SCIENTIFIC DISCUSSION This module reflects the initial scientific discussion for the approval of Faslodex. For information on changes after approval please refer to module 8. 1. Introduction This marketing authorization application concerns Faslodex, solution for injection 250 mg/5ml, which contains the active substance fulvestrant (ICI 182,780, ZD9238). This is a full application for approval of a new active substance. The therapeutic indication for Faslodex is for the treatment of postmenopausal women with oestrogen receptor positive, locally advanced or metastatic breast cancer for disease relapse on or after adjuvant antioestrogen therapy or disease progression on therapy with an antioestrogen. The proposed dose is 250 mg to be administered intramuscularly into the buttock at intervals of 1 month as a single 5 ml injection. Breast cancer Breast cancer is the most common form of cancer in women with as many as one in eight women in developed countries being affected by the disease at some point during their lifetime. The aging population is set to give rise to an increase in the prevalence of breast cancer with estimates suggesting an annual rise of 1%, particularly among postmenopausal women. Treatment of breast cancer is determined by the extent of the disease. Early or localized breast cancer is treated by a combination of surgery and radiotherapy. Adjuvant systemic therapy, consisting of chemotherapy and/or endocrine therapy, in tumours deemed hormone responsive, can prolong the disease-free interval and improve overall survival. However, approximately 30% to 40% of patients with early breast cancer will ultimately relapse, with either local recurrence or distant metastases, and require further systemic treatment for advanced disease (ref: Forbes 1997). Since breast cancer that recurs or progresses after initial treatment is considered incurable, the therapy options available for advanced disease are concerned with disease control and palliation of symptoms (ref: Osborne, 1998). Hormonal therapy has become the treatment of choice in postmenopausal women with hormone sensitive breast cancer. Historically, the selective oestrogen receptor modulator, tamoxifen has been used extensively with success to treat advanced disease (ref: Litherland and Jackson, 1988; Osborne, 1998). Resistance to tamoxifen develops and the mechanism is complex. For postmenopausal women with breast cancer whose disease has recurred or progressed following treatment with tamoxifen or related non-steroidal anti-oestrogen, the choice of additional hormonal treatment lies between aromatase inhibitors (eg, anastrozole, examestane, letrozole) and progestins (eg, megestrol acetate, medroxyprogesterone). Progestins can be poorly tolerated because of adverse effects, notably weight gain, oedema, and thromboembolic complications. As a result, progestins are often reserved as third- line treatment or are avoided if the patient is deemed at risk of these complications. Even though the treatment of advanced breast cancer in postmenopausal women has improved with the introduction of agents such as aromatase inhibitors, these agents still have limitations, and disease management continues to be sub-optimal. About the product Fulvestrant is claimed to be the first agent in a new class of anti-oestrogen described by the term Oestrogen Receptor Downregulator (ER Downregulator [ref: Wakeling, 2000]). It is an anti-oestrogen without agonist properties. It blocks the trophic actions of oestrogens without itself having any partial agonist (oestrogen-like) activity on the endometrium of post-menopausal women. Fulvestrant binds to oestrogen receptors (ERs) in a competitive manner with a high affinity comparable with that of oestradiol. Data from pre-clinical studies have shown that fulvestrant is effective against human breast cancer cells and xenografts displaying acquired resistance to tamoxifen or letrozole (ref: Osborne et al, 1994, 1995; Long et al, 2002). A lack of significant issues from single and multiple dose safety studies in animals indicates a potential for a good safety profile. These data have provided a rationale for clinical development of fulvestrant in breast cancer patients whose disease has recurred or progressed following endocrine treatment. 1/33 EMEA 2005 Faslodex is presented as a sterile oily solution in a 5 ml pre-filled syringe. It is a long acting (LA) injection, designed to deliver the required dose of 250 mg of fulvestrant over a 1 month period from a single intramuscular injection into the buttock. 