods including ELISA were developed to monitor the drug concentrations as well as antibodies against ranibizumab in various tissues and blood. The nonclinical ADME studies included rabbit and monkey distribution studies following intravitreal administration of the drug and a distribution study in rabbits evaluating the pharmacokinetics of LUCENTIS™ following subconjunctival, intracameral, and intravitreal administration. Ranibizumab was absorbed in most of the ocular tissues (vitreous humor, retina, aqueous humor, ICB, corneal endothelium) and serum in both rabbits and monkeys with elimination half-life of 2–3 days. The serum concentration was minimal and the maximal separation between the vitreous humor concentrations and serum concentrations was observed with intravitreal administration compared to subconjunctival and intracameral administration suggesting that the intravitreal route is the better route of administration. Ranibizumab elicited an antibody response in the vitreous humor and serum in rabbits but not in monkeys. In an effort to extrapolate the results to humans, the sponsor developed a pharmacokinetic model to predict the retina and serum exposure of ranibizumab under simulated dosing regimens after intravitreal and intravenous administration. The nonclinical toxicology package consisted of local tolerance studies in rabbits and four repeat dose toxicology studies in monkeys ranging in doses from 0.25 to 2.0 mg/eye. The local tolerance studies in rabbits were conducted following a single intravitreal injection of the drug at 2.0 or 2.5 mg/ eye followed by a 7-day observation. Ocular inflammation was observed in these animals. In the repeat dose toxicology studies in monkeys, dose-related inflammatory responses were observed in the anterior and posterior chambers at all doses, possibly due to the lyophilized nature of the test article and suggesting that monkey is the more sensitive model; however, these were transient and mostly reversible. None of the animals exhibited any drug-induced systemic toxicity. The antibody did not exhibit any cross reactivity to human tissues and was compatible at up to 20 mg/mL with human and monkey serum and plasma and human vitreal fluid. Since the serum concentrations of the drug following intravitreal administration were deemed negligible, genetic toxicity studies, carcinogenicity studies, and reproductive and developmental toxicity studies were not conducted at the time of BLA (Biological License Application) submission. Since the reproductive and developmental toxicity studies were not conducted, the review indicated that ranibizumab