2. Chemical, pharmaceutical and biological aspects Composition Faslodex is presented as a sterile oily solution for intramuscular injection containing 50 mg/ml of the active substance fulvestrant. Other ingredients include ethanol, benzyl alcohol, benzyl benzoate and castor oil. Faslodex is packaged in a single use pre-filled syringe consisting of a siliconised Type I glass barrel fitted with a tamper evident closure/luer lock connector, a siliconised bromobutyl rubber plunger, a bromobutyl/synthetic isoprene rubber tip-cap, a polystyrene plunger rod and a polypropylene back stop. Each pre-filled syringe is enclosed in a black line carton to provide light protection. Active substance The chemical name of fulvestrant is 7α-[9-(4,4,5,5,5-Pentafluoropentylsulphinyl) -nonyl]estra- 1,3,5(10)-triene-3,17β-diol. It is is a white crystalline solid compound with very high lipophilicity and extremely low aqueous solubility; it does not ionise except at very high pH. The compound is stable to hydrolysis, but has some susceptibility to oxidation. It contains 6 asymmetric carbon atoms and a stereogenic sulphoxide in the side chain. The active ingredient is a mixture of 2 diastereoisomers: Fulvestrant Sulphoxide A and B, having the same absolute configuration at each of the stereogenic centres in the steroid system but different absolute configurations at the sulphur atom. The ratio of Fulvestrant Sulphoxide A : Fulvestrant Sulphoxide B in fulvestrant is controlled by the clause for optical purity by HPLC. The synthesis of fulvestrant is a 6-stage process, which will give a mixture of the two diastereoisomers (Fulvestrant Sulphoxide A and B), whose ratio is tightly controlled by HPLC. The route of synthesis has been sufficiently described, and the major steps in the synthesis of Fulvestrant are adequately controlled during the reaction. There are thirty-four potential synthetic and degradation impurities, which may arise from the route of synthesis. Only 13 of these impurities have been detected in batches of fulvestrant during development. The presence or absence of impurities has been examined by spectroscopy and/or chromatography in all batches used in toxicological or clinical studies. Active substance specification The specification of the active substance includes tests for description, identification (IR), assay (HPLC), organic impurities (HPLC), residual solvents (GC), optical purity (HPLC), water content (Karl Fischer titration), sulphated ash, microbial content and endotoxins (LAL). The limits for the identified and unidentified but specified impurities are justified by toxicological and stability studies. Batch analysis data have been provided for 23 batches of fulvestrant. The analytical results for these batches comply with the proposed specification. In conclusion it has been proven that the tests and limits in the specification are appropriate for controlling the quality of the active substance. Stability Stability studies have been performed on 6 batches of fulvestrant in accordance with ICH guidelines. Samples were stored at 25 oC/ 60% RH for up to 36 months, 30 oC/ 60 and 80% RH for 12 months and 40 oC/ 75% RH for 6 months. Additional sudies were performed for six months under thermal stress (50 and 60oC) and humidity stress conditions (50 and 60 oC/ 80% RH). The parameters tested are description, assay, organic impurities (HPLC), degradation products (TLC), specific optical rotation, optical purity, water content, appearance, colour and clarity of solution and melting point. The methods used are the same as those used for routine control of fulvestrant with the 2/33 EMEA 2005 addition of TLC as a complementary technique to HPLC for detection of degradation products. All methods employed were stability indicating. All parameters evaluated comply with the active substance specification. The stability data presented support the proposed re-tests period for fulvestrant, when stored in a double polythene liner inside an aluminium foil lined fibreboard drum under the specified conditions. Other ingredients All materials used are of non-animal origin. Ethanol, benzyl alcohol and benzyl benzoate comply with the Eur. Ph. requirements. The castor oil complies with USP. Product development and finished product As already discussed the active ingredient is a mixture of two diastereoisomers. The use of the mixture of these diastereroisomers is justified from the fact that the manufacture of individual diastereoisomers is not practical, their ratio is consistent, adequately controlled and does not change during storage neither in the drug substance or the drug product nor in vivo and the individual diastereoisomers have similar pharmacological potency. Oral delivery has been explored, but this route could not achieve adequate bioavailability. Faslodex has therefore been developed for administration by intramuscular injection. The goal of the development was to achieve effective and convenient delivery of fulvestrant, using the formulation to control